U.S. patent application number 15/957739 was filed with the patent office on 2018-10-25 for pd-1/pd-l1 inhibitors.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Evangelos Aktoudianakis, Todd Appleby, Aesop Cho, Zhimin Du, Michael Graupe, Juan A. Guerrero, Salman Y. Jabri, Lateshkumar Thakorlal Lad, Paulo A. Machicao Tello, Jonathan William Medley, Samuel E. Metobo, Prasenjit Kumar Mukherjee, Devan Naduthambi, Gregory Notte, Eric Q. Parkhill, Barton W. Phillips, Scott Preston Simonovich, Neil H. Squires, Chandrasekar Venkataramani, Peiyuan Wang, William J. Watkins, Jie Xu, Kin Shing Yang, Christopher Allen Ziebenhaus.
Application Number | 20180305315 15/957739 |
Document ID | / |
Family ID | 62117030 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180305315 |
Kind Code |
A1 |
Aktoudianakis; Evangelos ;
et al. |
October 25, 2018 |
PD-1/PD-L1 INHIBITORS
Abstract
Compounds according to formula (I), methods of using said
compounds singly or in combination with additional agents and
compositions of said compounds for the treatment of cancer are
disclosed.
Inventors: |
Aktoudianakis; Evangelos;
(Redwood City, CA) ; Appleby; Todd; (San
Francisco, CA) ; Cho; Aesop; (Mountain View, CA)
; Du; Zhimin; (Belmont, CA) ; Graupe; Michael;
(Pacifica, CA) ; Guerrero; Juan A.; (Concord,
CA) ; Jabri; Salman Y.; (San Francisco, CA) ;
Lad; Lateshkumar Thakorlal; (Belmont, CA) ; Machicao
Tello; Paulo A.; (San Mateo, CA) ; Medley; Jonathan
William; (San Mateo, CA) ; Metobo; Samuel E.;
(Newark, CA) ; Mukherjee; Prasenjit Kumar; (South
San Francisco, CA) ; Naduthambi; Devan; (San Bruno,
CA) ; Notte; Gregory; (Redwood City, CA) ;
Parkhill; Eric Q.; (San Francisco, CA) ; Phillips;
Barton W.; (San Mateo, CA) ; Simonovich; Scott
Preston; (Oakland, CA) ; Squires; Neil H.;
(San Francisco, CA) ; Venkataramani; Chandrasekar;
(San Carlos, CA) ; Wang; Peiyuan; (San Mateo,
CA) ; Watkins; William J.; (Saratoga, CA) ;
Xu; Jie; (Foster City, CA) ; Yang; Kin Shing;
(San Mateo, CA) ; Ziebenhaus; Christopher Allen;
(San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
62117030 |
Appl. No.: |
15/957739 |
Filed: |
April 19, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62507678 |
May 17, 2017 |
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62488017 |
Apr 20, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/10 20130101;
C07D 401/04 20130101; C07D 405/14 20130101; C07D 213/69 20130101;
C07D 519/00 20130101; C07D 295/088 20130101; C07D 213/85 20130101;
A61K 31/4545 20130101; A61K 31/444 20130101; C07D 401/14 20130101;
A61K 31/44 20130101; C07D 491/107 20130101; A61P 35/00 20180101;
C07D 213/64 20130101; C07D 213/61 20130101; C07D 213/30 20130101;
C07D 498/04 20130101; A61P 35/02 20180101; A61K 31/5377 20130101;
C07D 487/08 20130101; A61K 31/497 20130101; A61K 45/06
20130101 |
International
Class: |
C07D 213/69 20060101
C07D213/69; A61K 45/06 20060101 A61K045/06; A61K 31/444 20060101
A61K031/444; C07D 401/14 20060101 C07D401/14; A61K 31/4545 20060101
A61K031/4545; C07D 213/85 20060101 C07D213/85; A61K 31/44 20060101
A61K031/44; C07D 213/30 20060101 C07D213/30; C07D 295/088 20060101
C07D295/088; A61K 31/5377 20060101 A61K031/5377 |
Claims
1. A compound of formula (VIII): ##STR01023## wherein: each of
X.sup.4 and X.sup.5 are independently N, CH or CZ.sup.3; each Z is
independently is halo, --OR.sup.a, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl, --C.sub.2-6 alkynyl,
--O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, or --C.sub.1-6 alkyl-C.sub.3-8 cycloalkyl; and wherein
each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally
substituted with 1 to 4 groups independently selected from oxo,
--NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano; each w is
independently 0, 1 or 2; each Z.sup.3 is independently halo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and wherein the alkyl,
alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--O--C.sub.1-6-cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --O--C.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a, or
##STR01024## wherein: L.sup.1 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl; wherein
each alkyl, alkenyl, or alkynyl is optionally independently
substituted with OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or
--C.sub.3-8 cycloalkyl; L.sup.2 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; ring A is independently cycloalkyl,
aryl, heteroaryl, or heterocyclyl; wherein each cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --O--C.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and wherein the alkyl, alkenyl,
or alkynyl group is optionally independently substituted with
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; each t is independently 0, 1 or 2; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --O--C.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.a--C.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --S--C.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.a--SO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.a--C.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2-C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or ##STR01025##
wherein: V.sup.2 is independently a bond, O, NR.sup.a, S, SO,
SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O), SO.sub.2NR.sup.1, or
NR.sup.aSO.sub.2; L.sup.3 is independently a bond, O, NR.sup.a, S,
SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O), SO.sub.2NR.sup.1, or
NR.sup.aSO.sub.2; ring B is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; p is independently 0, 1, 2, 3, 4, or
5; q is independently 0, 1, 2, 3, 4, or 5; u is 0, 1, 2, 3, or 4; z
is 0, 1, 2, or 3; and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl of R.sup.E or R.sup.W is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of NR.sup.aR.sup.b, halo, cyano, oxo,
OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH,
--C.sub.3-8 cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8cycloalkyl;
provided that at least one of V.sup.2, L.sup.3, ring B and T
contains a nitrogen atom; each R.sup.1 is independently selected
from H, --C.sub.1-8 alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6
alkynyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; wherein each alkyl, alkenyl, cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from --OR.sup.a, --CN, halo,
C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl,
--C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b, NR.sup.aC(O)OR.sup.b,
--C.sub.1-6 alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--C.sub.1-6 alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C.sub.1-6 alkylSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aSO.sub.2R.sup.b, --NR.sup.aC(O)R.sup.b, and
--C.sub.1-6alkylNR.sup.aC(O)R.sup.b; each R.sup.2 is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.a, --CN, halo, C.sub.1-6alkyl,
--C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
haloalkyl, --C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; each R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; each R.sup.a is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; each R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; each R.sup.c is independently selected from
H, OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --O--C.sub.1-6alkyl, --C.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --O--C.sub.3-8 cycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
each R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and each
R.sup.g is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, solvate, or tautomer thereof.
2. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIa): ##STR01026##
3. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIb): ##STR01027##
4. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIc): ##STR01028##
5. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIId): ##STR01029##
6. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIe): ##STR01030## wherein: each of
X.sup.4 and X.sup.5 are independently N, CH or CZ.sup.3; each
Z.sup.1 is independently halo, --OR.sup.a, --CN, or --C.sub.1-6
alkyl; each w is independently 0, 1 or 2; each Z.sup.3 is
independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and wherein the alkyl,
alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--O--C.sub.1-6-cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --O--C.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.a--C.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6 alkylC(O)OR.sup.1,
--S--C.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
##STR01031## wherein: L.sup.1 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl; wherein
each alkyl, alkenyl, or alkynyl is optionally independently
substituted with OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or
--C.sub.3-8 cycloalkyl; L.sup.2 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; ring A is independently cycloalkyl,
aryl, heteroaryl, or heterocyclyl; wherein each cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --O--C.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and wherein the alkyl, alkenyl,
or alkynyl group is optionally independently substituted with
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; each t is independently 0, 1 or 2; each R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; wherein each alkyl, alkenyl, cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from --OR.sup.a, --CN, halo,
C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl,
--C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.b,
--C.sub.1-6 alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--C.sub.1-6 alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C.sub.1-6 alkylSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aSO.sub.2R.sup.b, --NR.sup.aC(O)R.sup.b, and
--C.sub.1-6alkylNR.sup.aC(O)R.sup.b; each R.sup.2 is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.a, --CN, halo, C.sub.1-6alkyl,
--C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
haloalkyl, --C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; each R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; each R.sup.a is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; each R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; each R.sup.c is independently selected from
H, OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.f is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; and each R.sup.g is independently selected from
H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers, solvate, or tautomer
thereof.
7. The compound of claim 6, wherein the compound is represented by
a compound of formula (VIIIf): ##STR01032##
8. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIg): ##STR01033##
9. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIh): ##STR01034##
10. The compound of claim 1, wherein the compound is represented by
a compound of formula (VIIIi): ##STR01035##
11. The compound of any preceding claim, wherein each Z.sup.3 is
independently halo.
12. The compound of any preceding claim, wherein each Z.sup.3 is
independently halo or C.sub.1-6 alkoxy.
13. The compound of any preceding claim, wherein each Z.sup.3 is
independently chloro.
14. The compound of any preceding claim, wherein each Z.sup.3 is
independently chloro or methoxy.
15. A compound of formula (I)
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) wherein: Ar.sup.E and Ar.sup.W are each independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; wherein each alkyl, alkenyl, alkynyl,
and cycloalkyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, and cyano; L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, ##STR01036## wherein
each m is independently 0, 1, 2, 3 or 4; Q.sup.E and Q.sup.W are
each independently aryl, heteroaryl, or heterocyclyl, wherein each
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from halo, oxo, --OR.sup.a,
--N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; wherein each alkyl,
alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; wherein R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a, or
##STR01037## wherein L.sup.1 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl; wherein
each alkyl, alkenyl, or alkynyl is optionally independently
substituted with OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or
--C.sub.3-8 cycloalkyl; L.sup.2 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; ring A is independently cycloalkyl,
aryl, heteroaryl, or heterocyclyl; wherein each cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; wherein each alkyl, alkenyl, or
alkynyl is optionally independently substituted with OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; R.sup.E
and R.sup.W are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uNR.sup.c(CH.sub.2).sub.uP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or ##STR01038##
wherein: V.sup.2 is independently a bond, O, NR.sup.a, S, SO,
SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or
NR.sup.aSO.sub.2; L.sup.3 is independently a bond, O, NR.sup.a, S,
SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2,
or NR.sup.aSO.sub.2; ring B is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, (CH.sub.2).sub.qOR.sup.a, or
(CH.sub.2).sub.qC(O)R.sup.e; p is independently 0, 1, 2, 3, 4, or
5; q is independently 0, 1, 2, 3, 4, or 5; u is 0, 1, 2, 3, or 4;
and z is 0, 1, 2, or 3; wherein each cycloalkyl, aryl, heteroaryl,
or heterocyclyl of R.sup.E or R.sup.W is optionally substituted
with 1 to 3 substituents independently selected from
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; provided that at least
one of V.sup.2, L.sup.3, ring B and T contains a nitrogen atom;
R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; wherein each alkyl, alkenyl, cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from --OR.sup.a, --CN, halo,
C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl,
--C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b, NR.sup.aC(O)OR.sup.b,
--C.sub.1-6 alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--C.sub.1-6 alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C.sub.1-6 alkylSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aSO.sub.2R.sup.b, --NR.sup.aC(O)R.sup.b, and
--C.sub.1-6alkylNR.sup.aC(O)R.sup.b; R.sup.2 is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.a, --CN, halo, C.sub.1-6alkyl,
--C.sub.1-6 alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
haloalkyl, --C.sub.3-8 cycloalkyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
16. The compound according to claim 1 wherein: Ar.sup.E and
Ar.sup.W are each independently a cycloalkyl, aryl, heteroaryl, or
heterocyclyl; wherein each cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl,
and --C.sub.3-8 cycloalkyl; wherein each alkyl, and cycloalkyl
group is optionally substituted with 1 to 4 groups independently
selected from NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano; or
a pharmaceutically acceptable salt, thereof.
17. The compound according to claim 15, wherein: Ar.sup.E and
Ar.sup.W are each independently an aryl, heteroaryl, or
heterocyclyl; wherein each aryl, heteroaryl, or heterocyclyl is
optionally substituted with 1 to 2 groups independently selected
from halo, --OR.sup.a, --CN, --C.sub.1-6 alkyl, --C.sub.1-6
haloalkyl, and --OC.sub.1-6 alkyl; wherein each alkyl group is
optionally substituted with 1 to 4 groups independently selected
from --OR.sup.a, halo, or cyano; or a pharmaceutically acceptable
salt, thereof.
18. The compound according to claim 15, wherein: Ar.sup.W is the
same as Ar.sup.E and is selected from phenyl, pyridinyl, indanyl,
and indolinyl, wherein each phenyl, pyridinyl, indanyl, and
indolinyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, CN, --C.sub.1-6alkyl,
--OC.sub.1-6alkyl, --C.sub.1-6alkyl-OR.sup.a, --C.sub.1-6haloalkyl,
and --C.sub.1-6cyanoalkyl; or a pharmaceutically acceptable salt,
thereof.
19. The compound according to any one of claims 15-17, wherein
Ar.sup.E and Ar.sup.W are phenyl each substituted with a methyl
group.
20. The compound according to any one of claims 15-18, wherein:
Ar.sup.W is phenyl and Ar.sup.E is phenyl wherein each is
optionally substituted with halo.
21. The compound according to claim 1 wherein Ar.sup.E and Ar.sup.W
are each indanyl.
22. The compound according to any one of claims 15-18, wherein
Ar.sup.W is indolinyl and Ar.sup.E is indolinyl, each optionally
substituted with 1 to 2 groups independently selected from methyl,
ethyl, methoxy, chloro, and CF.sub.3.
23. The compound according to any one of claims 15-18, wherein
Ar.sup.E is phenyl and Ar.sup.W is phenyl each optionally
substituted with 1 to 2 groups independently selected from methyl,
ethyl, methoxy, chloro, and CF.sub.3.
24. The compound according to claims 15-18, wherein Ar.sup.E is the
same as Ar.sup.W wherein each is optionally substituted with 1 to 2
groups independently selected from methyl, chloro, bromo, CN,
OCF.sub.3, CF.sub.3 CH.sub.2CF.sub.3, and ethyl.
25. The compound according to claims 15-18, wherein Ar.sup.E is
different from Ar.sup.W wherein each is optionally substituted with
1 to 2 groups independently selected from methyl, chloro, bromo,
CN, OCF.sub.3, CF.sub.3 CH.sub.2CF.sub.3, and ethyl.
26. The compound according to any one of claims 15-18, wherein
L.sup.E and L.sup.W are each independently a bond, --O--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, ##STR01039##
and each m is independently 0, 1, 2, 3 or 4; or a pharmaceutically
acceptable salt thereof.
27. The compound according to any one of claims 15-18, wherein:
L.sup.E and L.sup.W are each independently a bond,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--, --C(O)--,
##STR01040## wherein each m is independently 0, 1, 2 or 3; R.sup.3
is independently H, --C.sub.1-6alkyl, --OH, --OCH.sub.3, or
--OCH.sub.2CH.sub.3; and R.sup.4 is independently H, halo,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3; or a
pharmaceutically acceptable salt thereof.
28. The compound according to any one of claims 15-18, wherein:
L.sup.E and L.sup.W are each independently O--, --S--, --SO--,
--SO.sub.2--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--, or
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
wherein each m is independently 0, 1, or 2; and R.sup.3 and R.sup.4
are each independently H, or --C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
29. The compound according to any one of claims 15-18, wherein:
L.sup.E and L.sup.W are each independently
--(CR.sup.3R.sup.4).sub.m--, --O(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO--, or --C(O)--: wherein each m is
independently 0, 1, 2, or 3; and R.sup.3 and R.sup.4 are each
independently H, or --C.sub.1-6alkyl; or a pharmaceutically
acceptable salt thereof.
30. The compound according to any one of claims 15-18, wherein:
L.sup.E and L.sup.W are each independently --CH.sub.2--,
--OCH.sub.2--, --CH.sub.2O-- or --C(O)--; or a pharmaceutically
acceptable salt thereof.
31. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently aryl, heteroaryl, or
heterocyclyl; wherein each aryl, heteroaryl, or heterocyclyl is
optionally substituted with 1 to 2 groups independently selected
from halo, oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-6 alkylC.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, and R.sup.N; wherein the alkyl, alkenyl, alkynyl,
C.sub.3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is
optionally substituted with 1 to 2 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--SO.sub.2R.sup.a, --NR.sup.aSO.sub.2R.sup.b,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
wherein the heteroaryl or heterocyclic group may be oxidized on a
nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOR.sup.a, or ##STR01041## wherein L.sup.1 is independently a
bond, O, NR.sup.a or S; L.sup.2 is independently a bond, O,
NR.sup.a or S; V is independently selected from a bond,
C.sub.1-6alkyl, and C.sub.2-6alkenyl; and ring A is independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein the
cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally
independently substituted with 1 or 2 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl;
halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; or a pharmaceutically acceptable salt
thereof.
32. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently aryl, heteroaryl, or
heterocyclyl, wherein each aryl, heteroaryl, or heterocyclyl is
optionally substituted with R.sup.N; and R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a, or
##STR01042## wherein L.sup.1 is independently a bond, O, NR.sup.a
or S; L.sup.2 is independently a bond, O, NR.sup.a or S; V is
independently selected from a bond, C.sub.1-6alkyl, and
C.sub.2-6alkenyl; and ring A is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; wherein the cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally independently
substituted with 1 to 2 groups independently selected from oxo,
--NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl; or
a pharmaceutically acceptable salt thereof.
33. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently phenyl, pyridine,
indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl,
benzimidazolyl, thiazolyl, imidazolyl, or thienyl; wherein each
phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl,
benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or
thienyl is optionally substituted with 1 to 3 groups independently
selected from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, and --C.sub.1-6alkylC.sub.3-8 cycloalkyl; or
a pharmaceutically acceptable salt thereof.
34. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently phenyl, pyridine,
indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl,
benzimidazolyl, thiazolyl, imidazolyl, or thienyl; wherein each
phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl,
benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or
thienyl is optionally substituted with 1 to 2 groups independently
selected from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, --C.sub.1-6alkylC.sub.3-8 cycloalkyl, and R.sup.N; and
R.sup.N is independently --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a, or
##STR01043## wherein L.sup.1 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; L.sup.2 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl; wherein the
alkyl, alkenyl, or alkynyl group is optionally independently
substituted with OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or
--C.sub.3-8 cycloalkyl; and ring A is independently cycloalkyl,
aryl, heteroaryl, or heterocyclyl; wherein each cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally independently
substituted with 1 to 2 groups independently selected from oxo,
--NO.sub.2, --N.sub.3, --OR.sup.a, halo, CN, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl; or
a pharmaceutically acceptable salt thereof.
35. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently phenyl, pyridine,
indazolyl, thiazolyl, or indolinyl; wherein each phenyl, pyridine,
indazolyl, thiazolyl, or indolinyl is optionally substituted with 1
to 3 groups independently selected from halo, --OR.sup.a, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.2-6 alkynyl, --C.sub.3-8 cycloalkyl, and R.sup.N; and
R.sup.N is independently --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a, or
##STR01044## wherein L.sup.1 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; L.sup.2 is independently a bond, O, NR.sup.a,
S, SO, or SO.sub.2; V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl; wherein each
alkyl, alkenyl, or alkynyl group is optionally independently
substituted with OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or
--C.sub.3-8 cycloalkyl; and ring A is independently cycloalkyl,
aryl, heteroaryl, or heterocyclyl; wherein the cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally independently
substituted with 1 to 2 groups selected from oxo, --NO.sub.2,
--N.sub.3, --OR.sup.a, halo, CN, NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)OR.sup.a, --C(O)N(R.sup.a)OR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl; or
a pharmaceutically acceptable salt thereof.
36. The compound according to any one of claims 15-30, wherein:
Q.sup.E and Q.sup.W are each independently aryl, heteroaryl, or
heterocyclyl; wherein each aryl, heteroaryl, or heterocyclyl is
optionally substituted with 1 to 2 groups independently selected
from OH, halo, CN, --C.sub.1-6 alkyl, --C.sub.1-6haloalkyl
--OC.sub.1-6 alkyl, --OC.sub.1-6haloalkyl,
--SO.sub.2C.sub.1-6alkyl, ##STR01045## or a pharmaceutically
acceptable salt thereof.
37. The compound according to any one of claims 1-36, wherein
R.sup.E an R.sup.W are independently selected from
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2)N.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d), and
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a); R.sup.1 is
selected from H, --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.3 is independently H, --C.sub.1-6
alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl; R.sup.a is
independently H or --C.sub.1-6 alkyl; R.sup.b is independently H or
--C.sub.1-6 alkyl; R.sup.c is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8 cycloalkyl; R.sup.d is independently selected from
H, --C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, and
--C.sub.1-3alkylC.sub.3-8cycloalkyl; u is 0, 1, 2, or 3; or a
pharmaceutically acceptable salt thereof.
38. The compound according to any one of claims 1-36, wherein
R.sup.E an R.sup.W are independently selected from
--C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2, and
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b; and R.sup.1
is selected from H, --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or --C.sub.1-6
alkyl; R.sup.b is independently H or --C.sub.1-6 alkyl; and u is 0,
1, 2, or 3; or a pharmaceutically acceptable salt thereof.
39. The compound according to any one of claims 1-36, wherein
R.sup.E an R.sup.W are independently selected from
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(o)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d), and
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a); R.sup.1 is
selected from H, --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or --C.sub.1-6
alkyl; R.sup.b is independently H or --C.sub.1-6 alkyl; R.sup.c is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8 cycloalkyl; R.sup.d is
independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-C.sub.8cycloalkyl, and
--C.sub.1-3alkylC.sub.3-8cycloalkyl; and u is 0, 1, 2, or 3; or a
pharmaceutically acceptable salt thereof.
40. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each independently --NR.sup.1R.sup.2,
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, or ##STR01046## wherein V.sup.2 is
independently a bond, O, NR.sup.a, S, SO or SO.sub.2; L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; ring B is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
p is independently 0, 1, 2, or 3; q is independently 0, 1, 2, or 3;
and z is 0, 1, 2, or 3; and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl of R.sup.E or R.sup.W is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of NR.sup.aR.sup.b, halo, cyano, OR.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl,
--C.sub.1-6 alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8
cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; provided that
at least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or --C.sub.1-6
alkyl; R.sup.b is independently H or --C.sub.1-6 alkyl; R.sup.e is
independently selected from H, OH, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-C.sub.8cycloalkyl; R.sup.e is
selected from H, --C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --OC.sub.3-8
cycloalkyl, --Oaryl, --Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; and R.sup.g is independently selected from
H, --C.sub.1-6 alkyl, and --C.sub.3-8 cycloalkyl; or a
pharmaceutically acceptable salt thereof.
41. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each ##STR01047## wherein V.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; R.sup.c is
independently selected from H, OH, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-C.sub.8cycloalkyl; L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; ring B is
cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is independently
H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; R.sup.e is selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.g is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-8 cycloalkyl; p is independently
0, 1, 2, or 3; q is independently 0, 1, 2, or 3; and z is 0, 1, 2,
or 3; and wherein the alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl of R.sup.E or R.sup.W is optionally substituted with 1
to 3 substituents independently selected from the group consisting
of NR.sup.aR.sup.b, halo, cyano, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; provided that at least
one of V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; or
a pharmaceutically acceptable salt thereof.
42. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each independently --NR.sup.1R.sup.2,
--C.sub.1-6 alkylNR.sup.1R.sup.2, or --OC.sub.1-6
alkylNR.sup.1R.sup.2; R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or --C.sub.1-6
alkyl; and R.sup.b is independently H or --C.sub.1-6 alkyl; or a
pharmaceutically acceptable salt thereof.
43. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each --C.sub.1-6alkylOC.sub.1-6
alkylNR.sup.1R.sup.2; R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl group optionally containing an additional
heteroatom selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or
--C.sub.1-6alkyl; and R.sup.b is independently H or
--C.sub.1-6alkyl; or a pharmaceutically acceptable salt
thereof.
44. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each --OC.sub.1-6 alkylNR.sup.1R.sup.2;
R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl optionally containing an additional
heteroatom selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or
--C.sub.1-6alkyl; and R.sup.b is independently H or
--C.sub.1-6alkyl; or a pharmaceutically acceptable salt
thereof.
45. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each --NR.sup.1R.sup.2; R.sup.1 is selected
from H, --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl, heterocyclyl,
--C.sub.2-6alkyl-OR.sup.a, and --C.sub.1-6alkylC(O)OR.sup.a;
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally
substituted with 1 to 2 groups independently selected from
--OR.sup.a, --CN, halo, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkyl C(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
--C.sub.1-6alkylC(O)NR.sup.aR.sup.b; R.sup.2 is selected from
--C.sub.1-6alkyl, --C.sub.3-6cycloalkyl, heterocyclyl,
--C.sub.2-6alkyl-OR.sup.a, and --C.sub.1-6alkylC(O)OR.sup.a;
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally
substituted with 1 to 2 groups independently selected from
--OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
--C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl group optionally containing an additional
heteroatom selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or
--C.sub.1-6alkyl; and R.sup.b is independently H or
--C.sub.1-6alkyl; or a pharmaceutically acceptable salt
thereof.
46. The compound according to any one of claims 1-36, wherein the
groups R.sup.E and R.sup.W are each independently: ##STR01048##
##STR01049##
47. The compound according to any one of claims 1-36, wherein
R.sup.E and R.sup.W are each independently selected from:
##STR01050##
48. The compound according to claim 15, wherein Ar.sup.E and
Ar.sup.W are each independently aryl, heteroaryl, or heterocyclyl;
wherein each aryl, heteroaryl, or heterocyclyl optionally
substituted with 1 to 2 groups independently selected from halo,
--OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6
haloalkyl, and --C.sub.3-8 cycloalkyl; L.sup.E and L.sup.W are each
independently a bond, --O--, --(CR.sup.3R.sup.4).sub.m--,
--O(CR.sup.3R.sup.4).sub.m, --(CR.sup.3R.sup.4).sub.mO,
--(CR.sup.3R.sup.4).sub.mNR.sup.3--,
--NR.sup.3(CR.sup.3R.sup.4).sub.m--, or --C(O)--; m is
independently 0, 1, 2, 3 or 4; and Q.sup.E and Q.sup.W are each
independently aryl, heteroaryl, or heterocyclyl; wherein each aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 4
groups independently selected from halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and R.sup.N; wherein
R.sup.N is ##STR01051## L.sup.1 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; V is independently selected from a
bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl;
wherein each alkyl, alkenyl, or alkynyl group is optionally
independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; ring A is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally independently substituted with 1 to 2 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2, or ##STR01052##
wherein V.sup.2 is independently a bond, O, NR.sup.a, S, SO or
SO.sub.2 L.sup.3 is independently a bond, O, NR.sup.a, S, SO, or
SO.sub.2; ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl;
T is (CH.sub.2).sub.qNR.sup.1R.sup.2 or
(CH.sub.2).sub.qC(O)R.sup.e; p is 0, 1, 2, or 3; q is 0, 1, 2, or
3; z is 0, 1, 2, or 3; and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally substituted with 1
to 3 substituents independently selected from the group consisting
of NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; provided that at least
one of V.sup.2, L.sup.3, ring B and T contains a nitrogen atom;
R.sup.1 is selected from H, --C.sub.1-6 alkylaryl, heterocyclyl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a, and
C.sub.1-6 alkylC.sub.3-8cycloalkyl; wherein each alkyl, cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 2 groups independently selected from --OR.sup.a, oxo, --CN,
halo, C.sub.1-6 alkyl, --C.sub.1-6 alkylOR.sup.a, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a; wherein
each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 3 groups independently selected
from --OR.sup.a, --CN, halo, --C.sub.1-6 alkylOR.sup.a, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a, --C.sub.1-6
alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen,
and optionally substituted with 1 to 3 groups independently
selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H, halo,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3;
R.sup.4 is independently H, halo, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; R.sup.a is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.c is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8 cycloalkyl; R.sup.d is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl,
and --C.sub.1-3alkylC.sub.3-8cycloalkyl; or wherein any two
R.sup.c, any two R.sup.d or any R.sup.c and R.sup.d optionally
combine to form a 3-6 membered cycloalkyl ring; R.sup.e is
independently selected from H, --C.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl,
--Oheterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g,
--C.sub.1-6 alkylNR.sup.fR.sup.g, C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt thereof.
49. The compound ##STR01053## or a pharmaceutically acceptable salt
thereof.
50. The compound ##STR01054## or a pharmaceutically acceptable salt
thereof.
51. The compound ##STR01055## or a pharmaceutically acceptable salt
thereof.
52. The compound ##STR01056## or a pharmaceutically acceptable salt
thereof.
53. The compound ##STR01057## or a pharmaceutically acceptable salt
thereof.
54. The compound ##STR01058## or a pharmaceutically acceptable salt
thereof.
55. The compound ##STR01059## or a pharmaceutically acceptable salt
thereof.
56. The compound ##STR01060## or a pharmaceutically acceptable salt
thereof.
57. The compound ##STR01061## or a pharmaceutically acceptable salt
thereof.
58. The compound ##STR01062## or a pharmaceutically acceptable salt
thereof.
59. A method for inhibiting PD-1, PD-L1 and/or the PD-1/PD-L1
interaction comprising administering a compound according to any
one of claims 1-58 or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers or tautomer thereof, to a
patient in need thereof.
60. A method for treating cancer comprising administering a
therapeutically effective amount of a compound according to any one
of claims 1-58 or a pharmaceutically acceptable salt, stereoisomer,
mixture of stereoisomers, or tautomer thereof, to a patient in need
thereof.
61. The method according to claim 60, wherein the cancer is
pancreatic cancer, bladder cancer, colorectal cancer, breast
cancer, prostate cancer, renal cancer, hepatocellular cancer, lung
cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal
cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS
cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small
cell lung cancer, small-cell lung cancer or colon cancer.
62. The method according to claim 60, wherein the cancer is acute
lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),
myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),
chronic myeloid leukemia (CML), multiple myeloma (MM),
non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL),
follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell
lymphoma, B-cell lymphoma or diffuse large B-cell lymphoma
(DLBCL).
63. The method according to claim 59 or 60 further comprising
administering at least one additional anticancer agent or therapy
selected from nivolumab, pembrolizumab, atezolizumab, ipilimumab,
chemotherapy, radiation therapy, and resection therapy, to a
patient in need thereof.
64. The method according to claim 59 or 60 wherein the additional
anticancer agent or therapy is nivolumab, pembrolizumab,
artezolizumab, and nivolumab, pembrolizumab, atezolizumab, or
ipilimumab.
65. A pharmaceutical composition comprising a compound according to
any one of claims 1-58 or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers or tautomer thereof, and at
least one pharmaceutically acceptable excipient.
66. The pharmaceutical composition according to claim 65, further
comprising at least one additional anticancer agent or therapy
selected from rituxan, doxorubicin, gemcitabine, nivolumab,
pembrolizumab, and ipilimumab, and at least one pharmaceutically
acceptable excipient.
67. The pharmaceutical composition according to claim 65 wherein
the additional anticancer agent is nivolumab, pembrolizumab a,
atezolizumab, or ipilimumab.
68. A compound according to any one of claims 1-58 or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof for use in therapy.
69. A compound according to any one of claims 1-58 or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof, for use in the manufacture of a
medicament for treating cancer.
70. A compound according to any one of claims 1-58 or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof, and at least one additional
anti-cancer agent selected from rituxan, doxorubicin, gemcitabine,
nivolumab, pembrolizumab, and ipilimumab for use in the manufacture
of a medicament for treating cancer.
71. A kit for treating or preventing cancer or a disease or
condition that is amenable to treatment by inhibiting PD-1, PD-L1
and/or the PD-1/PD-L1 interaction in a patient in need thereof,
comprising: a) a compound according to any of claims 1-58, or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof; b) a monoclonal antibody
checkpoint inhibitor or antigen binding fragment thereof; and
optionally c) a label or instructions for use.
72. A kit for treating or preventing cancer or a disease or
condition that is amenable to treatment by inhibiting PD-1, PD-L1
and/or the PD-1/PD-L1 interaction in a patient in need thereof,
comprising: a) a compound according to any of claims 1-58, or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof; b) a monoclonal antibody
checkpoint inhibitor or antigen binding fraction thereof; and
optionally c) an additional therapeutic agent; and optionally, d) a
label or instructions for use.
73. A kit for treating or preventing cancer or a disease or
condition in a subject in need thereof, comprising: a) a compound
according to any of claims 1-58, or a pharmaceutically acceptable
salt, stereoisomer, mixture of stereoisomers, or tautomer thereof;
b) an anti-MMP9 antibody or antigen binding fragment thereof; and
optionally c) an additional therapeutic agent; and optionally; d) a
label or instructions for use.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Application No. 62/488,017, filed Apr.
20, 2017, and U.S. Provisional Application No. 62/507,678, filed
May 17, 2017, which are hereby incorporated by reference in their
entirety.
FIELD
[0002] The present disclosure generally relates to compounds useful
as inhibitors of PD-1, PD-L1 or the PD-1/PD-L1 interaction.
Provided herein are compounds, compositions comprising such
compounds, and methods for their use.
BACKGROUND
[0003] Programmed death-1 (CD279) is a receptor on T cells that has
been shown to suppress activating signals from the T cell receptor
when bound by either of its ligands, Programmed death-ligand 1
(PD-L1, CD274, B7-H1) or PD-L2 (CD273, B7-DC). When PD-1 expressing
T cells contact cells expressing its ligands, functional activities
in response to antigenic stimuli, including proliferation, cytokine
secretion, and cytotoxicity are reduced. PD-1/PD-Ligand
interactions down regulate immune responses during resolution of an
infection or tumor, or during the development of self-tolerance.
Chronic antigen stimulation, such as that which occurs during tumor
disease or chronic infections, results in T cells that express
elevated levels of PD-1 and are dysfunctional with respect to
activity towards the chronic antigen. This is termed "T cell
exhaustion." B cells also display PD-1/PD-ligand suppression and
"exhaustion."
[0004] Blockade of the PD-1/PD-L1 ligation using antibodies to
PD-L1 has been shown to restore and augment T cell activation in
many systems. Patients with advanced cancer benefit from therapy
with a monoclonal antibody to PD-L1. Preclinical animal models of
tumors and chronic infections have shown that blockade of the
PD-1/PD-L1 pathway by monoclonal antibodies can enhance the immune
response and result in tumor rejection or control of infection.
Antitumor immunotherapy via PD-1/PD-L1 blockade may augment
therapeutic immune response to a number of histologically distinct
tumors.
[0005] Interference with the PD-1/PD-L1 interaction has also shown
enhanced T cell activity in chronic infection systems. Chronic
lymphocytic chorio meningitis virus infection of mice also exhibits
improved virus clearance and restored immunity with blockade of
PD-L1. Humanized mice infected with HIV-1 show enhanced protection
against viremia and viral depletion of CD4+ T cells. Blockade of
PD-1/PD-L1 through monoclonal antibodies to PD-L1 can restore in
vitro antigen-specific functionality to T cells from HIV patients,
HCV patients or HBV.
[0006] Accordingly, agents that block PD-1, PD-L1 and/or the
PD-1/PD-L1 interaction are desired. Small molecule agents that
block or inhibit PD-1, PD-L1 and/or the PD-1/PD-L1 interaction are
particularly desired. Applicants have discovered small molecule
compounds that have activity as inhibitors of PD-1, PD-L1 or
inhibitors of the interaction of PD-1 with PD-L1, and thus may be
useful for treating patients having cancer.
SUMMARY
[0007] The present disclosure provides a compound of formula
(I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) [0008] wherein: Ar.sup.E and Ar.sup.W are each independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0009] wherein each
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [0010] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl group is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; L.sup.E and L.sup.W are each
independently a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3 (CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0010] ##STR00001## [0011] wherein [0012] each m is independently
0, 1, 2, 3 or 4; Q.sup.E and Q.sup.W are each independently aryl,
heteroaryl, or heterocyclyl, [0013] wherein each aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from halo, oxo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0014] wherein each
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0015] wherein [0016] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or,
[0016] ##STR00002## [0017] wherein [0018] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0019] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0020] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0021] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0022] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0023] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [0024] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b and --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uNR.sup.c(CH.sub.2).sub.uP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0024] ##STR00003## [0025] wherein: [0026] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0027] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0028]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0029] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, (CH.sub.2).sub.qOR.sup.a, or
(CH.sub.2).sub.qC(O)R.sup.e; [0030] p is independently 0, 1, 2, 3,
4, or 5; [0031] q is independently 0, 1, 2, 3, 4, or 5; [0032] u is
0, 1, 2, 3, or 4; and [0033] z is 0, 1, 2, or 3; [0034] wherein
each cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from NR.sup.aR.sup.b, halo, cyano, oxo,
OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH,
--C.sub.3-8 cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8cycloalkyl;
[0035] provided that at least one of V.sup.2, L.sup.3, ring B and T
contains a nitrogen atom; R.sup.1 is independently selected from H,
--C.sub.1-8 alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0036] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0037] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl;
[0038] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, or tautomer thereof.
[0039] The present disclosure further provides a compound of
formula (I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) [0040] wherein: Ar.sup.E and Ar.sup.W are each independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0041] wherein each
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [0042] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl group is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; L.sup.E and L.sup.W are each
independently a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0042] ##STR00004## [0043] wherein [0044] each m is independently
1, 2, 3 or 4; [0045] provided that when one of Ar.sup.E and
Ar.sup.W is optionally substituted phenyl and the other is
optionally substituted phenyl or optionally substituted
2,3-dihydrobenzo[b][1,4]dioxine, and one of L.sup.E and L.sup.W is
--CH.sub.2O--, --CH.sub.2CH.sub.2--, --CHCH--, and --C(O)N--; then
the other of L.sup.E and L.sup.W is a bond, --O-- or --CH.sub.2O--
of the formula Ar--CH.sub.2O-Q; Q.sup.E and Q.sup.W are each
independently aryl, heteroaryl, or heterocyclyl, [0046] wherein
each aryl, heteroaryl, or heterocyclyl is optionally substituted
with 1 to 4 groups independently selected from halo, oxo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.1-6 alkylC.sub.3-8 cycloalkyl, and R.sup.N; [0047] wherein
each alkyl, alkenyl, alkynyl, is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
[0048] wherein [0049] R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)NR.sup.1R.sup.2,
--OC.sub.1-6 alkylC(O)OR.sup.1, --SC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOR.sup.a, or
[0049] ##STR00005## [0050] wherein [0051] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0052] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0053] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0054] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0055]
provided at least one of L.sup.1, V an L.sup.2 is other than a
bond; [0056] ring A is independently cycloalkyl, aryl, heteroaryl,
or heterocyclyl; [0057] wherein each cycloalkyl, aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [0058] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b and --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2)N.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uNR(CH.sub.2).sub.uP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0058] ##STR00006## [0059] wherein: [0060] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0061] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0062]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0063] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, (CH.sub.2).sub.qOR.sup.a, or
(CH.sub.2).sub.qC(O)R.sup.e; [0064] p is independently 0, 1, 2, 3,
4, or 5; [0065] q is independently 0, 1, 2, 3, 4, or 5; [0066] u is
0, 1, 2, 3, or 4; and [0067] z is 0, 1, 2, or 3; [0068] wherein
each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 3 substituents independently selected from
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0069] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom, and when each of V.sup.2 and L.sup.3 is a bond and p is 0,
then either (i) neither of L.sup.E or L.sup.W is a bond or (ii)
ring B is not a 5,6-membered fused heteroaryl where the 5-membered
ring of the fused heteroaryl is bound to the corresponding Q.sup.E
or Q.sup.W; R.sup.1 is independently selected from H, --C.sub.1-8
alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0070] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0071] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or
--C.sub.2-6 alkenylC(O)OR.sup.a; R.sup.4 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or
--C.sub.2-6 alkenylC(O)OR.sup.a; R.sup.a is independently selected
from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; R.sup.b is independently selected
from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl;
[0072] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, or tautomer thereof.
[0073] The present disclosure further provides a compound of
formula (I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I)
wherein: Ar.sup.E and Ar.sup.W are each independently a cycloalkyl,
aryl, heteroaryl, or heterocyclyl; [0074] wherein each cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from halo, --OR.sup.a,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, and --C.sub.1-6 alkylC.sub.3-8 cycloalkyl;
and [0075] wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is
optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano;
L.sup.E and L.sup.W are each independently a bond, --O--, --S--,
--SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00007##
[0076] wherein each m is independently 0, 1, 2, 3 or 4;
Q.sup.E and Q.sup.W are each independently aryl, heteroaryl, or
heterocyclyl; [0077] wherein each aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from halo, oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0078] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6-cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0079] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0079] ##STR00008## [0080] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0081] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0082] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0083] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0084] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0085] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0086] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0086] ##STR00009## [0087] wherein: [0088] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0089] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0090]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0091] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0092] p is independently 0, 1, 2, 3,
4, or 5; [0093] q is independently 0, 1, 2, 3, 4, or 5; [0094] u is
0, 1, 2, 3, or 4; [0095] z is 0, 1, 2, or 3; and [0096] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0097] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0098] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0099] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, solvate, or tautomer thereof.
[0100] In one embodiment of formula (I), both Ar.sup.E and Ar.sup.W
are optionally substituted bicyclic rings, wherein neither is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic ring.
In one embodiment of formula (I), both L.sup.E and L.sup.W are
--O--. In one embodiment of formula (I), both L.sup.E and L.sup.W
are -Q-O--CH.sub.2--Ar--. In one embodiment of formula (I), each of
Ar.sup.E, Ar.sup.W, Q.sup.E, and Q.sup.W are monocyclic, provided
at least two are heteroaryl, and neither of R.sup.E, and R.sup.W is
an optionally substituted fused 5,6-aromatic or 5,6-heteromatic
ring. In one embodiment of formula (I), at least one L is a bond,
and none of Ar.sup.E, Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E, and
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring. In one embodiment of formula (I), at least
one of the following occurs: a) both Ar.sup.E and Ar.sup.W are
optionally substituted bicyclic rings, wherein neither is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic ring;
or both L.sup.E and L.sup.W are --O--; b) both L.sup.E and L.sup.W
are -Q-O--CH.sub.2--Ar--; c) each of Ar.sup.E, Ar.sup.W, Q.sup.E,
and Q.sup.W are monocyclic, provided at least two are heteroaryl,
and neither of R.sup.E, and R.sup.W is an optionally substituted
fused 5,6-aromatic or 5,6-heteromatic ring; or d) at least one L is
a bond, and none of Ar.sup.E, Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E,
and R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0101] The present disclosure provides a method of inhibiting PD-1,
PD-L1 and/or the PD-1/PD-L1 interaction comprising administering a
compound of formula (I) or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers or tautomer thereof, to a
patient in need thereof.
[0102] The present disclosure provides a method of treating cancer
comprising administering a therapeutically effective amount of a
compound formula (I) or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers, or tautomer thereof, to a
patient in need thereof.
[0103] One embodiment provides the use of a compound of formula (I)
or a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, for the treatment of cancer or a
condition in a patient that is amenable to treatment by inhibiting
PD-1, PD-L1 or the PD-1/PD-L1 interaction comprising administering
said compound of formula (I) to said patient in need thereof.
[0104] In one embodiment, provided is a method for treating a
cancer wherein the cancer is pancreatic cancer, bladder cancer,
colorectal cancer, breast cancer, prostate cancer, renal cancer,
hepatocellular cancer, lung cancer, ovarian cancer, cervical
cancer, gastric cancer, esophageal cancer, head and neck cancer,
melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone
cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell
lung cancer or colon cancer, comprising administering a
therapeutically effective amount of formula (I) or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof to a patient in need
thereof.
[0105] In one embodiment, provided is a method for treating a
cancer or a condition in a patient that is amenable to treatment by
inhibiting PD-1, PD-L1 or the PD-1/PD-L1 interaction selected from
pancreatic cancer, bladder cancer, colorectal cancer, breast
cancer, prostate cancer, renal cancer, hepatocellular cancer, lung
cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal
cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS
cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small
cell lung cancer, small-cell lung cancer and colon cancer
comprising administering a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers, or tautomer thereof to a
patient in need thereof, further comprising at least one additional
anticancer agent or therapy selected from nivolumab, pembrolizumab,
atezolizumab, ipilimumab, chemotherapy, radiation therapy, and
resection therapy, to a patient in need thereof.
[0106] In one embodiment, provided is a method for treating HBV,
comprising administering a therapeutically effective amount of
formula (I) or a pharmaceutically acceptable salt, stereoisomer,
mixture of stereoisomers, or tautomer thereof to a patient in need
thereof.
[0107] In one embodiment, provided is a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, for the treatment of cancer or a
condition in a patient selected from lymphoma, multiple myeloma,
and leukemia. Additional diseases or conditions that may be treated
include, but are not limited to acute lymphocytic leukemia (ALL),
acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell
lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia
(WM), T-cell lymphoma, B-cell lymphoma and diffuse large B-cell
lymphoma (DLBCL).
[0108] In one embodiment, the present disclosure provides a
compound of formula (I) or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers or tautomer thereof, in
combination with at least one additional anti-cancer agent selected
from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab,
and ipilimumab.
[0109] In one embodiment, the present disclosure provides a
compound of formula (I) or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers or tautomer thereof, in
combination with at least one additional check-point inhibitor
selected from nivolumab, pembrolizumab, atezolizumab, and
ipilimumab.
[0110] In one embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, and a pharmaceutically
acceptable carrier or excipient.
[0111] In one embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, and at least one additional
anticancer agent and at least one pharmaceutically acceptable
carrier or excipient.
[0112] In one embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, at least one additional
therapeutic agent suitable for treating an HBV infection, and at
least one pharmaceutically acceptable carrier or excipient.
[0113] In one embodiment, the present disclosure provides a kit
that includes a compound of formula (I) or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers or tautomer
thereof, a label and/or instructions for use of the compound in the
treatment of cancer or a disease or condition mediated by PD-1,
PD-L1 activity or the PD-1/PD-L1 interaction.
[0114] In one embodiment, the present disclosure provides a kit
that includes a compound of formula (I) or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers or tautomer
thereof, at least one additional anticancer agent, a label(s)
and/or instructions for use of the compound(s) in the treatment of
a disease or condition mediated by PD-1, PD-L1 activity or
PD-1/PD-L1 interaction.
[0115] In one embodiment, the present disclosure provides articles
of manufacture that include a compound of formula (I) or a
pharmaceutically acceptable salt, or solvate thereof, and a
container. In one embodiment, the container may be a vial, jar,
ampoule, preloaded syringe, or an intravenous bag.
[0116] In one embodiment, the present disclosure provides a
compound of formula (I) for use in therapy.
[0117] In another embodiment, the present disclosure provides a
compound of formula (I) for use in the manufacture of a medicament
for treating cancer.
DETAILED DESCRIPTION
Definitions
[0118] As used in the present disclosure, the following words and
phrases are generally intended to have the meanings as set forth
below unless expressly indicated otherwise or the context in which
they are used indicates otherwise.
[0119] The following description sets forth exemplary methods,
parameters and the like. It should be recognized, however, that
such description is not intended as a limitation on the scope of
the present disclosure but is instead provided as a description of
exemplary embodiments.
[0120] As used in the present specification, the following words,
phrases and symbols are generally intended to have the meanings as
set forth below, except to the extent that the context in which
they are used indicates otherwise.
[0121] A dash ("--") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --C(O)NH.sub.2 is attached through the carbon atom. A dash
at the front or end of a chemical group is a matter of convenience;
chemical groups may be depicted with or without one or more dashes
without losing their ordinary meaning. Unless chemically or
structurally required, no directionality is indicated or implied by
the order in which a chemical group is written or named.
[0122] A squiggly line on a chemical group as shown below, for
example,
##STR00010##
indicates a point of attachment, i.e., it shows the broken bond by
which the group is connected to another described group.
[0123] The prefix "C.sub.u-v," indicates that the following group
has from u to v carbon atoms. For example, "C.sub.1-6 alkyl"
indicates that the alkyl group has from 1 to 6 carbon atoms.
[0124] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. In certain embodiments, the term "about" includes
the indicated amount .+-.10%. In other embodiments, the term
"about" includes the indicated amount .+-.5%. In certain other
embodiments, the term "about" includes the indicated amount .+-.1%.
Also, to the term "about X" includes description of "X". Also, the
singular forms "a" and "the" include plural references unless the
context clearly dictates otherwise. Thus, e.g., reference to "the
compound" includes a plurality of such compounds and reference to
"the assay" includes reference to one or more assays and
equivalents thereof known to those skilled in the art.
[0125] The term "substituted" means that any one or more hydrogen
atoms on the designated atom or group is replaced with one or more
substituents other than hydrogen, provided that the designated
atom's normal valence is not exceeded. The one or more substituents
include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy,
acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl,
carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl,
heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo,
nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate,
thiol, thione, or combinations thereof. Polymers or similar
indefinite structures arrived at by defining substituents with
further substituents appended ad infinitum (e.g., a substituted
aryl having a substituted alkyl which is itself substituted with a
substituted aryl group, which is further substituted by a
substituted heteroalkyl group, etc.) are not intended for inclusion
herein. Unless otherwise noted, the maximum number of serial
substitutions in compounds described herein is three. For example,
serial substitutions of substituted aryl groups with two other
substituted aryl groups are limited to ((substituted
aryl)substituted aryl) substituted aryl. Similarly, the above
definitions are not intended to include impermissible substitution
patterns (e.g., methyl substituted with 5 fluorines or heteroaryl
groups having two adjacent oxygen ring atoms). Such impermissible
substitution patterns are well known to the skilled artisan. When
used to modify a chemical group, the term "substituted" may
describe other chemical groups defined herein. For example, the
term "substituted aryl" includes, but is not limited to,
"alkylaryl." Unless specified otherwise, where a group is described
as optionally substituted, any substituents of the group are
themselves unsubstituted.
[0126] A "substituted" group also includes embodiments in which a
monoradical substituent is bound to a single atom of the
substituted group (e.g., forming a branch), and also includes
embodiments in which the substituent may be a diradical bridging
group bound to two adjacent atoms of the substituted group, thereby
forming a fused ring on the substituted group.
[0127] "Alkyl" refers to an unbranched or branched saturated
hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms
(i.e., C.sub.1-20 alkyl), 1 to 8 carbon atoms (i.e., C.sub.1-8
alkyl), 1 to 6 carbon atoms (i.e., C.sub.1-6 alkyl), or 1 to 4
carbon atoms (i.e., C.sub.1-4 alkyl). Examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,
hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue
having a specific number of carbons is named by chemical name or
identified by molecular formula, all positional isomers having that
number of carbons may be encompassed; thus, for example, "butyl"
includes n-butyl (i.e., --(CH.sub.2).sub.3CH.sub.3), sec-butyl
(i.e., --CH(CH.sub.3)CH.sub.2CH.sub.3), isobutyl (i.e.,
--CH.sub.2CH(CH.sub.3).sub.2) and tert-butyl (i.e.,
--C(CH.sub.3).sub.3); and "propyl" includes n-propyl (i.e.,
--(CH.sub.2).sub.2CH.sub.3) and isopropyl (i.e.,
--CH(CH.sub.3).sub.2).
[0128] "Alkenyl" refers to an aliphatic group containing at least
one carbon-carbon double bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkenyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkenyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkenyl), or 2 to 4
carbon atoms (i.e., C.sub.2-4 alkenyl). Examples of alkenyl groups
include ethenyl, propenyl, butadienyl (including 1,2-butadienyl,
and 1,3-butadienyl).
[0129] "Alkynyl" refers to an aliphatic group containing at least
one carbon-carbon triple bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkynyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkynyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkynyl), or 2 to 4
carbon atoms (i.e., C.sub.2-4 alkynyl). The term "alkynyl" also
includes those groups having one triple bond and one double
bond.
[0130] "Alkoxy" refers to the group "alkyl-O--" or "--O-alkyl".
Examples of alkoxy groups include methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,
n-hexoxy, and 1,2-dimethylbutoxy.
[0131] "Haloalkoxy" refers to an alkoxy group as defined above,
wherein one or more hydrogen atoms are replaced by a halogen.
[0132] "Amino" refers to the group --NR.sup.yR.sup.z wherein
R.sup.y and R.sup.z are independently selected from hydrogen,
alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;
each of which may be optionally substituted.
[0133] "Aryl" refers to a monoradical or diradical aromatic
carbocyclic group having a single ring (e.g., monocyclic) or
multiple rings (e.g., bicyclic or tricyclic) including fused ring
systems wherein one or more fused rings is/are fully or partially
unsaturated. As used herein, aryl has 6 to 20 ring carbon atoms
(i.e., C.sub.6-20 aryl), 6 to 12 carbon ring atoms (i.e.,
C.sub.6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C.sub.6-10
aryl). Non-limiting examples of aryl groups as used herein include
phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanuyl, and
anthryl. Aryl, however, does not encompass or overlap in any way
with heteroaryl defined below. If one or more aryl groups are fused
with a heteroaryl ring, the resulting ring system is heteroaryl.
The classification of mono or diradical indicates whether the aryl
group terminates the chain (monoradical) or is within a chain
(diradical). The above definition does not preclude additional
substituents on the aryl group. For example, as used herein, the
aryl group in "A-aryl-B" is a diradical whereas the aryl group in
"A-B-aryl" is monoradical, though additional substituents may be
present on each aryl group.
[0134] The term "alkylsulfinyl" refers to the group --SO-alkyl,
where alkyl is as defined above, and includes optionally
substituted alkyl groups as also defined above.
[0135] The term "alkylsulfonyl" refers to the group
--SO.sub.2-alkyl, where alkyl is as defined above, and includes
optionally substituted alkyl groups as also defined above.
[0136] "Cycloalkyl" refers to a saturated or partially saturated
cyclic alkyl group having a single ring or multiple rings including
fused, bridged, and spiro ring systems. As used herein, cycloalkyl
has from 3 to 20 ring carbon atoms (i.e., C.sub.3-20 cycloalkyl), 3
to 12 ring carbon atoms (i.e., C.sub.3-12 cycloalkyl), 3 to 10 ring
carbon atoms (i.e., C.sub.3-10 cycloalkyl), 3 to 8 ring carbon
atoms (i.e., C.sub.3-8 cycloalkyl), or 3 to 6 ring carbon atoms
(i.e., C.sub.3-6 cycloalkyl). Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0137] As used herein the term "cycloalkenyl" groups means the
non-aromatic carbocyclic group having at least one double bond.
[0138] "Cyanoalkyl" refers to an alkyl group substituted with cyano
(CN).
[0139] "Halogen" or "halo" includes fluoro, chloro, bromo, and
iodo.
[0140] The term "haloalkyl" refers to a monoradical or diradical
having the indicated carbon atoms of the alkyl group wherein one or
more hydrogen atoms have been substituted by a halogen. Examples of
haloalkyl groups include --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --CHFCH.sub.2F, --CF.sub.2--, --CHF--, and the
like. Similarly, the term "haloalkoxy", e.g.,
--O--C.sub.1-3haloalkyl, refers to an alkoxy group wherein one or
more hydrogen atoms of the alkyl group have been substituted by a
halogen. Examples of haloalkoxy groups include --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, --OCH.sub.2CF.sub.3, --OCHFCH.sub.2F,
and the like. One of skill in the art is aware that similar
definitions apply for the alkenyl and alkynyl analogs (e.g.,
C.sub.2-4haloalkenyl, --O--C.sub.2-4haloalkynyl) of the above.
[0141] "Heteroalkyl" refers to an alkyl group in which one or more
of the carbon atoms (and any associated hydrogen atoms) are each
independently replaced with the same or different heteroatomic
group. The term "heteroalkyl" includes unbranched or branched
saturated chain having carbon and heteroatoms. By way of example,
1, 2 or 3 carbon atoms may be independently replaced with the same
or different heteroatomic group. Heteroatomic groups include, but
are not limited to, --NR--, --O--, --S--, --SO--, --SO.sub.2--, and
the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl,
heteroaryl, or heterocycloalkyl, each of which may be optionally
substituted. Examples of heteroalkyl groups include --OCH.sub.3,
--CH.sub.2OCH.sub.3, --SCH.sub.3, --CH.sub.2SCH.sub.3,
--NRCH.sub.3, and --CH.sub.2NRCH.sub.3, where R is hydrogen, alkyl,
aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be
optionally substituted. As used herein, heteroalkyl includes 1 to
10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1
to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
[0142] "Heteroaryl" refers to a monoradical or diradical aromatic
group having a single ring, multiple rings, or multiple fused
rings, with one or more ring heteroatoms independently selected
from nitrogen, oxygen, and sulfur. The term includes fused ring
systems wherein one or more fused rings is/are fully or partially
unsaturated. As used herein, heteroaryl include 1 to 20 ring carbon
atoms (i.e., C.sub.1-20 heteroaryl), 3 to 12 ring carbon atoms
(i.e., C.sub.3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e.,
C.sub.3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms,
1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring
heteroatom independently selected from nitrogen, oxygen, and
sulfur. Non-limiting examples of heteroaryl groups include
pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl,
benzodioxanyl, indolinyl, and pyrazolyl. The classification of mono
or diradical indicates whether the heteroaryl group terminates the
chain (monoradical) or is within a chain (diradical). The above
definition does not preclude additional substituents on the
heteroaryl group. For example, the heteroaryl group in
"A-heteroaryl-B" is a diradical whereas the heteroaryl group in
"A-B-heteroaryl" is monoradical, though additional substituents may
be present on each heteroaryl group. Heteroaryl does not encompass
or overlap with aryl as defined above.
[0143] "Heterocycloalkyl" refers to a saturated or unsaturated
cyclic alkyl group, with one or more ring heteroatoms independently
selected from nitrogen, oxygen and sulfur. A heterocycloalkyl may
be a single ring or multiple rings wherein the multiple rings may
be fused, bridged, or spiro. As used herein, heterocycloalkyl has 2
to 20 ring carbon atoms (i.e., C.sub.2-20 heterocycloalkyl), 2 to
12 ring carbon atoms (i.e., C.sub.2-12 heterocycloalkyl), 2 to 10
ring carbon atoms (i.e., C.sub.2-10 heterocycloalkyl), 2 to 8 ring
carbon atoms (i.e., C.sub.2-8 heterocycloalkyl), 3 to 12 ring
carbon atoms (i.e., C.sub.3-12 heterocycloalkyl), 3 to 8 ring
carbon atoms (i.e., C.sub.3-8 heterocycloalkyl), or 3 to 6 ring
carbon atoms (i.e., C.sub.3-6 heterocycloalkyl); having 1 to 5 ring
heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to
2 ring heteroatoms, or 1 ring heteroatom independently selected
from nitrogen, sulfur or oxygen. Examples of heterocycloalkyl
groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,
dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term
"bridged-heterocycloalkyl" refers to a four- to ten-membered cyclic
moiety connected at two non-adjacent atoms of the heterocycloalkyl
with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety
having at least one heteroatom where each heteroatom is
independently selected from nitrogen, oxygen, and sulfur. As used
herein, bridged-heterocycloalkyl includes bicyclic and tricyclic
ring systems. Also used herein, the term "spiro-heterocycloalkyl"
refers to a ring system in which a three- to ten-membered
heterocycloalkyl has one or more additional ring, wherein the one
or more additional ring is three- to ten-membered cycloalkyl or
three- to ten-membered heterocycloalkyl, where a single atom of the
one or more additional ring is also an atom of the three- to
ten-membered heterocycloalkyl. Examples of spiro-heterocycloalkyl
include bicyclic and tricyclic ring systems, such as
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and
6-oxa-1-azaspiro[3.3]heptanyl.
[0144] The term "heterocyclyl," "heterocycle," or "heterocyclic"
refers to a monoradical or diradical saturated or unsaturated group
having a single ring or multiple condensed rings, having from 3 to
12 carbon atoms, from 1 to 6 hetero atoms, or from 1 to 4
heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or
oxygen within the ring. Where the group does not terminate the
molecule, it is a diradical and is construed as such i.e., also
referred to as heterocyclylene or heterocyclene.
[0145] Exemplary "heterocyclyl" groups include, but are not limited
to, pyrrolidin-2-one, azetidine, piperidine, pyrrolidine,
4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, morpholine,
piperazin-2-one, 2,6-diazaspiro[3.3]heptane,
2,6-diazaspiro[3.4]octan-7-one, 2,5-diazaspiro[3.4]octan-6-one,
2,7-diazaspiro[4.4]nonan-3-one, 2,9-diazaspiro[5.5]undecan-1-one,
1,7-diazaspiro[3.5]nonan-2-one, 2,8-diazaspiro[4.5]decan-3-one,
piperazine, 2-azaspiro[3.3]heptane, and
2-azabicyclo[2.2.2]octane.
[0146] The term "heterocyclyl" includes heterocycloalkenyl groups
(i.e., the heterocyclyl group having at least one double bond),
bridged-heterocyclyl groups, fused-heterocyclyl groups, and
spiro-heterocyclyl groups. A heterocyclyl may be a single ring or
multiple rings wherein the multiple rings may be fused, bridged, or
spiro. Any non-aromatic ring containing at least one heteroatom is
considered a heterocyclyl, regardless of the attachment (i.e., can
be bound through a carbon atom or a heteroatom). Further, the term
heterocyclyl is intended to encompass any non-aromatic ring
containing at least one heteroatom, which ring may be fused to an
aryl or heteroaryl ring, regardless of the attachment to the
remainder of the molecule. A heterocyclyl may contain one or more
oxo and/or thioxo groups.
[0147] "Acyl" refers to a group --C(.dbd.O)R, wherein R is
hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl,
or heteroaryl; each of which may be optionally substituted, as
defined herein. Examples of acyl include formyl, acetyl,
cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
[0148] The term "N-alkylated" means an alkyl group is substituted
for one of the hydrogen atoms of a mono substituted amine, or a
di-substituted amine group or a tri substituted amine group. When
the alkylation is on a tri-substituted amine group an alkonium salt
is generated i.e., a positive charge is generated on the nitrogen
atom. N-alkylation is commonly associated with alkyl substitution
on a ring nitrogen atom.
[0149] The term "oxo" refers to a group .dbd.O.
[0150] The term "carboxy" refers to a group --C(O)--OH.
[0151] The term "ester" or "carboxyl ester" refers to the group
--C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl, which may be optionally further substituted, for
example, by alkyl, alkoxy, halogen, CF.sub.3, amino, substituted
amino, cyano or --SO.sub.nR.sup.f, in which R.sup.f is alkyl, aryl,
or heteroaryl, and n is 0, 1 or 2.
[0152] The term "substituted amino" refers to the group --NRR,
where each R is independently hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl, each of which may be optionally
substituted, or a group as described or exemplified herein, or
where both R groups are joined to form a heterocyclic group (e.g.,
morpholino) as described or exemplified herein, which also may be
optionally substituted.
[0153] The term "amido" refers to the group --C(O)NRR where each R
is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl, each of which may be optionally substituted, or a
group as described or exemplified herein, or where both R groups
are joined to form a heterocyclic group (e.g., morpholino) as
described or exemplified herein, which also may be optionally
substituted.
[0154] The term "sulfoxide" refers to a group --SOR, in which R is
alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which
may be optionally substituted.
[0155] The term "sulfone" refers to a group --SO.sub.2R, in which R
is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of
which may be optionally substituted.
[0156] As used herein, the terms "alkylcycloalkyl," "alkylaryl,"
"alkylheteroaryl" and "alkylheterocyclyl" are intended to refer to
a cycloalkyl, aryl, heteroaryl or heterocyclyl group which is bound
to the remainder of the molecule via an alkyl moiety, where the
terms "alkyl," "cycloalkyl," "aryl," "heteroaryl" and
"heterocyclyl" are as defined herein. Exemplary alkylaryl groups
include benzyl, phenethyl, and the like.
[0157] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not.
[0158] Certain commonly used alternative chemical names may be
used. For example, a divalent group such as a divalent "alkyl"
group, a divalent "aryl" group, etc., may also be referred to as an
"alkylene" group or an "alkylenyl" group, an "arylene" group or an
"arylenyl" group, respectively. Also, unless indicated explicitly
otherwise, where combinations of groups are referred to herein as
one moiety, e.g., arylalkyl, the last mentioned group contains the
atom by which the moiety is attached to the rest of the
molecule.
[0159] Where a group is represented by a bond, multiple adjacent
groups whether the same or different, when represented by bonds,
constitute a single bond. For example the group
"-L.sup.1-V.sup.1-L.sup.2-" constitutes a single bond if each of
L.sup.1, V.sup.1 and L.sup.2 is a bond.
[0160] Where a given group (moiety) is described herein as being
attached to a second group and the site of attachment is not
explicit, the given group may be attached at any available site of
the given group or to any available site of the second group. For
example, an "alkyl-substituted phenyl", where the attachment sites
are not explicit, may have any available site of the alkyl group
attached to any available site of the phenyl group. In this regard,
an "available site" is a site of the group at which hydrogen of the
group may be replaced with a substituent.
[0161] It is understood that in all substituted groups defined
above, polymers arrived at by defining substituents with further
substituents to themselves (e.g., substituted aryl having a
substituted aryl group as a substituent which is itself substituted
with a substituted aryl group, etc.) are not intended for inclusion
herein. Also not included are infinite numbers of substituents,
whether the substituents are the same or different. In such cases,
the maximum number of such substituents is three. Each of the above
definitions is thus constrained by a limitation that, for example,
substituted aryl groups are limited to -substituted
aryl-(substituted aryl)-substituted aryl.
[0162] "Isomers" are different compounds that have the same
molecular formula. Isomers include stereoisomers, enantiomers and
diastereomers.
[0163] "Stereoisomers" are isomers that differ only in the way the
atoms are arranged in space.
[0164] "Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term "(+)" is used
to designate a racemic mixture where appropriate.
[0165] "Diastereoisomers" are stereoisomers that have at least two
asymmetric atoms, but which are not mirror-images of each
other.
[0166] The compounds of the disclosure may possess one or more
asymmetric centers and may be produced as a racemic mixture or as
individual enantiomers or diastereoisomers. The number of
stereoisomers present in any given compound of a given formula
depends upon the number of asymmetric centers present (there are
2.sup.n stereoisomers possible where n is the number of asymmetric
centers). The individual stereoisomers may be obtained by resolving
a racemic or non-racemic mixture of an intermediate at some
appropriate stage of the synthesis or by resolution of the compound
by conventional means. The individual stereoisomers (including
individual enantiomers and diastereoisomers) as well as racemic and
non-racemic mixture of stereoisomers are encompassed within the
scope of the present disclosure, all of which are intended to be
depicted by the structures of this specification unless otherwise
specifically indicated.
[0167] The absolute stereochemistry is specified according to the
Cahn Ingold Prelog R S system. When the compound is a pure
enantiomer the stereochemistry at each chiral carbon may be
specified by either R or S. A resolved compound whose absolute
configuration is unknown may be designated (+) or (-) depending on
the direction (dextro- or laevorotary) that it rotates the plane of
polarized light at the wavelength of the sodium D line.
[0168] Some of the compounds exist as tautomeric isomers.
Tautomeric isomers are in equilibrium with one another. For
example, amide containing compounds may exist in equilibrium with
imidic acid tautomers. Regardless of which tautomer is shown, and
regardless of the nature of the equilibrium among tautomers, the
compounds are understood by one of ordinary skill in the art to
comprise both amide and imidic acid tautomers. Thus, the amide
containing compounds are understood to include their imidic acid
tautomers. Likewise, the imidic acid containing compounds are
understood to include their amide tautomers.
[0169] The term "polymorph" refers to different crystal structures
of a crystalline compound. The different polymorphs may result from
differences in crystal packing (packing polymorphism) or
differences in packing between different conformers of the same
molecule (conformational polymorphism).
[0170] The term "solvate" refers to a complex formed by combining a
compound of formula (I), or any other formula as disclosed herein
and a solvent.
[0171] The term "hydrate" refers to the complex formed by the
combining of a compound of formula (I), or any formula disclosed
herein, and water.
[0172] The term "prodrug" refers to compounds of formula (I), or
derivatives of formula (I) disclosed herein, that include chemical
groups which, in vivo, can be converted and/or can be split off
from the remainder of the molecule to provide for the active drug.
Pharmaceutically acceptable salts or biologically active
metabolites thereof of the prodrug of a compound of formula (I) are
also within the ambit of the present disclosure.
[0173] Any formula or structure given herein, including formula
(I), or any formula disclosed herein, is intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an isotope having a selected atomic mass or mass
number. Examples of isotopes that can be incorporated into
compounds of the disclosure include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but
not limited to .sup.2H (deuterium, D), .sup.3H (tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.31P, .sup.32P,
.sup.35S, .sup.36Cl, and .sup.125I. Various isotopically labeled
compounds of the present disclosure, for example those into which
radioactive isotopes such as .sup.3H, .sup.13C and .sup.14C are
incorporated, are within the ambit of the present disclosure. Such
isotopically labelled compounds may be useful in metabolic studies,
reaction kinetic studies, detection or imaging techniques, such as
positron emission tomography (PET) or single-photon emission
computed tomography (SPECT) including drug or substrate tissue
distribution assays or in treatment of patients. Such isotopically
labeled analogs of compounds of the present disclosure may also be
useful for treatment of diseases disclosed herein because they may
provide improved pharmacokinetic and/or pharmacodynamic properties
over the unlabeled forms of the same compounds. Such isotopically
leveled forms of or analogs of compounds herein are within the
ambit of the present disclosure. One of skill in the art is able to
prepare and use such isotopically labeled forms following
procedures for isotopically labeling compounds or aspects of
compounds to arrive at isotopic or radiolabeled analogs of
compounds disclosed herein.
[0174] The term "pharmaceutically acceptable salt" of a given
compound refers to salts that retain the biological effectiveness
and properties of the given compound, and which are not
biologically or otherwise undesirable. Pharmaceutically acceptable
base addition salts can be prepared from inorganic and organic
bases. Salts derived from inorganic bases include, by way of
example only, sodium, potassium, lithium, ammonium, calcium and
magnesium salts. Salts derived from organic bases include, but are
not limited to, salts of primary, secondary and tertiary amines,
such as alkyl amines, dialkyl amines, trialkyl amines, substituted
alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl)
amines, alkenyl amines, dialkenyl amines, trialkenyl amines,
substituted alkenyl amines, di(substituted alkenyl) amines,
tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl)
amines, tri(cycloalkyl) amines, substituted cycloalkyl amines,
di-substituted cycloalkyl amine, tri-substituted cycloalkyl amines,
cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)
amines, substituted cycloalkenyl amines, di-substituted
cycloalkenyl amine, tri-substituted cycloalkenyl amines, aryl
amines, diaryl amines, triaryl amines, heteroaryl amines,
diheteroaryl amines, triheteroaryl amines, heterocyclic amines,
diheterocyclic amines, triheterocyclic amines, mixed di- and
tri-amines where at least two of the substituents on the amine are
different and are selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,
heterocyclic, and the like.
[0175] Also included are amines where the two or three
substituents, together with the amino nitrogen, form a heterocyclic
or heteroaryl group. Amines are of general structure
N(R.sup.30)(R.sup.31)(R.sup.32), wherein mono-substituted amines
have two of the three substituents on nitrogen (R.sup.30, R.sup.31,
and R.sup.32) as hydrogen, di-substituted amines have one of the
three substituents on nitrogen (R.sup.30, R.sup.31, and R.sup.32)
as hydrogen, whereas tri-substituted amines have none of the three
substituents on nitrogen (R.sup.30, R.sup.31, and R.sup.32) as
hydrogen. R.sup.30, R.sup.31, and R.sup.32 are selected from a
variety of substituents such as hydrogen, optionally substituted
alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl,
and the like.
[0176] Specific examples of suitable amines include, by way of
example only, isopropyl amine, trimethyl amine, diethyl amine,
tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,
diethanolamine, 2-dimethylamino ethanol, lysine, arginine,
histidine, caffeine, procaine, hydrabamine, choline, betaine,
ethylenediamine, glucosamine, N-alkylglucamines, theobromine,
purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and
the like.
[0177] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
[0178] As used herein, "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial, and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, or unless
otherwise indicated herein, its use in the therapeutic compositions
is contemplated. Supplementary active ingredients can also be
incorporated into the compositions.
[0179] The term "anticancer agent" is any drug that is effective in
the treatment of a malignant, or cancerous disease. Effectiveness
may mean inhibition, partial, or full remission, prolongation of
life, improvement in quality of life, or cure. There are several
major classes of anticancer drugs including chemical compositions
as disclosed herein or known to one of skill in the art e.g., PD-1,
PD-L1, PD-1/PD-L1 interaction inhibitors, alkylating agents,
antimetabolites, natural products, and hormones.
[0180] The term "additional anticancer agent" as used herein means
the use or combination of a second, third, fourth, fifth, etc.,
anticancer agent(s) in addition to a compound according to formula
(I) disclosed herein.
[0181] The term "anticancer therapy" means any currently known
therapeutic methods for the treatment of cancer.
[0182] The term "blockade agent" or "check point inhibitors" are
classes of immune oncology agents that inhibit PD-1, PD-L1, or the
PD-1/PD-L1 interaction.
[0183] The term "treatment" or "treating" means any administration
of a compound or compounds according to the present disclosure to a
subject (e.g., a human) having or susceptible to a condition or
disease disclosed herein for the purpose of: 1) preventing or
protecting against the disease or condition, that is, causing the
clinical symptoms not to develop; 2) inhibiting the disease or
condition, that is, arresting or suppressing the development of
clinical symptoms; or 3) relieving the disease or condition that is
causing the regression of clinical symptoms. In some embodiments,
the term "treatment" or "treating" refers to relieving the disease
or condition or causing the regression of clinical symptoms.
[0184] As used herein, the term "preventing" refers to the
prophylactic treatment of a patient in need thereof. The
prophylactic treatment can be accomplished by providing an
appropriate dose of a therapeutic agent to a subject at risk of
suffering from an ailment, thereby substantially averting onset of
the ailment. The presence of a genetic mutation or the
predisposition to having a mutation may not be alterable. However,
prophylactic treatment (prevention) as used herein has the
potential to avoid/ameliorate the symptoms or clinical consequences
of having the disease engendered by such genetic mutation or
predisposition.
[0185] It will be understood by those of ordinary skill in the art
that in human medicine, it is not always possible to distinguish
between "preventing" and "suppressing" since the ultimate inductive
event or events may be unknown, latent, or the patient is not
ascertained until well after the occurrence of the event or events.
Therefore, as used herein, the term "prophylaxis" is intended as an
element of "treatment" to encompass both "preventing" and
"suppressing" as defined herein. The term "protection," as used
herein, is meant to include "prophylaxis."
[0186] The term "patient" typically refers to a "mammal" which
includes, without limitation, human, monkeys, rabbits, mice,
domestic animals, such as dogs and cats, farm animals, such as
cows, horses, or pigs, and laboratory animals. In some embodiments,
the term patient refers to a human in need of treatment as defined
herein.
Compounds
[0187] Provided herein are compounds that function as PD-1
inhibitors, PD-L1 inhibitors, and/or PD-1/PD-L1 interaction
inhibitors, methods of using such compounds and compositions
comprising such compounds optionally in combination with one or
more additional anticancer agents or therapies. In all embodiments
discussed herein where there is more than one occurrence of a group
or variable, it is intended that the group or variable is
independently selected the list that follows. It is further
contemplated that all embodiments directed to compounds include any
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, solvate, prodrug or tautomer thereof.
[0188] The present disclosure provides a compound of formula
(I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) [0189] wherein: Ar.sup.E and Ar.sup.W are each independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0190] wherein each
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [0191] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl group is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; L.sup.E and L.sup.W are each
independently a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0191] ##STR00011## [0192] wherein [0193] each m is independently
0, 1, 2, 3 or 4; Q.sup.E and Q.sup.W are each independently aryl,
heteroaryl, or heterocyclyl, [0194] wherein each aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from halo, oxo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0195] wherein each
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0196] wherein [0197] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0197] ##STR00012## [0198] wherein [0199] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0200] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0201] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0202] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0203] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0204] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [0205] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b and --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uNR.sup.c(CH.sub.2).sub.uP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0205] ##STR00013## [0206] wherein: [0207] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0208] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0209]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0210] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, (CH.sub.2).sub.qOR.sup.a, or
(CH.sub.2).sub.qC(O)R.sup.e; [0211] p is independently 0, 1, 2, 3,
4, or 5; [0212] q is independently 0, 1, 2, 3, 4, or 5; [0213] u is
0, 1, 2, 3, or 4; and [0214] z is 0, 1, 2, or 3; [0215] wherein
each cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from NR.sup.aR.sup.b, halo, cyano, oxo,
OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH,
--C.sub.3-8 cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8cycloalkyl;
[0216] provided that at least one of V.sup.2, L.sup.3, ring B and T
contains a nitrogen atom; R.sup.1 is independently selected from H,
--C.sub.1-8 alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0217] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0218] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl;
[0219] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, or tautomer thereof.
[0220] The present disclosure further provides a compound of
formula (I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) [0221] wherein: Ar.sup.E and Ar.sup.W are each independently
cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0222] wherein each
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [0223] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl group is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; L.sup.E and L.sup.W are each
independently a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0223] ##STR00014## [0224] wherein [0225] each m is independently
1, 2, 3 or 4; [0226] provided that when one of Ar.sup.E and
Ar.sup.W is optionally substituted phenyl and the other is
optionally substituted phenyl or optionally substituted
2,3-dihydrobenzo[b][1,4]dioxine, and one of L.sup.E and L.sup.W is
--CH.sub.2O--, --CH.sub.2CH.sub.2--, --CHCH--, and --C(O)N--; then
the other of L.sup.E and L.sup.W is a bond, --O-- or --CH.sub.2O--
of the formula Ar--CH.sub.2O-Q; Q.sup.E and Q.sup.W are each
independently aryl, heteroaryl, or heterocyclyl, [0227] wherein
each aryl, heteroaryl, or heterocyclyl is optionally substituted
with 1 to 4 groups independently selected from halo, oxo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.1-6 alkylC.sub.3-8 cycloalkyl, and R.sup.N; [0228] wherein
each alkyl, alkenyl, alkynyl, is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
[0229] wherein [0230] R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)NR.sup.1R.sup.2,
--OC.sub.1-6 alkylC(O)OR.sup.1, --SC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOR.sup.a, or
[0230] ##STR00015## [0231] wherein [0232] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0233] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0234] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0235] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0236]
provided at least one of L.sup.1, V an L.sup.2 is other than a
bond; [0237] ring A is independently cycloalkyl, aryl, heteroaryl,
or heterocyclyl; [0238] wherein each cycloalkyl, aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [0239] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b and --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uNR.sup.c(CH.sub.2).sub.uP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0239] ##STR00016## [0240] wherein: [0241] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0242] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0243]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0244] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, (CH.sub.2).sub.qOR.sup.a, or
(CH.sub.2).sub.qC(O)R.sup.e; [0245] p is independently 0, 1, 2, 3,
4, or 5; [0246] q is independently 0, 1, 2, 3, 4, or 5; [0247] u is
0, 1, 2, 3, or 4; and [0248] z is 0, 1, 2, or 3; [0249] wherein
each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 3 substituents independently selected from
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0250] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom, and when each of V.sup.2 and L.sup.3 is a bond and p is 0,
then either (i) neither of L.sup.E or L.sup.W is a bond or (ii)
ring B is not a 5,6-membered fused heteroaryl where the 5-membered
ring of the fused heteroaryl is bound to the corresponding Q.sup.E
or Q.sup.W; R.sup.1 is independently selected from H, --C.sub.1-8
alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0251] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0252] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or
--C.sub.2-6 alkenylC(O)OR.sup.a; R.sup.4 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or
--C.sub.2-6 alkenylC(O)OR.sup.a; R.sup.a is independently selected
from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; R.sup.b is independently selected
from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl;
[0253] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, or tautomer thereof.
[0254] The present disclosure further provides a compound of
formula (I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I)
wherein: Ar.sup.E and Ar.sup.W are each independently a cycloalkyl,
aryl, heteroaryl, or heterocyclyl; [0255] wherein each cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 4 groups independently selected from halo, --OR.sup.a,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, and --C.sub.1-6 alkylC.sub.3-8 cycloalkyl;
and [0256] wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is
optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano;
L.sup.E and L.sup.W are each independently a bond, --O--, --S--,
--SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0256] ##STR00017## [0257] wherein each m is independently 0, 1, 2,
3 or 4; Q.sup.E and Q.sup.W are each independently aryl,
heteroaryl, or heterocyclyl; [0258] wherein each aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 4 groups
independently selected from halo, oxo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0259] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6-cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0260] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0260] ##STR00018## [0261] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0262] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0263] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0264] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0265] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0266] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0267] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0267] ##STR00019## [0268] wherein: [0269] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0270] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0271]
ring B is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0272] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0273] p is independently 0, 1, 2, 3,
4, or 5; [0274] q is independently 0, 1, 2, 3, 4, or 5; [0275] u is
0, 1, 2, 3, or 4; [0276] z is 0, 1, 2, or 3; and [0277] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0278] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0279] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0280] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, solvate, or tautomer thereof.
[0281] In one embodiment, provided is a compound of formula
(I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I)
wherein: Ar.sup.E and Ar.sup.W are each independently a cycloalkyl,
aryl, heteroaryl, or heterocyclyl; [0282] wherein each cycloalkyl,
aryl, heteroaryl, or heterocyclyl is optionally substituted with 1
to 2 groups independently selected from halo, --OR.sup.a,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, and --C.sub.3-8 cycloalkyl; [0283] wherein
each alkyl, and cycloalkyl group is optionally substituted with 1
to 4 groups independently selected from NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano.
[0284] In one embodiment, Ar.sup.E and Ar.sup.W are each
independently an aryl, heteroaryl, or heterocyclyl; [0285] wherein
each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 2 groups independently selected from halo,
--OR.sup.a, CN, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, and
--OC.sub.1-6 alkyl; and [0286] wherein each alkyl group is
optionally substituted with 1 to 4 groups independently selected
from OR.sup.a, halo, or cyano.
[0287] In one embodiment, Ar.sup.W and Ar.sup.E are each
independently selected from phenyl, pyridinyl, indanyl, and
indolinyl; [0288] wherein each phenyl, pyridinyl, indanyl, and
indolinyl is optionally substituted with 1 to 2 groups
independently selected from halo, cyano, --OR.sup.a,
--C.sub.1-6alkyl, --C.sub.1-6alkyl-OR.sup.a, --C.sub.1-6haloalkyl,
--OC.sub.1-6haloalkyl, and --C.sub.1-6cyanoalkyl.
[0289] In one embodiment, Ar.sup.W is the same as Ar.sup.E and is
selected from phenyl, pyridinyl, indanyl, and indolinyl; [0290]
wherein each phenyl, pyridinyl, indanyl, and indolinyl is
optionally substituted with 1 to 3 groups independently selected
from halo, cyano, --OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6alkyl-OR.sup.a, --C.sub.1-6haloalkyl, and
--C.sub.L-6cyanoalkyl.
[0291] In one embodiment, the group Ar.sup.W is selected from
phenyl, pyridinyl, indanyl, naphthyl, indazolyl, indolinyl,
quinolinyl, quinazolinyl, benzimidazolinyl, benzthiazolyl,
thiazolyl, and thienyl. In another embodiment, the group Ar.sup.W
is selected from phenyl, pyridinyl, indanyl, indolinyl, quinolinyl,
and benzimidazolinyl.
[0292] In one embodiment, the group Ar.sup.E is selected from
phenyl, pyridinyl, indanyl, naphthyl, indazolyl, indolinyl,
quinolinyl, quinazolinyl, benzimidazolinyl, benzthiazolyl,
thiazolyl, and thienyl. In another embodiment, the group Ar.sup.E
is selected from phenyl, pyridinyl, indanyl, indolinyl, quinolinyl,
and benzimidazolinyl.
[0293] In one embodiment, the groups Ar.sup.W and Ar.sup.E are the
same. In one embodiment, the groups Ar.sup.W and Ar.sup.E are the
same and have the same substituents. In one embodiment, the groups
Ar.sup.W and Ar.sup.E are both phenyl each optionally substituted
with methyl. In one embodiment, the groups Ar.sup.W and Ar.sup.E
are both phenyl each optionally substituted with chloro. In one
embodiment, the groups Ar.sup.W and Ar.sup.E are both indanyl each
optionally substituted with methyl. In one embodiment, the groups
Ar.sup.W and Ar.sup.E are both indolinyl each optionally
substituted with methyl. In one embodiment, the groups Ar.sup.W and
Ar.sup.E are both benzimidazole each optionally substituted with
methyl. In one embodiment, the groups Ar.sup.W and Ar.sup.E are
both indolyl. In one embodiment, the groups Ar.sup.W and Ar.sup.E
are both indolyl each optionally substituted with methyl. In
another embodiment of the disclosure, the groups Ar.sup.W and
Ar.sup.E are different and are independently selected from phenyl,
indanyl, thienyl, benzimidazolyl, indolyl, and indolinyl.
[0294] In one embodiment, the optional substituents on Ar.sup.W and
Ar.sup.E are independently selected from halo, cyano,
C.sub.1-6alkyl, C.sub.1-3haloalkyl, C.sub.2-5alkynyl, and
--O--C.sub.1-6alkyl.
[0295] In one embodiment, Ar.sup.E is the same as Ar.sup.W and each
is optionally substituted with 1 to 2 groups independently selected
from methyl, chloro, bromo, CN, --OCF.sub.3, CF.sub.3,
CH.sub.2CF.sub.3, and ethyl.
[0296] In one embodiment, Ar.sup.E is different from Ar.sup.W and
each is optionally substituted with 1 to 2 groups independently
selected from methyl, chloro, bromo, CN, --OCF.sub.3, CF.sub.3,
CH.sub.2CF.sub.3, and ethyl.
[0297] In one embodiment, Ar.sup.W is indolinyl and Ar.sup.E is
indolinyl each optionally substituted with 1 to 2 groups
independently selected from methyl, ethyl, methoxy, chloro, and
CF.sub.3.
[0298] In one embodiment, Ar.sup.W is phenyl and Ar.sup.E is phenyl
each optionally substituted with 1 to 2 groups independently
selected from methyl, ethyl, methoxy, chloro, and CF.sub.3.
[0299] In another embodiment of the disclosure, the optional
substituents on Ar.sup.W and Ar.sup.E are independently selected
from CN, Cl, F, --OCF.sub.3, --O--CH.sub.3, CH.sub.3, and
C.sub.2H.sub.5.
[0300] In another embodiment of the disclosure, the optional
substituents on Ar.sup.W and Ar.sup.E are independently selected
from CN, Cl, F, --OCF.sub.3, --OCH.sub.3, --CH.sub.3, and
--C.sub.2H.sub.5.
[0301] In another embodiment of the disclosure, the optional
substituents on Ar.sup.W and Ar.sup.E is CH.sub.3.
[0302] In one embodiment, the present disclosure provides a
compound of formula (I) wherein the group --Ar.sup.W--Ar.sup.E-- is
selected from:
##STR00020## ##STR00021##
wherein each ring is optionally substituted with 1 or 2 groups
independently selected from halo, cyano, C.sub.1-6alkyl,
C.sub.1-3haloalkyl, --OC.sub.1-6alkyl, and
--OC.sub.1-3haloalkyl.
[0303] In one embodiment, L.sup.E and L.sup.W are each
independently a bond, --O--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00022## [0304] wherein each m is independently 0, 1, 2, 3 or
4.
[0305] In one embodiment, L.sup.E and L.sup.W are each
independently a bond, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
##STR00023## [0306] wherein [0307] each m is independently 0, 1, 2
or 3; [0308] R.sup.3 is independently H, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; and [0309] R.sup.4 is
independently H, halo, --C.sub.1-6alkyl, --OH, --OCH.sub.3, or
--OCH.sub.2CH.sub.3.
[0310] In one embodiment,
L.sup.E and L.sup.W are each independently a bond,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--, --C(O)--,
##STR00024## [0311] wherein [0312] each m is independently 0, 1 or
2; [0313] R.sup.3 is independently H, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; and [0314] R.sup.4 is
independently H, halo, --C.sub.1-6alkyl, --OH, --OCH.sub.3, or
--OCH.sub.2CH.sub.3.
[0315] In one embodiment, L.sup.E and L.sup.W are each
independently O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--, or
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
[0316] wherein [0317] each m is independently 0, 1, or 2; and
[0318] R.sup.3 and R.sup.4 are each independently H, or
--C.sub.1-6alkyl.
[0319] In one embodiment, L.sup.E and L.sup.W are each
independently a bond, --(CR.sup.3R.sup.4).sub.m--,
--O(CR.sup.3R.sup.4).sub.m, --(CR.sup.3R.sup.4).sub.mO, or
--C(O)--, [0320] wherein [0321] m is independently 0, 1, 2, or 3;
and [0322] R.sup.3 and R.sup.4 are each independently H,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3.
[0323] In one embodiment, L.sup.E and L.sup.W are each
independently a bond, --(CR.sup.3R.sup.4).sub.m--,
--O(CR.sup.3R.sup.4).sub.m, --(CR.sup.3R.sup.4).sub.mO, or
--C(O)--: [0324] wherein [0325] m is independently 0, 1 or 2; and
[0326] R.sup.3 and R.sup.4 are each independently H, or
--C.sub.1-6alkyl.
[0327] In one embodiment, L.sup.E and L.sup.W are each
independently a bond, --CH.sub.2--, --OCH.sub.2, --CH.sub.2O-- or
--C(O)--.
[0328] In one embodiment, L.sup.W is --O(CR.sup.3R.sup.4).sub.m--
or --(CR.sup.3R.sup.4).sub.mO--.
[0329] In another embodiment, L.sup.W is
--(CR.sup.3R.sup.4).sub.m--. In another embodiment, L.sup.W is
--NR.sup.3(CHR.sup.4).sub.n or --(CHR.sup.4).sub.nNR.sup.3--. In
another embodiment, L.sup.W is --NR.sup.3(CHR.sup.4).sub.m. In
another embodiment, the group L.sup.W is --C(O)--. In yet another
embodiment, L.sup.W is a bond.
[0330] In one embodiment, L.sup.E is --(CR.sup.3R.sup.4).sub.mO--
or --(CR.sup.3R.sup.4).sub.mO--.
[0331] In another embodiment, L.sup.E is
--(CR.sup.3R.sup.4).sub.m--. In another embodiment, L.sup.E is
--NR.sup.3(CHR.sup.4).sub.n or --(CHR.sup.4).sub.nNR.sup.3--. In
another embodiment, L.sup.E is --NR.sup.3(CHR.sup.4).sub.m. In
another embodiment, the group L.sup.E is --C(O)--. In yet another
embodiment, L.sup.E is a bond.
[0332] In one embodiment, one of L.sup.W and L.sup.E is a bond and
the other is --OCH.sub.2-- or --CH.sub.2O--.
[0333] In one embodiment, Q.sup.E and Q.sup.W are each
independently an aryl, heteroaryl, or heterocyclyl; [0334] wherein
each aryl, heteroaryl, or heterocyclyl is optionally substituted
with 1 to 2 groups independently selected from halo, oxo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0335] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--SO.sub.2R.sup.a, --NR.sup.aSO.sub.2R.sup.b,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
[0336] wherein the heteroaryl or heterocyclic group may be oxidized
on a nitrogen atom to form an N-oxide, or may be C.sub.1-6
alkylated to form a N--C.sub.1-6 alkylated ion, or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0337] wherein [0338]
R.sup.N is independently --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0338] ##STR00025## [0339] wherein L.sup.1 is independently a bond,
O, NR.sup.a or S; [0340] wherein L.sup.2 is independently a bond,
O, NR.sup.a or S; [0341] V is independently selected from a bond,
C.sub.1-6alkyl, and C.sub.2-6alkenyl; and [0342] ring A is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0343]
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally independently substituted with 1 to 3 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0344] In one embodiment, Q.sup.E and Q.sup.W are each
independently an aryl, heteroaryl, or heterocyclyl optionally
substituted with R.sup.N; [0345] wherein R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOR.sup.a, or
[0345] ##STR00026## [0346] wherein [0347] L.sup.1 is independently
a bond, O, NR.sup.a or S; [0348] L.sup.2 is independently a bond,
O, NR.sup.a or S; [0349] V is independently selected from a bond,
C.sub.1-6alkyl, and C.sub.2-6alkenyl; [0350] ring A is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0351]
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally independently substituted with 1 to 3 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0352] In one embodiment, Q.sup.E and Q.sup.W are each
independently an aryl, or heteroaryl group optionally substituted
with R.sup.N; wherein [0353] R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOR.sup.a, or
[0353] ##STR00027## [0354] wherein [0355] L.sup.1 is independently
a bond, O, NR.sup.a or S; [0356] L.sup.2 is independently a bond,
O, NR.sup.a or S; [0357] V is independently selected from a bond,
C.sub.1-6alkyl, and C.sub.2-6alkenyl; and [0358] ring A is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0359]
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally independently substituted with 1 to 3 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0360] In one embodiment, Q.sup.E and Q.sup.W are each
independently phenyl, pyridine, indanyl, naphthyl, indolyl,
indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, imidazolyl,
thiazolyl, or thienyl; wherein each phenyl, pyridine, indanyl,
naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl,
benzimidazolyl, imidazolyl, thiazolyl, or thienyl is optionally
substituted with 1 to 3 groups independently selected from halo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.aR.sup.b,
--C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and
--C.sub.1-6alkylC.sub.3-8 cycloalkyl.
[0361] In one embodiment, Q.sup.E and Q.sup.W are each
independently phenyl, pyridine, indanyl, naphthyl, indolyl,
indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, imidazolyl,
thiazolyl, or thienyl; [0362] wherein each phenyl, pyridine,
indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl,
benzimidazolyl, imidazolyl, thiazolyl, or thienyl is optionally
substituted with 1 to 3 groups independently selected from halo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.aR.sup.b,
--C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, --C.sub.1-6alkylC.sub.3-8
cycloalkyl, and R.sup.N; [0363] wherein [0364] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0364] ##STR00028## [0365] L.sup.1 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; [0366] L.sup.2 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0367] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0368] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; and [0369] ring A is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0370]
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally substituted with 1 to 2 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, --CN,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0371] In one embodiment, Q.sup.E and Q.sup.W are each
independently phenyl, pyridine, indanyl, naphthyl, indolyl,
indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, or
benzthiazolyl; [0372] wherein each group is optionally substituted
with 1 to 3 groups independently selected from halo, --OR.sup.a,
--N.sub.3, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, --C.sub.1-6alkylC.sub.3-8 cycloalkyl, and
R.sup.N; [0373] wherein [0374] R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)NR.sup.1R.sup.2,
--OC.sub.1-6 alkylC(O)OR.sup.1, --SC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOR.sup.a, or
[0374] ##STR00029## [0375] wherein [0376] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0377] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0378] V is
independently selected from a bond, C.sub.1-6alkyl,
C.sub.2-6alkenyl, and C.sub.2-6alkynyl; [0379] wherein the alkyl,
alkenyl, or alkynyl is optionally independently substituted with
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; [0380] ring A is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; [0381] wherein the cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, CN, --NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)OR.sup.a, --C(O)N(R.sup.a)OR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0382] In one embodiment, Q.sup.E and Q.sup.W are each
independently phenyl, indanyl, naphthyl, indolyl, indolinyl,
benzthiazolyl, indazolyl, benzimidazolyl, or benzthiazolyl; [0383]
wherein each phenyl, indanyl, naphthyl, indolyl, indolinyl,
benzthiazolyl, indazolyl, benzimidazolyl, or benzthiazolyl is
optionally substituted with 1 to 3 groups independently selected
from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl,
--C.sub.1-6alkylC.sub.3-8 cycloalkyl, and R.sup.N; [0384] wherein
[0385] R.sup.N is independently --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0385] ##STR00030## [0386] wherein [0387] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0388] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0389] V is
independently selected from a bond, C.sub.1-6alkyl,
C.sub.2-6alkenyl, and C.sub.2-6alkynyl; [0390] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl; and [0391] ring A is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; [0392] wherein the cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, --CN, NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)OR.sup.a, --C(O)N(R.sup.a)OR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, and C.sub.3-8
cycloalkyl.
[0393] In one embodiment, Q.sup.E and Q.sup.W are each
independently phenyl, pyridine, indazolyl, thiazolyl, or indolinyl;
[0394] wherein each phenyl, pyridine, indazolyl, thiazolyl, or
indolinyl is optionally substituted with 1 to 3 groups
independently selected from halo, --OR.sup.a, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.2-6 alkynyl, --C.sub.3-8 cycloalkyl, and R.sup.N; [0395]
wherein [0396] R.sup.N is independently --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOR.sup.a, or
[0396] ##STR00031## [0397] wherein [0398] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0399] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0400] V is
independently selected from a bond, C.sub.1-6alkyl,
C.sub.2-6alkenyl, and C.sub.2-6 alkynyl; [0401] wherein each alkyl,
alkenyl, or alkynyl is optionally independently substituted with
OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl; [0402] ring A is independently cycloalkyl, aryl,
heteroaryl, or heterocyclyl; [0403] wherein the cycloalkyl, aryl,
heteroaryl, or heterocyclyl is optionally independently substituted
with 1 to 2 groups independently selected from oxo, --NO.sub.2,
--N.sub.3, --OR.sup.a, halo, --CN, NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)OR.sup.a, --C(O)N(R.sup.a)OR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and C.sub.3-8 cycloalkyl.
[0404] In another embodiment, Q.sup.W is selected from phenyl,
pyridinyl, indazolyl, and thienyl, wherein each phenyl, pyridinyl,
indazolyl, and thienyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and
--C.sub.1-6alkylC.sub.3-8 cycloalkyl.
[0405] In another embodiment, Q.sup.W is selected from phenyl,
pyridine and indanyl, wherein each phenyl, pyridine and indanyl is
optionally substituted with 1 to 3 groups independently selected
from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, and --C.sub.1-6alkylC.sub.3-8 cycloalkyl.
[0406] In one embodiment, Q.sup.E is selected from phenyl,
pyridinyl, indazolyl, and thienyl, wherein each phenyl, pyridinyl,
indazolyl, and thienyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and
--C.sub.1-6alkylC.sub.3-8 cycloalkyl.
[0407] In another embodiment, Q.sup.E is selected from phenyl,
pyridine and indanyl, wherein each phenyl, pyridine and indanyl is
optionally substituted with 1 to 3 groups independently selected
from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, and --C.sub.1-6alkylC.sub.3-8 cycloalkyl.
[0408] In one embodiment, Q.sup.W and Q.sup.E are each
independently
##STR00032## [0409] wherein each Z.sup.3 is independently halo,
--OR, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0410] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0411] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0411] ##STR00033## [0412] wherein [0413] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0414] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0415] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0416] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0417] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0418] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a, [0419]
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0420] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl.
[0421] In one embodiment, t is 0, 1, 2 or 3. In one embodiment, t
is 1, 2 or 3. In one embodiment, t is 0, 1 or 2. In one embodiment,
t is 0. In one embodiment, t is 1. In one embodiment, t is 2. In
one embodiment, t is 3.
[0422] In one embodiment, substituents on Q.sup.W or Q.sup.E are
independently selected from
##STR00034##
or a pharmaceutically acceptable salt thereof.
[0423] In one embodiment, Q.sup.E and Q.sup.W are each optionally
substituted with halo. In one embodiment, Q.sup.E and Q.sup.W are
each optionally substituted with --C.sub.1-6alkyl. In one
embodiment, Q.sup.E and Q.sup.W are each optionally substituted
with --OC.sub.1-6alkyl. In one embodiment, Q.sup.E and Q.sup.W are
each optionally substituted with methoxy.
[0424] In one embodiment, Q.sup.E and Q.sup.W are different and
each is optionally substituted with 1 to 3 groups independently
selected from OH, halo, CN, --SO.sub.2R.sup.a, --C.sub.1-6alkyl,
and --OC.sub.1-6alkyl.
[0425] In one embodiment, Q.sup.E and Q.sup.W are the same and each
is optionally substituted with 1 to 3 groups independently selected
from OH, halo, CN, --SO.sub.2R.sup.a, --C.sub.1-6alkyl, and
--OC.sub.1-6alkyl.
[0426] In one embodiment, R.sup.E an R.sup.W are independently
selected from --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d);
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d), and
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a); wherein [0427]
R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; [0428] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
[0429] R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6
cycloalkyl, heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and
--C.sub.1-6 alkylC(O)OR.sup.a; [0430] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; [0431] or R.sup.1 and R.sup.2 combine to
form a heterocyclyl group optionally containing an additional
heteroatom selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; [0432] R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl; [0433]
R.sup.a is independently H or --C.sub.1-6 alkyl; [0434] R.sup.b is
independently H or --C.sub.1-6 alkyl; [0435] R.sup.c is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8 cycloalkyl; [0436]
R.sup.d is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-C.sub.8cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; and [0437] u is 0, 1, 2, or 3.
[0438] In one embodiment, R.sup.E an R.sup.W are independently
selected from --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2, and
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b; wherein
[0439] R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; [0440] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
[0441] R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6
cycloalkyl, heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and
--C.sub.1-6 alkylC(O)OR.sup.a; [0442] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; [0443] or R.sup.1 and R.sup.2 combine to
form a heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; [0444] R.sup.a is independently H or
--C.sub.1-6 alkyl; [0445] R.sup.b is independently H or --C.sub.1-6
alkyl; and [0446] u is 0, 1, 2, or 3.
[0447] In one embodiment, R.sup.E an R.sup.W are independently
selected from --(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d), and
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a); wherein [0448]
R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; [0449] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
[0450] R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6
cycloalkyl, heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and
--C.sub.1-6 alkylC(O)OR.sup.a; [0451] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; [0452] or R.sup.1 and R.sup.2 combine to
form a heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; [0453] R.sup.a is independently H or
--C.sub.1-6 alkyl; [0454] R.sup.b is independently H or --C.sub.1-6
alkyl; [0455] R.sup.c is independently selected from H, --C.sub.1-6
alkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8
cycloalkyl; [0456] R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; and [0457] u is 0, 1, 2 or 3.
[0458] In one embodiment, R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, or
##STR00035## [0459] wherein [0460] V.sup.2 is independently a bond,
O, NR.sup.a, S, SO or SO.sub.2; [0461] R.sup.c is independently
selected from H, OH, --C.sub.1-6 alkyl, and --C.sub.3-8 cycloalkyl;
[0462] R.sup.d is independently selected from H, --C.sub.1-6 alkyl,
and --C.sub.3-C.sub.8cycloalkyl; [0463] L.sup.3 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0464] ring B is
independently cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0465]
T is independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0466] R.sup.e is independently selected from H, --C.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl,
--Oheterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g,
--C.sub.1-6 alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g,
--C.sub.1-6 alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f,
--C.sub.1-6 alkylSO.sub.2R.sup.f, and --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g; [0467] p is independently 0, 1, 2, 3,
4, or 5; [0468] q is independently 0, 1, 2, 3, 4, or 5; and [0469]
z is 0, 1, or 2; [0470] and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl of R.sup.E or R.sup.W is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of NR.sup.aR.sup.b, halo, cyano, OR.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl,
--C.sub.1-6 alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8
cycloalkyl, and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0471]
provided that at least one of V.sup.2, L.sup.3, ring B and T
contains a nitrogen atom; R.sup.1 is selected from H,
--C.sub.1-6alkyl, --C.sub.3-6cycloalkyl, heterocyclyl,
--C.sub.2-6alkyl-OR.sup.a, or --C.sub.1-6alkylC(O)OR.sup.a; [0472]
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally
substituted with 1 to 2 groups independently selected from
--OR.sup.a, --CN, halo, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; R.sup.2 is selected from --C.sub.1-6
alkyl, --C.sub.3-6 cycloalkyl, heterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, and --C.sub.1-6 alkylC(O)OR.sup.a; [0473] wherein
each alkyl, cycloalkyl, or heterocyclyl is optionally substituted
with 1 to 2 groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; [0474] R.sup.a is independently H or
--C.sub.1-6 alkyl; and [0475] R.sup.b is independently H or
--C.sub.1-6 alkyl.
[0476] In one embodiment,
R.sup.E and R.sup.W are each independently --NR.sup.1R.sup.2,
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, or
##STR00036## [0477] wherein [0478] V.sup.2 is independently a bond,
O, NR.sup.a, S, SO or SO.sub.2; [0479] L.sup.3 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0480] ring B is cycloalkyl,
aryl, heteroaryl, or heterocyclyl; [0481] T is independently H,
OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0482] p is independently 0, 1, 2, or 3; [0483] q is independently
0, 1, 2, or 3; [0484] z is 0, 1, 2, or 3; [0485] and wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0486] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; [0487] wherein each alkyl,
cycloalkyl, or heterocyclyl group is optionally substituted with 1
to 2 groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl,
heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, and --C.sub.1-6
alkylC(O)OR.sup.a; [0488] wherein each alkyl, cycloalkyl, or
heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing an additional heteroatom
selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or --C.sub.1-6
alkyl; R.sup.b is independently H or --C.sub.1-6 alkyl; R.sup.c is
independently selected from H, OH, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-C.sub.8cycloalkyl; R.sup.e is
selected from H, --C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --OC.sub.3-8
cycloalkyl, --Oaryl, --Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.g is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-8 cycloalkyl.
[0489] In one embodiment, R.sup.E and R.sup.W are each
##STR00037##
wherein V.sup.2 is independently a bond, O, NR.sup.a, S, SO or
SO.sub.2; R.sup.c is independently selected from H, OH, --C.sub.1-6
alkyl, and --C.sub.3-8 cycloalkyl; R.sup.d is independently
selected from H, --C.sub.1-6 alkyl, and
--C.sub.3-C.sub.8cycloalkyl; L.sup.3 is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; ring B is cycloalkyl, aryl,
heteroaryl, or heterocyclyl; T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
R.sup.e is selected from H, --C.sub.1-6 alkyl, --OC.sub.1-6alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl,
--OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl, --Oheterocyclyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl, and
--C.sub.3-8 cycloalkyl; R.sup.g is independently selected from H,
--C.sub.1-6 alkyl, and --C.sub.3-8 cycloalkyl; p is independently
0, 1, 2, or 3; q is independently 0, 1, 2, or 3; z is 0, 1, 2, or
3; and wherein the alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl of R.sup.E or R.sup.W is optionally substituted with 1
to 3 substituents independently selected from the group consisting
of NR.sup.aR.sup.b, halo, cyano, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; provided that at least
one of V.sup.2, L.sup.3, ring B and T contains a nitrogen atom.
[0490] In one embodiment, R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
or --OC.sub.1-6 alkylNR.sup.1R.sup.2;
R.sup.1 is independently selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, or
--C.sub.1-6alkylC(O)OR.sup.a; [0491] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is independently selected from --C.sub.1-6 alkyl,
--C.sub.3-6 cycloalkyl, heterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
and --C.sub.1-6 alkylC(O)OR.sup.a; [0492] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and C.sub.1-6
alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing 1 or 2 additional heteroatoms
independently selected from oxygen, sulfur or nitrogen, and
optionally substituted with 1 to 3 groups independently selected
from oxo, --C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, and --C(O)NR.sup.aR.sup.b; R.sup.a is
independently H or --C.sub.1-6 alkyl; R.sup.b is independently H or
--C.sub.1-6 alkyl.
[0493] In one embodiment, R.sup.E and R.sup.W are each
--C.sub.1-6alkylOC.sub.1-6 alkylNR.sup.1R.sup.2;
R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; [0494] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; [0495] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl optionally containing 1 or 2 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen,
and optionally substituted with 1 to 3 groups independently
selected from oxo, --C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a,
--C(O)R.sup.a, C.sub.1-6alkylC(O)R.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, and --C(O)NR.sup.aR.sup.b; R.sup.a
is independently H or --C.sub.1-6alkyl; and R.sup.b is
independently H or --C.sub.1-6alkyl.
[0496] In one embodiment, provided is a compound of formula (I),
wherein
R.sup.E and R.sup.W are each --OC.sub.1-6 alkylNR.sup.1R.sup.2;
R.sup.1 is selected from H, --C.sub.1-6alkyl,
--C.sub.3-6cycloalkyl, heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; [0497] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN, halo,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C(O)R.sup.a, --C.sub.1-6alkyl C(O)R.sup.a,
--C(O)OR.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, and --C.sub.1-6alkylC(O)NR.sup.aR.sup.b;
R.sup.2 is selected from --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl,
heterocyclyl, --C.sub.2-6alkyl-OR.sup.a, and
--C.sub.1-6alkylC(O)OR.sup.a; [0498] wherein each alkyl,
cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from --OR.sup.a, --CN,
--C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl group optionally containing 1 or 2
additional heteroatoms independently selected from oxygen, sulfur
or nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6alkyl, --OR.sup.a,
--C(O)OR.sup.a, --C(O)R.sup.a, C.sub.1-6alkylC(O)R.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, and --C(O)NR.sup.aR.sup.b; R.sup.a
is independently H or --C.sub.1-6alkyl; and R.sup.b is
independently H or --C.sub.1-6alkyl.
[0499] In one embodiment,
R.sup.E and R.sup.W are each --NR.sup.1R.sup.2; R.sup.1 is selected
from H, --C.sub.1-6alkyl, --C.sub.3-6cycloalkyl, heterocyclyl,
--C.sub.2-6alkyl-OR.sup.a, and --C.sub.1-6alkylC(O)OR.sup.a; [0500]
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally
substituted with 1 to 2 groups independently selected from
--OR.sup.a, --CN, halo, --C.sub.1-6alkylOR.sup.a,
--C.sub.1-6cyanoalkyl, --C.sub.1-3haloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkyl C(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
--C.sub.1-6alkylC(O)NR.sup.aR.sup.b; R.sup.2 is selected from
--C.sub.1-6alkyl, --C.sub.3-6cycloalkyl, heterocyclyl,
--C.sub.2-6alkyl-OR.sup.a, and --C.sub.1-6alkylC(O)OR.sup.a; [0501]
wherein each alkyl, cycloalkyl, or heterocyclyl group is optionally
substituted with 1 to 2 groups independently selected from
--OR.sup.a, --CN, --C.sub.1-6alkylOR.sup.a, --C.sub.1-6cyanoalkyl,
--C.sub.1-3haloalkyl, --C.sub.3-8cycloalkyl,
--C.sub.1-3alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, and
C.sub.1-6alkylC(O)NR.sup.aR.sup.b; or R.sup.1 and R.sup.2 combine
to form a heterocyclyl group optionally containing an additional
heteroatom selected from oxygen, sulfur or nitrogen, and optionally
substituted with 1 to 3 groups independently selected from oxo,
--C.sub.1-6alkyl, --OR.sup.a, --C(O)OR.sup.a, --C(O)R.sup.a,
C.sub.1-6alkylC(O)R.sup.a, --C.sub.1-6alkylC(O)OR.sup.a,
--NR.sup.aR.sup.b, --C.sub.1-6alkylNR.sup.aR.sup.b, and
--C(O)NR.sup.aR.sup.b; R.sup.a is independently H or
--C.sub.1-6alkyl; and R.sup.b is independently H or
--C.sub.1-6alkyl.
[0502] In one embodiment, R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
or --OC.sub.1-6 alkylNR.sup.1R.sup.2; wherein
R.sup.1 and R.sup.2 combine to form a heterocyclyl selected
from
##STR00038##
wherein each is optionally substituted with 1 to 3 groups
independently selected from --C.sub.1-6alkyl, --OR.sup.a,
--C(O)OR.sup.a, --C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a,
--C.sub.1-6alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, and --C(O)NR.sup.aR.sup.b; R.sup.a is
independently H or --C.sub.1-6 alkyl; and R.sup.b is independently
H or --C.sub.1-6 alkyl.
[0503] In one embodiment, R.sup.W and R.sup.E are each
independently selected from:
##STR00039## ##STR00040##
[0504] In one embodiment, each R.sup.W and R.sup.E is independently
selected from:
##STR00041##
[0505] In one embodiment, each R.sup.W and R.sup.E is independently
selected from:
##STR00042## ##STR00043##
[0506] In one embodiment, each R.sup.W and R.sup.E is independently
selected from:
##STR00044##
[0507] In another embodiment of the disclosure, provided is a
compound of formula (I):
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I) [0508] wherein: Ar.sup.E and Ar.sup.W are each independently
aryl, heteroaryl, or heterocyclyl, [0509] wherein each aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 2
groups independently selected from halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, and --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --(CR.sup.3R.sup.4).sub.m--, --O(CR.sup.3R.sup.4).sub.m,
--(CR.sup.3R.sup.4).sub.mO, --(CR.sup.3R.sup.4).sub.mNR.sup.3--,
--NR.sup.3(CR.sup.3R.sup.4).sub.m--, or --C(O)--, [0510] m is
independently 0, 1, 2, 3 or 4; Q.sup.E and Q.sup.W are each
independently aryl, heteroaryl, or heterocyclyl, wherein each aryl,
heteroaryl, or heterocyclyl is optionally substituted with 1 to 4
groups independently selected from halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and R.sup.N; [0511]
wherein [0512] R.sup.N is
[0512] ##STR00045## [0513] wherein [0514] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0515] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0516] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with --OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0517] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0518] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0519] wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is
optionally independently substituted with 1 to 2 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2 or
[0519] ##STR00046## [0520] wherein [0521] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO or SO.sub.2 [0522] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0523] ring
B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0524] T is
(CH.sub.2).sub.qNR.sup.1R.sup.2 or (CH.sub.2).sub.qC(O)R.sup.e;
[0525] p is 0, 1, 2, or 3; [0526] q is 0, 1, 2, or 3; [0527] u is
0, 1, 2, or 3; and wherein the alkyl, cycloalkyl, aryl, heteroaryl,
or heterocyclyl group is optionally substituted with 1 to 3
substituents independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0528] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-6
alkylaryl, heterocyclyl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, and C.sub.1-6 alkylC.sub.3-8cycloalkyl; [0529]
wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, oxo, --CN, halo, C.sub.1-6 alkyl, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a; [0530]
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or
heterocycle is optionally substituted with 1 to 3 groups
independently selected from --OR.sup.a, --CN, halo, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen,
and optionally substituted with 1 to 3 groups independently
selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H, halo,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3;
R.sup.4 is independently H, halo, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; R.sup.a is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.c is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8 cycloalkyl; R.sup.d is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; or wherein any two
R.sup.c, any two R.sup.d or any R.sup.c and R.sup.d optionally
combine to form a 3-6 membered cycloalkyl ring; R.sup.e is
independently selected from H, --C.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl,
--Oheterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g,
--C.sub.1-6 alkylNR.sup.fR.sup.g, C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl, or a
pharmaceutically acceptable salt thereof.
[0531] In another embodiment of the disclosure, provided is a
compound of formula (I)
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I)
wherein: Ar.sup.E and Ar.sup.W are each independently aryl,
heteroaryl, or heterocyclyl; [0532] wherein each aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, and --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --(CR.sup.3R.sup.4).sub.m--, --O(CR.sup.3R.sup.4).sub.m,
--(CR.sup.3R.sup.4).sub.mO, --(CR.sup.3R.sup.4).sub.mNR.sup.3--,
--NR.sup.3(CR.sup.3R.sup.4).sub.m--, or --C(O)--; [0533] m is
independently 0, 1, 2, 3, or 4; Q.sup.E and Q.sup.W are each
independently an aryl or heteroaryl, wherein each aryl or
heteroaryl is optionally substituted with 1 to 4 groups
independently selected from halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and R.sup.N; [0534]
wherein [0535] R.sup.N is
##STR00047##
[0535] and [0536] L is independently a bond, O, NR.sup.a, S, SO, or
SO.sub.2; [0537] V is independently selected from a bond,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl; [0538]
wherein the alkyl, alkenyl, or alkynyl group is optionally
independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0539] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0540]
wherein ring A is independently cycloalkyl, aryl, heteroaryl, or
heterocyclyl; [0541] wherein each cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally independently substituted with 1 to 2
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)OR.sup.a, --C(O)N(R.sup.a)OR.sup.b,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.b, --NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2, or
[0541] ##STR00048## [0542] wherein [0543] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2 [0544] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0545] ring
B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0546] T is
(CH.sub.2).sub.qNR.sup.1R.sup.2, or (CH.sub.2).sub.qC(O)R.sup.e;
[0547] p is 0, 1, 2, or 3; [0548] q is 0, 1, 2, or 3; [0549] u is
0, 1, 2, or 3; [0550] and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally substituted with 1
to 3 substituents independently selected from the group consisting
of --NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0551] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is selected from H, --C.sub.1-6 alkylaryl,
heterocyclyl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, and C.sub.1-6 alkylC.sub.3-8cycloalkyl; [0552]
wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, oxo, --CN, halo, C.sub.1-6 alkyl, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a; [0553]
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or
heterocycle is optionally substituted with 1 to 3 groups
independently selected from --OR.sup.a, --CN, halo, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen,
and optionally substituted with 1 to 3 groups independently
selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H, halo,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3;
R.sup.4 is independently H, halo, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; R.sup.a is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.c is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8 cycloalkyl; R.sup.d is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl,
and --C.sub.1-3alkylC.sub.3-8cycloalkyl; and wherein any two
R.sup.c, any two R.sup.d or any R.sup.c and R.sup.d optionally
combine to form a 3-6 membered cycloalkyl ring; R.sup.e is
independently selected from H, --C.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl,
--Oheterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g,
--C.sub.1-6 alkylNR.sup.fR.sup.g, C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl, or a
pharmaceutically acceptable salt thereof.
[0554] In another embodiment of the disclosure is provided a
compound of formula (I)
R.sup.W-Q.sup.W-L.sup.W-Ar.sup.W--Ar.sup.E-L.sup.E-Q.sup.E-R.sup.E
(I)
wherein: Ar.sup.E and Ar.sup.W are each independently aryl,
heteroaryl, or heterocyclyl; [0555] wherein each aryl, heteroaryl,
or heterocyclyl is optionally substituted with 1 to 2 groups
independently selected from halo, --OR.sup.a, --C.sub.1-6 alkyl,
--OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, and --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --(CR.sup.3R.sup.4).sub.m--, --O(CR.sup.3R.sup.4).sub.m,
--(CR.sup.3R.sup.4).sub.mO, --(CR.sup.3R.sup.4).sub.mNR.sup.3--,
--NR.sup.3(CR.sup.3R.sup.4).sub.m--, or --C(O)-- [0556] m is
independently 0, 1, 2, 3 or 4; and Q.sup.E and Q.sup.W are each an
aryl group optionally substituted with 1 to 4 groups independently
selected from halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, and R.sup.N; [0557] wherein [0558] R.sup.N
is
[0558] ##STR00049## [0559] wherein [0560] L.sup.1 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0561] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0562] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0563] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0564] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0565] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally independently substituted with 1 to 2 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; R.sup.E and R.sup.W are each
independently --NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2,
--OC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2 or
[0565] ##STR00050## [0566] wherein [0567] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, or SO.sub.2 [0568] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0569] ring
B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0570] T is
(CH.sub.2).sub.qNR.sup.1R.sup.2 or (CH.sub.2).sub.qC(O)R.sup.e;
[0571] p is 0, 1, 2, or 3; [0572] q is 0, 1, 2, or 3; [0573] u is
0, 1, 2, or 3; [0574] and wherein the alkyl, cycloalkyl, aryl,
heteroaryl, or heterocyclyl group is optionally substituted with 1
to 3 substituents independently selected from the group consisting
of NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0575] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is selected from H, --C.sub.1-6 alkylaryl,
heterocyclyl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6
alkenylC(O)OR.sup.a, and C.sub.1-6 alkylC.sub.3-8cycloalkyl; [0576]
wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 2 groups independently selected
from --OR.sup.a, oxo, --CN, halo, C.sub.1-6 alkyl, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is selected from --C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, --C.sub.1-6
alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, and --C.sub.2-6 alkenylC(O)OR.sup.a; [0577]
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl is optionally substituted with 1 to 3 groups
independently selected from --OR.sup.a, --CN, halo, --C.sub.1-6
alkylOR.sup.a, --C.sub.1-6cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6alkylC(O)R.sup.a, --C(O)OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen,
and optionally substituted with 1 to 3 groups independently
selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H, halo,
--C.sub.1-6alkyl, --OH, --OCH.sub.3, or --OCH.sub.2CH.sub.3;
R.sup.4 is independently H, halo, --C.sub.1-6alkyl, --OH,
--OCH.sub.3, or --OCH.sub.2CH.sub.3; R.sup.a is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8cycloalkyl; R.sup.c is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, and
--C.sub.1-3 alkylC.sub.3-8 cycloalkyl; R.sup.d is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl,
and --C.sub.1-3alkylC.sub.3-8cycloalkyl; and wherein any two
R.sup.c, any two R.sup.d or any R.sup.c and R.sup.d optionally
combine to form a 3-6 membered cycloalkyl ring; R.sup.e is
independently selected from H, --C.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl, --Oheteroaryl,
--Oheterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g,
--C.sub.1-6 alkylNR.sup.fR.sup.g, C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl, or a
pharmaceutically acceptable salt thereof.
[0578] In one embodiment, at least one of Ar.sup.E and Ar.sup.W is
other than optionally substituted aryl. In one embodiment, at least
one of Ar.sup.E and Ar.sup.W is other than optionally substituted
phenyl.
[0579] In one embodiment, when both of Ar.sup.E and Ar.sup.W are
optionally substituted aryl, then the moiety
-L.sup.E-Ar.sup.E--Ar.sup.W-L.sup.W- is
--O--(CR.sup.3R.sup.4).sub.m--Ar.sup.E--Ar.sup.W-L.sup.W-(CR.sup.3R.sup.4-
).sub.m--O--. In one embodiment, the moiety
-L.sup.E-Ar.sup.E--Ar.sup.W-L.sup.W- is
--O--(CR.sup.3R.sup.4).sub.m--Ar.sup.E--Ar.sup.W-L.sup.W-(CR.sup.3R.sup.4-
).sub.m--O--.
[0580] In one embodiment, both of Q.sup.E and Q.sup.W are
independently optionally substituted aryl. In one embodiment, both
of Q.sup.E and Q.sup.W are independently optionally substituted
phenyl. In one embodiment, both of Q.sup.E and Q.sup.W are
independently optionally substituted pyridyl.
[0581] In one embodiment of any compound described herein, both
Ar.sup.E and Ar.sup.W are optionally substituted bicyclic rings,
wherein neither is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring. In one embodiment of any compound described
herein, both L.sup.E and L.sup.W are --O--. In one embodiment of
any compound described herein, both L.sup.E and L.sup.W are
-Q-O--CH.sub.2--Ar--. In one embodiment of any compound described
herein, each of Ar.sup.E, Ar.sup.W, Q.sup.E, and Q.sup.W are
monocyclic, provided at least two are heteroaryl, and neither of
R.sup.E, and R.sup.W is an optionally substituted fused
5,6-aromatic or 5,6-heteromatic ring. In one embodiment of any
compound described herein, at least one L is a bond, and none of
Ar.sup.E, Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E, and R.sup.W is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic ring.
In one embodiment of any compound described herein, at least one of
the following occurs: a) both Ar.sup.E and Ar.sup.W are optionally
substituted bicyclic rings, wherein neither is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring; b) both
L.sup.E and L.sup.W are --O--; c) both L.sup.E and L.sup.W are
-Q-O--CH.sub.2--Ar--; d) each of Ar.sup.E, Ar.sup.W, Q.sup.E, and
Q.sup.W are monocyclic, provided at least two are heteroaryl, and
neither of R.sup.E, and R.sup.W is an optionally substituted fused
5,6-aromatic or 5,6-heteromatic ring; or e) at least one L is a
bond, and none of Ar.sup.E, Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E,
and R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0582] In one embodiment provided is a compound selected from
Example 92, 209, 124, 121, 402, 123, 43, 122, 16, 240, 167, 90,
210, 178, 42, 148, 93, 32, 111, 74, 172, 166, 160, 183, 225, 125,
162, 214, 40, 220, 213, 114, 41, 127, 113, 185, 34, 144, 94, 143,
286, 128, 142, 140, 279, 29, 49, 221, 241, 112, 133, 242, 35, 253,
168, 66, 161, 126, 153, 232, 252, 163, 57, 165, 110, 145, 79, 75,
244, 132, 138, 243, 78, 48, 215, 258, 182, 234, 282, 260, 157, 281,
164, 47, 259, 216, 91, 136, 159, 248, 68, 219, 217, 280, 152, 227,
95, 12, 179, 257, 134, 109, 28, 149, 218, 31, 254, 203, 116, 53,
256, 226, 247, 117, 175, 135, 230, 58, 118, 404, 222, 200, 37, 70,
96, 204, 231, 131, 268, 54, 71, 76, 36, 201, 246, 147, 405, 59,
264, 120, 67, 21, 266, 184, 137, 284, 55, 207, 17, 83, 82, 69, 202,
276, 22, 199, 146, 73, 38, 261, 245, 88, 236, 19, 15, 155, 61, 265,
85, 64, 84, 233, 14, 62, 1394, 158, 272, 30, 77, 150, 80, 151, 81,
154, 255, 235, 56, 141, 23, 86, 104, 39, 60, 269, 87, 115, 173,
174, 270, 271, 223, 273, 406, 237, 277, 249, 170, 18, 63, 105,
((5-bromo-6-((3'-(((3-bromo-5-(((carboxymethyl)amino)methyl)-6-(((R)-5-ox-
opyrrolidin-2-yl)methoxy)pyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)-2-(((S)-5-oxopyrrolidin-2-yl)methoxy)pyridin-3-yl)meth-
yl)glycine,
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzo[b]thiophen-2-yl)methyl)amino)-3-hydroxybutanoic
acid, and
(S)-4-((5-bromo-4-((3'-((2-bromo-4-((((S)-3-carboxy-2-hydroxypropyl)amino-
)methyl)-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,-
1'-biphenyl]-3-yl)methoxy)-2-((5-isocyanopyridin-3-yl)methoxy)benzyl)amino-
)-3-hydroxybutanoic acid, or a pharmaceutically acceptable salt
thereof.
[0583] In one embodiment provided is a compound selected from
Example 191, 198, 197, 193, 189, 196, 192, 195, 190, 20, 194, 186,
188, 72, 187, 25, and 285, or a pharmaceutically acceptable salt
thereof.
[0584] In one embodiment provided is a compound selected from
Example 4, 5, 3, 7, 6, 8, 9, 2, 10, 1, 407, and 13, or a
pharmaceutically acceptable salt thereof.
[0585] In one embodiment provided is a compound selected from
Example 267, 180, 181, 408, 409, 410, 411, 412, 413, 414, 415, 416,
417, 418, 419, and 420, or a pharmaceutically acceptable salt
thereof.
[0586] In one embodiment provided is a compound selected from
Example 191, 198, 197, 193, 189, 196, 192, 195, 190, 20, 194, 186,
188, 72, 187, 25, and 285, or a pharmaceutically acceptable salt
thereof.
[0587] In one embodiment provided is a compound selected from
Example 287, 102, 103, 27, 251, and 107, or a pharmaceutically
acceptable salt thereof.
[0588] In one embodiment provided is a compound selected from
Example 239 and 238, or a pharmaceutically acceptable salt
thereof.
[0589] In one embodiment provided is a compound selected from
Example 97, 44, 98, 50, 51, 45, 99, 169, 100, 89, 274, 422, 24,
176, 65, 171, 26, 52, 156, and 263, or a pharmaceutically
acceptable salt thereof.
[0590] In one embodiment provided is a compound selected from
Example 423, 29, 113, 34, 240, 6, 7, 66, 16, and 19, or a
pharmaceutically acceptable salt thereof.
[0591] In one embodiment, the compound is represented by formula
(Ia):
##STR00051##
where, each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0592] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; and t is 0, 1 or 2; and each of
Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, L.sup.E, L.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0593] In one embodiment of formula (Ia), L.sup.E is other than
--CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and --C(O)NH--.
In one embodiment of formula (Ia), none of Ar.sup.E, Ar.sup.W,
Q.sup.E, Q.sup.W, R.sup.E, and R.sup.W is an optionally substituted
fused 5,6-aromatic or 5,6-heteromatic ring.
[0594] In one embodiment, the compound is represented by any one of
formula (Ib):
##STR00052##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0595] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; and t is 0, 1 or 2; and each of
Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, L.sup.E, L.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0596] In one embodiment of formula (Ib), L.sup.W and L.sup.E are
other than --CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and
--C(O)NH--. In one embodiment of formula (Ib), L.sup.E is other
than --CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and
--C(O)NH--. In one embodiment of formula (Ib), L.sup.W is other
than --CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and
--C(O)NH--. In one embodiment of formula (Ib), none of Ar.sup.E,
Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E, and R.sup.W is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring.
[0597] In one embodiment, the compound is represented by formula
(Ic):
##STR00053##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0598] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; and t is 0, 1 or 2; and each of
Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, L.sup.E, L.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0599] In one embodiment of formula (Ic), none of Ar.sup.E,
Ar.sup.W, Q.sup.E, Q.sup.W, R.sup.E, and R.sup.W is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring.
[0600] In one embodiment, the compound is represented by formula
(Id):
##STR00054##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0601] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; t is 0, 1 or 2; and each Ar.sup.E,
Ar.sup.W, R.sup.2, R.sup.N, R.sup.a, and R.sup.b are as defined
herein.
[0602] In one embodiment, the compound is represented by formulas
(Ie):
##STR00055##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0603] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; t is 0, 1 or 2; and each Ar.sup.E,
Ar.sup.W, R.sup.2, R.sup.N, R.sup.a, and R.sup.b are as defined
herein.
[0604] In one embodiment, the compound is represented by formula
(If):
##STR00056##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0605] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; t is 0, 1 or 2; and each Ar.sup.E,
Ar.sup.W, R.sup.2, R.sup.N, R.sup.a, and R.sup.b are as defined
herein.
[0606] In one embodiment, the compound is represented by formula
(Ig):
##STR00057##
where each Z.sup.3 is independently halo, OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0607] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; each t is independently 0, 1 or 2; and
each L.sup.W, Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0608] In one embodiment of formula (Ig), none of Ar.sup.E,
Ar.sup.W, R.sup.E, and R.sup.W is an optionally substituted fused
5,6-aromatic or 5,6-heteromatic ring.
[0609] In one embodiment, the compound is represented by formula
(Ih):
##STR00058##
where each Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0610] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; each t is independently 0, 1 or 2; and
each L.sup.W, Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0611] In one embodiment of formula (Ig), none of Ar.sup.E,
Ar.sup.W, R.sup.E, and R.sup.W is an optionally substituted fused
5,6-aromatic or 5,6-heteromatic ring.
[0612] In one embodiment, the compound is represented by formula
(Ii):
##STR00059##
where each Z.sup.3 is independently halo, OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0613] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; each t is independently 0, 1 or 2; and
each L.sup.W, Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0614] In one embodiment of formula (Ii), L.sup.W is a bond, --O--,
or --CH.sub.2O--, where the O is bonded to the pyridine ring and
the --CH.sub.2-- is bonded to Ar.sup.W. In one embodiment of
formula (Ii), none of Ar.sup.E, Ar.sup.W, R.sup.E and R.sup.W is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic
ring.
[0615] In one embodiment, the compound is represented by formula
(Ij):
##STR00060##
where each Z.sup.3 is independently halo, OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0616] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; each t is independently 0, 1 or 2; and
each L.sup.W, Ar.sup.E, Ar.sup.W, R.sup.E, R.sup.W, R.sup.N,
R.sup.a, and R.sup.b are as defined herein.
[0617] In one embodiment of formula (Ij), L.sup.W is a bond, --O--,
or --CH.sub.2O--, where the O is bonded to the pyridine ring and
the --CH.sub.2-- is bonded to Ar.sup.W. In one embodiment of
formula (Ij), none of Ar.sup.E, Ar.sup.W, R.sup.E and R.sup.W is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic
ring.
[0618] In one embodiment, Ar.sup.W and Ar.sup.E are each
independently
##STR00061##
wherein ring C is independently a 5- or 6-membered ring, optionally
comprising 1 or 2 heteroatoms; Z.sup.1 is independently halo,
--OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6
haloalkyl, or --C.sub.3-8 cycloalkyl; and w is 0, 1, or 2.
[0619] In one embodiment, Ar.sup.W and Ar.sup.E are each
independently
##STR00062##
wherein ring C is independently a non-aromatic 5- or 6-membered
ring, optionally comprising 1 or 2 heteroatoms; Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; and w is
0, 1, or 2.
[0620] In one embodiment, Ar.sup.W and Ar.sup.E are each
independently
##STR00063##
wherein each X.sup.1 is independently N or CH; Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; and w is
0, 1, or 2.
[0621] In one embodiment, Ar.sup.W and Ar.sup.E are each
independently
##STR00064##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and u is 0, 1, or 2. In one embodiment, Ar.sup.W and
Ar.sup.E are each
##STR00065##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and w is 0, 1, or 2. In one embodiment, Ar.sup.W and
Ar.sup.E are each
##STR00066##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and w is 0, 1, or 2. In one embodiment, Ar.sup.W and
Ar.sup.E are each
##STR00067##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and w is 0, 1, or 2. In one embodiment, Ar.sup.W and
Ar.sup.E are each
##STR00068##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and w is 0, 1, or 2. In one embodiment, Ar.sup.W and
Ar.sup.E are each
##STR00069##
wherein each Z.sup.1 is independently halo, --OR.sup.a, --C.sub.1-6
alkyl, --OC.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8
cycloalkyl, and w is 0, 1, or 2.
[0622] In one embodiment, the compound is represented by formula
(IIa):
##STR00070##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0623] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0624] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0624] ##STR00071## [0625] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0626] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0627] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0628] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0629] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0630] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0631] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00072##
[0631] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00073## [0632] wherein: [0633] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0634] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0635]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0636] p is independently 0, 1, 2, 3, 4, or 5; [0637] q is
independently 0, 1, 2, 3, 4, or 5; [0638] u is 0, 1, 2, 3, or 4;
[0639] z is 0, 1, 2, or 3; and [0640] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0641] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0642] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0643] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0644] In one embodiment of formula (IIa), when one of L.sup.E or
L.sup.W is --CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, or
--C(O)NH--; then the other of L.sup.E and L.sup.W is a bond, --O--,
or --O--CH.sub.2--, where the oxygen is bonded to the Q ring and
the --CH.sub.2-- is bonded to the Ar ring. In one embodiment of
formula (IIa), both L.sup.E and L.sup.W are --O--CH.sub.2--, where
the oxygen is bonded to the Q ring and the CH.sub.2 is bonded to
the Ar ring. In one embodiment of formula (IIa), one or both of
L.sup.E or L.sup.W is a bond or --O--. In one embodiment of formula
(IIa), one or both of X.sup.1 is N. In one embodiment of formula
(IIa), neither of R.sup.E or R.sup.W is an optionally substituted
fused 5,6-aromatic or 5,6-heteromatic ring.
[0645] In one embodiment, the compound is represented by formula
(IIb):
##STR00074##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0646] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0647] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0647] ##STR00075## [0648] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0649] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0650] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0651] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0652] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0653] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0654] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3 (CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00076##
[0654] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00077## [0655] wherein: [0656] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0657] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0658]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0659] T
is independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0660] p is independently 0, 1, 2, 3, 4, or 5; [0661] q is
independently 0, 1, 2, 3, 4, or 5; [0662] u is 0, 1, 2, 3, or 4;
[0663] z is 0, 1, 2, or 3; and [0664] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0665] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0666] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0667] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0668] In one embodiment of formula (IIb), L.sup.W is other than
--CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and --C(O)NH--.
In one embodiment of formula (IIb), L.sup.E is --O--CH.sub.2--,
where the oxygen is bonded to the Q group and the CH.sub.2 is
bonded to the Ar group. In one embodiment of formula (IIb), L.sup.E
is a bond. In one embodiment of formula (IIb), one or both of
L.sup.E or L.sup.W is a bond or --O--. In one embodiment of formula
(IIb), one or both of X.sup.1 is N. In one embodiment of formula
(IIb), neither of R.sup.E or R.sup.W is an optionally substituted
fused 5,6-aromatic or 5,6-heteromatic ring.
[0669] In one embodiment, the compound is represented by formula
(IIc):
##STR00078##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0670] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0671] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0671] ##STR00079## [0672] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0673] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0674] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0675] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0676] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0677] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0678] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00080##
[0678] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00081## [0679] wherein: [0680] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0681] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0682]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0683] p is independently 0, 1, 2, 3, 4, or 5; [0684] q is
independently 0, 1, 2, 3, 4, or 5; [0685] u is 0, 1, 2, 3, or 4;
[0686] z is 0, 1, 2, or 3; and [0687] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0688] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0689] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0690] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-s cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0691] In one embodiment of formula (IIc), L.sup.E is other than
--CH.sub.2O--, --(CH.sub.2).sub.2--, --CH.dbd.CH--, and --C(O)NH--.
In one embodiment of formula (IIc), L.sup.W is --O--CH.sub.2--,
where the oxygen is bonded to the Q ring and the CH.sub.2 is bonded
to the Ar ring. In certain embodiments of formula (IIc), one or
both of L.sup.E or L.sup.W is a bond or --O--. In certain
embodiments of formula (IIc), one or both of X.sup.1 is N. In
certain embodiments of formula (IIc), neither of R.sup.E or R.sup.W
is an optionally substituted fused 5,6-aromatic or 5,6-heteromatic
ring.
[0692] In one embodiment, the compound is represented by formula
(IId):
##STR00082##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0693] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0694] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0694] ##STR00083## [0695] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0696] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0697] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0698] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0699] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0700] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0701] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00084##
[0701] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00085## [0702] wherein: [0703] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0704] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0705]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0706] p is independently 0, 1, 2, 3, 4, or 5; [0707] q is
independently 0, 1, 2, 3, 4, or 5; [0708] u is 0, 1, 2, 3, or 4;
[0709] z is 0, 1, 2, or 3; and [0710] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0711] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0712] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0713] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0714] In one embodiment of formula (IId), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0715] In one embodiment, the compound is represented by any one of
formula (IIe):
##STR00086##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0716] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0717] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0717] ##STR00087## [0718] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0719] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0720] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0721] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0722] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0723] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0724] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E is a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00088##
[0724] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00089## [0725] wherein: [0726] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0727] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0728]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0729] p is independently 0, 1, 2, 3, 4, or 5; [0730] q is
independently 0, 1, 2, 3, 4, or 5; [0731] u is 0, 1, 2, 3, or 4;
[0732] z is 0, 1, 2, or 3; and [0733] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0734] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0735] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0736] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0737] In one embodiment of formula (IIe), L.sup.E is a bond,
--O--, or --O--CH.sub.2--, where the oxygen is bonded to the Q ring
and the CH.sub.2 is bonded to the Ar ring. In one embodiment of
formula (IIe), one or both X.sup.1 is N. In one embodiment of
formula (IIe), neither of R.sup.E or R.sup.W is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring.
[0738] In one embodiment, the compound is represented by formula
(IIf):
##STR00090##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0739] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0740] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0740] ##STR00091## [0741] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0742] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0743] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0744] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0745] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0746] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0747] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; L.sup.E is a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00092##
[0747] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00093## [0748] wherein: [0749] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0750] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0751]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0752] p is independently 0, 1, 2, 3, 4, or 5; [0753] q is
independently 0, 1, 2, 3, 4, or 5; [0754] u is 0, 1, 2, 3, or 4;
[0755] z is 0, 1, 2, or 3; and [0756] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0757] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0758] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0759] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0760] In one embodiment of formula (IIf), L.sup.E is a bond,
--O--, or --O--CH.sub.2--, where the oxygen is bonded to the Q ring
and the CH.sub.2 is bonded to the Ar ring. In one embodiment of
formula (IIf), one or both of X.sup.1 is N. In one embodiment of
formula (IIf), neither of R.sup.E or R.sup.W is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring.
[0761] In one embodiment, the compound is represented by formula
(IIg):
##STR00094##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0762] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0763] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0763] ##STR00095## [0764] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0765] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0766] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0767] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0768] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0769] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0770] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E is a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00096##
[0770] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00097## [0771] wherein: [0772] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0773] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0774]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0775] p is independently 0, 1, 2, 3, 4, or 5; [0776] q is
independently 0, 1, 2, 3, 4, or 5; [0777] u is 0, 1, 2, 3, or 4;
[0778] z is 0, 1, 2, or 3; and [0779] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0780] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0781] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0782] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0783] In one embodiment of formula (IIg), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0784] In one embodiment, the compound is represented by formula
(IIh):
##STR00098##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0785] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0786] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0786] ##STR00099## [0787] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0788] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0789] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0790] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0791] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0792] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0793] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl L.sup.E is a bond, --O--, --S--, --SO--, --SO.sub.2--,
--(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00100##
[0793] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00101## [0794] wherein: [0795] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0796] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0797]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; [0798] T
is independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0799] p is independently 0, 1, 2, 3, 4, or 5; [0800] q is
independently 0, 1, 2, 3, 4, or 5; [0801] u is 0, 1, 2, 3, or 4;
[0802] z is 0, 1, 2, or 3; and [0803] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0804] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0805] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0806] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0807] In one embodiment of formula (IIg), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0808] In one embodiment of formulas (IIe), (IIf), (IIg), or (IIh),
L.sup.E is --O--CH.sub.2--, where the oxygen is bonded to the Q
ring and the --CH.sub.2-- is bonded to the Ar ring. In one
embodiment of formulas (IIe), (IIf), (IIg), or (IIh), L.sup.E is a
bond. In one embodiment of formulas (IIe), (IIf), (IIg), or (IIh),
L.sup.E is --O--CH.sub.2--, neither of R.sup.E or R.sup.W is an
optionally substituted fused 5,6-aromatic or 5,6-heteromatic
ring.
[0809] In one embodiment, the compound is represented by formula
(IIIa):
##STR00102##
wherein each X.sup.1 is independently N or CH; Z.sup.3 is halo,
--OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0810] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0811] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0811] ##STR00103## [0812] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0813] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0814] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0815] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0816] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0817] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0818] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0818] ##STR00104## [0819] wherein each m is independently 0, 1, 2,
3 or 4; Q.sup.E is aryl, heteroaryl, or heterocyclyl; [0820]
wherein each aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0821] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0822] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0822] ##STR00105## [0823] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0824] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0825] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0826] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0827] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0828] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0829] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0829] ##STR00106## [0830] wherein: [0831] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0832] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0833]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0834] p is independently 0, 1, 2, 3, 4, or 5; [0835] q is
independently 0, 1, 2, 3, 4, or 5; [0836] u is 0, 1, 2, 3, or 4;
[0837] z is 0, 1, 2, or 3; and [0838] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0839] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0840] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0841] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0842] In one embodiment of formula (IIIa), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0843] In one embodiment, the compound is represented by formula
(IIIb):
##STR00107##
wherein each X.sup.1 is independently N or CH; Z.sup.1 is halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [0844] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; Z.sup.3 is halo, --OR.sup.a,
--N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0845] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0846] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0846] ##STR00108## [0847] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0848] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0849] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl; [0850] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0851] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0852] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0853] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
[0853] ##STR00109## [0854] wherein each m is independently 0, 1, 2,
3 or 4; Q.sup.E is aryl, heteroaryl, or heterocyclyl; [0855]
wherein each aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0856] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0857] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0857] ##STR00110## [0858] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0859] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0860] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0861] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0862] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0863] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0864] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0864] ##STR00111## [0865] wherein: [0866] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0867] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0868]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e or (CH.sub.2).sub.qC(O)R.sup.e;
[0869] p is independently 0, 1, 2, 3, 4, or 5; [0870] q is
independently 0, 1, 2, 3, 4, or 5; [0871] u is 0, 1, 2, 3, or 4;
[0872] z is 0, 1, 2, or 3; and [0873] wherein the alkyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or R.sup.W
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of NR.sup.aR.sup.b, halo, cyano,
oxo, OR.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl, and --C.sub.1-3
alkylC.sub.3-8cycloalkyl; [0874] provided that at least one of
V.sup.2, L.sup.3, ring B and T contains a nitrogen atom; R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0875] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0876] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b, and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0877] In one embodiment of formula (IIIb), none of Q.sup.E,
R.sup.E or R.sup.W is an optionally substituted fused 5,6-aromatic
or 5,6-heteromatic ring.
[0878] In one embodiment, the compound is represented by formula
(IVa):
##STR00112##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0879] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0880] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0880] ##STR00113## [0881] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0882] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0883] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0884] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0885] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0886] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0887] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00114##
[0887] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00115## [0888] wherein: [0889] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0890] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0891]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0892] p is independently 0, 1, 2, 3,
4, or 5; [0893] q is independently 0, 1, 2, 3, 4, or 5; [0894] u is
0, 1, 2, 3, or 4; [0895] z is 0, 1, 2, or 3; and [0896] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0897] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0898] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkyl C(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0899] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0900] In one embodiment of formula (IVa), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0901] In one embodiment, the compound is represented by formulas
(IVb):
##STR00116##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0902] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0903] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0903] ##STR00117## [0904] wherein: L is independently a bond, O,
NR.sup.a, S, SO, or SO.sub.2; [0905] V is independently selected
from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0906] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0907] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0908] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0909] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0910] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00118##
[0910] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00119## [0911] wherein: [0912] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0913] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0914]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0915] p is independently 0, 1, 2, 3,
4, or 5; [0916] q is independently 0, 1, 2, 3, 4, or 5; [0917] u is
0, 1, 2, 3, or 4; [0918] z is 0, 1, 2, or 3; and [0919] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0920] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0921] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0922] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0923] In one embodiment of formula (IVb), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0924] In one embodiment, the compound is represented by formula
(IVc):
##STR00120##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0925] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0926] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0926] ##STR00121## [0927] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0928] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0929] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0930] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0931] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0932] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0933] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl; L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3 (CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00122##
[0933] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00123## [0934] wherein: [0935] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0936] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0937]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0938] p is independently 0, 1, 2, 3,
4, or 5; [0939] q is independently 0, 1, 2, 3, 4, or 5; [0940] u is
0, 1, 2, 3, or 4; [0941] z is 0, 1, 2, or 3; and [0942] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0943] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0944] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0945] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0946] In one embodiment of formula (IVc), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0947] In one embodiment, the compound is represented by formula or
(IVd):
##STR00124##
wherein each X.sup.1 is independently N or CH; each Z.sup.1 is
independently halo, --OR.sup.a, --C.sub.1-6 alkyl, --OC.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, or --C.sub.3-8 cycloalkyl; each
Z.sup.3 is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2,
--CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0948] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0949] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0949] ##STR00125## [0950] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0951] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0952] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0953] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0954] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0955] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0956] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl L.sup.E and L.sup.W are each independently a bond,
--O--, --S--, --SO--, --SO.sub.2--, --(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mO(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mS(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3(CR.sup.3R.sup.4).sub.m--,
--C(O)--, --(CR.sup.3R.sup.4).sub.mC(O)(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mC(O)NR.sup.3(CR.sup.3R.sup.4).sub.m--,
--(CR.sup.3R.sup.4).sub.mNR.sup.3C(O)(CR.sup.3R.sup.4).sub.m--,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
##STR00126##
[0956] each m is independently 0, 1, 2, 3 or 4; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --OC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
##STR00127## [0957] wherein: [0958] V.sup.2 is independently a
bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0959] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0960]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0961] p is independently 0, 1, 2, 3,
4, or 5; [0962] q is independently 0, 1, 2, 3, 4, or 5; [0963] u is
0, 1, 2, 3, or 4; [0964] z is 0, 1, 2, or 3; and [0965] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [0966] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [0967] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [0968] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[0969] In one embodiment of formula (IVd), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[0970] In one embodiment, the compound is represented by formula or
(Va):
##STR00128##
wherein the dotted lines are optionally a single bond or absent,
such that when the dotted lines are absent, each Y.sup.1 is
independently halo, --OR.sup.a, --NO.sub.2, --CN,
--NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl, --C.sub.2-6 alkynyl,
--OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
and --C.sub.1-6 alkylC.sub.3-8 cycloalkyl; [0971] wherein each
alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted
with 1 to 4 groups independently selected from oxo, --NO.sub.2,
--N.sub.3, --OR.sup.a, halo, and cyano; or the dotted lines are
single bonds and Y.sup.1 is CH.sub.2, such that they form a fused
5-membered ring; k is 0, 1, 2, 3, 4, 5, or 6; each X.sup.1 is
independently N or CH;
X.sup.2 is N or CH;
[0972] each Z.sup.1 is independently halo, --OR.sup.a, --NO.sub.2,
--CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a, --C.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl, --C.sub.2-6
alkynyl, --OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, and --C.sub.1-6 alkylC.sub.3-8 cycloalkyl; [0973]
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally
substituted with 1 to 4 groups independently selected from oxo,
--NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano; each Z.sup.3 is
independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [0974] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [0975] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0975] ##STR00129## [0976] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0977] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0978] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [0979] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0980] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0981] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0982] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl R.sup.6 is --NO.sub.2, --N.sub.3, --OR.sup.a, halo,
cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [0983] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; Q.sup.E is aryl, heteroaryl, or heterocyclyl; [0984]
wherein each aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [0985] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [0986] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[0986] ##STR00130## [0987] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [0988] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [0989] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [0990] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [0991] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[0992] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [0993] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2)C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[0993] ##STR00131## [0994] wherein: [0995] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0996] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [0997]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [0998] p is independently 0, 1, 2, 3,
4, or 5; [0999] q is independently 0, 1, 2, 3, 4, or 5; [1000] u is
0, 1, 2, 3, or 4; [1001] z is 0, 1, 2, or 3; and [1002] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [1003] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [1004] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [1005] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[1006] In one embodiment of formula (Va), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[1007] In one embodiment, the compound is represented by formula or
(Vb):
##STR00132##
wherein the dotted lines are optionally a single bond or absent,
such that when the dotted lines are absent, Y.sup.1 is halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl; [1008] wherein each alkyl, alkenyl,
alkynyl, and cycloalkyl is optionally substituted with 1 to 4
groups independently selected from oxo, --NO.sub.2, --N.sub.3,
--OR.sup.a, halo, and cyano; or the dotted lines are single bonds
and Y.sup.1 is CH.sub.2, such that they form a fused 5-membered
ring; k is 0, 1, 2, 3, 4, 5, or 6; each X.sup.1 is independently N
or CH;
X.sup.2 is N or CH;
[1009] each Z.sup.1 is independently halo, --OR.sup.a, --NO.sub.2,
--CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a, --C.sub.1-6
alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl, --C.sub.2-6
alkynyl, --OC.sub.1-6 alkyl, --OC.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, and --C.sub.1-6 alkylC.sub.3-8 cycloalkyl; [1010]
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally
substituted with 1 to 4 groups independently selected from oxo,
--NO.sub.2, --N.sub.3, --OR.sup.a, halo, and cyano; each Z.sup.3 is
independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; [1011] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; [1012] R.sup.N is independently
--C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[1012] ##STR00133## [1013] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [1014] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [1015] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b, or --C.sub.3-8 cycloalkyl; [1016] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [1017] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[1018] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [1019] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b, or --C.sub.3-8
cycloalkyl R.sup.6 is --NO.sub.2, --N.sub.3, --OR.sup.a, halo,
cyano, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl,
NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6
alkylCN, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; [1020] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; Q.sup.E is aryl, heteroaryl, or heterocyclyl; [1021]
wherein each aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from halo,
oxo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [1022] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [1023] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[1023] ##STR00134## [1024] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [1025] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [1026] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [1027] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [1028] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[1029] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --OC.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [1030] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; R.sup.E and R.sup.W are each independently
--NR.sup.1R.sup.2, --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylOC.sub.1-6alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --SC.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[1030] ##STR00135## [1031] wherein: [1032] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [1033] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1R.sup.2, or NR.sup.aSO.sub.2; [1034]
ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl; T is
independently H, OR.sup.a, (CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [1035] p is independently 0, 1, 2, 3,
4, or 5; [1036] q is independently 0, 1, 2, 3, 4, or 5; [1037] u is
0, 1, 2, 3, or 4; [1038] z is 0, 1, 2, or 3; and [1039] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [1040] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; R.sup.1 is independently selected from H, --C.sub.1-8 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [1041] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [1042] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, --C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; R.sup.4 is independently H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl,
--C.sub.1-6 alkylheterocyclyl, --C.sub.2-6 alkyl-OR.sup.a,
--C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6 alkenylC(O)OR.sup.a;
R.sup.a is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6alkylheterocyclyl; R.sup.b is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or R.sup.a and
R.sup.b may combine together to form a ring consisting of 3-8 ring
atoms that are C, N, O, or S; wherein the ring is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.f, --CN, halo, --C.sub.1-6 alkylOR.sup.f, --C.sub.1-6
cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl,
--C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.f, --C.sub.1-6
alkylC(O)R.sup.f, --C(O)OR.sup.f, --C.sub.1-6 alkylC(O)OR.sup.f,
--NR.sup.fR.sup.g, --C.sub.1-6 alkylNR.sup.fR.sup.g,
--C(O)NR.sup.fR.sup.g, --C.sub.1-6 alkylC(O)NR.sup.fR.sup.g,
--SO.sub.2R.sup.f, --C.sub.1-6 alkylSO.sub.2R.sup.f,
--SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; R.sup.c is independently selected from H,
OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --OC.sub.1-6alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --OC.sub.3-8 cycloalkyl, --Oaryl,
--Oheteroaryl, --Oheterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and R.sup.g is
independently selected from H, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, or tautomer thereof.
[1043] In one embodiment of formula (Vb), neither of R.sup.E or
R.sup.W is an optionally substituted fused 5,6-aromatic or
5,6-heteromatic ring.
[1044] In one embodiment, provided is a compound of formula
(VIa):
##STR00136##
wherein R.sup.E, R.sup.W, Z.sup.1 and Z.sup.3 are as defined
herein, each w is independently 0, 1 or 2, each t is independently
0, 1 or 2, and each X is independently CZ.sup.3, CH or N. In one
embodiment, provided is a compound of formula (VIb):
##STR00137##
wherein R.sup.E, R.sup.W, Z.sup.1 and Z.sup.3 are as defined
herein, each w is independently 0, 1 or 2, each t is independently
0, 1 or 2, and each X is independently CZ.sup.3, CH or N. In one
embodiment, provided is a compound of formula (VIc):
##STR00138##
wherein R.sup.E, R.sup.W, Z.sup.1 and Z.sup.3 are as defined
herein, each w is independently 0, 1 or 2, each t is independently
0, 1 or 2, and each X is independently CZ.sup.3, CH or N. In one
embodiment, provided is a compound of formula (VId):
##STR00139##
wherein R.sup.E, R.sup.W, Z.sup.1 and Z.sup.3 are as defined
herein, each w is independently 0, 1 or 2, each t is independently
0, 1 or 2, and Q.sup.E is heteroaryl. In one embodiment, provided
is a compound of formula (VIe):
##STR00140##
wherein R.sup.E, R.sup.W, Z.sup.1, Z.sup.3 and Q.sup.W are as
defined herein, each w is independently 0, 1 or 2, each t is
independently 0, 1 or 2. In one embodiment, provided is a compound
of formula (VIf):
##STR00141##
wherein R.sup.E, R.sup.W, Z.sup.1 and Z.sup.3 are as defined
herein, each w is independently 0, 1 or 2, each t is independently
0, 1 or 2. In one embodiment, provided is a compound of formula
(VIIa):
##STR00142##
wherein R.sup.W, Q.sup.W, Z.sup.1 and R.sup.E are as defined
herein. In one embodiment, provided is a compound of formula
(VIIb):
##STR00143##
wherein R.sup.W, R.sup.N, Z.sup.3, Z.sup.1 and R.sup.E are as
defined herein.
[1045] In certain embodiments of any one of formulas (VIa)-(VIf) or
formulas (VIIa)-(VIIb), each Z.sup.1 is independently halo. In
certain embodiments of any one of formulas (VIa)-(VIf) or formulas
(VIIa)-(VIIb), each Z.sup.3 is independently C.sub.1-6 alkoxy.
[1046] In certain embodiments of any one of formulas (VIa)-(VIf) or
formulas (VIIa)-(VIIb), each Z.sup.1 is chloro. In certain
embodiments of any one of formulas (VIa)-(VIf) or formulas
(VIIa)-(VIIb), each Z.sup.3 is methoxy.
[1047] In certain embodiments of formula (VIa)-(VIf) or formulas
(VIIa)-(VIIb), neither of R.sup.E or R.sup.W is an optionally
substituted fused 5,6-aromatic or 5,6-heteromatic ring directly
bound to the Q ring via a covalent bond.
[1048] In one embodiment, provided is a compound of formula
(VIII):
##STR00144##
wherein: each of X.sup.4 and X.sup.5 are independently N, CH or
CZ.sup.3; each Z.sup.1 is independently is halo, --OR.sup.a,
--NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3, --SO.sub.2R.sup.a,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6
haloalkyl, --C.sub.3-8 cycloalkyl, or --C.sub.1-6 alkylC.sub.3-s
cycloalkyl; and [1049] wherein each alkyl, alkenyl, alkynyl, and
cycloalkyl is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, and cyano; each w is independently 0, 1 or 2; each Z.sup.3 is
independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [1050] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--O--C.sub.1-6-cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3-8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [1051] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --OC.sub.1-6 alkylC(O)OR.sup.1,
--SC.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[1051] ##STR00145## [1052] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [1053] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [1054] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [1055] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [1056] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[1057] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --O--C.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [1058] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; each t is independently 0, 1 or 2; R.sup.E and R.sup.W
are each independently --NR.sup.1R.sup.2, --C.sub.1-6
alkylNR.sup.1R.sup.2, --O--C.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylOC.sub.1-6alkylNR.sup.1R.sup.2,
--NR.sup.a--C.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6
alkylN.sup.+R.sup.1R.sup.2R.sup.3, --S--C.sub.1-6
alkylNR.sup.1R.sup.2, --C(O)NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--(CH.sub.2).sub.uSO.sub.2NR.sup.1R.sup.2,
--(CH.sub.2).sub.uNR.sup.aSO.sub.2NR.sup.aR.sup.b,
--SO.sub.2NR.sup.aC.sub.1-6 alkylNR.sup.1R.sup.2,
--NR.sup.aSO.sub.2C.sub.1-6 alkylNR.sup.1R.sup.2,
--(CH.sub.2).sub.uC(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--(CH.sub.2).sub.uN.sup.+R.sup.1R.sup.2O.sup.-,
--(CH.sub.2).sub.uP.sup.+R.sup.bR.sup.cR.sup.d,
--(CH.sub.2).sub.uP.sup.+R.sup.cR.sup.dO.sup.-,
--(CH.sub.2).sub.uP.sup.+O[NR.sup.aR.sup.b][NR.sup.cR.sup.d],
--(CH.sub.2).sub.uNR.sup.cP(O)(OR.sup.c).sub.2,
--(CH.sub.2).sub.uCH.sub.2OP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)(OR.sup.c)(OR.sup.d),
--(CH.sub.2).sub.uOP(O)NR.sup.aR.sup.b)(OR.sup.a), or
[1058] ##STR00146## [1059] wherein: [1060] V.sup.2 is independently
a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a, NR.sup.aC(O),
SO.sub.2NR.sup.1, or NR.sup.aSO.sub.2; [1061] L.sup.3 is
independently a bond, O, NR.sup.a, S, SO, SO.sub.2, C(O)NR.sup.a,
NR.sup.aC(O), SO.sub.2NR.sup.1, or NR.sup.aSO.sub.2; [1062] ring B
is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[1063] T is independently H, OR.sup.a,
(CH.sub.2).sub.qNR.sup.1R.sup.2,
(CH.sub.2).sub.qNR.sup.aC(O)R.sup.e, or
(CH.sub.2).sub.qC(O)R.sup.e; [1064] p is independently 0, 1, 2, 3,
4, or 5; [1065] q is independently 0, 1, 2, 3, 4, or 5; [1066] u is
0, 1, 2, 3, or 4; [1067] z is 0, 1, 2, or 3; and [1068] wherein the
alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R.sup.E or
R.sup.W is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of
NR.sup.aR.sup.b, halo, cyano, oxo, OR.sup.a, --C.sub.1-6 alkyl,
--C.sub.1-6 haloalkyl, --C.sub.1-6 cyanoalkyl, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C.sub.1-6 alkylOH, --C.sub.3-8 cycloalkyl,
and --C.sub.1-3 alkylC.sub.3-8cycloalkyl; [1069] provided that at
least one of V.sup.2, L.sup.3, ring B and T contains a nitrogen
atom; each R.sup.1 is independently selected from H, --C.sub.1-8
alkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6
cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6 alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl,
--C.sub.1-6 alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [1070] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
each R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [1071] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; each R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; each R.sup.a is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; R.sup.b is independently selected
from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; each R.sup.c is independently selected from
H, OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.e is independently selected from H,
--C.sub.1-6 alkyl, --O--C.sub.1-6alkyl, --C.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --O--C.sub.3-8 cycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocyclyl, --C.sub.1-3
alkylC.sub.3-8cycloalkyl, --C.sub.1-6 alkylaryl,
--C.sub.1-6alkylheteroaryl, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --NHSO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, and --C.sub.1-6 alkylSO.sub.2NR.sup.fR.sup.g;
each R.sup.f is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; and each
R.sup.g is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, --C.sub.1-3
alkylC.sub.3-8 cycloalkyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, and --C.sub.1-6 alkylheterocyclyl; or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, solvate, or tautomer thereof.
[1072] In one embodiment, provided is a compound of formula
(VIIIa):
##STR00147##
wherein X.sup.4, X.sup.5, Z.sup.1, Z.sup.3, t, R.sup.W and R.sup.E
are as defined herein. In one embodiment, provided is a compound of
formula (VIIIb):
##STR00148##
wherein Z.sup.1, Z.sup.3, t, R.sup.W and R.sup.E are as defined
herein. In one embodiment, provided is a compound of formula
(VIIIc):
##STR00149##
wherein Z.sup.1, Z.sup.3, t, R.sup.W and R.sup.E are as defined
herein. In one embodiment, provided is a compound of formula
(VIIId):
##STR00150##
wherein Z.sup.1, Z.sup.3, t, R.sup.W and R.sup.E are as defined
herein.
[1073] In one embodiment, provided is a compound of formula
(VIIIe):
##STR00151##
wherein: each of X.sup.4 and X.sup.5 are independently N, CH or
CZ.sup.3; each Z.sup.1 is independently halo, --OR.sup.a, --CN, or
--C.sub.1-6 alkyl; each w is independently 0, 1 or 2; each Z.sup.3
is independently halo, --OR.sup.a, --N.sub.3, --NO.sub.2, --CN,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2R.sup.a, --NR.sup.aC(O)R.sup.a, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --O--C.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N; and [1074] wherein the
alkyl, alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--O--C.sub.1-6cyanoalkyl, --C(O)NR.sup.aR.sup.b,
NR.sup.aC(O)R.sup.a, --NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3- 8 cycloalkyl;
and further wherein the heteroaryl or heterocyclic group may be
oxidized on a nitrogen atom to form an N-oxide or oxidized on a
sulfur atom to form a sulfoxide or sulfone; [1075] R.sup.N is
independently --C.sub.1-6 alkylNR.sup.1R.sup.2, --OC.sub.1-6
alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOC.sub.1-6
alkylNR.sup.1R.sup.2, --NR.sup.a--C.sub.1-6 alkylNR.sup.1R.sup.2,
--C.sub.1-6 alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6
alkylC(O)NR.sup.1R.sup.2, --O--C.sub.1-6 alkylC(O)OR.sup.1,
--S--C.sub.1-6 alkylNR.sup.1R.sup.2, --C.sub.1-6 alkylOR.sup.a,
or
[1075] ##STR00152## [1076] wherein: L.sup.1 is independently a
bond, O, NR.sup.a, S, SO, or SO.sub.2; [1077] V is independently
selected from a bond, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; [1078] wherein each alkyl, alkenyl, or alkynyl is
optionally independently substituted with OR.sup.a, halo, cyano,
--NR.sup.aR.sup.b or --C.sub.3-8 cycloalkyl; [1079] L.sup.2 is
independently a bond, O, NR.sup.a, S, SO, or SO.sub.2; [1080] ring
A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
[1081] wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl
is optionally substituted with 1 to 4 groups independently selected
from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a, halo, cyano,
--C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --C.sub.2-6alkenyl,
--C.sub.2-6 alkynyl, --O--C.sub.1-6 haloalkyl, NR.sup.aR.sup.b,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC.sub.1-6 alkylCN,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a,
--C(O)N(R.sup.a)OR.sup.b, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, and
C.sub.1-6alkylC.sub.3-8 cycloalkyl; and [1082] wherein the alkyl,
alkenyl, or alkynyl group is optionally independently substituted
with --OR.sup.a, halo, cyano, --NR.sup.aR.sup.b or --C.sub.3-8
cycloalkyl; each t is independently 0, 1 or 2; each R.sup.1 is
independently selected from H, --C.sub.1-8 alkyl, --C.sub.2-6
alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.1-6
alkylC(O)OR.sup.a, --C.sub.2-6 alkenylC(O)OR.sup.a,
--SO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2R.sup.a, and C.sub.1-6
alkylC.sub.3-8cycloalkyl; [1083] wherein each alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
NR.sup.aC(O)OR.sup.b, --C.sub.1-6 alkylNR.sup.aR.sup.b,
--C(O)NR.sup.aR.sup.b, --C.sub.1-6 alkylC(O)NR.sup.aR.sup.b,
--SO.sub.2R.sup.a, --C.sub.1-6 alkylSO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b,
--C.sub.1-6 alkylC(O)NR.sup.aSO.sub.2R.sup.b,
--NR.sup.aC(O)R.sup.b, and --C.sub.1-6alkylNR.sup.aC(O)R.sup.b;
each R.sup.2 is independently selected from H, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, and --C.sub.2-6
alkenylC(O)OR.sup.a; [1084] wherein each alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally
substituted with 1 to 4 groups independently selected from
--OR.sup.a, --CN, halo, C.sub.1-6alkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl, --C.sub.3-8
cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C(O)R.sup.a,
--C.sub.1-6 alkylC(O)R.sup.a, --C(O)OR.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b, --C.sub.1-6
alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, --C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b, --C(O)NR.sup.aSO.sub.2R.sup.b and
--NR.sup.aC(O)R.sup.b; or R.sup.1 and R.sup.2 combine to form a
heterocyclyl group optionally containing 1, 2, or 3 additional
heteroatoms independently selected from oxygen, sulfur and
nitrogen, and optionally substituted with 1 to 3 groups
independently selected from oxo, --C.sub.1-6 alkyl, --C.sub.3-8
cycloalkyl, --C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OR.sup.a,
--C(O)OR.sup.a, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylOR.sup.a,
--C.sub.1-6 haloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.a, C.sub.1-6 alkylC(O)R.sup.a, --C.sub.1-6
alkylC(O)OR.sup.a, --NR.sup.aR.sup.b,
--C.sub.1-6alkylNR.sup.aR.sup.b, --C(O)NR.sup.aR.sup.b, --C.sub.1-6
alkylC(O)NR.sup.aR.sup.b, --SO.sub.2R.sup.a, --C.sub.1-6
alkylSO.sub.2R.sup.a, --SO.sub.2NR.sup.aR.sup.b, and C.sub.1-6
alkylSO.sub.2NR.sup.aR.sup.b; each R.sup.3 is independently H,
--C.sub.1-6 alkyl, --C.sub.2-6 alkenyl, --C.sub.3-6 cycloalkyl,
aryl, heteroaryl, heterocyclyl, --C.sub.1-6 alkylaryl, --C.sub.1-6
alkylheteroaryl, --C.sub.1-6 alkylheterocyclyl, --C.sub.2-6
alkyl-OR.sup.a, --C.sub.1-6 alkylC(O)OR.sup.a, or --C.sub.2-6
alkenylC(O)OR.sup.a; each R.sup.a is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and
--C.sub.1-6alkylheterocyclyl; each R.sup.b is independently
selected from H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl,
heteroaryl, heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C.sub.1-6 alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or R.sup.a and R.sup.b may combine together to
form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
wherein the ring is optionally substituted with 1 to 4 groups
independently selected from --OR.sup.f, --CN, halo, --C.sub.1-6
alkylOR.sup.f, --C.sub.1-6 cyanoalkyl, --C.sub.1-6 haloalkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl,
--C(O)R.sup.f, --C.sub.1-6 alkylC(O)R.sup.f, --C(O)OR.sup.f,
--C.sub.1-6 alkylC(O)OR.sup.f, --NR.sup.fR.sup.g, --C.sub.1-6
alkylNR.sup.fR.sup.g, --C(O)NR.sup.fR.sup.g, --C.sub.1-6
alkylC(O)NR.sup.fR.sup.g, --SO.sub.2R.sup.f, --C.sub.1-6
alkylSO.sub.2R.sup.f, --SO.sub.2NR.sup.fR.sup.g, --C.sub.1-6
alkylSO.sub.2NR.sup.fR.sup.g, --C(O)NR.sup.fSO.sub.2R.sup.g and
--NR.sup.fC(O)R.sup.g; each R.sup.c is independently selected from
H, OH, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; R.sup.d is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; each R.sup.f is independently selected from H,
--C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; and each R.sup.g is independently selected from
H, --C.sub.1-6 alkyl, --C.sub.3-8 cycloalkyl, aryl, heteroaryl,
heterocyclyl, --C.sub.1-3 alkylC.sub.3-8 cycloalkyl, --C.sub.1-6
alkylaryl, --C.sub.1-6 alkylheteroaryl, and --C.sub.1-6
alkylheterocyclyl; or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers, solvate, or tautomer
thereof.
[1085] In one embodiment, provided is a compound of formula
(VIIIf):
##STR00153##
wherein X.sup.4, X.sup.5, Z.sup.1, Z.sup.3, t, R.sup.1 and R.sup.2
are as defined herein. In one embodiment, provided is a compound of
formula (VIIIg):
##STR00154##
wherein Z.sup.1, Z.sup.3, t, R.sup.1 and R.sup.2 are as defined
herein. In one embodiment, provided is a compound of formula
(VIIIh):
##STR00155##
wherein Z.sup.1, Z.sup.3, t, R.sup.1 and R.sup.2 are as defined
herein. In one embodiment, provided is a compound of formula
(VIIIi):
##STR00156##
wherein Z.sup.1, Z.sup.3, t, R.sup.1 and R.sup.2 are as defined
herein.
[1086] In certain embodiments of any one of formulas
(VIII)-(VIIIi), each Z.sup.1 is independently halo. In certain
embodiments of any one of formulas (VIII)-(VIIIi), each Z.sup.3 is
independently halo or C.sub.1-6 alkoxy.
[1087] In certain embodiments of any one of formulas
(VIII)-(VIIIi), each Z.sup.1 is independently chloro. In certain
embodiments of any one of formulas (VIII)-(VIIIi), each Z.sup.3 is
independently chloro or methoxy.
[1088] In one embodiment provided is a compound selected from
Examples 637-803.
[1089] In certain embodiments, the compound as provided herein has
a molecular weight of less than about 1200 g/mol, or less than
about 1100 g/mol, or less than about 1000 g/mol, or less than about
900 g/mol, or less than about 800 g/mol, or between about 1200 to
about 600 g/mol, or between about 1000 to about 700 g/mol, or
between about 1000 to about 800 g/mol.
[1090] One of skill in the art is aware that each and every
embodiment of a group (e.g., Ar.sup.E) disclosed herein may be
combined with any other embodiment of each of the remaining groups
(e.g., Q.sup.E, Ar.sup.W, Q.sup.W, etc.) to generate a complete
compound of formula (I) as disclosed herein; each of which is
deemed within the ambit of the present disclosure.
[1091] Formulations and Methods
[1092] Methods
[1093] In one embodiment, the present disclosure provides a
compound of formula (I) useful as an inhibitor of PD-1, PD-L1
and/or the PD-1/PD-L1 interaction. In some embodiments, compounds
disclosed herein inhibit the PD-1/PD-L1 interaction by dimerizing
PD-L1, or by inducing or stabilizing PD-L1 dimer formation.
[1094] In one embodiment, the present disclosure provides a method
of treating cancer comprising administering a compound of formula
(I) in combination with one or more check-point inhibitors selected
from nivolumab, pembrolizumab, and artezolizumab.
[1095] In one embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound of formula (I) and
a pharmaceutically acceptable carrier.
[1096] In one embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, and at least one additional
anticancer agent and at least one pharmaceutically acceptable
excipient.
[1097] The present disclosure provides a compound of formula (I)
for use in therapy.
[1098] In another embodiment, the present disclosure provides a
compound of formula (I) for use in the manufacture of a medicament
for treating cancer.
[1099] In one embodiment, provided is a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, useful for the treatment of
cancer or a condition in a patient that is amenable to treatment by
inhibiting PD-1, PD-L1 or the PD-1/PD-L1 interaction. Cancers that
may be treated with the compounds of formula (I) disclosed herein
include pancreatic cancer, bladder cancer, colorectal cancer,
breast cancer, prostate cancer, renal cancer, hepatocellular
cancer, lung cancer, ovarian cancer, cervical cancer, gastric
cancer, esophageal cancer, head and neck cancer, melanoma,
neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft
tissue sarcoma, non-small cell lung cancer, small-cell lung cancer
and colon cancer.
[1100] In one embodiment, provided is a compound of formula (I) or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof, useful for the treatment of
cancer or a condition in a patient that is amenable to treatment by
inhibiting PD-1, PD-L1 or the PD-1/PD-L1 interaction including, but
not limited to, lymphoma, multiple myeloma, and leukemia.
Additional diseases or conditions that may be treated include, but
are not limited to acute lymphocytic leukemia (ALL), acute myeloid
leukemia (AML), chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell
lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia
(WM), T-cell lymphoma, B-cell lymphoma and diffuse large B-cell
lymphoma (DLBCL).
[1101] In one embodiment, provided is a method of treating HBV,
comprising administering to a patient in need thereof a compound of
formula (I), or a pharmaceutically acceptable salt, stereoisomer,
mixture of stereoisomers or tautomer thereof.
[1102] "Administering" or "administration" refers to the delivery
of one or more therapeutic agents to a patient. In one embodiment,
the administration is a monotherapy wherein a compound of formula
(I) is the only active ingredient administered to the patient in
need of therapy. In another embodiment, the administration is
co-administration such that two or more therapeutic agents are
delivered together during the course of the treatment. In one
embodiment, two or more therapeutic agents may be co-formulated
into a single dosage form or "combined dosage unit", or formulated
separately and subsequently combined into a combined dosage unit,
as is typically for intravenous administration or oral
administration as a mono or bilayer tablet or capsule.
[1103] In one embodiment, the compound of formula (I) or a
pharmaceutically acceptable salt thereof is administered to a human
patient in need thereof in an effective amount, such as, from about
0.1 mg to about 1000 mg per day of said compound. In one
embodiment, the effective amount is from about 0.1 mg to about 200
mg per day. In one embodiment, the effective amount is from about 1
mg to about 100 mg per day. In other embodiments, the effective
amount is about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15
mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60
mg, about 80 mg, or about 100 mg per day.
[1104] In one embodiment, the compound of formula (I) or a
pharmaceutically acceptable salt thereof and at least one
additional anticancer agent is administered to a human patient in
need thereof in an effective amount of each agent, independently
from about 0.1 mg to about 1000 mg per compound or formulation per
day per compounds. In one embodiment, the effective amount of the
combination treatment of a compound of formula (I) and an
additional compound is independently from about 0.1 mg to about 200
mg per compound per day. In one embodiment, the effective amount of
the combination treatment of a compound of formula (I) and an
additional compound is independently from about 1 mg to about 100
mg per compound per day. In other embodiments, the effective amount
of the combination treatment of a compound of formula (I) and an
additional compound is for each component, about 1 mg, about 3 mg,
about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg,
about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg,
about 200 mg, or about 500 mg each per day.
[1105] In one embodiment, the compound of formula (I) and/or a
combination of the compound of formula (I) and an additional
anticancer agent or a pharmaceutically acceptable salt thereof is
administered once a day. In yet another embodiment, the compound of
formula (I) and/or an additional anticancer agent or a
pharmaceutically acceptable salt thereof is administered as a
loading dose of from about 10 mg to about 500 mg per compound on
the first day and each day or on alternate days or weekly for up to
a month followed by a regular regimen of a compound of formula (I)
and/or one or more additional anticancer agents or therapies. The
maintenance dose may be 1-500 mg daily or weekly for each component
of a multi component drug regimen. A qualified care giver or
treating physician is aware of what dose regimen is best for a
particular patient or particular presenting conditions and will
make appropriate treating regimen decisions for that patient. Thus,
in another embodiment, the qualified caregiver is able to tailor a
dose regimen of the compound of formula (I) and/or an additional
agent(s) as disclosed herein to fit with the particular needs of
the patient. Thus, it will be understood that the amount of the
compound of formula (I), or a pharmaceutically acceptable salt
thereof and the amount of an additional agent actually administered
will usually be determined by a physician, in light of the relevant
circumstances, including the condition(s) to be treated, the chosen
route of administration, the actual compound (e.g., salt or free
base) administered and its relative activity, the age, weight, and
response of the individual patient, the severity of the patient's
symptoms, and the like.
[1106] Co-administration may also include administering component
drugs e.g., one on more compounds of formula (I) and one or more
additional (e.g., a second, third, fourth or fifth) anticancer or
other therapeutic agent(s). Such combination of one on more
compounds of formula (I) and one or more additional anticancer or
other therapeutic agent(s) may be administered simultaneously or in
sequence (one after the other) within a reasonable period of time
of each administration (e.g., about 1 minute to 24 hours) depending
on the pharmacokinetic and/or pharmacodynamics properties of each
agent or the combination. Co-administration may also involve
treatment with a fixed combination wherein agents of the treatment
regimen are combinable in a fixed dosage or combined dosage medium
e.g., solid, liquid or aerosol. In one embodiment, a kit may be
used to administer the drug or drug components.
[1107] Thus, one embodiment of the present disclosure is a method
of treating a disease amenable to treatment with a PD-1, PD-L1
inhibitor or a PD-1/PD-L1 interaction inhibitor e.g., cancer
comprising administering therapeutically effective amounts of
formulations of one on more compounds of formula (I) and one or
more additional anticancer agents, including for example, via a kit
to a patient in need thereof. It will be understood that a
qualified care giver will administer or direct the administration
of a therapeutically effective amount of any of the compound(s) or
combinations of compounds of the present disclosure.
[1108] "Intravenous administration" is the administration of
substances directly into a vein, or "intravenously." Compared with
other routes of administration, the intravenous (IV) route is a
faster way to deliver fluids and medications throughout the body.
An infusion pump can allow precise control over the flow rate and
total amount of medication delivered. However, in cases where a
change in the flow rate would not have serious consequences, or if
pumps are not available, the drip is often left to flow simply by
placing the bag above the level of the patient and using the clamp
to regulate the rate. Alternatively, a rapid infuser can be used if
the patient requires a high flow rate and the IV access device is
of a large enough diameter to accommodate it. This is either an
inflatable cuff placed around the fluid bag to force the fluid into
the patient or a similar electrical device that may also heat the
fluid being infused. When a patient requires medications only at
certain times, intermittent infusion is used which does not require
additional fluid. It can use the same techniques as an intravenous
drip (pump or gravity drip), but after the complete dose of
medication has been given, the tubing is disconnected from the IV
access device. Some medications are also given by IV push or bolus,
meaning that a syringe is connected to the IV access device and the
medication is injected directly (slowly, if it might irritate the
vein or cause a too-rapid effect). Once a medicine has been
injected into the fluid stream of the IV tubing there must be some
means of ensuring that it gets from the tubing to the patient.
Usually this is accomplished by allowing the fluid stream to flow
normally and thereby carry the medicine into the bloodstream;
however, a second fluid injection is sometimes used, as a "flush",
following the injection to push the medicine into the bloodstream
more quickly. Thus in one embodiment, compound(s) or combination of
compounds described herein may be administered by IV administration
alone or in combination with administration of certain components
of the treatment regimen by oral or parenteral routes.
[1109] "Oral administration" is a route of administration where a
substance is taken through the mouth, and includes buccal, sub
labial, and sublingual administration, as well as enteral
administration and that through the respiratory tract, unless made
through e.g., tubing so the medication is not in direct contact
with any of the oral mucosa. Typical form for the oral
administration of therapeutic agents includes the use of tablets or
capsules. Thus in one embodiment, compound(s) or combination of
compounds described herein may be administered by oral route alone
or in combination with administration of certain components of the
treatment regimen by IV or parenteral routes.
[1110] Pharmaceutical Formulations
[1111] The compound(s) of formula (I) or a pharmaceutically
acceptable salt thereof may be administered in a pharmaceutical
formulation. Pharmaceutical formulations/compositions contemplated
by the present disclosure comprise, in addition to a carrier, the
compound of formula (I), or a pharmaceutically acceptable salt
thereof, or a combination of compound of formula (I), or a
pharmaceutically acceptable salt thereof, optionally in combination
with an additional agent such as for example, ipilimumab, or a
pharmaceutically acceptable salt thereof.
[1112] Pharmaceutical formulations/compositions contemplated by the
present disclosure may also be intended for administration by
injection and include aqueous solutions, oil suspensions, emulsions
(with sesame oil, corn oil, cottonseed oil, or peanut oil) as well
as elixirs, mannitol, dextrose, or a sterile aqueous solution, and
similar pharmaceutical vehicles. Aqueous solutions in saline are
also conventionally used for injection. Ethanol, glycerol,
propylene glycol, liquid polyethylene glycol, and the like (and
suitable mixtures thereof), cyclodextrin derivatives, and vegetable
oils may also be employed. The proper fluidity can be maintained,
for example, by the use of a coating, such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and/or by the use of surfactants. The prevention of the action of
microorganisms can be brought about by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
sorbic acid, thimerosal, and the like.
[1113] Sterile injectable solutions are prepared by incorporating
the component compound(s) in the required amount in the appropriate
solvent with various other ingredients as enumerated above or as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum-drying and freeze-drying techniques which
yield a powder of the active ingredient(s) plus any additional
desired ingredient from a previously sterile-filtered solution
thereof.
[1114] In making pharmaceutical compositions that comprise compound
of formula (I), or a pharmaceutically acceptable salt thereof,
optionally in combination with an additional agent/therapy useful
for the purpose or pharmaceutically acceptable salt thereof, the
active ingredient is usually diluted by an excipient or carrier
and/or enclosed or mixed with such a carrier that may be in the
form of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material (as above), which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in
the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), ointments containing, for example, up
to 20% by weight of the active compounds, soft and hard gelatin
capsules, sterile injectable solutions, and sterile packaged
powders.
[1115] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents.
[1116] The compositions of the disclosure may be formulated so as
to provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art. In one embodiment, sustained release
formulations are used. Controlled release drug delivery systems for
oral administration include osmotic pump systems and dissolutional
systems containing polymer-coated reservoirs or drug-polymer matrix
formulations.
[1117] Certain compositions are preferably formulated in a unit
dosage form. The term "unit dosage forms" or "combined dosage unit"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of one or more of the active materials
(e.g., compound (I), optionally in combination with an additional
agent calculated to produce the desired effect, in association with
a suitable pharmaceutical excipient in for example, a tablet,
capsule, ampoule or vial for injection. It will be understood,
however, that the amount of each active agent actually administered
will be determined by a physician, in the light of the relevant
circumstances, including the condition to be treated, the chosen
route of administration, the actual compounds administered and
their relative activity, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[1118] For preparing solid compositions such as tablets, the
principal active ingredient(s) is/are mixed with a pharmaceutical
excipient to form a solid pre-formulation composition containing a
homogeneous mixture of a compound of the present disclosure. When
referring to these pre-formulation compositions as homogeneous, it
is meant that the active ingredient(s) are dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective unit dosage forms such as
tablets, pills and capsules.
[1119] The tablets or pills comprising compound of formula (I) or a
pharmaceutically acceptable salt thereof of the present disclosure
optionally in combination with the second agent may be coated or
otherwise compounded to provide a dosage form affording the
advantage of prolonged action, or to protect from the acidic
conditions of the stomach. For example, the tablet or pill can
comprise an inner dosage and an outer dosage element, the latter
being in the form of an envelope over the former. In one
embodiment, the inner dosage element may comprise the compound (I)
and the outer dosage element may comprise the second or additional
agent or vice versa. Alternatively, the combined dosage unit may be
side by side configuration as in a capsule or tablet where one
portion or half of the tablet or capsule is filled with a
formulation of the compound of formula (I) while the other portion
or half of the table or capsule comprises the additional agent
[1120] A variety of materials may be used for such enteric layers
or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac,
cetyl alcohol, and cellulose acetate. One of ordinary skill in the
art is aware of techniques and materials used in the manufacture of
dosages of formulations disclosed herein.
[1121] A "sustained release formulation" or "extended release
formulation" is a formulation which is designed to slowly release a
therapeutic agent into the body over an extended period of time,
whereas an "immediate release formulation" is a formulation which
is designed to quickly release a therapeutic agent into the body
over a shortened period of time. In some cases the immediate
release formulation may be coated such that the therapeutic agent
is only released once it reaches the desired target in the body
(e.g., the stomach). One of ordinary skill in the art is able to
develop sustained release formulations of the presently disclosed
compounds without undue experimentation. Thus in one embodiment,
compound(s) or combination of compounds described herein may be
delivered via sustained released formulations alone or in
combination with administration of certain components of the
treatment regimen by oral, IV or parenteral routes.
[1122] A lyophilized formulation may also be used to administer a
compound of formula (I) singly or in combination with an additional
anticancer agent. One of skill in the art is aware of how to make
and use lyophilized formulations of drug substances amenable to
lyophilization.
[1123] Spray-dried formulation may also be used to administer a
compound of formula (I) singly or in combination with an additional
anti-cancer agent. One of skill in the art is aware of how to make
and use spray-dried formulations of drug substances amenable to
spray-drying. Other known formulation techniques may also be
employed to formulate a compound or combination of compounds
disclosed herein.
[1124] Combination Therapy
[1125] Also provided are methods of treatment in which a compound
of formula (I) or a pharmaceutically acceptable salt thereof, is
given to a patient in combination with one or more additional
active agents or therapy.
[1126] Thus in one embodiment, a method of treating cancer and/or
diseases or symptoms that co-present or are exacerbated or
triggered by the cancer e.g., an allergic disorder and/or an
autoimmune and/or inflammatory disease, and/or an acute
inflammatory reaction, comprises administering to a patient in need
thereof an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, optionally in combination
with an additional agent (e.g., a second, third, fourth or fifth
active agent) which can be useful for treating a cancer, an
allergic disorder and/or an autoimmune and/or inflammatory disease,
and/or an acute inflammatory reaction incident to or co-presenting
with a cancer. Treatment with the second, third, fourth or fifth
active agent may be prior to, concomitant with, or following
treatment with a compound of formula (I) or a pharmaceutically
acceptable salt thereof. In one embodiment, a compound of formula
(I) or a pharmaceutically acceptable salt thereof is combined with
another active agent in a single dosage form. Suitable antitumor or
anticancer therapeutics that may be used in combination with a
compound of formula (I) or a pharmaceutically acceptable salt
thereof include, but are not limited to, chemotherapeutic agents,
for example mitomycin C, carboplatin, taxol, cisplatin, paclitaxel,
etoposide, doxorubicin, or a combination comprising at least one of
the foregoing chemotherapeutic agents. Radiotherapeutic antitumor
agents may also be used, alone or in combination with
chemotherapeutic agents.
[1127] A compound of formula (I) or a pharmaceutically acceptable
salt thereof can be useful as chemo-sensitizing agents, and thus,
can be useful in combination with other chemotherapeutic drugs, in
particular, drugs that induce apoptosis. Thus, in one embodiment,
the present disclosure provides a method for increasing sensitivity
of cancer cells to chemotherapy, comprising administering to a
patient in need of or undergoing chemotherapy, a chemotherapeutic
agent together with a compound of formula (I), or a
pharmaceutically acceptable salt thereof in an amount sufficient to
increase the sensitivity of cancer cells to the chemotherapeutic
agent.
[1128] Examples of other chemotherapeutic drugs that can be used in
combination with compounds of formula (I), or a pharmaceutically
acceptable salt thereof include topoisomerase I inhibitors
(camptothesin or topotecan), topoisomerase II inhibitors (e.g.,
daunomycin and etoposide), alkylating agents (e.g.,
cyclophosphamide, melphalan and BCNU), tubulin directed agents
(e.g., taxol and vinblastine), and biological agents (e.g.,
antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and
cytokines).
[1129] In some embodiments, the compound(s) of formula (I), or a
pharmaceutically acceptable salt thereof is used in combination
with Rituxan.RTM. (Rituximab) and/or other agents that work by
selectively depleting CD20+ B-cells.
[1130] Included herein are methods of treatment in which a compound
of formula (I), or a pharmaceutically acceptable salt thereof is
administered in combination with an anti-inflammatory agent.
Anti-inflammatory agents include but are not limited to NSAIDs,
non-specific and COX-2 specific cyclooxgenase enzyme inhibitors,
gold compounds, corticosteroids, methotrexate, tumor necrosis
factor receptor (TNF) receptors antagonists, immunosuppressants and
methotrexate.
[1131] Examples of NSAIDs include, but are not limited to
ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac,
combinations of diclofenac sodium and misoprostol, sulindac,
oxaprozin, diflunisal, piroxicam, indomethacin, etodolac,
fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine,
tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also
include COX-2 specific inhibitors (i.e., a compound that inhibits
COX-2 with an IC.sub.50 that is at least 50-fold lower than the
IC.sub.50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib,
etoricoxib and/or rofecoxib.
[1132] In a further embodiment, the anti-inflammatory agent is a
salicylate. Salicylates include but are not limited to
acetylsalicylic acid or aspirin, sodium salicylate, and choline and
magnesium salicylates.
[1133] The anti-inflammatory agent may also be a corticosteroid.
For example, the corticosteroid may be chosen from cortisone,
dexamethasone, methylprednisolone, prednisolone, prednisolone
sodium phosphate, and prednisone.
[1134] In some embodiments, the anti-inflammatory therapeutic agent
is a gold compound such as gold sodium thiomalate or auranofin.
[1135] In some embodiments, the anti-inflammatory agent is a
metabolic inhibitor such as a dihydrofolate reductase inhibitor,
such as methotrexate or a dihydroorotate dehydrogenase inhibitor,
such as leflunomide.
[1136] In one embodiment, the compound(s) of formula (I), or a
pharmaceutically acceptable salt thereof is used in combination
with at least one anti-inflammatory compound that is an anti-C5
monoclonal antibody (such as eculizumab or pexelizumab), a TNF
antagonist, such as entanercept, or infliximab, which is an
anti-TNF alpha monoclonal antibody.
[1137] In one embodiment, the compound(s) of formula (I), or a
pharmaceutically acceptable salt thereof is used in combination
with at least one active agent that is an immunosuppressant
compound such as methotrexate, leflunomide, cyclosporine,
tacrolimus, azathioprine, or mycophenolate mofetil.
[1138] In other embodiments, the compound(s) of formula (I), or a
pharmaceutically acceptable salt thereof is used in combination
with one or more phosphatidylinositol 3-kinase (PI3K) inhibitors,
including for example, Compounds A, B and C (whose structures are
provided below), or a pharmaceutically acceptable salt thereof.
##STR00157##
[1139] Compounds A, B and C are disclosed in WO2015/017460 and
WO2015/100217. Additional examples of PI3K inhibitors include, but
are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186,
BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib),
CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0941, GDC-0980,
GSK2636771, GSK2269557, idelalisib (Zydelig.RTM.), IPI-145,
IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A,
PA799, PX-866, RG7604, rigosertib, RP5090, taselisib, TG100115,
TGR-1202, TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499,
XL756, wortmannin, ZSTK474, and the compounds described in WO
2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO
2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga),
WO 2014/100767 (Gilead Calistoga), and WO 2014/201409 (Gilead
Sciences).
[1140] In yet another embodiment, the compound(s) of formula (I)
may be used in combination with Spleen Tyrosine Kinase (SYK)
Inhibitors. Examples of SYK inhibitors include, but are not limited
to,
6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,
BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib
(R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and
those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) and
those described in U.S. 2015/0175616.
[1141] In yet another embodiment, the compounds of formula (I) may
be used in combination with Tyrosine-kinase Inhibitors (TKIs). TKIs
may target epidermal growth factor receptors (EGFRs) and receptors
for fibroblast growth factor (FGF), platelet-derived growth factor
(PDGF), and vascular endothelial growth factor (VEGF). Examples of
TKIs include, but are not limited to, afatinib, ARQ-087, asp5878,
AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib,
crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib,
erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713,
icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib,
midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291),
ponatinib, poziotinib, quizartinib, radotinib, rociletinib,
sulfatinib (HMPL-012), sunitinib, and TH-4000.
[1142] In yet other embodiments, the compound(s) of formula (I), or
a pharmaceutically acceptable salt thereof is used in combination
with one or more inhibitors of lysyl oxidase-like 2 (LOXL) or a
substance that binds to LOXL, including for example, a humanized
monoclonal antibody (mAb) with an immunoglobulin IgG4 isotype
directed against human LOXL2. Examples of LOXL inhibitors include,
but are not limited to, the antibodies described in WO 2009/017833
(Arresto Biosciences). Examples of LOXL2 inhibitors include, but
are not limited to, the antibodies described in WO 2009/017833
(Arresto Biosciences), WO 2009/035791 (Arresto Biosciences), and WO
2011/097513 (Gilead Biologics).
[1143] In yet another embodiment, the compounds of formula (I) may
be used in combination with Toll-like receptor 8 (TLR8) inhibitors.
Examples of TLR8 inhibitors include, but are not limited to,
E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197,
motolimod, resiquimod, VTX-1463, and VTX-763.
[1144] In yet another embodiment, the compounds of formula (I) may
be used in combination with Toll-like receptor (TLR9) inhibitors.
Examples of TLR9 inhibitors include, but are not limited to,
IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and
PUL-042.
[1145] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a BTK (Bruting's
Tyrosine kinase) inhibitor. An example of such BTK inhibitor is a
compound disclosed in U.S. Pat. No. 7,405,295. Additional examples
of BTK inhibitors include, but are not limited to,
(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-pur-
in-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, HM71224,
ibrutinib, M-2951, tirabrutinib (ONO-4059), PRN-1008, spebrutinib
(CC-292), and TAK-020.
[1146] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a BET inhibitor. An
example of such BET inhibitor is a compound disclosed in
WO2014/182929, the entire contents of which are incorporated herein
by reference.
[1147] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a TBK (Tank Binding
kinase) inhibitor. An example of such TBK inhibitor is a compound
disclosed in WO2016/049211.
[1148] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a OX40 inhibitor. An
example of such OX40 inhibitor is a compound disclosed in U.S. Pat.
No. 8,450,460, the entire contents of which are incorporated herein
by reference.
[1149] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a JAK-1 inhibitor. An
example of such JAK-1 inhibitor is a compound disclosed in
WO2008/109943. Examples of other JAK inhibitors include, but are
not limited to, AT9283, AZD1480, baricitinib, BMS-911543,
fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),
INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib
(SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly
tasocitinib), and XL019.
[1150] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with an
Indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitors. An example of
such IDO inhibitor is a compound disclosed in WO2016/186967. In one
embodiment, the compounds of formula (I) are useful for the
treatment of cancer in combination with IDO 1 inhibitors including
but not limited to BLV-0801, epacadostat, F-001287, GBV-1012,
GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine,
PF-06840003, pyranonaphthoquinone derivatives (SN-35837),
resminostat, SBLK-200802, and shIDO-ST.
[1151] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a Mitogen-activated
Protein Kinase (MEK) Inhibitors. MEK inhibitors useful for
combination treatment with a compound(s) of formula (I) includes
antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144,
selumetinib (AZD6244), sorafenib, trametinib (GSK1120212),
uprosertib and trametinib.
[1152] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with an Apoptosis
Signal-Regulating Kinase (ASK) Inhibitors: ASK inhibitors include
but are not limited to those described in WO 2011/008709 (Gilead
Sciences) and WO 2013/112741 (Gilead Sciences) including for
example selonsertib.
[1153] In one embodiment, the compounds of formula (I) may be
combined with Cluster of Differentiation 47 (CD47) inhibitors.
Examples of CD47 inhibitors include, but are not limited to
anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108),
CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4),
NI-1701, NI-1801, RCT-1938, and TTI-621.
[1154] In one embodiment, the compounds of formula (I) may be
combined with Cyclin-dependent Kinase (CDK) Inhibitors. CDK
inhibitors include inhibitors of CDK 1, 2, 3, 4, 6 and 9, such as
abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, FLX-925,
LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, and
TG-02.
[1155] In one embodiment, the compounds of formula (I) may be
combined with Discoidin Domain Receptor (DDR) Inhibitors for the
treatment of cancer. DDR inhibitors include inhibitors of DDR1
and/or DDR2. Examples of DDR inhibitors include, but are not
limited to, those disclosed in WO 2014/047624 (Gilead Sciences), US
2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed
Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO
2013/034933 (Imperial Innovations).
[1156] In one embodiment, the compounds of formula (I) may be
combined with Histone Deacetylase (HDAC) Inhibitors such as those
disclosed in U.S. Pat. No. 8,575,353 and equivalents thereof.
Additional examples of HDAC inhibitors include, but are not limited
to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581,
CS-055 (HBI-8000), CUDC-907, entinostat, givinostat, mocetinostat,
panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat,
ricolinostat, SHP-141, valproic acid (VAL-001), vonnostat.
[1157] In one embodiment, the compound of formula (I) is useful for
the treatment of cancer in combination with a standard of care in
the treatment of the respective cancer. One of skill in the art is
aware of the standard of care as of a given date in the particular
field of cancer therapy or with respect to a given cancer.
[1158] Certain embodiments of the present application include or
use one or more additional therapeutic agent. The one or more
additional therapeutic agent may be an agent useful for the
treatment of cancer, inflammation, autoimmune disease and/or
related conditions. The one or more additional therapeutic agent
may be a chemotherapeutic agent, an anti-angiogenic agent, an
antifibrotic agent, an anti-inflammatory agent, an immune
modulating agent, an immunotherapeutic agent, a therapeutic
antibody, a radiotherapeutic agent, an anti-neoplastic agent, an
anti-cancer agent, an anti-proliferation agent, or any combination
thereof. In some embodiments, the compound(s) described herein may
be used or combined with a chemotherapeutic agent, an
anti-angiogenic agent, an anti-fibrotic agent, an anti-inflammatory
agent, an immune modulating agent, an immunotherapeutic agent, a
therapeutic antibody, a radiotherapeutic agent, an antineoplastic
agent or an anti-cancer agent, an anti-proliferation agent, or any
combination thereof.
[1159] In one embodiment, a compound(s) of formula (I) optionally
in combination with an additional anticancer agent described
herein, may be used or combined with an anti-neoplastic agent or an
anti-cancer agent, anti-fibrotic agent, an anti-anti-inflammatory
agent, or an immune modulating agent.
[1160] In one embodiment, provided are kits comprising a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt, or a compound of formula (I)
and at least one additional anticancer agent, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable carrier. In one embodiment, the kit comprises
instructions for use in the treatment of cancer or inflammatory
conditions. In one embodiment, the instructions in the kit are
directed to use of the pharmaceutical composition for the treatment
of cancer selected from pancreatic cancer, bladder cancer,
colorectal cancer, breast cancer, prostate cancer, renal cancer,
hepatocellular cancer, lung cancer, ovarian cancer, cervical
cancer, gastric cancer, esophageal cancer, head and neck cancer,
melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone
cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell
lung cancer and colon cancer.
[1161] The application also provides method for treating a subject
who is undergoing one or more standard therapies, such as
chemotherapy, radiotherapy, immunotherapy, surgery, or combination
thereof comprising administering or co-administering a compound of
formula (I) to said subject. Accordingly, one or more compound(S)
of formula (I), or pharmaceutically acceptable salt thereof, may be
administered before, during, or after administration of a
chemotherapy, radiotherapy, immunotherapy, surgery or combination
thereof.
[1162] In one embodiment, the subject may be a human who is (i)
substantially refractory to at least one chemotherapy treatment, or
(ii) in relapse after treatment with chemotherapy, or both (i) and
(ii). In some of embodiments, the subject is refractory to at least
two, at least three, or at least four chemotherapy treatments
(including standard or experimental chemotherapies).
[1163] In one embodiment, the subject is refractory to at least
one, at least two, at least three, or at least four chemotherapy
treatment (including standard or experimental chemotherapy)
selected from fludarabine, rituximab, obinutuzumab, alkylating
agents, alemtuzumab and other chemotherapy treatments such as CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP
(rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide,
vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine);
R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine,
cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine,
cyclophosphamide, mitoxantrone); bortezomib and rituximab;
temsirolimus and rituximab; temsirolimus and Velcade.RTM.;
Iodine-131 tositumomab (Bexxar.RTM.) and CHOP; CVP
(cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);
ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE);
FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine,
rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin,
Adriamycin.RTM., cyclophosphamide, etoposide).
[1164] Other examples of chemotherapy treatments (including
standard or experimental chemotherapies) are described below. In
addition, treatment of certain lymphomas is reviewed in Cheson, B.
D., Leonard, J. P., "Monoclonal Antibody Therapy for B-Cell
Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008,
359(6), p. 613-626; and Wierda, W. G., "Current and Investigational
Therapies for Patients with CLL" Hematology 2006, p. 285-294.
Lymphoma incidence patterns in the United States is profiled in
Morton, L. M., et al. "Lymphoma Incidence Patterns by WHO Subtype
in the United States, 1992-2001" Blood 2006, 107(1), p.
265-276.
[1165] Examples of immunotherapeutic agents treating lymphoma or
leukemia include, but are not limited to, rituximab (such as
Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19
antibodies, anti-CD20 antibodies, anti-MN-14 antibodies,
anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74
antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab
(hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab
tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40,
WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine,
tositumomab, autologous human tumor-derived HSPPC-96, and
veltuzumab. Additional immunotherapy agents includes using cancer
vaccines based upon the genetic makeup of an individual patient's
tumor, such as lymphoma vaccine example is GTOP-99
(MyVax.RTM.).
[1166] Examples of chemotherapy agents for treating lymphoma or
leukemia include aldesleukin, alvocidib, antineoplaston AS2-1,
antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate,
aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family
protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade.RTM.),
bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103,
carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine
(Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,
Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),
cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,
dolastatin 10, Doxorubicin (Adriamycin.RTM., Adriblastine),
doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide,
Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna,
Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG),
ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide
(Revlimid.RTM., CC-5013), lymphokine-activated killer cells,
melphalan, methotrexate, mitoxantrone hydrochloride, motexafin
gadolinium, mycophenolate mofetil, nelarabine, oblimersen
(Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate,
omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated
liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin
(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine
(Selicilib, CYC202), recombinant interferon alfa, recombinant
interleukin-12, recombinant interleukin-11, recombinant flt3
ligand, recombinant human thrombopoietin, rituximab, sargramostim,
sildenafil citrate, simvastatin, sirolimus, Styryl sulphones,
tacrolimus, tanespimycin, Temsirolimus (CCl-779), Thalidomide,
therapeutic allogeneic lymphocytes, thiotepa, tipifarnib,
Velcade.RTM. (bortezomib or PS-341), Vincristine (Oncovin),
vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA),
vorinostat, and FR (fludarabine, rituximab), CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone), CVP
(cyclophosphamide, vincristine and prednisone), FCM (fludarabine,
cyclophosphamide, mitoxantrone), FCR (fludarabine,
cyclophosphamide, rituximab), hyperCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone,
methotrexate, cytarabine), ICE (iphosphamide, carboplatin and
etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone),
R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM
(rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP
(Rituximab-MCP).
[1167] In some embodiments, the cancer is melanoma. Suitable agents
for use in combination with the compounds described herein include,
without limitation, dacarbazine (DTIC), optionally, along with
other chemotherapy drugs such as carmustine (BCNU) and cisplatin;
the "Dartmouth regimen," which consists of DTIC, BCNU, cisplatin
and tamoxifen; a combination of cisplatin, vinblastine, and DTIC,
temozolomide or YERVOY.TM.. Compounds disclosed herein may also be
combined with immunotherapy drugs, including cytokines such as
interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in
the treatment of melanoma.
[1168] Compounds described here may also be used in combination
with vaccine therapy in the treatment of melanoma. Anti-melanoma
vaccines are, in some ways, similar to the anti-virus vaccines
which are used to prevent diseases caused by viruses such as polio,
measles, and mumps. Weakened melanoma cells or parts of melanoma
cells called antigens may be injected into a patient to stimulate
the body's immune system to destroy melanoma cells.
[1169] Melanomas that are confined to the arms or legs may also be
treated with a combination of agents including one or more
compounds described herein, using for example, a hyperthermic
isolated limb perfusion technique. This treatment protocol
temporarily separates the circulation of the involved limb from the
rest of the body and injects high doses of chemotherapy into the
artery feeding the limb, thus providing high doses to the area of
the tumor without exposing internal organs to these doses that
might otherwise cause severe side effects. Usually the fluid is
warmed to 102.degree. to 104.degree. F. Melphalan is the drug most
often used in this chemotherapy procedure. This can be given with
another agent called tumor necrosis factor (TNF) and optionally in
combination with a compound of formula (I).
[1170] The therapeutic treatments can be supplemented or combined
with any of the aforementioned therapies with stem cell
transplantation or treatment. One example of modified approach is
radioimmunotherapy, wherein a monoclonal antibody is combined with
a radioisotope particle, such as indium In 111, yttrium Y 90,
iodine I-131. Examples of combination therapies include, but are
not limited to, Iodine-131 tositumomab (Bexxar.RTM.), Yttrium-90
ibritumomab tiuxetan (Zevalin.RTM.), Bexxar.RTM. with CHOP.
[1171] Other therapeutic procedures useful in combination with
treatment with a compound of formula (I) include peripheral blood
stem cell transplantation, autologous hematopoietic stem cell
transplantation, autologous bone marrow transplantation, antibody
therapy, biological therapy, enzyme inhibitor therapy, total body
irradiation, infusion of stem cells, bone marrow ablation with stem
cell support, in vitro-treated peripheral blood stem cell
transplantation, umbilical cord blood transplantation, immunoenzyme
technique, pharmacological study, low-LET cobalt-60 gamma ray
therapy, bleomycin, conventional surgery, radiation therapy, and
nonmyeloablative allogeneic hematopoietic stem cell
transplantation.
[1172] In some embodiments, the application provides pharmaceutical
compositions comprising a compound of formula (I) in combination
with an MMP9 binding protein and/or one or more additional
therapeutic agent, and a pharmaceutically acceptable diluent,
carrier or excipient. In one embodiment, the pharmaceutical
compositions comprise an MMP9 binding protein, one or more
additional therapeutic agent, and a pharmaceutically acceptable
excipient, carrier or diluent. In some embodiments, the
pharmaceutical compositions comprise the compound of formula (I)
and anti-MMP9 antibody AB0045.
[1173] In one embodiment, the pharmaceutical compositions comprise
the compound of formula (I), anti-MMP9 antibody AB0045, at least
one additional therapeutic agent that is an immunomodulating agent,
and a pharmaceutically acceptable diluent, carrier or excipient. In
certain other embodiments, the pharmaceutical compositions comprise
the anti-MMP9 antibody AB0045, at least one additional therapeutic
agent that is an anti-inflammatory agent, and a pharmaceutically
acceptable diluent, carrier or excipient. In certain other
embodiments, the pharmaceutical compositions comprise compound of
formula (I), the anti-MMP9 antibody AB0045, at least one additional
therapeutic agent that is an antineoplastic agent or anti-cancer
agent, and a pharmaceutically acceptable diluent, carrier or
excipient. In one embodiment, MMP9 compounds useful for combination
treatment with a compound of formula (I) include but are not
limited to marimastat (BB-2516), cipemastat (Ro 32-3555) and those
described in WO 2012/027721 (Gilead Biologics).
[1174] In one embodiment, the one or more additional therapeutic
agent is an immune modulating agent, e.g., an immunostimulant or an
immunosuppressant. In certain other embodiments, an immune
modulating agent is an agent capable of altering the function of
immune checkpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4,
Tim3, BTLA, KIR, A2aR, CD200 and/or PD-1 pathways. In other
embodiments, the immune modulating agent is immune checkpoint
modulating agents. Exemplary immune checkpoint modulating agents
include anti-CTLA-4 antibody (e.g., ipilimumab), anti-LAG-3
antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-Tim3
antibody, anti-BTLA antibody, anti-KIR antibody, anti-A2aR
antibody, anti CD200 antibody, anti-PD-1 antibody, anti-PD-L1
antibody, anti-CD28 antibody, anti-CD80 or -CD86 antibody,
anti-B7RP1 antibody, anti-B7-H3 antibody, anti-HVEM antibody,
anti-CD137 or -CD137L antibody, anti-OX40 or -OX40L antibody,
anti-CD40 or -CD40L antibody, anti-GAL9 antibody, anti-IL-10
antibody and A2aR drug. For certain such immune pathway gene
products, the use of either antagonists or agonists of such gene
products is contemplated, as are small molecule modulators of such
gene products. In one embodiment, the immune modulatory agent is an
anti-PD-1 or anti-PD-L1 antibody. In some embodiments, immune
modulating agents include those agents capable of altering the
function of mediators in cytokine mediated signaling pathways.
[1175] In some embodiments, the one or more additional therapy or
anti-cancer agent is cancer gene therapy or cell therapy. Cancer
gene therapy and cell therapy include the insertion of a normal
gene into cancer cells to replace a mutated or altered gene;
genetic modification to silence a mutated gene; genetic approaches
to directly kill the cancer cells; including the infusion of immune
cells designed to replace most of the patient's own immune system
to enhance the immune response to cancer cells, or activate the
patient's own immune system (T cells or Natural Killer cells) to
kill cancer cells, or find and kill the cancer cells; genetic
approaches to modify cellular activity to further alter endogenous
immune responsiveness against cancer. Non limiting examples are
Algenpantucel-L (2 pancreatic cell lines), Sipuleucel-T, SGT-53
liposomal nanodelivery (scL) of gene p53; T-cell therapy, such as
CD19 CAR-T tisagenlecleucel-T (CTL019) WO2012079000, WO2017049166,
axicabtagene ciloleucel (KTE-C19) U.S. Pat. No. 7,741,465, U.S.
Pat. No. 6,319,494, JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014,
JCAR-020, JCAR-024, JCAR-023, JTCR-016, JCAR-018 WO2016090190,
JCAR-017, (WO2016196388, WO2016033570, WO2015157386), BPX-501 U.S.
Pat. No. 9,089,520, WO2016100236, AU-105, UCART-22, ACTR-087,
P-BCMA-101; activated allogeneic natural killer cells
CNDO-109-AANK, FATE-NK100, LFU-835 hematopoietic stem cells.
[1176] In one embodiment, the one or more additional therapeutic
agent is an immune checkpoint inhibitor. Tumors subvert the immune
system by taking advantage of a mechanism known as T-cell
exhaustion, which results from chronic exposure to antigens and is
characterized by the up-regulation of inhibitory receptors. These
inhibitory receptors serve as immune checkpoints in order to
prevent uncontrolled immune reactions.
[1177] PD-1 and co-inhibitory receptors such as cytotoxic
T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator
(BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3),
Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often
referred to as a checkpoint regulators. They act as molecular
determinants to influence whether cell cycle progression and other
intracellular signaling processes should proceed based upon
extracellular information.
[1178] In addition to specific antigen recognition through the
T-cell receptor (TCR), T-cell activation is regulated through a
balance of positive and negative signals provided by costimulatory
receptors. These surface proteins are typically members of either
the TNF receptor or B7 superfamilies. Agonistic antibodies directed
against activating co-stimulatory molecules and blocking antibodies
against negative co-stimulatory molecules may enhance T-cell
stimulation to promote tumor destruction.
[1179] Programmed Cell Death Protein 1, (PD-1 or CD279), a 55-kD
type 1 transmembrane protein, is a member of the CD28 family of T
cell co-stimulatory receptors that include immunoglobulin
superfamily member CD28, CTLA-4, inducible co-stimulator (ICOS),
and BTLA. PD-1 is highly expressed on activated T cells and B
cells. PD-1 expression can also be detected on memory T-cell
subsets with variable levels of expression. Two ligands specific
for PD-1 have been identified: programmed death-ligand 1 (PD-L1,
also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or
CD273). PD-L1 and PD-L2 have been shown to down-regulate T cell
activation upon binding to PD-1 in both mouse and human systems
(Okazaki et al., Int. Immunol., 2007; 19: 813-824). The interaction
of PD-1 with its ligands, PD-L1 and PD-L2, which are expressed on
antigen-presenting, cells (APCs) and dendritic cells (DCs),
transmits negative regulatory stimuli to down-modulate the
activated T cell immune response. Blockade of PD-1 suppresses this
negative signal and amplifies T cell responses. Numerous studies
indicate that the cancer microenvironment manipulates the
PD-L1/PD-1 signaling pathway and that induction of PD-L1 expression
is associated with inhibition of immune responses against cancer,
thus permitting cancer progression and metastasis. The PD-L1/PD-1
signaling pathway is a primary mechanism of cancer immune evasion
for several reasons. This pathway is involved in negative
regulation of immune responses of activated T effector cells found
in the periphery. PD-L1 is up-regulated in cancer
microenvironments, while PD-1 is also up-regulated on activated
tumor infiltrating T cells, thus possibly potentiating a vicious
cycle of inhibition. This pathway is also intricately involved in
both innate and adaptive immune regulation through bi-directional
signaling. These factors make the PD-1/PD-L1 complex a central
point through which cancer can manipulate immune responses and
promote its own progression.
[1180] The first immune-checkpoint inhibitor to be tested in a
clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), a
CTLA-4 mAb. CTLA-4 belongs to the immunoglobulin superfamily of
receptors, which also includes PD-1, BTLA, TIM-3, and V-domain
immunoglobulin suppressor of T cell activation (VISTA). Anti-CTLA-4
mAb is a powerful checkpoint inhibitor which removes "the break"
from both naive and antigen-experienced cells.
[1181] Therapy enhances the antitumor function of CD8+ T cells,
increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells,
and inhibits the suppressive function of T regulatory cells. TIM-3
has been identified as another important inhibitory receptor
expressed by exhausted CD8+ T cells. In mouse models of cancer, it
has been shown that the most dysfunctional tumor-infiltrating CD8+
T cells actually co-express PD-1 and LAG-3. LAG-3 is another
recently identified inhibitory receptor that acts to limit effector
T-cell function and augment the suppressive activity of T
regulatory cells. It has recently been revealed that PD-1 and LAG-3
are extensively co-expressed by tumor-infiltrating T cells in mice,
and that combined blockade of PD-1 and LAG-3 provokes potent
synergistic antitumor immune responses in mouse models of
cancer.
[1182] Thus in one embodiment, the present disclosure provides the
use of immune checkpoint inhibitors of formula (I) disclosed herein
in combination with one or more additional immune checkpoint
inhibitors. In one embodiment, the present disclosure provides the
use of immune checkpoint inhibitors of formula (I) disclosed herein
in combination with one or more additional immune checkpoint
inhibitors and an anti-MMP9 antibody or antigen binding fragment
thereof to treat or prevent cancer. In some embodiments, the immune
checkpoint inhibitors may be an anti-PD-1 and/or an anti-PD-L1
antibody or an anti PD-1/PD-L1 interaction inhibitor. In some
embodiments, the anti-PD-L1 antibody may be B7-H1 antibody, BMS
936559 antibody, MPDL3280A (atezolizumab) antibody, MEDI-4736
antibody, MSB0010718C antibody or combinations thereof. According
to another embodiment, the anti-PD-1 antibody may be nivolumab
antibody, pembrolizumab antibody, pidilizumab antibody or
combinations thereof.
[1183] In addition, PD-1 may also be targeted with AMP-224, which
is a PD-L2-IgG recombinant fusion protein. Additional antagonists
of inhibitory pathways in the immune response include IMP321, a
soluble LAG-3 Ig fusion protein and MHC class II agonist, which is
used to increase an immune response to tumors. Lirilumab is an
antagonist to the KIR receptor and BMS 986016 is an antagonist of
LAG3. The TIM-3-Galectin-9 pathway is another inhibitory checkpoint
pathway that is also a promising target for checkpoint inhibition.
RX518 targets and activates the glucocorticoid-induced tumor
necrosis factor receptor (GITR), a member of the TNF receptor
superfamily that is expressed on the surface of multiple types of
immune cells, including regulatory T cells, effector T cells, B
cells, natural killer (NK) cells, and activated dendritic cells.
Thus, in one embodiment, the compound(s) of formula (I) may be used
in combination with IMP321, Lirilumab and/or BMS 986016.
[1184] Anti-PD-1 antibodies that may be used in the compositions
and methods described herein include but are not limited to:
Nivolumab/MDX-1106/BMS-936558/ONO1152, a fully human lgG4 anti-PD-1
monoclonal antibody; pidilizumab (MDV9300/CT-011), a humanized IgG1
monoclonal antibody; pembrolizumab
(MK-3475/pembrolizumab/lambrolizumab), a humanized monoclonal IgG4
antibody; durvalumab (MEDI-4736) and atezolizumab. Anti-PD-L1
antibodies that may be used in compositions and methods described
herein include but are not limited to: avelumab; BMS-936559, a
fully human IgG4 antibody; atezolizumab (MPDL3280A/RG-7446), a
human monoclonal antibody; MEDI4736; MSB0010718C, and
MDX1105-01.
[1185] In one embodiment, the compound of formula (I) is
administered in combination with the anti-PD-1 antibody nivolumab,
pembrolizumab, and/or pidilizumab to a patient in need thereof. In
one embodiment, the anti-PD-L1 antibody useful for combination
treatment with a compound of formula (I) is BMS-936559,
atezolizumab, or avelumab. In one embodiment, the immune modulating
agent inhibits an immune checkpoint pathway. In another embodiment,
the immune checkpoint pathway is selected from CTLA-4, LAG-3,
B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200 and PD-1. Additional
antibodies that may be used in combination with a compound of
formula (I) in compositions and methods described herein include
the anti-PD-1 and anti-PD-L1 antibodies disclosed in U.S. Pat. Nos.
8,008,449 and 7,943,743, respectively.
[1186] In one embodiment, the one or more additional therapeutic
agent is an anti-inflammatory agent. In certain other embodiments,
the anti-inflammatory agent is a tumor necrosis factor alpha
(TNF-.alpha.) inhibitor. As used herein, the terms "TNF alpha,"
"TNF-.alpha.," and "TNF.alpha.," are interchangeable. TNF-.alpha.
is a pro-inflammatory cytokine secreted primarily by macrophages
but also by a variety of other cell types including lymphoid cells,
mast cells, endothelial cells, cardiac myocytes, adipose tissue,
fibroblasts, and neuronal tissue. TNF-.alpha. is also known as
endotoxin-induced factor in serum, cachectin, and differentiation
inducing factor. The tumor necrosis factor (TNF) family includes
TNF alpha, TNF beta, CD40 ligand (CD40L), Fas ligand (FasL),
TNF-related apoptosis inducing ligand (TRAIL), and LIGHT
(homologous to lymphotoxins, exhibits inducible expression, and
competes with HSV glycoprotein D for HVEM, a receptor expressed by
T lymphocytes), some of the most important cytokines involved in,
among other physiological processes, systematic inflammation, tumor
lysis, apoptosis and initiation of the acute phase reaction.
[1187] The above therapeutic agents when employed in combination
with a compound(s) disclosed herein, may be used, for example, in
those amounts indicated in the referenced manuals e.g., Physicians
Desk Reference or in amounts generally known to a qualified care
giver, i.e., one of ordinary skill in the art. In the methods of
the present disclosure, such other therapeutic agent(s) may be
administered prior to, simultaneously with, or following the
administration of the compound(s) of formula (I). Certain other
therapeutic agents may be combined into a single formulation or kit
when amenable to such. For example, tablet, capsule or liquid
formulations may be combined with other tablet, capsule or liquid
formulations into one fixed or combined dose formulation or
regimen. Other combinations may be given separately,
contemporaneously or otherwise.
[1188] In one embodiment, the instructions are directed to use of
the pharmaceutical composition for the treatment of cancer,
including for example, leukemia or lymphoma. In specific
embodiments, the cancer is acute lymphocytic leukemia (ALL), acute
myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL),
refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma
(MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM),
T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma
(DLBCL). In one embodiment, the cancer is T-cell acute
lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic
leukemia (B-ALL). The non-Hodgkin lymphoma encompasses the indolent
B-cell diseases that include, for example, follicular lymphoma,
lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and
marginal zone lymphoma, as well as the aggressive lymphomas that
include, for example, Burkitt lymphoma, diffuse large B-cell
lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment,
the cancer is indolent non-Hodgkin's lymphoma (iNHL)
[1189] In a particular variation, the instructions are directed to
use of the pharmaceutical composition for the treatment of an
autoimmune disease. Specific embodiments of an autoimmune disease
include asthma, rheumatoid arthritis, multiple sclerosis, and
lupus.
[1190] Combination Therapy for HBV
[1191] In certain embodiments, a method for treating or preventing
an HBV infection in a human having or at risk of having the
infection is provided, comprising administering to the human a
therapeutically effective amount of a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, in combination with a
therapeutically effective amount of one or more (e.g., one, two,
three, four, one or two, one to three, or one to four) additional
therapeutic agents. In one embodiment, a method for treating an HBV
infection in a human having or at risk of having the infection is
provided, comprising administering to the human a therapeutically
effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, in combination with a
therapeutically effective amount of one or more (e.g., one, two,
three, four, one or two, one to three, or one to four) additional
therapeutic agents.
[1192] In certain embodiments, the present disclosure provides a
method for treating an HBV infection, comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound disclosed herein or a pharmaceutically acceptable salt
thereof, in combination with a therapeutically effective amount of
one or more (e.g., one, two, three, four, one or two, one to three,
or one to four) additional therapeutic agents which are suitable
for treating an HBV infection.
[1193] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with one,
two, three, four, or more additional therapeutic agents. In certain
embodiments, a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, is combined with two additional
therapeutic agents. In other embodiments, a compound disclosed
herein, or a pharmaceutically acceptable salt thereof, is combined
with three additional therapeutic agents. In further embodiments, a
compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with four additional therapeutic agents. The
one, two, three, four, or more additional therapeutic agents can be
different therapeutic agents selected from the same class of
therapeutic agents, and/or they can be selected from different
classes of therapeutic agents.
[1194] Administration of HBV Combination Therapy
[1195] In certain embodiments, when a compound disclosed herein is
combined with one or more additional therapeutic agents as
described above, the components of the composition are administered
as a simultaneous or sequential regimen. When administered
sequentially, the combination may be administered in two or more
administrations.
[1196] Co-administration of a compound disclosed herein with one or
more additional therapeutic agents generally refers to simultaneous
or sequential administration of a compound disclosed herein and one
or more additional therapeutic agents, such that therapeutically
effective amounts of each agent are present in the body of the
patient.
[1197] Co-administration includes administration of unit dosages of
the compounds disclosed herein before or after administration of
unit dosages of one or more additional therapeutic agents. The
compound disclosed herein may be administered within seconds,
minutes, or hours of the administration of one or more additional
therapeutic agents. For example, in some embodiments, a unit dose
of a compound disclosed herein is administered first, followed
within seconds or minutes by administration of a unit dose of one
or more additional therapeutic agents. Alternatively, in other
embodiments, a unit dose of one or more additional therapeutic
agents is administered first, followed by administration of a unit
dose of a compound disclosed herein within seconds or minutes. In
some embodiments, a unit dose of a compound disclosed herein is
administered first, followed, after a period of hours (e.g., 1-12
hours), by administration of a unit dose of one or more additional
therapeutic agents. In other embodiments, a unit dose of one or
more additional therapeutic agents is administered first, followed,
after a period of hours (e.g., 1-12 hours), by administration of a
unit dose of a compound disclosed herein.
[1198] In certain embodiments, a compound disclosed herein is
combined with one or more additional therapeutic agents in a
unitary dosage form for simultaneous administration to a patient,
for example as a solid dosage form for oral administration.
[1199] In certain embodiments a compound of Formula (I) is
formulated as a tablet, which may optionally contain one or more
other compounds useful for treating HBV. In certain embodiments,
the tablet can contain another active ingredient for treating
HBV.
[1200] In certain embodiments, such tablets are suitable for once
daily dosing.
[1201] The compounds described herein may be used or combined with
one or more of a chemotherapeutic agent, an immunomodulator, an
immunotherapeutic agent, a therapeutic antibody, a therapeutic
vaccine, a bispecific antibody and "antibody-like" therapeutic
protein (such as DARTs.RTM., Duobodies.RTM., Bites.RTM.,
XmAbs.RTM., TandAbs.RTM., Fab derivatives), an antibody-drug
conjugate (ADC), gene modifiers or gene editors (such as CRISPR
Cas9, zinc finger nucleases, homing endonucleases, synthetic
nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen
receptor T-cell), and TCR-T (an engineered T cell receptor) agent
or any combination thereof.
[1202] In the above embodiments, the additional therapeutic agent
may be an anti-HBV agent. For example, the additional therapeutic
agent may be selected from the group consisting of HBV combination
drugs, other drugs for treating HBV, 3-dioxygenase (IDO)
inhibitors, antisense oligonucleotide targeting viral mRNA,
Apolipoprotein A1 modulator, arginase inhibitors, B- and
T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK)
inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160
inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds
targeting HBcAg, compounds targeting hepatitis B core antigen
(HBcAg), covalently closed circular DNA (cccDNA) inhibitors,
cyclophilin inhibitors, cytokines, cytotoxic
T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase
inhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid
X receptor agonist, gene modifiers or editors, HBsAg inhibitors,
HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA
polymerase inhibitors, HBV replication inhibitors, HBV RNAse
inhibitors, HBV vaccines, HBV viral entry inhibitors, HBx
inhibitors, Hepatitis B large envelope protein modulator, Hepatitis
B large envelope protein stimulator, Hepatitis B structural protein
modulator, hepatitis B surface antigen (HBsAg) inhibitors,
hepatitis B surface antigen (HBsAg) secretion or assembly
inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B
virus replication inhibitors, Hepatitis virus structural protein
inhibitor, HIV-1 reverse transcriptase inhibitor, Hyaluronidase
inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,
Immunoglobulin agonist, Immunoglobulin G modulator,
immunomodulators, indoleamine-2, inhibitors of ribonucleotide
reductase, Interferon agonist, Interferon alpha 1 ligand,
Interferon alpha 2 ligand, Interferon alpha 5 ligand modulator,
Interferon alpha ligand, Interferon alpha ligand modulator,
interferon alpha receptor ligands, Interferon beta ligand,
Interferon ligand, Interferon receptor modulator, Interleukin-2
ligand, ipi4 inhibitors, lysine demethylase inhibitors, histone
demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killer
cell lectin-like receptor subfamily G member 1 inhibitors,
lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptor
activators, microRNA (miRNA) gene therapy agents, modulators of
Axl, modulators of B7-H3, modulators of B7-H4, modulators of CD160,
modulators of CD161, modulators of CD27, modulators of CD47,
modulators of CD70, modulators of GITR, modulators of HEVEM,
modulators of ICOS, modulators of Mer, modulators of NKG2A,
modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,
modulators of TIGIT, modulators of Tim-4, modulators of Tyro,
Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors,
natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulator,
Nucleoprotein inhibitor, nucleoprotein modulators, PD-1 inhibitors,
PD-L1 inhibitors, PEG-Interferon Lambda, Peptidylprolyl isomerase
inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors,
recombinant scavenger receptor A (SRA) proteins, recombinant
thymosin alpha-1, Retinoic acid-inducible gene 1 stimulator,
Reverse transcriptase inhibitor, Ribonuclease inhibitor, RNA DNA
polymerase inhibitor, short interfering RNAs (siRNA), short
synthetic hairpin RNAs (sshRNAs), SLC10A1 gene inhibitor, SMAC
mimetics, Src tyrosine kinase inhibitor, stimulator of interferon
gene (STING) agonists, stimulators of NOD1, T cell surface
glycoprotein CD28 inhibitor, T-cell surface glycoprotein CD8
modulator, Thymosin agonist, Thymosin alpha 1 ligand, Tim-3
inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 gene
stimulator, toll-like receptor (TLR) modulators, Viral
ribonucleotide reductase inhibitor, zinc finger nucleases or
synthetic nucleases (TALENs), and combinations thereof.
[1203] In certain embodiments, a compound of Formula (I) is
formulated as a tablet, which may optionally contain one or more
other compounds useful for treating HBV. In certain embodiments,
the tablet can contain another active ingredient for treating HBV,
such as 3-dioxygenase (IDO) inhibitors, Apolipoprotein A1
modulator, arginase inhibitors, B- and T-lymphocyte attenuator
inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2
chemokine antagonist, CD137 inhibitors, CD160 inhibitors, CD305
inhibitors, CD4 agonist and modulator, compounds targeting HBcAg,
compounds targeting hepatitis B core antigen (HBcAg), core protein
allosteric modulators, covalently closed circular DNA (cccDNA)
inhibitors, cyclophilin inhibitors, cytotoxic
T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase
inhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid
X receptor agonist, HBsAg inhibitors, HBsAg secretion or assembly
inhibitors, HBV DNA polymerase inhibitors, HBV replication
inhibitors, HBV RNAse inhibitors, HBV viral entry inhibitors, HBx
inhibitors, Hepatitis B large envelope protein modulator, Hepatitis
B large envelope protein stimulator, Hepatitis B structural protein
modulator, hepatitis B surface antigen (HBsAg) inhibitors,
hepatitis B surface antigen (HBsAg) secretion or assembly
inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B
virus replication inhibitors, Hepatitis virus structural protein
inhibitor, HIV-1 reverse transcriptase inhibitor, Hyaluronidase
inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,
immunomodulators, indoleamine-2 inhibitors, inhibitors of
ribonucleotide reductase, Interleukin-2 ligand, ipi4 inhibitors,
lysine demethylase inhibitors, histone demethylase inhibitors, KDM1
inhibitors, KDM5 inhibitors, killer cell lectin-like receptor
subfamily G member 1 inhibitors, lymphocyte-activation gene 3
inhibitors, lymphotoxin beta receptor activators, modulators of
Axl, modulators of B7-H3, modulators of B7-H4, modulators of CD160,
modulators of CD161, modulators of CD27, modulators of CD47,
modulators of CD70, modulators of GITR, modulators of HEVEM,
modulators of ICOS, modulators of Mer, modulators of NKG2A,
modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,
modulators of TIGIT, modulators of Tim-4, modulators of Tyro,
Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors,
natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulator,
Nucleoprotein inhibitor, nucleoprotein modulators, PD-1 inhibitors,
PD-L1 inhibitors, Peptidylprolyl isomerase inhibitor,
phosphatidylinositol-3 kinase (PI3K) inhibitors, Retinoic
acid-inducible gene 1 stimulator, Reverse transcriptase inhibitor,
Ribonuclease inhibitor, RNA DNA polymerase inhibitor, SLC10A1 gene
inhibitor, SMAC mimetics, Src tyrosine kinase inhibitor, stimulator
of interferon gene (STING) agonists, stimulators of NOD1, T cell
surface glycoprotein CD28 inhibitor, T-cell surface glycoprotein
CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand, Tim-3
inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 gene
stimulator, toll-like receptor (TLR) modulators, Viral
ribonucleotide reductase inhibitor, and combinations thereof.
[1204] In certain embodiments, a compound of the present
disclosure, or a pharmaceutically acceptable salt thereof, is
combined with one, two, three, four or more additional therapeutic
agents selected from HBV combination drugs, HBV vaccines, HBV DNA
polymerase inhibitors, immunomodulators toll-like receptor (TLR)
modulators, interferon alpha receptor ligands, hyaluronidase
inhibitors, hepatitis b surface antigen (HBsAg) inhibitors,
cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors,
cyclophilin inhibitors, HBV viral entry inhibitors, antisense
oligonucleotide targeting viral mRNA, short interfering RNAs
(siRNA) and ddRNAi endonuclease modulators, ribonucelotide
reductase inhibitors, HBV E antigen inhibitors, covalently closed
circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists,
HBV antibodies, CCR2 chemokine antagonists, thymosin agonists,
cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1
stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K)
inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors,
PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1,
bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV
replication inhibitors, arginase inhibitors, and other HBV
drugs.
[1205] HBV Combination Drugs
[1206] Examples of combination drugs for the treatment of HBV
include TRUVADA.RTM. (tenofovir disoproxil fumarate and
emtricitabine); ABX-203, lamivudine, and PEG-IFN-alpha; ABX-203
adefovir, and PEG-IFNalpha; and INO-1800 (INO-9112 and RG7944).
[1207] Other HBV Drugs
[1208] Examples of other drugs for the treatment of HBV include
alpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine
nucleosides, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin
A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide,
birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide,
mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon,
WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3,
BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2,
HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen,
DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210,
OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613,
TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and
ZH-2N, and the compounds disclosed in US20150210682, (Roche), US
2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A
(Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A
(Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A
(Roche), WO16102438A1 (Roche), WO2016012470A1 (Roche),
US2016220586A (Roche), and US2015031687A (Roche).
[1209] HBV Vaccines
[1210] HBV vaccines include both prophylactic and therapeutic
vaccines. Examples of HBV prophylactic vaccines include Vaxelis,
Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B,
D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine,
Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay,
hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07,
GSK-223192A, ENGERIX B.RTM., recombinant hepatitis B vaccine
(intramuscular, Kangtai Biological Products), recombinant hepatitis
B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan
Biological Engineering), recombinant hepatitis B surface antigen
vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B,
HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib,
Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax,
DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB,
Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,
SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,
Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG
vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and
DTaP-rHB-Hib vaccine.
[1211] Examples of HBV therapeutic vaccines include HBsAG-HBIG
complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous),
ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine
(epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC,
Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB,
VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax,
im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v,
RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV
infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,
ChronVac-B, TG-1050, and Lm HBV.
[1212] HBV DNA Polymerase Inhibitors
[1213] Examples of HBV DNA polymerase inhibitors include adefovir
(HEPSERA.RTM.), emtricitabine (EMTRIVA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate,
tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir
(BARACLUDE.RTM.), entecavir maleate, telbivudine (TYZEKA.RTM.),
pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV.RTM.),
phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA,
AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate,
tenofovir disoproxil orotate, and HS-10234.
[1214] Immunomodulators
[1215] Examples of immunomodulators include rintatolimod, imidol
hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine),
proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester
derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12,
INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,
BMS-936559, RO-7011785, RO-6871765, AIC-649, and IR-103.
[1216] Toll-Like Receptor (TLR) Modulators
[1217] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4,
TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.
Examples of TLR3 modulators include rintatolimod, poly-ICLC,
RIBOXXON.RTM., Apoxxim, RIBOXXIM.RTM., IPH-33, MCT-465, MCT-475,
GS-9688 and ND-1.1.
[1218] Examples of TLR7 modulators include GS-9620, GSK-2245035,
imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465,
MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202,
RG-7863, RG-7795, RG-7854, and the compounds disclosed in
US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences),
and US20090047249 (Gilead Sciences).
[1219] Examples of TLR8 modulators include motolimod, resiquimod,
3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the
compounds disclosed in US20140045849 (Janssen), US20140073642
(Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen),
WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813
(Janssen), US20080234251 (Array Biopharma), US20080306050 (Array
Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx
Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx
Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx
Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira
Therapeutics), and US20130251673 (Novira Therapeutics).
[1220] Examples of TLR9 modulators include BB-001, BB-006, CYT-003,
IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200,
agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod
(MGN-1703), litenimod, and CYT-003-QbG10.
[1221] Interferon Alpha Receptor Ligands
[1222] Examples of interferon alpha receptor ligands include
interferon alpha-2b (INTRON A.RTM.), pegylated interferon alpha-2a
(PEGASYS.RTM.), PEGylated interferon alpha-1b, interferon alpha 1b
(HAPGEN.RTM.), Veldona, Infradure, Roferon-A, YPEG-interferon
alfa-2a (YPEG-rhlFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron
(interferon gamma), rSIFN-co (recombinant super compound
interferon), Ypeginterferon alfa-2b (YPEG-rhlFNalpha-2b), MOR-22,
peginterferon alfa-2b (PEG-INTRON.RTM.), Bioferon, Novaferon,
Inmutag (Inferon), MULTIFERON.RTM., interferon alfa-n1
(HUMOFERON.RTM.), interferon beta-1a (AVONEX.RTM.), Shaferon,
interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b
(BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG,
BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion,
Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN,
Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano,
Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon
alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b
(Amega), interferon alfa-2b (Virchow), ropeginterferon alfa-2b,
rHSA-IFN alpha-2a (recombinant human serum albumin intereferon
alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human
interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b (Amega),
peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron,
interferon alfa-2b (Changchun Institute of Biological Products),
Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN,
SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, SFR-9216, and
Interapo (Interapa).
[1223] Hyaluronidase Inhibitors
[1224] Examples of hyaluronidase inhibitors include astodrimer.
[1225] Hepatitis B Surface Antigen (HBsAg) Inhibitors
[1226] Examples of HBsAg inhibitors include HBF-0259, PBHBV-001,
PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139,
REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053,
REP-2031 and REP-006, and REP-9AC'.
[1227] Examples of HBsAg secretion inhibitors include BM601.
[1228] Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4)
Inhibitors
[1229] Examples of Cytotoxic T-lymphocyte-associated protein 4
(ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab,
belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and
JHL-1155.
[1230] Cyclophilin Inhibitors
[1231] Examples of cyclophilin inhibitors include CPI-431-32,
EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and
the compounds disclosed in U.S. Pat. No. 8,513,184 (Gilead
Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead
Sciences), and US20130344029 (Gilead Sciences).
[1232] HBV Viral Entry Inhibitors
[1233] Examples of HBV viral entry inhibitors include Myrcludex
B.
[1234] Antisense Oligonucleotide Targeting Viral mRNA
[1235] Examples of antisense oligonucleotide targeting viral mRNA
include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404,
RG-6004.
[1236] Short Interfering RNAs (siRNA) and ddRNAi.
[1237] Examples of siRNA include TKM-HBV (TKM-HepB), ALN--HBV,
SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.
[1238] Examples of DNA-directed RNA interference (ddRNAi) include
BB-HB-331.
[1239] Endonuclease Modulators
[1240] Examples of endonuclease modulators include PGN-514.
[1241] Ribonucelotide Reductase Inhibitors
[1242] Examples of inhibitors of ribonucleotide reductase include
Trimidox.
[1243] HBVE Antigen Inhibitors
[1244] Examples of HBV E antigen inhibitors include wogonin.
[1245] Covalently Closed Circular DNA (cccDNA) Inhibitors
[1246] Examples of cccDNA inhibitors include BSBI-25, and
CHR-101.
[1247] Farnesoid X Receptor Agonist
[1248] Example of farnesoid x receptor agonist such as EYP-001.
[1249] HBV Antibodies
[1250] Examples of HBV antibodies targeting the surface antigens of
the hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV
Hepabulin SN, and fully human monoclonal antibody therapy
(hepatitis B virus infection, Humabs BioMed). Examples of HBV
antibodies, including monoclonal antibodies and polyclonal
antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big
(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP,
HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin
(intravenous, pH4, HBV infection, Shanghai RAAS Blood Products),
and Fovepta (BT-088). Fully human monoclonal antibodies such as
HBC-34.
[1251] CCR2 Chemokine Antagonists
[1252] Examples of CCR2 chemokine antagonists include
propagermanium.
[1253] Thymosin Agonists
[1254] Examples of thymosin agonists include Thymalfasin,
recombinant thymosin alpha 1 (GeneScience).
[1255] Cytokines
[1256] Examples of cytokines include recombinant IL-7, CYT-107,
interleukin-2 (IL-2, Immunex), recombinant human interleukin-2
(Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin.
[1257] Nucleoprotein Modulators
[1258] Nucleoprotein modulators may be either HBV core or capsid
protein inhibitors. Examples of nucleoprotein modulators include
AB-423, AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109,
morphothiadine mesilate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158 and
DVR-23.
[1259] Examples of capsid inhibitors include the compounds
disclosed in US20140275167 (Novira Therapeutics), US20130251673
(Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche),
US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176
(Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen),
WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281
(Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen),
WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355
(Novira), US20140178337 (Novira), US20150315159 (Novira),
US20150197533 (Novira), US20150274652 (Novira), US20150259324,
(Novira), US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira),
WO2014184350 (Janssen), WO2013144129 (Roche).
[1260] Retinoic Acid-Inducible Gene 1 Stimulators
[1261] Examples of stimulators of retinoic acid-inducible gene 1
include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537,
ORI-9020, ORI-9198, and ORI-7170, RGT-100.
[1262] NOD2 Stimulators
[1263] Examples of stimulators of NOD2 include SB-9200.
[1264] Phosphatidylinositol 3-Kinase (PI3K) Inhibitors
[1265] Examples of PI3K inhibitors include idelalisib, ACP-319,
AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib,
neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202,
alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765,
gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, perifosine,
RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458,
CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, puquitinib
mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117,
SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117,
HMPL-689, tenalisib, voxtalisib, and CLR-1401.
[1266] Indoleamine-2,3-dioxygenase (IDO) Pathway Inhibitors
[1267] Examples of IDO inhibitors include epacadostat (INCB24360),
resminostat (4SC-201), indoximod, F-001287, SN-35837, NLG-919,
GDC-0919, GBV-1028, GBV-1012, NKTR-218, and the compounds disclosed
in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.),
WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus
Biosciences, Inc.).
[1268] PD-1 Inhibitors
[1269] Examples of PD-1 inhibitors include nivolumab,
pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001,
PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400.
[1270] PD-L1 Inhibitors
[1271] Examples of PD-L1 inhibitors include atezolizumab, avelumab,
AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033,
MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, and
BMS-936559.
[1272] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with
compounds such as those disclosed in WO2018026971, US20180044329,
US20180044305, US20180044304, US20180044303, US20180044350,
US20180057455, US20180057486, US20180045142, WO20180044963,
WO2018044783, WO2018009505, WO20180044329, WO2017066227,
WO2017087777, US20170145025, WO2017079669, WO2017070089,
US2017107216, WO2017222976, US20170262253, WO2017205464,
US20170320875, WO2017192961, WO2017112730, US20170174679,
WO2017106634, WO2017202744, WO2017202275, WO2017202273,
WO2017202274, WO2017202276, WO2017180769, WO2017118762,
WO2016041511, WO2016039749, WO2016142835, WO2016142852,
WO2016142886, WO2016142894, and WO2016142833.
[1273] Recombinant Thymosin Alpha-1
[1274] Examples of recombinant thymosin alpha-1 include NL-004 and
PEGylated thymosin alpha-1.
[1275] Bruton's Tyrosine Kinase (BTK) Inhibitors
[1276] Examples of BTK inhibitors include ABBV-105, acalabrutinib
(ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853,
PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447,
RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158,
TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the
compounds disclosed in US20140330015 (Ono Pharmaceutical),
US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono
Pharmaceutical).
[1277] KDM Inhibitors
[1278] Examples of KDM5 inhibitors include the compounds disclosed
in WO2016057924 (Genentech/Constellation Pharmaceuticals),
US20140275092 (Genentech/Constellation Pharmaceuticals),
US20140371195 (Epitherapeutics) and US20140371214
(Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469
(Quanticel), US20140171432, US20140213591 (Quanticel),
US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708
(Quanticel).
[1279] Examples of KDM1 inhibitors include the compounds disclosed
in U.S. Pat. No. 9,186,337B2 (Oryzon Genomics), and GSK-2879552,
RG-6016, ORY-2001.
[1280] HBV Replication Inhibitors
[1281] Examples of hepatitis B virus replication inhibitors include
isothiafludine, IQP-HBV, RM-5038, and Xingantie.
[1282] Arginase Inhibitors
[1283] Examples of Arginase inhibitors include CB-1158, C-201, and
resminostat.
[1284] Gene Therapy and Cell Therapy
[1285] Gene Therapy and Cell Therapy including the genetic
modification to silence a gene; genetic approaches to directly kill
the infected cells; the infusion of immune cells designed to
replace most of the patient's own immune system to enhance the
immune response to infected cells, or activate the patient's own
immune system to kill infected cells, or find and kill the infected
cells; genetic approaches to modify cellular activity to further
alter endogenous immune responsiveness against the infection.
[1286] Gene Editors
[1287] The genome editing system is selected from the group
consisting of: a CRISPR/Cas9 system, a zinc finger nuclease system,
a TALEN system, a homing endonucleases system, and a meganuclease
system; e.g., cccDNA elimination via targeted cleavage, and
altering one or more of the hepatitis B virus (HBV) viral genes.
Altering (e.g., knocking out and/or knocking down) the PreC, C, X,
PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminating
PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2)
interfering with Precore, Core, X protein, Long surface protein,
middle surface protein, S protein (also known as HBs antigen and
HBsAg), polymerase protein, and/or Hepatitis B spliced protein
function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and/or HBSP or (3)
reducing or eliminating the intracellular, serum and/or
intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol,
and/or HBSP proteins. Knockdown of one or more of the PreC, C, X,
PreSI, PreS2, S, P and/or SP gene(s) is performed by targeting the
gene(s) within HBV cccDNA and/or integrated HBV DNA.
[1288] CAR-T Cell Therapy
[1289] A population of immune effector cells engineered to express
a chimeric antigen receptor (CAR), wherein the CAR comprises an HBV
antigen-binding domain. The immune effector cell is a T cell or an
NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T
cell, or a combination thereof. Cells can be autologous or
allogeneic.
[1290] TCR-T Cell Therapy
[1291] T cells expressing HBV-specific T cell receptors. TCR-T
cells are engineered to target HBV derived peptides presented on
the surface of virus-infected cells.
[1292] T-Cells expressing HBV surface antigen (HBsAg)-specific
TCR.
[1293] TCR-T therapy directed to treatment of HBV, such as
LTCR-H2-1
[1294] HBV Combination Therapy
[1295] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with one,
two, three, or four additional therapeutic agent selected from the
group consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.). In a particular
embodiment, a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, is combined with a first additional
therapeutic agent selected from the group consisting of adefovir
(HEPSERA.RTM.), tenofovir disoproxil fumarate (VIREAD.RTM.),
tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir
alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir
(BARACLUDE.RTM.), telbivudine (TYZEKA.RTM.), or lamivudine
(EPIVIR-HBV.RTM.). In one embodiment, pharmaceutical compositions
comprising a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, in combination with one or more (e.g.,
one, two, three, four, one or two, or one to three, or one to four)
additional therapeutic agents and a pharmaceutically acceptable
carrier, diluent, or excipient are provided.
[1296] HBV DNA Polymerase Inhibitor Combination Therapy
[1297] In a specific embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with an HBV
DNA polymerase inhibitor. In another specific embodiment, a
compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with an HBV DNA polymerase inhibitor and at
least one additional therapeutic agent selected from the group
consisting of: immunomodulators, TLR modulators, interferon alpha
receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg
inhibitors, HBsAg secretion or assembly inhibitors, compounds
targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral
entry inhibitors, NTCP inhibitors, antisense oligonucleotide
targeting viral mRNA, siRNA, miRNA gene therapy agents,
endonuclease modulators, inhibitors of ribonucleotide reductase,
hepatitis B virus E antigen inhibitors, recombinant SRA proteins,
src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNAs,
HBV antibodies including HBV antibodies targeting the surface
antigens of the hepatitis B virus and bispecific antibodies and
"antibody-like" therapeutic proteins (such as DARTs.RTM.,
DUOBODIES.RTM., BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives, or TCR-like antibodies), CCR2 chemokine antagonists,
thymosin agonists, cytokines, nucleoprotein modulators (HBV core or
capsid protein modulators), stimulators of retinoic acid-inducible
gene 1, stimulators of RIG-I like receptors, stimulators of NOD2,
stimulators of NOD1, Arginase inhibitors, STING agonists, PI3K
inhibitors, lymphotoxin beta receptor activators, natural killer
cell receptor 2B4 inhibitors, Lymphocyte-activation gene 3
inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated
protein 4 (ipi4) inhibitors, CD137 inhibitors, Killer cell
lectin-like receptor subfamily G member 1 inhibitors, TIM-3
inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305
inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon
Lambda, recombinant thymosin alpha-1, BTK inhibitors, modulators of
TIGIT, modulators of CD47, modulators of SIRPalpha, modulators of
ICOS, modulators of CD27, modulators of CD70, modulators of OX40,
epigenetic modifiers, modulators of NKG2D, modulators of Tim-4,
modulators of B7-H4, modulators of B7-H3, modulators of NKG2A,
modulators of GITR, modulators of CD160, modulators of HEVEM,
modulators of CD161, modulators of Axl, modulators of Mer,
modulators of Tyro, gene modifiers or editors such as CRISPR
(including CRISPR Cas9), zinc finger nucleases or synthetic
nucleases (TALENs), IAPs inhibitors, SMAC mimetics, KDM5
inhibitors, IDO inhibitors, and hepatitis B virus replication
inhibitors.
[1298] In another specific embodiment, a compound disclosed herein,
or a pharmaceutically acceptable salt thereof, is combined with an
HBV DNA polymerase inhibitor, one or two additional therapeutic
agents selected from the group consisting of immunomodulators, TLR
modulators, HBsAg inhibitors, HBsAg secretion or assembly
inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV
antibodies targeting the surface antigens of the hepatitis B virus
and bispecific antibodies and "antibody-like" therapeutic proteins
(such as DARTs.RTM., DUOBODIES.RTM., BITES.RTM., XmAbs.RTM.,
TandAbs.RTM., Fab derivatives, or TCR-like antibodies), cyclophilin
inhibitors, stimulators of retinoic acid-inducible gene 1,
stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1
inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors,
and stimulators of NOD2, and one or two additional therapeutic
agents selected from the group consisting of HBV viral entry
inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV
antibodies targeting the surface antigens of the hepatitis B virus,
siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and
nucleoprotein modulators (HBV core or capsid protein
modulators).
[1299] In another specific embodiment, a compound disclosed herein,
or a pharmaceutically acceptable salt thereof, is combined with an
HBV DNA polymerase inhibitor and at least a second additional
therapeutic agent selected from the group consisting of:
immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic
vaccines, HBV antibodies including HBV antibodies targeting the
surface antigens of the hepatitis B virus and bispecific antibodies
and "antibody-like" therapeutic proteins (such as DARTs.RTM.,
DUOBODIES.RTM., BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives, or TCR-like antibodies), cyclophilin inhibitors,
stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I
like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginase
inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of
NOD2.
[1300] In another specific embodiment, a compound disclosed herein,
or a pharmaceutically acceptable salt thereof, is combined with an
HBV DNA polymerase inhibitor and at least a second additional
therapeutic agent selected from the group consisting of: HBV viral
entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA
inhibitors, HBV antibodies targeting the surface antigens of the
hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5
inhibitors, and nucleoprotein modulators (HBV core or capsid
protein inhibitors).
[1301] HBV Drug Combination Therapy
[1302] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.), and at least a
second additional therapeutic agent selected from the group
consisting of immunomodulators, TLR modulators, interferon alpha
receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg
inhibitors, HBsAg secretion or assembly inhibitors, compounds
targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral
entry inhibitors, NTCP inhibitors, antisense oligonucleotide
targeting viral mRNA, siRNA, miRNA gene therapy agents,
endonuclease modulators, inhibitors of ribonucleotide reductase,
hepatitis B virus E antigen inhibitors, recombinant SRA proteins,
src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNAs,
HBV antibodies including HBV antibodies targeting the surface
antigens of the hepatitis B virus and bispecific antibodies and
"antibody-like" therapeutic proteins (such as DARTs.RTM.,
DUOBODIES.RTM., BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives, and TCR-like antibodies), CCR2 chemokine antagonists,
thymosin agonists, cytokines, nucleoprotein modulators (HBV core or
capsid protein modulators), stimulators of retinoic acid-inducible
gene 1, stimulators of RIG-I like receptors, stimulators of NOD2,
stimulators of NOD1, IDO inhibitors, recombinant thymosin alpha-1,
Arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin
beta receptor activators, natural killer cell receptor 2B4
inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160
inhibitors, ipi4 inhibitors, CD137 inhibitors, killer cell
lectin-like receptor subfamily G member 1 inhibitors, TIM-3
inhibitors, B- and T-lymphocyte attenuator inhibitors, epigenetic
modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors,
PEG-Interferon Lambd, BTK inhibitors, modulators of TIGIT,
modulators of CD47, modulators of SIRPalpha, modulators of ICOS,
modulators of CD27, modulators of CD70, modulators of OX40,
modulators of NKG2D, modulators of Tim-4, modulators of B7-H4,
modulators of B7-H3, modulators of NKG2A, modulators of GITR,
modulators of CD160, modulators of HEVEM, modulators of CD161,
modulators of Axl, modulators of Mer, modulators of Tyro, gene
modifiers or editors such as CRISPR (including CRISPR Cas9), zinc
finger nucleases or synthetic nucleases (TALENs), IAPs inhibitors,
SMAC mimetics, KDM5 inhibitors, and hepatitis B virus replication
inhibitors.
[1303] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine (TYZEKA.RTM.)
or lamivudine (EPIVIR-HBV.RTM.) and at least a second additional
therapeutic agent selected from the group consisting of
peginterferon alfa-2b (PEG-INTRON.RTM.), MULTIFERON.RTM.,
interferon alpha 1b (HAPGEN.RTM.), interferon alpha-2b (INTRON
A.RTM.), pegylated interferon alpha-2a (PEGASYS.RTM.), interferon
alfa-n1 (HUMOFERON.RTM.), ribavirin, interferon beta-1a
(AVONEX.RTM.), Bioferon, Ingaron, Inmutag (Inferon), Algeron,
Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b
(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,
interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,
BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon,
PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma),
alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep,
interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon,
interferon alfa-2b (Amega), interferon alfa-2b (Virchow),
peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon,
Urifron, interferon alfa-2b (Changchun Institute of Biological
Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2,
Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),
Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN,
Fukangtai, Alloferon, and celmoleukin.
[1304] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.), and at least a
second additional therapeutic agent selected from the group
consisting of immunomodulators, TLR modulators, HBsAg inhibitors,
HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines,
HBV antibodies including HBV antibodies targeting the surface
antigens of the hepatitis B virus and bispecific antibodies and
"antibody-like" therapeutic proteins (such as DARTs.RTM.,
DUOBODIES.RTM., BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives, or TCR-like antibodies), cyclophilin inhibitors,
stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I
like receptors, Arginase inhibitors, PI3K inhibitors, PD-1
inhibitors, PD-L1 inhibitors, IDO inhibitors, and stimulators of
NOD2.
[1305] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of: adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.), and at least a
second additional therapeutic agent selected from the group
consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx
inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface
antigens of the hepatitis B virus, siRNA, miRNA gene therapy
agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV
core or capsid protein modulators).
[1306] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.); one, two, or three
additional therapeutic agents selected from the group consisting of
immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion
or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies
including HBV antibodies targeting the surface antigens of the
hepatitis B virus and bispecific antibodies and "antibody-like"
therapeutic proteins (such as DARTs.RTM., DUOBODIES.RTM.,
BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab derivatives, or TCR-like
antibodies), cyclophilin inhibitors, stimulators of retinoic
acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1
inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors,
IDO inhibitors, and stimulators of NOD2; and one or two additional
therapeutic agents selected from the group consisting of HBV viral
entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA
inhibitors, HBV antibodies targeting the surface antigens of the
hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5
inhibitors, and nucleoprotein modulators (HBV core or capsid
protein modulators).
[1307] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.); one or two
additional therapeutic agents selected from the group consisting of
immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion
or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies
including HBV antibodies targeting the surface antigens of the
hepatitis B virus and bispecific antibodies and "antibody-like"
therapeutic proteins (such as DARTs.RTM., DUOBODIES.RTM.,
BITES.RTM., XmAbs.RTM., TandAbs.RTM., Fab derivatives, or TCR-like
antibodies), cyclophilin inhibitors, stimulators of retinoic
acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1
inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors,
IDO inhibitors, and stimulators of NOD2; and one or two additional
therapeutic agents selected from the group consisting of HBV viral
entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA
inhibitors, HBV antibodies targeting the surface antigens of the
hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5
inhibitors, and nucleoprotein modulators (HBV core or capsid
protein modulators).
[1308] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with a
first additional therapeutic agent selected from the group
consisting of adefovir (HEPSERA.RTM.), tenofovir disoproxil
fumarate (VIREAD.RTM.), tenofovir alafenamide, tenofovir, tenofovir
disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, entecavir (BARACLUDE.RTM.), telbivudine
(TYZEKA.RTM.), or lamivudine (EPIVIR-HBV.RTM.); and one, two,
three, or four additional therapeutic agents selected from the
group consisting of immunomodulators, TLR7 modulators, TLR8
modulators, HBsAg inhibitors, HBsAg secretion or assembly
inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV
antibodies targeting the surface antigens of the hepatitis B virus
and bispecific antibodies and "antibody-like" therapeutic proteins
(such as DARTs.RTM., DUOBODIES.RTM., BITES.RTM., XmAbs.RTM.,
TandAbs.RTM., Fab derivatives, or TCR-like antibodies), cyclophilin
inhibitors, stimulators of retinoic acid-inducible gene 1,
stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1
inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors,
stimulators of NOD2 HBV viral entry inhibitors, NTCP inhibitors,
HBx inhibitors, cccDNA inhibitors, siRNA, miRNA gene therapy
agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV
core or capsid protein modulators).
[1309] In a particular embodiment, a compound disclosed herein, or
a pharmaceutically acceptable salt thereof, is combined with
compounds such as those disclosed in U.S. Publication No.
2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248
(Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead
Sciences), U.S. Pat. No. 8,722,054 (Gilead Sciences), U.S.
Publication No. 2014/0045849 (Janssen), U.S. Publication No.
2014/0073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221
(Janssen), WO2014/128189 (Janssen), U.S. Publication No.
2014/0350031 (Janssen), WO2014/023813 (Janssen), U.S. Publication
No. 2008/0234251 (Array Biopharma), U.S. Publication No.
2008/0306050 (Array Biopharma), U.S. Publication No. 2010/0029585
(Ventirx Pharma), U.S. Publication No. 2011/0092485 (Ventirx
Pharma), US2011/0118235 (Ventirx Pharma), U.S. Publication No.
2012/0082658 (Ventirx Pharma), U.S. Publication No. 2012/0219615
(Ventirx Pharma), U.S. Publication No. 2014/0066432 (Ventirx
Pharma), U.S. Publication No. 2014/0088085 (Ventirx Pharma), U.S.
Publication No. 2014/0275167 (Novira Therapeutics), U.S.
Publication No. 2013/0251673 (Novira Therapeutics), U.S. Pat. No.
8,513,184 (Gilead Sciences), U.S. Publication No. 2014/0030221
(Gilead Sciences), U.S. Publication No. 2013/0344030 (Gilead
Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences),
US20140275167 (Novira Therapeutics), US20130251673 (Novira
Therapeutics), U.S. Publication No. 2014/0343032 (Roche),
WO2014037480 (Roche), U.S. Publication No. 2013/0267517 (Roche),
WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170
(Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),
WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365
(Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen),
WO2013096744 (Novira), US20150225355 (Novira), US20140178337
(Novira), US20150315159 (Novira), US20150197533 (Novira),
US20150274652 (Novira), US20150259324, (Novira), US20150132258
(Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350 (Janssen),
WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus
Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.),
WO2015188085 (Flexus Biosciences, Inc.), U.S. Publication No.
2014/0330015 (Ono Pharmaceutical), U.S. Publication No.
2013/0079327 (Ono Pharmaceutical), U.S. Publication No.
2013/0217880 (Ono pharmaceutical), WO2016057924
(Genentech/Constellation Pharmaceuticals), US20140275092
(Genentech/Constellation Pharmaceuticals), US20140371195
(Epitherapeutics) and US20140371214 (Epitherapeutics),
US20160102096 (Epitherapeutics), US20140194469 (Quanticel),
US20140171432, US20140213591 (Quanticel), US20160039808
(Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel),
U.S. Pat. No. 9,186,337B2 (Oryzon Genomics), and other drugs for
treating HBV, and combinations thereof.
[1310] In certain embodiments, a compound as disclosed herein
(e.g., any compound of Formula I) may be combined with one or more
(e.g., one, two, three, four, one or two, one to three, or one to
four) additional therapeutic agents in any dosage amount of the
compound of Formula (I) (e.g., from 10 mg to 1000 mg of
compound).
[1311] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 5-30 mg
tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,
or tenofovir alafenamide. In certain embodiments, a compound
disclosed herein, or a pharmaceutically acceptable salt thereof, is
combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30
mg tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, or tenofovir alafenamide. In certain embodiments, a
compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with 10 mg tenofovir alafenamide fumarate,
tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In
certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 25 mg
tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,
or tenofovir alafenamide. A compound as disclosed herein (e.g., a
compound of Formula I) may be combined with the agents provided
herein in any dosage amount of the compound (e.g., from 50 mg to
500 mg of compound) the same as if each combination of dosages were
specifically and individually listed.
[1312] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 100-400
mg tenofovir disoproxil fumarate, tenofovir disoproxil
hemifumarate, or tenofovir disoproxil. In certain embodiments, a
compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with 100 mg to 150 mg; 100 mg to 200 mg; 100
mg to 250 mg; 100 mg to 300 mg; 100 mg to 350 mg; 150 mg to 200 mg;
150 mg to 250 mg; 150 mg to 300 mg; 150 mg to 350 mg; 150 mg to 400
mg; 200 mg to 250 mg; 200 mg to 300 mg; 200 mg to 350 mg; 200 mg to
400 mg; 250 mg to 350 mg; 250 mg to 400 mg; 350 mg to 400 or 300 mg
to 400 mg tenofovir disoproxil fumarate, tenofovir disoproxil
hemifumarate, or tenofovir disoproxil. In certain embodiments, a
compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with 300 mg tenofovir disoproxil fumarate,
tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In
certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 250 mg
tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate,
or tenofovir disoproxil. In certain embodiments, a compound
disclosed herein, or a pharmaceutically acceptable salt thereof, is
combined with 150 mg tenofovir disoproxil fumarate, tenofovir
disoproxil hemifumarate, or tenofovir disoproxil. A compound as
disclosed herein (e.g., a compound of Formula I) may be combined
with the agents provided herein in any dosage amount of the
compound (e.g., from 50 mg to 500 mg of compound) the same as if
each combination of dosages were specifically and individually
listed.
[1313] In one embodiment, kits comprising a compound disclosed
herein, or a pharmaceutically acceptable salt thereof, in
combination with one or more (e.g., one, two, three, four, one or
two, or one to three, or one to four) additional therapeutic agents
are provided.
[1314] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification are incorporated herein by reference, in their
entirety to the extent not inconsistent with the present
description.
[1315] Any pharmaceutical composition provided in the present
disclosure may be used in the kits, the same as if each and every
composition were specifically and individually listed for use in a
kit.
[1316] Articles of Manufacture
[1317] Articles of manufacture comprising a container in which a
compound of formula (I) or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable carrier are
contained are provided. The article of manufacture may be a bottle,
vial, ampoule, single-use disposable applicator, or the like,
containing the pharmaceutical composition provided in the present
disclosure. The container may be formed from a variety of
materials, such as glass or plastic and in one aspect also contains
a label on, or associated with, the container which indicates
directions for use in the treatment of cancer or inflammatory
conditions.
[1318] It should be understood that the active ingredient may be
packaged in any material capable of providing reasonable chemical
and physical stability, such as an aluminum foil bag.
[1319] Unit dosage forms of the pharmaceutical composition
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable carrier are also provided.
[1320] Any pharmaceutical composition provided in the present
disclosure may be used in the articles of manufacture, the same as
if each and every composition were specifically and individually
listed for use an article of manufacture.
[1321] Also provided is a kit that includes a compound of formula
(I) or a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers or tautomer thereof; a label, and/or instructions for
use of the compound in the treatment of a disease or condition
mediated by PD-1, PD-L1 activity or PD-1/PD-L1 interaction.
[1322] Also provided is an article of manufacture which includes a
compound of formula (I) or a pharmaceutically acceptable salt,
prodrug, or solvate thereof; and a container. In one embodiment,
the container may be a vial, jar, ampoule, preloaded syringe, or an
intravenous bag.
[1323] Formulations of compound(s) of the present disclosure i.e.,
a compound of formula (I) or the combination of a compound of
formula (I) and an additional agent may be accomplished by admixing
said compounds or salt thereof with one or more non-toxic,
pharmaceutically acceptable vehicles, carriers and/or diluents
and/or adjuvants collectively referred to herein as excipients or
carrier materials. The compounds of the disclosure may be
administered by any suitable route, preferably in the form of a
pharmaceutical composition adapted to such route, and in a
therapeutically effective dose. The compounds or the combination of
compounds for the disclosure may be delivered orally, mucosally,
parenterally, including intravascularly, intravenously,
intraperitoneally, subcutaneously, intramuscularly, and
intranasally in dosage formulations containing conventional
pharmaceutical excipients.
[1324] In one embodiment, the combination of a compound formula
(I), or a pharmaceutically acceptable salt thereof, and an
additional agent useful for the treatment of cancer may be
formulated in a fixed dose or combined dose formulation in a
tablet, capsule or premixed IV solution. In another embodiment, the
fixed dose combination preferably comprises of compound formula
(I), and an additional anticancer agent. Other fixed dose
formulations may include premixed liquids, suspensions, elixirs,
aerosolized sprays or patch presentations. As used herein fixed
dose or combined dose formulations are synonymous with simultaneous
co-administration of the active ingredients of the compound (I) and
at least one additional agent.
[1325] Synthesis
[1326] The compounds of the disclosure may be prepared using
methods disclosed herein and routine modifications thereof which
will be apparent given the disclosure herein and methods well known
in the art. Conventional and well-known synthetic methods may be
used in addition to the teachings herein.
[1327] The synthesis of typical compounds of formula (I), or a
pharmaceutically acceptable salt thereof, e.g., compounds having
structures described by one or more of formula (I), or other
formulas or compounds disclosed herein, may be accomplished as
described in the following examples. If available, reagents may be
purchased commercially, e.g., from Sigma Aldrich or other chemical
suppliers.
[1328] General Syntheses
[1329] Typical embodiments of compounds in accordance with the
present disclosure may be synthesized using the general reaction
schemes and/or examples described below. It will be apparent given
the description herein that the general schemes may be altered by
substitution of the starting materials with other materials having
similar structures to result in products that are correspondingly
different. Descriptions of syntheses follow to provide numerous
examples of how the starting materials may vary to provide
corresponding products. Starting materials are typically obtained
from commercial sources or synthesized using published methods for
synthesizing compounds which are embodiments of the present
disclosure, inspection of the structure of the compound to be
synthesized will provide the identity of each substituent group.
The identity of the final product will generally render apparent
the identity of the necessary starting materials by a simple
process of inspection, given the examples herein. Group labels
(e.g., R.sup.1, R.sup.a, R.sup.b) used in the reaction schemes
herein are for illustrative purposes only and unless otherwise
specified do not necessarily match by name or function the labels
used elsewhere to describe compounds of formula (I) or aspects or
fragments thereof.
[1330] Synthetic Reaction Parameters
[1331] The compounds of this disclosure can be prepared from
readily available starting materials using, for example, the
following general methods and procedures. It will be appreciated
that where typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given; other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be
determined by one skilled in the art by routine optimization
procedures.
[1332] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions.
Suitable protecting groups for various functional groups as well as
suitable conditions for protecting and deprotecting particular
functional groups are well known in the art. For example, numerous
protecting groups are described in T. W. Greene and G. M. Wuts
(1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley,
New York, and references cited therein.
[1333] Furthermore, the compounds of this disclosure may contain
one or more chiral centers. Accordingly, if desired, such compounds
can be prepared or isolated as pure stereoisomers, i.e., as
individual enantiomers or diastereomers or as stereoisomer-enriched
mixtures. All such stereoisomers (and enriched mixtures) are
included within the scope of this disclosure, unless otherwise
indicated. Pure stereoisomers (or enriched mixtures) may be
prepared using, for example, optically active starting materials or
stereoselective reagents well-known in the art. Alternatively,
racemic mixtures of such compounds can be separated using, for
example, chiral column chromatography, chiral resolving agents, and
the like.
[1334] The starting materials for the following reactions are
generally known compounds or can be prepared by known procedures or
obvious modifications thereof. For example, many of the starting
materials are available from commercial suppliers such as Aldrich
Chemical Co. (Milwaukee, Wis., USA). Others may be prepared by
procedures or obvious modifications thereof, described in standard
reference texts such as Fieser and Fieser's Reagents for Organic
Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's
Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals
(Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40
(John Wiley, and Sons, 1991), March's Advanced Organic Chemistry,
(John Wiley, and Sons, 5.sup.th Edition, 2001), and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc.,
1989).
[1335] The terms "solvent," "inert organic solvent" or "inert
solvent" refer to a solvent inert under the conditions of the
reaction being described in conjunction therewith (including, for
example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, pyridine and the like).
Unless specified to the contrary, the solvents used in the
reactions of the present disclosure are inert organic solvents, and
the reactions are carried out under an inert gas, preferably
nitrogen.
[1336] The term "q.s." means adding a quantity sufficient to
achieve a stated function, e.g., to bring a solution to the desired
volume (i.e., 100%).
[1337] The compounds as disclosed herein may be prepared according
to the general schemes provided below. Scheme 1 shows the general
synthesis of building block 7.
##STR00158##
[1338] Suitably substituted 3-bromobenzyl alcohol (1) is converted
to boronate ester (2) using standard conditions
(4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), a
suitable palladium catalyst such as
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) and
base such as potassium acetate, in a suitable solvent such as
1,4-dioxane under heating. The alcohol is converted to a leaving
group such as mesylate, chloride, bromide or iodide (3) which is
used to selectively alkylate dihydroxybenzaldehyde (4) using a mild
base such as sodium bicarbonate. The second hydroxyl group is
alkylated with an appropriate alkylating agent (6) to provide
building block (7).
[1339] As used in the following schemes, Z.sup.1 is halo,
--OR.sup.a, --NO.sub.2, --CN, --NR.sup.aR.sup.b, --N.sub.3,
--SO.sub.2R.sup.a, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--OC.sub.1-6 haloalkyl, --C.sub.3-8 cycloalkyl, and --C.sub.1-6
alkylC.sub.3-8 cycloalkyl, wherein each alkyl, alkenyl, alkynyl,
and cycloalkyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, OR.sup.a,
halo, and cyano; Z.sup.3 is halo, --OR.sup.a, --N.sub.3,
--NO.sub.2, --CN, --NR.sup.1R.sup.2, --SO.sub.2R.sup.a,
--SO.sub.2NR.sup.aR.sup.b, --NR.sup.aSO.sub.2R.sup.a,
--NR.sup.aC(O)R.sup.a, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --NR.sup.aC(O)OR.sup.a,
--NR.sup.aC(O)NR.sup.1R.sup.2, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b, --C.sub.1-6 alkyl,
--C.sub.2-6 alkenyl, --C.sub.2-6 alkynyl, --OC.sub.1-6 alkyl,
--C.sub.3-8 cycloalkyl, --C.sub.1-6 alkylC.sub.3-8 cycloalkyl,
aryl, heteroaryl, heterocyclyl, and R.sup.N, wherein the alkyl,
alkenyl, alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or
heterocyclyl group is optionally substituted with 1 to 4 groups
independently selected from oxo, --NO.sub.2, --N.sub.3, --OR.sup.a,
halo, cyano, --NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC.sub.1-6 alkylCN, --C(O)NR.sup.aR.sup.b, NR.sup.aC(O)R.sup.a,
--NR.sup.aC(O)OR.sup.a, --SO.sub.2R.sup.a,
--NR.sup.aSO.sub.2R.sup.b, --SO.sub.2NR.sup.aR.sup.b,
--NR.sup.aSO.sub.2NR.sup.aR.sup.b,
--C(O)NR.sup.aSO.sub.2NR.sup.aR.sup.b and --C.sub.3- 8 cycloalkyl;
and wherein the heteroaryl or heterocyclic group may be oxidized on
a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to
form a sulfoxide or sulfone; m is 0, 1, 2, 3, or 4; R.sup.5 may be
any appropriate substituent on Q as defined herein, such as
##STR00159##
or R.sup.a; and the remaining variables are as defined herein.
[1340] Scheme 2 shows the general synthesis of building block (11)
using similar chemistry as in Scheme 1.
##STR00160##
[1341] Building blocks (7) and (11) can be coupled in a palladium
catalyzed reaction to form dialdehyde (12) (Scheme 3). For example,
boronic ester (7) is coupled with coupling partner (11) using a
palladium catalyst, such as Pd(PPh.sub.3).sub.4, to afford (14).
Palladium mediated cross-coupling reactions that enable the biaryl
formation but employ alternative coupling partners and reagents
include, for example, the Negishi, Kumada, and Stille reactions.
Dialdehyde (12) is subjected to reductive amination conditions in
the presence of an appropriate amine to give target compound (14).
Reducing agents which can be used for this reaction include but are
not limited to sodium cyanoborohydride, sodium
triacetoxyborohydride, borane-picoline complex in the presence or
absence of an acid such as acetic acid in a variety of solvents and
solvent mixtures including but not limited to
N,N-dimethylformamide, methanol, ethanol, and dimethyl
sulfoxide.
##STR00161##
[1342] Alternatively, compounds disclosed herein can be built as
shown in scheme 4 using similar chemistry as described above.
##STR00162##
[1343] Alternatively, an already suitably substituted phenol (27)
can be used in the dialkylation reaction. (Scheme 5).
##STR00163##
[1344] Scheme 6 shows the general synthesis of pyridine containing
compounds. A bis-benzylic alcohol can be coupled to a suitably
substituted 2-chloropyridine (20) using either a strong base such
as sodium hydride under heating, or alternatively using transition
metal catalyzed coupling conditions (as described in the
literature, such as Ullmann ether synthesis, which uses copper
based catalysts, and Buchwald-Hartwig reaction, which uses a
palladium catalyst, such as Pd(dba).sub.2, a suitable ligand, such
as XPhos, in the presence of a base, such as cesium carbonate) to
give (21). If desired, a halogen (X=Cl, Br, I) can be introduced
via electrophilic aromatic substitution, using a N-halosuccinimide,
Palau'Chlor, bromine, or similar, to give (22). After removal of
the protecting group, the hydroxypyridine (23) is alkylated with a
suitable alkylating agent (6) to provide dialdehyde (24). The
dialdehyde (24) is then converted to the target compound (25) using
an appropriate amine (13) under reductive amination conditions.
##STR00164## ##STR00165##
[1345] Alternatively (Scheme 7), a substituted 2-chloropyridine
(26) can be coupled with a substituted 3-bromobenzyl alcohol (1)
using a strong base (such as sodium hydride) under heating followed
by borylation and biaryl formation to give dialdehyde (24). Target
compound (25) can be achieved as described in Scheme 6.
##STR00166##
[1346] General synthesis of bis-indanols is shown in Scheme 8. A
suitably substituted bromoindanone (29) is reduced to the indanol
(30) using one of the many available reduction conditions (sodium
borohydride, lithium aluminum hydride, and others). If
enantiomerically enriched (30) is desired, asymmetric reduction
conditions are also available, for example Corey's CBS reduction.
Borylation followed by transition metal catalyzed biaryl coupling
gives bis-indanol (32), which can be further elaborated to target
compounds as shown in Schemes 4, 5, and 6.
##STR00167##
[1347] Bromoindanol (30) can be coupled to a substituted
2-chloropyridine (26), using either a strong base such as sodium
hydride under heating, or alternatively using transition metal
catalyzed coupling conditions (as described in the literature, such
as Ullmann ether synthesis, which uses copper based catalysts, and
Buchwald-Hartwig reaction, which uses a palladium catalyst, such as
Pd(dba)2, a ligand, such as XPhos, in the presence of a base, such
as cesium carbonate), optionally followed by borylation to give
building blocks (33) and (34) (Scheme 9).
##STR00168##
[1348] Generic synthesis of non-symmetric compounds is shown in
Scheme 10 (R.sup.0 is alkyl). Building blocks (35) and (36) as well
as (37) and (38) can be coupled in a palladium catalyzed reaction
to give (39). Boronic ester (35 or 38) is coupled with the
respective coupling partner (36 or 37) using a palladium catalyst,
such as Pd(PPh.sub.3).sub.4, to afford (39). Palladium mediated
cross-coupling reactions that enable the formation of the
Ar.sup.E--Ar.sup.W bond, but employ alternative coupling partners
and reagents, include for example the Negishi, Kumada, and Stille
reactions. (36) can be obtained from (43) via standard acetal
formation from an aldehyde and can be converted to boronate (38)
using standard borylation conditions. Treatment of (39) with a
suitable amine (13) under reductive amination conditions gives
(40). Acetal deprotection under acidic conditions followed by a
second reductive amination using a different amine gives
non-symmetric compound (42).
##STR00169##
[1349] Generic synthesis of compounds where L.sup.E is a bond and
Q.sup.E is phenyl is shown in Scheme 11. A boronate ester (35) and
a substituted 1,3-dibromobenzene (43) can be coupled in a palladium
catalyzed reaction to give arylbromide (44). A second palladium
catalyzed coupling reaction with boronate (45) gives (46), which
can undergo reductive amination with an amine (13) to give (47).
Acetal hydrolysis of (47) under acidic conditions gives aldehyde
(48), which can undergo another reductive amination with a
different amine (13) to give (50). Acidic hydrolysis of the acetal
(46) gives dialdehyde (49), which is subjected to reductive
amination with an appropriate amine to give (51).
##STR00170## ##STR00171##
[1350] Building block (44) can be converted to boronate (52)
(Scheme 12) and coupled to a substituted heteroaryl bromide (53) in
a palladium catalyzed reaction to give (55). Conversion to target
compounds (58) and (59) can be performed similar to Scheme 11.
##STR00172##
[1351] Generic synthesis of indoline containing compounds is shown
in Scheme 13. Substituted 4-bromoindole (60) can be converted to
boronate (61) and coupled with another substituted 4-bromoindole in
a palladium catalyzed reaction to give bis-indole (63). Reduction
using a suitable reducing agent such as sodium cyanoborohydride in
acetic acid gives bis-indoline (64), which can be acylated with a
suitable carboxylic acid (65) in the presence of a coupling agent
such as HATU or EDCI to give dialdehyde (66). Treatment with an
amine under reductive amination conditions gives compound (67).
##STR00173##
[1352] Boronate (52) can be coupled to a substituted, N-protected
4-bromoindoline (68) in a palladium catalyzed reaction to give
(69). Removal of the protecting group followed by acylation with
carboxylic acid (71) in the presence of a coupling agent such as
HATU or EDCI gives dialdehyde (72). Treatment with an amine under
reductive amination conditions gives compound (73).
##STR00174##
[1353] Alternatively, compound (73) can be made by acylating a
substituted 4-bromoindoline (74) with a suitable carboxylic acid
(71) in the presence of a coupling agent such as HATU or EDCI to
(75) followed by coupling with boronate (52) in a palladium
catalyzed reaction to give dialdehyde (72). Treatment with an amine
under reductive amination conditions gives compound (73).
##STR00175##
EXAMPLES
[1354] The compounds were named using the IUPAC naming convention
or using ChemBioDraw Ultra Version 14.0. Structures are drawn
ChemBioDraw Ultra Version 14.0.
[1355] When production of starting materials is not particularly
described, the compounds are known or may be prepared analogously
to methods known in the art or as disclosed in the Examples. One of
skill in the art will appreciate that synthetic methodologies
described herein are only representative of methods for preparation
of the compounds described herein, and that other known methods and
variants of methods described herein may be used. The methods or
features described in various Examples may be combined or adapted
in various ways to provide additional ways of making the compounds
described herein.
Intermediate 1:
(1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diol
##STR00176##
[1357] Step 1: To a 500 mL round bottom flask was added
(R)-(+)-2-methyl-CBS-oxazaborolidine (985 mg, 3.55 mmol), toluene
(5 mL) and borane-dimethylsulfide (12.36 mL, 130 mmol) under
N.sub.2. The reaction was stirred at room temperature for 10 min
then diluted with DCM (20 mL) and cooled to -20.degree. C. A
solution of 4-Bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in
DCM (20 mL) was added dropwise over 30 min while maintaining the
reaction temperature at -20.+-.5.degree. C. The reaction was
stirred for 2 h after the addition was complete, then quenched by
the dropwise addition of MeOH (50 mL). The reaction mixture was
diluted with an additional MeOH (60 mL) and the solvent distilled
at atmospheric pressure. MeOH (60 mL) was added in two portions and
the distillation was repeated twice. Finally all the solvent was
evaporated under reduced pressure to give a solid which was
purified by silica gel column chromatography (EA/hexanes) provided
(S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a solid. Product can be
recrystallized from 5:1 hexanes-EtOAc.
[1358] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.47-7.37 (m,
1H), 7.31 (d, J=7.4 Hz, 1H), 7.23-7.05 (m, 1H), 5.36 (dd, J=6.1,
2.0 Hz, 1H), 5.10 (q, J=6.2 Hz, 1H), 2.97-2.79 (m, 1H), 2.68 (dt,
J=15.6, 7.6 Hz, 1H), 2.41-2.22 (m, 1H), 1.77 (dt, J=19.0, 7.0 Hz,
1H).
[1359] Step 2: To a solution of
(S)-4-bromo-2,3-dihydro-1H-inden-1-ol (1.10 g, 5.16 mmol) in
dioxane (15 mL) was added bis(pinacolato)diboron (1.57 g, 6.195
mmol), KOAc (1.52 g, 15 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (377
mg, 0.516 mmol). N.sub.2 was bubbled thru the mixture for 2 min,
and the flask heated to 90.degree. C. for 2 h. The reaction was
cooled to room temperature (rt) and diluted with 100 mL EtOAc,
washed with water (3 times), dried with Na.sub.2SO.sub.4 and
concentrated to yield an oil. This was purified by silica gel
chromatography, eluting with EtOAc and hexanes to provide
(S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden--
1-ol as an oil that slowly crystallized on standing. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.49 (d, J=7.2 Hz, 1H), 7.41 (d,
J=7.4 Hz, 1H), 7.16 (t, J=7.1 Hz, 1H), 5.20-5.08 (m, 1H), 4.98 (q,
J=6.1, 5.6 Hz, 1H), 3.18-3.01 (m, 1H), 2.78 (dt, J=16.3, 7.9 Hz,
1H), 2.36-2.19 (m, 1H), 1.82-1.61 (m, 1H), 1.27 (d, J=1.9 Hz, 14H).
LCMS-ESI.sup.+ (m/z): [M-OH].sup.+ calc'd for
C.sub.15H.sub.20BO.sub.2: 243.1; found: 243.2.
[1360] Step 3: A mixture of
(S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden--
1-ol (1.53 g, 5.90 mmol), (S)-4-bromo-2,3-dihydro-1H-inden-1-ol
(1.32 g, 6.19 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.431 g,
0.59 mmol) and Na.sub.2CO.sub.3 (5.89 mL, 12 mmol, 2M) under
N.sub.2 in 30 mL dioxane was heated to 85.degree. C. in a heating
block for 2 h, at which time all SM was consumed by LCMS. After
cooling to room temperature, the reaction was diluted with EtOAc
and water. The organic layer was separated, dried with
Na.sub.2SO.sub.4 and concentrated. Purified by silica gel
chromatography (eluting with EtOAc-Hex) to provide
(1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diol as a
light oil that crystallized on standing. [M-OH].sup.+=249.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.49 (d, J=7.2 Hz, 1H),
7.41 (d, J=7.4 Hz, 1H), 7.16 (t, J=7.1 Hz, 1H), 5.20-5.08 (m, 1H),
4.98 (q, J=6.1, 5.6 Hz, 1H), 3.18-3.01 (m, 1H), 2.78 (dt, J=16.3,
7.9 Hz, 1H), 2.36-2.19 (m, 1H), 1.82-1.61 (m, 1H), 1.27 (d, J=1.9
Hz, 14H). LCMS-ESI.sup.+ (m/z): [M-OH].sup.+ calc'd for
C.sub.18H.sub.17O: 249.1; found: 249.2.
Intermediate 2:
5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))di-
nicotinonitrile
##STR00177## ##STR00178##
[1362] Step 1:
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) was prepared
using the same method as Intermediate 3, by substituting
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde for
6-chloro-2-methoxynicotinaldehyde. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 10.25 (s, 2H), 8.06 (d, J=8.4 Hz, 2H), 7.46
(d, J=7.3 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.00 (s, 2H), 6.59 (dd,
J=6.8, 4.7 Hz, 2H), 6.38 (d, J=8.3 Hz, 2H), 4.67-4.51 (m, 5H), 4.12
(q, J=7.1 Hz, 2H), 3.08-2.85 (m, 4H), 2.78 (dt, J=15.8, 7.0 Hz,
2H), 2.62 (dq, J=13.6, 7.1 Hz, 2H), 2.50 (s, 2H), 2.29-2.14 (m,
2H), 0.08 (s, 18H).
[1363] Step 2 A solution of
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (200 mg,
0.231 mmol) and cesium fluoride (140 mg, 0.923 mmol) in DMF (2 mL)
heated to 60.degree. C. for 2 h. The reaction was cooled to rt and
diluted with 100 mL DCM, washed with pH 3.0 citrate buffer (3
times), dried with Na.sub.2SO.sub.4 and concentrated to yield
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-hydroxynicotinaldehyde) as an oil.
[1364] .sup.1H NMR (400 MHz, Chloroform-d) .delta. 10.18 (s, 2H),
8.25 (s, 2H), 7.48 (d, J=7.4 Hz, 2H), 7.38-7.23 (m, 4H), 6.57 (t,
J=6.2 Hz, 2H), 4.67-4.58 (m, 4H), 3.03 (ddd, J=15.9, 8.7, 4.3 Hz,
2H), 2.88-2.63 (m, 4H), 2.31-2.15 (m, 2H), 1.32-1.17 (m, 4H), 0.08
(s, 18H).
[1365] Step 3:
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-hydroxynicotinaldehyde (100 mg, 0.15 mmol) was
taken up in 2 mL DMF in a 20 mL vial and treated with K2CO3 (155
mg, 1.12 mmol), 5-(chloromethyl)nicotinonitrile hydrochloride (71
mg, 0.325 mmol) and sodium iodide (45 mg, 0.3 mmol). Stirred under
N.sub.2 at 65.degree. C. for 2 h. The reaction was partitioned
between pH 3 citrate buffer and DCM. The organic was washed with
water 3 times, dried with MgSO4, filtered and concentrated to
provide
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-hydroxynicotinaldehyde) as a semi-solid. This
material was used in the reaction below without purification.
[1366] Step 4: A mixture of
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-hydroxynicotinaldehyde) (100 mg, 0.15 mmol),
5-(chloromethyl)nicotinonitrile hydrochloride (74 mg, 0.357 mmol),
K.sub.2CO.sub.3 (155 mg, 1.13 mmol) and NaI (45 mg, 0.30 mmol) in 2
mL DMF was heated to 85.degree. C. in a heating block for 1 h, by
which time all SM appeared consumed by LCMS. After cooling to room
temperature, the reaction was diluted with DCM and water. The
organic layer was separated, dried with Na.sub.2SO.sub.4 and
concentrated. Purified by silica gel chromatography (eluting with
EtOAc-DCM) to provide
5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))di-
nicotinonitrile as a powder.
[1367] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C44H30Br2N6O6: 898.07; found: 898.06.
Intermediate 3:
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(2-methoxynicotinaldehyde)
##STR00179##
[1369] A solution of Intermediate 1 (250 mg, 0.939 mmol) and
6-chloro-2-methoxynicotinaldehyde (403 mg, 2.43 mmol) was taken up
in 4 mL toluene and N.sub.2 was bubbled thru the solution for 5
min. Palladium (II) acetate (32 mg, 0.141 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (60 mg,
0.141 mmol) and Cs.sub.2CO.sub.3 (1.22 g, 3.76 mmol) were added and
N.sub.2 was bubbled for an additional 2 min. The reaction was then
heated to 85.degree. C. with vigorous stirring for 16 h. After
cooling to rt the reaction was diluted with 50 mL DCM and filtered
thru Celite.RTM.. The filtrate was purified by silica gel
chromatography (eluting with EtOAc-hexanes) to provide
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(2-methoxynicotinaldehyde) as a solid. .sup.1H NMR (400
MHz, Chloroform-d) .delta. 10.24 (d, J=0.8 Hz, 2H), 8.07 (d, J=8.3
Hz, 2H), 7.47 (d, J=7.3 Hz, 2H), 7.37-7.22 (m, 6H), 6.66 (dd,
J=7.0, 4.6 Hz, 2H), 6.41 (dd, J=8.3, 0.7 Hz, 2H), 4.11 (s, 6H),
3.02 (ddd, J=15.7, 8.6, 5.3 Hz, 2H), 2.79 (ddd, J=16.1, 8.4, 5.8
Hz, 2H), 2.64 (dddd, J=13.6, 8.4, 7.0, 5.2 Hz, 2H), 2.22 (ddt,
J=13.7, 8.7, 5.4 Hz, 2H).
Intermediate 4:
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-methoxynicotinaldehyde)
##STR00180##
[1371] A solution of Intermediate 3 (468 mg, 0.87 mmol) in 20 mL
CHCl.sub.3 was diluted with 10 mL DMF and treated with NBS (310 mg,
1.74 mmol) and TFA (0.01 mL, 0.131 mmol). The reaction was stirred
at 50.degree. C. for 2 h, then cooled to rt and stirred overnight.
Reaction was diluted with 50 mL DCM and stirred with sat. sodium
thiosulfate solution for 15 min. The organic layer was dried with
sodium sulfate and concentrated. Purification by silica gel
chromatography, eluting with EtOAc-hexanes provided
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-bromo-2-methoxynicotinaldehyde) as a solid. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 10.17 (s, 2H), 8.26 (s, 2H), 7.49
(d, J=7.4 Hz, 2H), 7.39-7.26 (m, 6H), 6.64 (t, J=6.2 Hz, 2H), 4.11
(s, 6H), 3.03 (ddd, J=16.0, 8.7, 4.4 Hz, 2H), 2.83 (dt, J=15.7, 7.2
Hz, 2H), 2.72 (ddd, J=13.8, 7.3, 4.6 Hz, 2H), 2.25 (ddt, J=14.2,
8.8, 6.0 Hz, 2H).
Intermediate 5:
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-chloro-2-methoxynicotinaldehyde) and
Intermediate 6:
5-chloro-6-(((1S,1'S)-1'-((5-formyl-6-methoxypyridin-2-yl)oxy)-2,2',3,3'--
tetrahydro-1H,1'H-[4,4'-biinden]-1-yl)oxy)-2-methoxynicotinaldehyde
##STR00181##
[1373] A solution of Intermediate 3 (94 mg, 0.175 mmol) in 720 mL
CHCl3 was diluted with 3 mL DMF and treated with Palau-Cl (81 mg,
0.38 mmol) and TFA (0.0033 mL, 0.044 mmol). The reaction was
stirred at 40.degree. C. for 2 days. Reaction was diluted with 50
mL DCM and stirred with sat. sodium thiosulfate for 15 min. The
organic layer was washed with pH 3 citrate buffer (2.times.) dried
with sodium sulfate and concentrated. Purification by silica gel
chromatography, eluting with EtOAc-hexanes provided Intermediate 5
and Intermediate 6.
[1374] Intermediate 5: .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.19 (s, 2H), 8.11 (s, 2H), 7.52-7.45 (m, 2H), 7.37-7.24 (m, 4H),
6.71-6.63 (m, 2H), 4.12 (s, 6H), 3.04 (ddd, J=16.0, 8.7, 4.6 Hz,
2H), 2.88-2.76 (m, 2H), 2.77-2.64 (m, 2H), 2.33-2.20 (m, 2H).
[1375] Intermediate 6: .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.29 (s, 1H), 10.19 (s, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.11 (s, 1H),
7.48 (m, 2H), 7.32 (m, 4H), 6.75 (d, J=8.2 Hz, 1H), 6.67 (t, J=6.1
Hz, 1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.03 (td, J=10.4, 8.7, 4.9 Hz,
2H), 2.82 (dt, J=15.8, 7.4 Hz, 2H), 2.71 (dt, J=13.7, 6.5 Hz, 2H),
2.27 (dd, J=16.4, 8.2 Hz, 2H).
Intermediate 7:
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
##STR00182##
[1377] To a solution of (3-bromo-2-methylphenyl)methanol (7.00 g,
34.8 mmol) in DMF (15 mL) was added bis(pinacolato)diboron (10.61
g, 41.8 mmol), KOAc (10.24 g, 104 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(2.545 g, 3.48 mmol). N.sub.2 was bubbled thru the mixture for 2
min, and the flask heated to 90 C for 2 h. The reaction was cooled
to rt and diluted with 100 mL EtOAc, washed with water (3 times),
dried with Na.sub.2SO.sub.4 and concentrated to yield an oil. This
was purified by silica gel chromatography, eluting with EtOAc and
hexanes to provide
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
as an oil that slowly crystallized on standing. [M-OH].sup.+=231. H
NMR (400 MHz, DMSO-d6) .delta. 7.52-7.40 (m, 2H), 7.17-7.09 (m,
1H), 5.04 (t, J=5.4 Hz, 1H), 4.47 (d, J=5.4 Hz, 2H), 2.38 (s, 3H),
1.28 (s, 12H).
Intermediate 8:
(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol
##STR00183##
[1379] To a mixture of
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
(1.728 g, 6.96 mmol), (3-bromo-2-methylphenyl)methanol (1.40 g,
6.96 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.509 g, 0.696 mmol)
and potassium carbonate (1.922 g, 13.93 mmol) under N.sub.2 was
added a mixture of solvents (20 mL dioxane and 5 mL water) and
heated to 85.degree. C. in a heating block for 2 h, at which time
all SM was consumed by LCMS. After cooling to room temperature, the
reaction was diluted with EtOAc and water. The organic layer was
separated, dried with Na.sub.2SO.sub.4 and concentrated. Purified
by silica gel chromatography (eluting with EtOAc-Hex) to provide
(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol as a light oil
that crystallized on standing. [M-OH].sup.+=225. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.37 (dd, J=7.6, 1.3 Hz, 2H), 7.19 (t, J=7.5
Hz, 2H), 6.92 (dd, J=7.6, 1.4 Hz, 2H), 5.10 (t, J=5.4 Hz, 2H), 4.52
(d, J=5.4 Hz, 4H), 1.88 (s, 6H).
Intermediate 9:
3,3'-bis(chloromethyl)-2,2'-dimethyl-1,1'-biphenyl
##STR00184##
[1381] (2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol (3.0 g,
12.8 mmol) was taken up in 10 mL DCM and cooled to 0 C. TEA (17.25
mL, 123.8 mmol) and MsCl (9.58 mL, 123.8 mmol) added and the
reaction allowed to warm to rt and stir for 24 h. The reaction was
diluted with water and DCM with vigorous stirring. The layers were
separated and the organic layer washed with 1N HCl, dried with
MgSO4 and concentrated. The residue was taken up in toluene and
concentrated again (2.times.) to provide the product as an oil.
Intermediate 10:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde)
##STR00185##
[1383] A mixture of Cesium carbonate (1.3 g, 4.04 mmol), palladium
(II) acetate (43 mg, 0.40 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos) (171 mg, 0.40 mmol), +6-chloro-2-methoxynicotinaldehyde (434
mg, 2.53 mmol) and
(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol (245 mg, 1.01
mmol) in toluene (3 mL) was heated at 85.degree. C. in 20 mL sealed
microwave vial (20 mL). After 4 h, reaction mixture was cooled down
and purified by column Chromatography (ISCO (40 g column, 1% ethyl
acetate/hexanes-50% ethyl acetate/hexanes over 15 min-load with dry
amount) to give the product as a solid. ES/MS m/z: 513.0 (M+1).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.08 (s, 2H), 8.02 (d,
J=8.3 Hz, 2H), 7.46 (dd, J=7.7, 1.4 Hz, 2H), 7.27 (t, J=7.6 Hz,
2H), 7.08 (dd, J=7.6, 1.4 Hz, 2H), 6.59 (dd, J=8.3, 0.8 Hz, 2H),
5.54 (s, 4H), 4.01 (s, 6H), 1.98 (d, J=12.3 Hz, 6H).
Intermediate 11:
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxybenzaldehyde)
##STR00186##
[1385] A suspension of 5-chloro-2,4-dihydroxybenzaldehyde (1.36 g,
8 mmol) in 10 mL DMF was treated with NaHCO.sub.3 (1.50 g, 8 mmol)
and stirred for 30 min under N.sub.2.
3,3'-bis(chloromethyl)-2,2'-dimethyl-1,1'-biphenyl (1.00 g, 8 mmol)
in 2 mL DMF was added, followed by NaI (1.07 g, 7 mmol). The
reaction mixture was heated at 55 C for 4 h, at which time the
reaction was cooled to rt and diluted with EtOAc and pH 4 citrate
buffer. After stirring for 5 min the mixture was filtered providing
a light colored precipitate. The filtrate was separated and the
aqueous layer washed with additional EtOAc. The organic layers were
combined, dried with Na.sub.2SO.sub.4 and concentrated to provide a
semi-solid. The precipitate and semisolid were combined to provide
the desire product
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxybenzaldehyde). [M+H]=550.72. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.14 (s, 2H), 10.01 (s, 2H), 7.69 (s,
2H), 7.50 (d, J=7.7 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.11 (d, J=7.4
Hz, 2H), 6.85 (s, 2H), 5.31 (s, 4H), 2.00 (s, 6H).
Intermediate 12:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinon-
itrile
##STR00187##
[1387] A solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))
bis(oxy))bis(5-chloro-2-hydroxybenzaldehyde) (277 mg, 0.502 mmol)
in 1 mL DMF under N.sub.2 was treated with Cs.sub.2CO.sub.3 (816
mg, 2.5 mmol) and the mixture stirred under N.sub.2 at rt for 15
min. 5-(Chloromethyl)nicotinonitrile (230 mg, 1.5 mmol) and NaI
(151 mg, 1.00 mmol) and the reaction stirred under N.sub.2 at 60 C
for 6 h. The mixture was diluted with EtOAc and water and stirred
vigorously for 15 min. The precipitate was filtered to provide the
desired product as a solid. The filtrate was washed with 5% LiCl
(2.times.), dried with Na.sub.2SO.sub.4 and concentrated.
Purification of the filtrate derived material by ISCO (DCM-MeOH)
provided additional product as a solid. An analytical sample was
prepared by RP-HPLC purification to provide a solid. [M+H]=783.01.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.21 (s, 2H), 9.02 (m,
4H), 8.54 (t, J=2.1 Hz, 2H), 7.71 (s, 2H), 7.53 (dd, J=7.7, 1.4 Hz,
2H), 7.36-7.25 (m, 4H), 7.14 (dd, J=7.7, 1.4 Hz, 2H), 5.47 (s, 4H),
5.42 (s, 4H), 2.02 (s, 3H).
Intermediate 13:
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile
##STR00188##
[1389] Step-1: To a stirred solution of
(3-bromo-2-methylphenyl)methanol (1.0 g, 5.0 mmol),
B.sub.2(pin).sub.2 (2.0 g, 8.0 mmol),
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (600 mg, 0.75 mmol) in dioxane
(200 mL) under argon atmosphere was added KOAc (1.5 g, 15 mmol) at
once. The reaction mixture was stirred at 85.degree. C. for 16 h,
filtered through pad of Celite and washed with EtOAc. The crude
product was purified by flash column chromatography (0-50% EtOAc in
hexanes). The fractions containing product were combined, solvent
was removed under reduced pressure to yield an oil which was
stirred in hexanes (or triturated) and filtered to yield product
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol.
.sup.1H NMR: (CDCl.sub.3, 400 MHz): .delta. 7.72-7.70 (m, 1H),
7.44-7.42 (m, 1H), 7.21-7.17 (m, 1H), 4.69 (s, 2H), 2.54 (s, 3H),
1.36 (s, 12H).
[1390] Step-2: To a stirred solution of
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol--
2 (250 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol) under argon
atmosphere was added methanesulfonyl chloride (140 mg, 1.2 mmol)
drop wise at 0.degree. C., and the reaction mixture was allowed to
warm to rt and stir overnight. After 16 hours, partitioned between
water and CH.sub.2Cl.sub.2, separated organic layer dried over
anhydrous Na.sub.2SO.sub.4. The solvent was concentrated under
reduced pressure and the crude product
2-(3-(chloromethyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola-
ne was used for next step without further purification. .sup.1H
NMR: (CDCl.sub.3, 400 MHz): .delta. 7.76-7.75 (m, 1H), 7.40-7.38
(m, 1H), 7.20-7.16 (m, 1H), 4.64 (s, 2H), 2.64 (s, 3H), 1.36 (s,
12H).
[1391] Step-3: To a stirred solution of
5-chloro-2,4-dihydroxybenzaldehyde-4 (170 mg, 0.81 mmol) in DMF (6
mL) was added sodium bicarbonate (120 mg, 1.4 mmol) under argon
atmosphere. The mixture was stirred for 15 minutes at room
temperature, and a solution of
2-(3-(chloromethyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola-
ne (180 mg, 0.68 mmol) in THF (6 mL) followed by sodium iodide (100
mg, 0.68 mmol) were added at once. The reaction was stirred at
60.degree. C. for 16 h. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, quenched with saturated aqueous NH.sub.4Cl, and
extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). The organic layer
was dried over Na.sub.2SO.sub.4, solvent was removed under reduced
pressure, and purified by flash column chromatography (0->50%
EtOAc in hexanes) to yield
5-chloro-2-hydroxy-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzyl)oxy)benzaldehyde. .sup.1H NMR: (CDCl.sub.3, 400
MHz): .delta. 11.43 (s, 1H), 9.68 (s, 1H), 7.80-7.78 (m, 1H),
7.62-7.45 (m, 2H), 7.26-7.22 (m, 1H), 6.59 (s, 1H), 5.17 (s, 2H),
2.58 (s, 3H), 1.37 (s, 12H).
[1392] Step-4: To a stirred solution of
5-chloro-2-hydroxy-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)benzyl)oxy)benzaldehyde (100 mg, 0.25 mmol) and cesium
carbonate (160 mg 0.50 mmol) in DMF (3 mL) under argon atmosphere
was added 5-(chloromethyl)nicotinonitrile (75 mg, 0.5 mmol) and
sodium iodide (37 mg, 0.25 mmol) at rt, then heated to 75.degree.
C. After two hours, quenched with sat. aq. NH.sub.4Cl, extracted
with CH.sub.2Cl.sub.2, dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed under reduced pressure, and purified by flash
column chromatography to yield product
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile. .sup.1H NMR:
(CDCl.sub.3, 400 MHz): .delta. 10.25 (s, 1H), 8.89-8.88 (m, 2H),
8.10-8.05 (m, 1H), 7.88 (s, 1H), 7.79-7.77 (m, 1H), 7.46-7.44 (m,
1H), 7.23-7.19 (m, 1H), 6.56 (s, 1H), 5.21 (s, 2H), 5.17 (s, 2H),
2.57 (s, 3H), 1.37 (s, 12H).
Intermediate 14:
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde
##STR00189##
[1394] Step-1
[1395] To a solution of (3-bromo-2-methylphenyl)methanol (5 g, 24.9
mmol), TEA (5.2 mL) in dichloromethane under argon atmosphere at
0.degree. C. was added MsCl (2.3 mL, 29.8 mmol) drop wise. The
solution was allowed to warm to ambient temperature and stirred for
16 h. The reaction mix was partitioned btw DCM/water, extracted,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
1-bromo-3-(chloromethyl)-2-methylbenzene as a liquid 5.1 g (>95%
pure, stable at RT over 2 weeks).
[1396] Step-2
[1397] To a solution of 5-chloro-2,4-dihydroxybenzaldehyde (1.6 g,
9.27 mmol) in DMF (15 mL) was added NaHCO.sub.3 (1.04 g, 16.86
mmol) under argon and stirred for 10 min. A solution of
1-bromo-3-(chloromethyl)-2-methylbenzene (1.85 g, 8.43 mmol) in THF
(15 mL) was added followed by NaI (1.26 g, 8.43 mmol) at once. The
mixture was heated at 60.degree. C. overnight. To the reaction was
added water (.about.50 mL) precipitation occur and stirred at RT
for 10 min (product crashes out with small impurity), the solid was
filtered, washed with water, dried under vacuum to afford crude
product. To the crude product (.about.85% pure) was added 2%
MeOH/DCM (.about.60-80 mL) warmed at 50.degree. C. for 5 min to
maximum dissolution (or sonicate 2 min), the insoluble mat (solid
impurity) was filtered, rinsed with ice-cold 2% MeOH/DCM (10
mL.times.2) and pure product crystallized out in the cold solution
while filtering. The filtrate was left at 0.degree. C. for 30 min.
The solid product (pure product) was filtered, rinsed with cold 2%
MeOH/DCM (10 mL.times.2) to afford
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde as a
solid and the mother liquor was left at 0.degree. C. for 30 min to
isolate second crop.
Intermediate 15:
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicot-
inonitrile
##STR00190##
[1399] A mixture of
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (1.7
g, 4.78 mmol) and Cs.sub.2CO.sub.3 (3.11 g, 9.56 mmol), DMF (25 mL)
were taken in a 100 mL RB-flask, and stirred for 5 min under argon.
To the well stirred mixture was added
5-(chloromethyl)nicotinonitrile (1.45 g, 9.56 mmol) followed by NaI
(716 mg, 4.78 mmol) at once and heated at 75.degree. C. for 3 h.
Diluted with water (.about.50-60 mL) precipitation occur and
stirred at RT for 10 min (product crashes out with small impurity)
the solid product was filtered, washed with water, dried under
vacuum to afford >80% pure product. To further purify, the
(>80% pure) material was added to 2% MeOH/DCM (.about.70 mL),
sonicated for 2 min (or warm at 50.degree. C. for 5 min) to
dissolve. Left it to cool at 0.degree. C. for 30 min. Filtered,
rinsed with cold solution of 2% MeOH/DCM (10 mL.times.2) to afford
pure
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicot-
inonitrile. The mother liquor was left to cool at 0.degree. C. for
1 h for second crop of product.
Intermediate 16:
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]--
3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
##STR00191##
[1401] A mixture of 1,3-dibromo-2-methylbenzene (7.5 g, 30 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.2 g, 10
mmol), DMF (15 mL) and 2N potassium carbonate (5 mL) was purged
with argon for 10 min.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (410 mg, 0.5 mmol) was then added. The
resulting mixture was stirred at 50.degree. C. for 16 h and then at
80.degree. C. for 2 h. After cooling, the mixture was partitioned
between ethyl acetate and 3% LiCl in water. The ethyl acetate layer
was taken and concentrated. The residue was purified by Combiflash,
affording 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-ol as a solid.
.sup.1H NMR (CDCl.sub.3) 7.53 (d, 1H), 7.13-7.16 (m, 3H), 7.05 (t,
1H), 6.87 (d, 2H), 4.74 (brs, 1H), 2.31 (s, 3H).
[1402] To a solution of 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-ol
(1.0 g, 3.8 mmol) in NMP (5 mL) was added 60% sodium hydride in
mineral oil (460 mg, 11 mmol). After the gas evolution had ceased,
2-bromo-1,1-diethoxyethane (2.25 g, 11.4 mmol) was added. The
resulting mixture was stirred at 80.degree. C. for 4 h. After
cooling, the mixture was partitioned between ethyl acetate and 3%
LiCl in water. The ethyl acetate layer was taken and concentrated.
The residue was purified by Combiflash, affording
3-bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl as an oil.
.sup.1H NMR (CDCl3) 7.52 (d, 1H), 7.13-7.20 (m, 3H), 7.05 (t, 1H),
6.96 (d, 2H), 4.86 (t, 1H), 4.05 (d, 2H), 3.78 (dq, 2H), 3.66 (dq,
2H), 2.30 (s, 3H), 1.26 (m, 6H).
[1403] A mixture of
3-bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (380 mg, 1
mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (519 mg, 1
mmol), DMF (4 mL) and 2N potassium carbonate (0.5 mL) was purged
with argon for 10 min.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (41 mg, 0.05 mmol) was then added. The
resulting mixture was stirred at 90.degree. C. for 1 h. After
cooling, the mixture was partitioned between ethyl acetate and 3%
LiCl in water. The ethyl acetate layer was taken and concentrated.
The residue was purified by Combiflash, affording
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terp-
henyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile as a
solid. [M+H].sup.+ 690.1.
[1404] To an ice-cold solution of
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terp-
henyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (390
mg, 0.56 mmol) in dioxane (5 mL) was added concentrated HCl (0.5
mL). The mixture was then stirred at room temperature for 1 h.
After neutralizing with saturated aqueous sodium bicarbonate, the
mixture was extracted with ethyl acetate. The ethyl acetate layer
was dried over sodium sulfate and concentrated, affording
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]--
3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, which was
used without further purification. [M+H].sup.+ 617.0.
Intermediate 17:
2-methoxy-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)nicotinaldehyde
##STR00192##
[1406] (3-Bromo-2-methylphenyl) methanol (300 mg, 1.49 mmol) was
dissolved in DMF (6 ml). Sodium hydride (60% dispersion in mineral
oil, 72 mg, and 1.79 mmol) was added. The suspension was stirred at
room temperature for 5 min before 6-chloro-2-methoxynicotinaldehyde
(256 mg, 1.49 mmol) was added in one portion. Complete conversion
was detected after stirring at room temperature for 30 min. EtOAc
and water were added to the mixture. The organic layer was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography using Hexanes/EtOAc as the eluent to
afford
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxynicotinaldehyde.
[1407] 6-((3-bromo-2-methylbenzyl)oxy)-2-methoxynicotinaldehyde
(348 mg, 1.035 mmol) was dissolved in DMF (5 mL), treated with
bis(pinacolato)diboron (551 mg, 2.17 mmol), Pd(dppf)Cl.sub.2-DCM
(114 mg, 0.156 mmol) and potassium acetate (406 mg, 4.14 mmol). The
mixture was purged with argon and then heated at 85.degree. C. for
1.5 h. After cooling to room temperature, the mixture was diluted
with EtOAc and water. The organic layer was concentrated and the
residue was purified by silica gel chromatography using
Hexanes/EtOAc as the eluent to afford
2-methoxy-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)nicotinaldehyde.
Intermediate 18:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde)
##STR00193##
[1409] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (10.1 g, 19.7 mmol) and Palau'Chlor
(9.08 g, 43.4 mmol) in DMF/CHCl.sub.3 (1:1 v/v, 600 mL) was added
HCl (4 M in dioxane, 10.8 mL, 43.3 mmol) dropwise. The mixture was
stirred at ambient temperature for 30 min, then diluted with
CH.sub.2Cl.sub.2 (500 mL), and washed with NaHCO.sub.3 (saturated
aq., 3.times.300 mL), then H.sub.2O (3.times.300 mL), then brine
(100 mL). The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated, and the residue was purified by column chromatography
(SiO.sub.2, 0-100% EtOAc in hexanes) to yield the product as a
solid.
Intermediate 19:
5-((5-((3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-f-
ormylphenoxy)methyl)nicotinonitrile
##STR00194##
[1411] A suspension of
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (600 mg, 1.16
mmol) and 1,3-dibromo-2-methylbenzene (578.1 mg, 2.31 mmol, 2
equiv) in 6 mL 9:1 dioxane:water was degassed by bubbling N.sub.2
for 30 minutes. To the reaction was added dichloro
1,1-bis(diphenylphosphino)ferrocene palladium(II) (8.46 mg, 0.0116
mmol, 1% mol), and potassium carbonate (0.16 g, 1.16 mmol) was
added to the reaction. The vessel was sealed and heated at
100.degree. C. for 16 h. The reaction was diluted with water and
extracted with DCM, the organic layer was dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica flash chromatography eluting with 70% EA:Hex to
afford product as a solid. LCMS 93% m/z=563.0.
Intermediate 20:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicoti-
nonitrile
##STR00195##
[1413] To a solution of 5-(hydroxymethyl)nicotinonitrile (1.51 g,
9.7 mmol, 1 equiv) in THF (10 mL) at 0.degree. C. was added NaH
(292 mg, 12.2 mmol, 1.25 equiv). After an additional 20 minutes of
stirring the slurry was added to a stirred solution of
2,5,6-trichloronicotinic acid (2.2 g, 9.7 mmol, 1 equiv) in THF at
0.degree. C. The solution was slowly allowed to warm to room
temperature and stirred for 1 hour. The reaction mixture was then
acidified with 1 M HCl and the precipitated
5,6-dichloro-2-((5-cyanopyridin-3-yl)methoxy)nicotinic acid was
collected by vacuum filtration.
[1414] To a stirred solution of
5,6-dichloro-2-((5-cyanopyridin-3-yl)methoxy)nicotinic acid (3.0 g,
9.4 mmol, 1 equiv) in THF was added catalytic DMF (1 drop),
followed by oxalyl chloride (1 equiv). After 10 minutes gas
evolution had ceased and the reaction was cooled to -78.degree. C.
Then Li((OtBu).sub.3AlH) (1 M, 11.3 mL, 1.2 equiv) was added
dropwise. After full consumption of starting material by LCMS the
reaction was quenched with excess 4M NaOH and water then warmed to
room temperature. The organic and aqueous layers were separated and
the aqueous layer was extracted with ethyl acetate. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. The crude material was used without any
further purification. LCMS found 310.1 (M+1).
[1415] To a slurry of
5-(((5,6-dichloro-3-(hydroxymethyl)pyridin-2-yl)oxy)methyl)nicotinonitril-
e (2.5 g, 8.06 mmol, 1 equiv) in methylene chloride at room
temperature was added Dess-Martin periodane (3.76 g, 8.87 mmol, 1.1
equiv). The solution was allowed to stir until LCMS showed full
consumption of alcohol. The reaction mixture was purified directly
by silica gel chromatography (Hex/EtOAc, 0 to 50%) to afford
5-(((5,6-dichloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile
as a solid.
[1416] To a solution of (3-bromo-2-methylphenyl)methanol (750 mg,
2.4 mmol, 1 equiv) in DMF (4 mL) at room temperature was added NaH
(97 mg, 2.4 mmol, 1.0 equiv). After an additional 20 minutes of
stirring the slurry was added to a stirred DMF (4 mL) solution of
5-(((5,6-dichloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile
(490 mg, 2.4 mmol, 1 equiv). Upon complete consumption of starting
material by LCMS the reaction was diluted with water (5 mL) and
extracted three times with 5 mL ethyl acetate. The combined organic
layers were washed with brine, dried over sodium sulfate, filtered,
and concentrated in vacuo. Purification by silica gel
chromatography (Hex/EtOAc, 0 to 100%) afforded
5-(((6-((3-bromo-2-methylbenzyl)oxy)-5-chloro-3-formylpyridin-2-yl)oxy)me-
thyl)nicotinonitrile as a solid.
[1417] A vial with a stir bar was charged with
5-(((6-((3-bromo-2-methylbenzyl)oxy)-5-chloro-3-formylpyridin-2-yl)oxy)me-
thyl)nicotinonitrile (80 mg, 0.17 mmol, 1 equiv),
bis(pinacolato)diboron (43 mg, 0.17 mmol, 1 equiv),
Pd(dppf)Cl.sub.2 (14 mg, 0.017 mmol, 0.1 equiv), and potassium
acetate (33 mg, 0.34 mmol, 2 equiv). The vial sealed and dioxane (2
mL) was added via syringe. The reaction mixture was sparged with
argon for 10 minutes then heated to 100 C until full consumption of
starting material was observed by LCMS. To the reaction mixture was
then added
5-(((6-((3-bromo-2-methylbenzyl)oxy)-5-chloro-3-formylpyridin-2-yl)oxy)me-
thyl)nicotinonitrile (80 mg, 0.17 mmol, 1 equiv), Pd(dppf)Cl.sub.2
(14 mg, 0.017 mmol, 0.1 equiv), and potassium carbonate (47 mg,
0.34 mmol, 2 equiv). The vial was sealed and water (0.4 mL) was
added via syringe. The reaction mixture was sparged with argon for
10 minutes then heated to 100 C until complete consumption of
starting materials was observed by LCMS. The reaction mixture was
then diluted with EtOAc, filtered through celites, and concentrated
in vacuo to dryness. Purification of crude material by silica gel
chromatography afforded
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicoti-
nonitrile as a solid.
Intermediate 21:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile
##STR00196## ##STR00197##
[1419] To a 20 mL vial added
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (500 mg, 1.9
mmol), cesium fluoride (591 mg, 3.9 mmol, 2.0 equiv.), and
N,N-dimethylformamide (7.0 mL, 0.27 M) at room temperature. The
vessel was heated at 60.degree. C. for 1 hour before being cooled
back to room temperature. To the vessel was then added
5-(chloromethyl)nicotinonitrile (350 mg, 2.3 mmol, 1.2 equiv),
potassium carbonate (390 mg, 2.9 mmol, 1.5 equiv), and sodium
iodide (72 mg, 0.47 mmol, 25 mol %). The reaction mixture was
stirred at 60.degree. C. for 1 hour before being cooled to room
temperature and diluted with ethyl acetate (40 mL). Finally, water
(30 mL) was added, and the organic layer was washed .times.1 (once)
with brine, dried over magnesium sulfate, filtered, and
concentrated under vacuum. The crude material was purified by
silica gel column chromatography using a 0-10% methanol in
methylene chloride eluent gradient to provide
5-(((6-chloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile.
[1420] To a 20 mL vial was added (3-bromo-2-methylphenyl)methanol
(220 mg, 1.1 mmol) and N,N-dimethylformamide (5.5 mL, 0.2 M) at
room temperature. To the vessel was added sodium hydride (53 mg, 60
wt % dispersion in mineral oil, 1.3 mmol, 1.2 equiv), and the
mixture was stirred for 30 minutes. In a separate 20 mL vial was
added 5-(((6-chloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile
(300 mg, 1.1 mmol, 1.0 equiv) and N,N-dimethylformamide (5.5 mL,
0.2 M) at room temperature. To the mixture was added the suspension
of (3-bromo-2-methylphenyl)methanol sodium salt in and
N,N-dimethylformamide dropwise at room temperature. The mixture was
stirred for 1 hour before being diluted with ethyl acetate (40 mL).
Finally, water (30 mL) was added, and the organic layer was washed
.times.1 with brine, dried over magnesium sulfate, filtered, and
concentrated under vacuum. The crude material was purified by
silica gel column chromatography using a 0-10% methanol in
methylene chloride eluent gradient to provide
5-(((6-((3-bromo-2-methylbenzyl)oxy)-3-formylpyridin-2-yl)oxy)methyl)nico-
tinonitrile.
[1421] To a 20 mL vial was added
5-(((6-((3-bromo-2-methylbenzyl)oxy)-3-formylpyridin-2-yl)oxy)methyl)nico-
tinonitrile (473 mg, 0.47 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (161
mg, 0.63 mmol, 1.35 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg,
0.05 mmol, 10 mol %), potassium acetate (94 mg, 0.94 mmol, 2.0
equiv), and 1,4-dioxane (4.7 mL, 0.1M) at room temperature. The
vessel was sealed, and the mixture was sparged with nitrogen for 5
minutes before being heated to 90.degree. C. for 3 hours. The
reaction mixture was then cooled to room temperature, ethyl acetate
(10 mL) was added, and the contents of the vial were filtered
through celite. The filtrate was concentrated under vacuum, and the
crude
5-(((3-formyl-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)benzyl)oxy)pyridin-2-yl)oxy)methyl)nicotinonitrile was used
without further purification.
[1422] To a 20 mL vial was added the crude
5-(((3-formyl-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)benzyl)oxy)pyridin-2-yl)oxy)methyl)nicotinonitrile, added
5-(((6-((3-bromo-2-methylbenzyl)oxy)-3-formylpyridin-2-yl)oxy)methyl)nico-
tinonitrile (473 mg, 0.47 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg,
0.05 mmol, 10 mol %), potassium carbonate (130 mg, 0.94 mmol, 2.0
equiv), N,N-dimethylformamide (4.7 mL, 0.1M), and water (0.5 mL) at
room temperature. The vessel was sealed, and the mixture was
sparged with nitrogen for 5 minutes before being heated to
90.degree. C. for 1 hours. The reaction mixture was then cooled to
room temperature, ethyl acetate (10 mL) was added, and the contents
of the vial were filtered through celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed .times.1 with water then
brine. The organic layer was then dried over magnesium sulfate,
filtered, and concentrated under vacuum. The crude material was
purified by silica gel column chromatography using a 0-10% methanol
in methylene chloride eluent gradient to provide
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotinonitrile-
.
[1423] To a 20 mL vial was added
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotinonitrile
(716 mg, 1.0 mmol), potassium acetate (294 mg, 3.0 mmol, 3.0
equiv), and acetic acid (6.7 mL, 0.15 M) at room temperature. To
the mixture was added bromine (2.2 mL, 1M in acetic acid, 2.2 mmol,
2.2 equiv) dropwise. After 1 hour, 1M aqueous sodium sulfite was
added until the red color disappeared. To this mixture was added 5N
aqueous sodium hydroxide until pH=7. Finally, ethyl acetate (10 mL)
and water (10 mL) were added, and the organic layer was washed
.times.1 with brine, dried over magnesium sulfate, filtered, and
concentrated under vacuum. The crude residue of
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile was used without further purification.
Intermediate 22:
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde
##STR00198##
[1425] 120 mL of THF was charged to a 500 mL RB containing 2.5 g
(62.5 mmol) of NaH. 2-Trimethylsilylethanol (6.7 mL, 46.9 mmol) was
added dropwise and the resulting suspension was stirred for 1 h at
rt. Dichloronicotinic acid (3 g, 15.6 mmol) in 100 mL of THF was
added drop-wise via addition funnel. After 2 h, borane-dimethyl
sulfide (2M, 75 mL) was added over 15 min. The reaction was stirred
for 15 h at rt. The reaction was quenched with slow addition of
MeOH (50 mL), 50 mL H.sub.2O and 10 mL sat aq. NH.sub.4Cl, followed
by heating to 90 C for 30 min. The solution was concentrated,
diluted with DCM 100 mL, and washed with sat aq. NH.sub.4Cl and
Brine. The organic layer was separated, and the aqueous extracted
once with 100 mL DCM. The combined organics were dried over
Na.sub.2SO.sub.4, and concentrated. The residual clear oil was
added a stirring bar, and stirred in vacuo (0.3 mmHg) for 4 h at
45.degree. C. to remove most of TMS-ethanol. Column 10% Ethyl
Acetate in Hexanes afforded the alcohol as a solid.
[1426] The alcohol (2.73 g, 10.51 mmol) was dissolved in 40 mL DCM
in a 250 mL round bottom flask. Dess-Martin Periodinane (4.97 g,
11.77 mmol)) added in one portion. The solution was stirred for 2
min before 0.21 mL (11.77 mmol) of H.sub.2O was added dropwise. The
clear solution becomes a milky suspension. The suspension was
stirred for 45 min before 50 mL of a 1M NaOH solution was added,
and the reaction was stirred vigorously for 15 min. The organic
layer was separated, and the aqueous extracted twice with DCM (25
mL). The combined organics were dried, concentrated, and flashed
through a column (10-20% EA) to afford the aldehyde as clusters.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 10.31 (d, J=0.8 Hz,
1H), 8.04 (d, J=7.9 Hz, 1H), 6.98 (dd, J=7.9, 0.9 Hz, 1H),
4.87-4.21 (m, 2H), 1.27-1.06 (m, 2H), 0.09 (s, 9H).
Intermediate 23:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinoni-
trile
##STR00199## ##STR00200##
[1428] To a 100 mL round bottom flask was added
2,4-dihydroxybenzaldehyde (1.0 g, 7.25 mmol, 3.0 equiv),
1-bromo-3-(chloromethyl)-2-methylbenzene (527 mg, 2.4 mmol),
potassium carbonate (828 mg, 6.0 mmol, 2.5 equiv), sodium iodide
(36 mg, 0.24 mmol, 10 mol %) and N,N-dimethylformamide (20 mL,
0.12M) at room temperature. The reaction mixture was stirred at
60.degree. C. for 2 hours before being cooled to room temperature
and diluted with ethyl acetate (50 mL). The mixture was then
acidified to pH=3 with 1N aqueous hydrochloric acid then washed
once with water and once with brine. The organic layer was then
dried over magnesium sulfate, filtered, and concentrated under
vacuum. The crude material was purified by silica gel column
chromatography using a 0-10% methanol in methylene chloride eluent
gradient to provide
4-((3-bromo-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde.
[1429] To a 100 mL round bottom flask was added
4-((3-bromo-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde (422 mg, 1.32
mmol), 5-(chloromethyl)nicotinonitrile (241 mg, 1.6 mmol, 1.2
equiv), potassium carbonate (273 mg, 2.0 mmol, 1.5 equiv), sodium
iodide (50 mg, 0.33 mmol, 25 mol %) and N,N-dimethylformamide (13.2
mL, 0.1M) at room temperature. The reaction mixture was stirred at
60.degree. C. for 1 hour before being cooled to room temperature
and diluted with ethyl acetate (40 mL). The mixture was washed once
with water and once with brine. The organic layer was then dried
over magnesium sulfate, filtered, and concentrated under vacuum.
The crude material was purified by silica gel column chromatography
using a 0-10% methanol in methylene chloride eluent gradient to
provide
5-((5-((3-bromo-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitril-
e.
[1430] To a 20 mL vial was added
5-((5-((3-bromo-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitril-
e (460 mg, 1.1 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (377
mg, 1.49 mmol, 1.35 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg,
0.11 mmol, 10 mol %), potassium acetate (215 mg, 2.20 mmol, 2.0
equiv), and 1,4-dioxane (11.0 mL, 0.1M) at room temperature. The
vessel was sealed, and the mixture was sparged with nitrogen for 5
minutes before being heated to 90.degree. C. for 3 hours. The
reaction mixture was then cooled to room temperature, ethyl acetate
(10 mL) was added, and the contents of the vial were filtered
through celite. The filtrate was concentrated under vacuum, and the
crude
5-((2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzyl)oxy)phenoxy)methyl)nicotinonitrile was used without further
purification.
[1431] To a 20 mL vial was added the crude
5-((2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzyl)oxy)phenoxy)methyl)nicotinonitrile,
5-((5-((3-bromo-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitril-
e (460 mg, 1.1 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) ((81
mg, 0.11 mmol, 10 mol %), potassium carbonate (304 mg, 2.2 mmol,
2.0 equiv), N,N-dimethylformamide (11.0 mL, 0.1M), and water (1.1
mL) at room temperature. The vessel was sealed, and the mixture was
sparged with nitrogen for 5 minutes before being heated to
90.degree. C. for 1 hours. The reaction mixture was then cooled to
room temperature, ethyl acetate (10 mL) was added, and the contents
of the vial were filtered through celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed once with water then brine.
The organic layer was then dried over magnesium sulfate, filtered,
and concentrated under vacuum. The crude material was purified by
silica gel column chromatography using a 0-10% methanol in
methylene chloride eluent gradient to provide
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile.
[1432] To a 20 mL vial was added
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile
(432 mg, 0.61 mmol), potassium acetate (180 mg, 1.8 mmol, 3.0
equiv), and acetic acid (4.0 mL, 0.15 M) at room temperature. To
the mixture was added bromine (1.3 mL, 1M in acetic acid, 1.3 mmol,
2.2 equiv) dropwise. After 1 hour, 1M aqueous sodium sulfite was
added until the red color disappeared. To this mixture was added 5N
aqueous sodium hydroxide until pH=7. Finally, ethyl acetate (10 mL)
and water (10 mL) were added, and the organic layer was washed once
with brine, dried over magnesium sulfate, filtered, and
concentrated under vacuum. The crude residue of
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinoni-
trile was used without further purification.
Intermediate 24:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-hydroxynicotinaldehyde)
##STR00201##
[1434] (2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol (969 mg,
4 mmol), 6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (2.37
g, 9.2 mmol),
2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (424.65 mg,
1 mmol), palladium (II) acetate (179.2 mg, 0.8 mmol), and cesium
carbonate (5.2 g, 16 mmol) were charged into a 150 mL sealed tube.
The contents were suspended in toluene (28 mL) and sparged with
argon for 15 minutes. The tube was sealed, and heated to 90.degree.
C. After 3 h, the solution was cooled to room temperature, and
filtered through a pad of celite. The celite pad was rinsed
thoroughly with methylene chloride, and the filtrate was
concentrated and purified via column chromatography to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) as a solid
(2.3 g 85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.08 (d,
J=0.9 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 7.47-7.33 (m, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.06 (dd, J=7.6, 1.4 Hz, 2H), 6.57 (dd, J=8.3, 0.8
Hz, 2H), 5.53 (s, 4H), 4.71-4.40 (m, 4H), 1.98 (s, 6H), 1.28-0.97
(m, 4H), 0.02 (s, 18H).
[1435]
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (2.3 g, 3.39
mmol), and sodium acetate (694 mg, 8.47 mmol) was suspended in 15
mL acetic acid, and the resulting suspension was sonicated for 5
min. Bromine (0.44 mL, 8.47 mmol) was diluted in acetic acid (2 mL)
and the resulting solution was added dropwise to the stirring
dialdehyde. After 40 min, the reaction was diluted with methylene
chloride (100 mL) and aqueous 2M NaOH (150 mL). After stirring for
10 min, the organic layer was separated, and the aqueous extracted
with methylene chloride (75 mL). The combined organic layers were
dried, concentrated, and purified via column chromatography to
provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (2.5 g,
88%) as a solid. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 10.15
(s, 2H), 8.24 (s, 2H), 7.54-7.35 (m, 2H), 7.29-7.24 (m, 2H), 7.14
(dd, J=7.7, 1.4 Hz, 2H), 5.55 (s, 4H), 4.65-4.39 (m, 4H), 2.10 (s,
6H), 1.24-1.14 (m, 4H), 0.09 (s, 18H).
[1436]
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-bromo-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (1.25
g, 1.48 mmol) and cesium fluoride (0.9 g, 5.93 mmol) were suspended
in N,N-dimethylformamide (10 mL). The suspension was heated to
60.degree. C. for 1.5 h. The reaction was diluted with sat. aqueous
ammonium chloride, brine, and extracted with ethyl acetate
(2.times.). The combined organics were dried over anhydrous sodium
sulfate, and concentrated to provide 0.9 g (94.5%) of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-hydroxynicotinaldehyde) as a powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.50 (s, 2H), 9.98 (s, 2H), 8.12 (s,
2H), 7.53 (dd, J=7.8, 1.4 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H), 7.10
(dd, J=7.8, 1.4 Hz, 2H), 5.53 (s, 4H), 2.01 (s, 6H).
Intermediate 25:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-methoxynicotinaldehyde)
##STR00202##
[1438]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-bromo-2-methoxynicotinaldehyde) was obtained from
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) using the same bromination procedure
as described for Intermediate 24.
Intermediate 26:
5-((4-chloro-2-formyl-5-((3'-((4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
##STR00203##
[1440] The title compound was prepared following a similar
procedure used to synthesize intermediate 11 and 12 using 1
equivalent of 5-chloro-2,4-dihydroxybenzaldehyde followed by
4-hydroxybenzaldehyde.
Intermediate 27:
3,3'-bis(((5-formyl-6-methoxypyridin-2-yl)oxy)methyl)-2'-methyl-[1,1'-bip-
henyl]-2-carbonitrile
##STR00204##
[1442] A mixture of
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
(399 mg, 1.6 mmol), 2-bromo-6-(hydroxymethyl)benzonitrile (310 mg,
1.46 mmol), and Pd(dppf)Cl2 (88 mg) in a mixture of DMF and water
2:1 5 mL was treated with K.sub.2CO.sub.3 (172 mg, 0.002 mol). The
mixture was heated at 85.degree. C. for 2 hrs. Mixture was diluted
with EtOAc and water. Organic phase was dried over Mg.sub.2SO.sub.4
and evaporated under reduced pressure to afford
3,3'-bis(hydroxymethyl)-2'-methyl-[1,1'-biphenyl]-2-carbonitrile.
[1443] A mixture of
3,3'-bis(hydroxymethyl)-2'-methyl-[1,1'-biphenyl]-2-carbonitrile
(150 mg, 0.59 mmol), 6-chloro-2-methoxynicotinaldehyde (223 mg, 1.3
mmol), Pd(OAc).sub.2 (25 mg, 0.237 mmol), t-Butyl-X-Phos (100 mg,
0.237 mmol) and Cs.sub.2CO.sub.3 (771 mg, 2.37 mmol) in toluene 9
mL was heated under stirring conditions at 85 C for 18 hrs. The
residue was purified by column chromatography (Hexanes:Ethyl
acetate=2:1) to give the title intermediate
3,3'-bis(((5-formyl-6-methoxypyridin-2-yl)oxy)methyl)-2'-methyl-[1,1'-bip-
henyl]-2-carbonitrile.
Intermediate 28: tert-Butyl
(S)-((2-methoxy-6-((4-(2-methyl-4'-(2-oxoethoxy)-[1,1'-biphenyl]-3-yl)-2,-
3-dihydro-1H-inden-1-yl)oxy)pyridin-3-yl)methyl)glycinate
##STR00205##
[1445] Step 1. A stirred mixture of 4-iodophenol (5.0 g, 23 mmol),
2-bromo-1,1-diethoxyethane (4.45 mL, 29.5 mmol), potassium
carbonate (4.71 g, 34.1 mmol), and potassium iodide (1.89 g, 11.4
mmol) in N,N-dimethylformamide (30 mL) was heated to 109.degree. C.
After 15 h, the resulting mixture was allowed to cool to room
temperature. Diethyl ether (500 mL) was added, and the organic
layer was washed with water (3.times.500 mL), was dried over
anhydrous magnesium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (0 to 10% ethyl acetate in hexanes) to give
1-(2,2-diethoxyethoxy)-4-iodobenzene.
[1446] Step 2. A stirred mixture of 3-bromo-2-methylphenol (8.17 g,
43.7 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.1
g, 43.7 mmol), potassium acetate (12.9 g, 131 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (640
mg, 0.87 mmol) in dioxane (80 mL) was heated to 110.degree. C.
After 3 h, 1-(2,2-diethoxyethoxy)-4-iodobenzene, aqueous sodium
carbonate solution (2 M, 68 mL, 140 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (640
mg, 0.87 mmol) were added. After 18 h, the reaction mixture was
allowed to cool to room temperature and ethyl acetate (500 mL) was
added. The organic layer was washed with a mixture of water and
brine (1:1 v:v, 300 mL), was dried over anhydrous sodium sulfate,
was filtered, and was concentrated under reduced pressure. The
residue was purified by flash column chromatography (0 to 30% ethyl
acetate in hexanes) to give
4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-ol.
[1447] Step 3. Trifluoromethanesulfonic anhydride (0.798 mL, 4.74
mmol) was added via syringe to a stirred mixture of
4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-ol (1.00 g, 3.16
mmol) and N,N-diisopropylethylamine (1.38 mL, 7.90 mmol) in
dichloromethane (10 mL) at 0.degree. C. After 30 min, ethanol (0.5
mL) was added. After 5 min, the reaction mixture was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (0 to 10% ethyl acetate in hexanes) to give
4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl
trifluoromethanesulfonate.
[1448] Step 4. A stirred mixture of
4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl
trifluoromethanesulfonate (1.06 g, 2.370 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (722
mg, 2.84 mmol), potassium acetate (744 mg, 7.59 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (173
mg, 0.237 mmol) in dioxane (8.0 mL) was heated to 95.degree. C.
After 17 h, the resulting mixture was allowed to cool to room
temperature, was filtered through celite, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (0 to 10% ethyl acetate in hexanes) to give
2-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolane.
[1449] Step 5. A stirred mixture of
2-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolane (785 mg, 1.84 mmol),
(S)-4-bromo-2,3-dihydro-1H-inden-1-ol (432 mg, 2.03 mmol), aqueous
sodium carbonate solution (2 M, 3.7 mL, 7 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (73 mg, 0.092 mmol) in
dioxane (8.0 mL) and water (0.5 mL) was heated to 200.degree. C.
After 15 h, the resulting mixture was allowed to cool to room
temperature, was filtered through celite, and the filter cake was
extracted with ethyl acetate (60 mL). The organic layer was washed
with a mixture of water and brine (1:1 v:v, 50 mL), was dried over
anhydrous sodium sulfate, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
(0 to 50% ethyl acetate in hexanes) to give
(S)-4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-dihydro-
-1H-inden-1-ol.
[1450] Step 6. A stirred mixture of
(S)-4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-dihydro-
-1H-inden-1-ol (797 mg, 1.84 mmol),
6-chloro-2-methoxynicotinaldehyde (442 mg, 2.58 mmol), cesium
carbonate (1.08 g, 3.32 mmol), and
[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-ami-
no-1,1'-biphenyl)]palladium(II) methanesulfonate (73 mg, 0.092
mmol) in toluene (8.0 mL) was heated to 200.degree. C. After 15 h,
the resulting mixture was allowed to cool to room temperature, was
filtered through celite, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
(0 to 40% ethyl acetate in hexanes) to give
(S)-6-((4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-dih-
ydro-1H-inden-1-yl)oxy)-2-methoxynicotinaldehyde.
[1451] Step 7. N,N-Diisopropylethylamine (0.77 mL, 4.4 mmol) was
added via syringe to a stirred mixture of
(S)-6-((4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-dih-
ydro-1H-inden-1-yl)oxy)-2-methoxynicotinaldehyde (250 mg, 0.44
mmol) and tert-butyl glycinate hydrochloride (591 mg, 3.52 mmol) in
N,N-dimethylformamide (3.0 mL) at room temperature. After 23 min,
acetic acid (0.3 mL), sodium cyanoborohydride (221 mg, 3.52 mmol),
and sodium triacetoxyborohydride (747 mg, 3.52 mmol) were added
sequentially. After 10 min, the reaction mixture was purified by
reverse phase preparative HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) to give tert-butyl
(S)-((6-((4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-d-
ihydro-1H-inden-1-yl)oxy)-2-methoxypyridin-3-yl)methyl)glycinate.
Intermediate 29:
5-((4-chloro-5-((2,2'-dimethyl-3''-nitro-4'-(2-oxoethoxy)-[1,1':3',1''-te-
rphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
##STR00206##
[1453] Step 1. A stirred mixture of 4-bromo-2-nitrophenol (1.00 g,
4.59 mmol), 2-bromo-1,1-diethoxyethane (1.04 mL, 6.88 mmol),
potassium carbonate (1.27 g, 9.17 mmol), and potassium iodide (152
mg, 0.917 mmol) in 1-methylpyrrolidin-2-one (7.0 mL) was heated to
100.degree. C. After 18 h, the resulting mixture was allowed to
cool to room temperature. Diethyl ether (150 mL) was added, and the
organic layer was washed with water (2.times.100 mL), was dried
over anhydrous magnesium sulfate, was filtered, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography (0 to 15% ethyl acetate in hexanes) to
give 4-bromo-1-(2,2-diethoxyethoxy)-2-nitrobenzene.
[1454] Step 2. A stirred mixture of
4-bromo-1-(2,2-diethoxyethoxy)-2-nitrobenzene (123 mg, 0.370 mmol),
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (150 mg, 0.246 mmol), aqueous sodium carbonate solution (2 M,
0.49 mL, 1 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (9.7 mg, 0.012 mmol) in dioxane
(2.0 mL) and water (0.5 mL) was heated to 91.degree. C. After 14 h,
the reaction mixture was allowed to cool to room temperature and
ethyl acetate (60 mL) was added. The organic layer was washed with
a mixture of water and brine (1:1 v:v, 30 mL), was dried over
anhydrous sodium sulfate, was filtered, and was concentrated under
reduced pressure. The residue was purified by flash column
chromatography (0 to 70% ethyl acetate in hexanes) to give
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-3''-nitro-[1,1':3-
',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[1455] Step 3. Concentrated hydrochloric acid (0.25 mL) was added
to a stirred solution of
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-3''-nitro-[1,1':3-
',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(181 mg, 0.246 mmol) in dioxane (3.0 mL) at room temperature. After
60 min, ethyl acetate (60 mL) and saturated aqueous sodium
bicarbonate solution (5.0 mL) were added sequentially. The organic
layer was washed with brine (30 mL), was dried over anhydrous
sodium sulfate, was filtered, and was concentrated under reduced
pressure to give
5-((4-chloro-5-((2,2'-dimethyl-3''-nitro-4''-(2-oxoethoxy)-[1,1':3',1''-t-
erphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile,
which was used without further purification.
Intermediate 30:
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-3''-(trifluoromethyl)-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
##STR00207##
[1457]
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-3''-(trifluorometh-
yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinon-
itrile was synthesized in a manner similar to
5-((4-chloro-5-((2,2'-dimethyl-3''-nitro-4''-(2-oxoethoxy)-[1,1':3',1''-t-
erphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
using 4-bromo-2-(trifluoromethyl)phenol in place of
4-bromo-2-nitrophenol.
Intermediate 31: 3-carboxy-3,3-difluoro-2-hydroxypropan-1-aminium
2,2,2-trifluoroacetate
##STR00208##
[1459] Aqueous sodium hydroxide solution (1 M, 10 mL, 10 mmol) was
added via syringe to a stirred solution of ethyl
4-((tert-butoxycarbonyl)amino)-2,2-difluoro-3-hydroxybutanoate
(1.44 g, 5.08 mmol) in tetrahydrofuran (10 mL) and methanol (20 mL)
at room temperature. After 20 min, diethyl ether (140 mL) was
added, and the organic layer was washed with a mixture of 0.5 M
aqueous hydrogen chloride solution and brine (1:2 v:v, 60 mL), was
dried over magnesium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was dissolved in
dichloromethane (10 mL), and the resulting mixture was stirred at
room temperature. Trifluoroacetic acid (5 mL) was added. After 2.5
h, the reaction mixture was concentrated under reduced pressure and
dried azeotropically by concentration of a toluene solution under
reduced pressure (3.times.20 mL) to give
3-carboxy-3,3-difluoro-2-hydroxypropan-1-aminium
2,2,2-trifluoroacetate.
Intermediate 32:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxynicotinaldehyde)
##STR00209##
[1461]
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (1.8 g, 2.65
mmol), and 2-chloro-1,3-bis(methoxycarbonyl)guanidine (1.19 g, 5.7
mmol) were dissolved in a 1:1 mixture of chloroform and
N,N-dimethylformamide (80 mL). 4M HCl in dioxane (1.46 mL, 5.8
mmol) was added dropwise to the stirring solution. After 30 min,
the reaction was diluted with methylene chloride (100 mL), and
washed with sat. aqueous sodium bicarbonate, and brine. The organic
layer was dried over anhydrous sodium sulfate, concentrated, and
purified via column chromatography to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde). .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 10.16 (s, 2H), 8.07 (s, 2H),
7.48-7.43 (m, 2H), 7.28-7.21 (m, 2H), 7.13 (dd, J=7.6, 1.4 Hz, 2H),
5.55 (s, 4H), 4.60-4.53 (m, 4H), 2.08 (s, 6H), 1.22-1.16 (m, 4H),
0.07 (s, 18H).
[1462]
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde)
(0.90 g, 1.2 mmol) and cesium fluoride (0.73 g, 4.8 mmol) were
suspended in N,N-dimethylformamide (8 mL). The suspension was
heated to 60.degree. C. for 1.5 h. The reaction was diluted with
sat. aqueous ammonium chloride, brine, and extracted with ethyl
acetate (2.times.). The combined organics were dried over anhydrous
sodium sulfate, and concentrated to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxynicotinaldehyde). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.48 (s, 2H), 10.00 (s, 2H), 8.01 (s, 2H),
7.52 (dd, J=7.8, 1.4 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H), 7.10 (dd,
J=7.6, 1.4 Hz, 2H), 5.55 (s, 4H), 2.01 (s, 6H).
Intermediate 33: (S)-4-amino-3-hydroxybutanamide
##STR00210##
[1464] 4N hydrogen chloride in 1,4-dioxane (7.4 mL, 7.34 mmol) was
added to a solution of the tert-butyl
(S)-(4-amino-2-hydroxy-4-oxobutyl)carbamate (811 mg, 3.72 mmol) in
methanol--gas evolution. After 1 h the solvent was removed under
reduced pressure. The residue was co-evaporated with
dichloromethane and the residue was subjected to high vacuum,
providing (S)-4-amino-3-hydroxybutanamide (402 mg, 91%).
[1465] tert-butyl (S)-(4-amino-2-hydroxy-4-oxobutyl)carbamate was
prepared following the procedure given in J. Med. Chem. 1985, 28,
1612-1617.
Intermediate 34: Ethyl (R)-3-amino-2-fluoropropanoate
hydrochloride
##STR00211##
[1467] A solution of hydrogen chloride in 1,4-dioxane (4N, 8.8 mL,
35.3 mmol) was added to a solution of (R)-3-amino-2-fluoropropanoic
acid hydrochloride (253 mg, 1.76 mmol) in ethanol (8 mL). After 2
hours the solvent was removed under reduced pressure. The residue
was co-evaporated with dichloromethane (10 mL). The residue was
subjected to high vacuum, providing ethyl
(R)-3-amino-2-fluoropropanoate hydrochloride (311 mg, 103%).
Intermediate 35:
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxybenzaldehyde)
##STR00212##
[1469] Step 1: In a microwave vial, 4-bromoindole (1.0 g, 5.1
mmol), Xphos (97.0 mg, 0.20 mmol) and Pd.sub.2(dba).sub.3 (52.0 mg,
0.057 mmol) were dissolved in 80.00 mL of dioxane at room
temperature. Vial was capped and purged with argon. To this vial,
4,4,5,5-tetramethyl-1,3,2-dioxoborolate (2.2 mL, 15.30 mmol) and
trimethylamine (2.1 mL, 15.30 mmol) were added at room temperature.
Mixture was stirred at 95.degree. C. for 3 hours under argon. Vial
was taken out of the heat and allowed to cold down to room
temperature. To this microwave vial, were added 4-bromoindole (1.0
g, 5.1 mmol), Pd.sub.2(dba).sub.3 (52.0 mg, 0.057 mmol), potassium
phosphate hydrate (3.5 g, 15.20 mmol) and 8.00 mL of water at room
temperature. Vial was capped and purged with argon. Mixture was
stirred at 95.degree. C. overnight. Vial was removed from heat and
crude was diluted with ethyl acetate and filtered through celite.
Then, organic layer was washed with brine and dried over magnesium
sulfate. Volatiles were removed under reduced pressure and crude
was dry-loaded to a silica column and eluted with 20%-60% ethyl
acetate/hexanes to afford 4,4'-biindole.
[1470] Step 2: In a round bottom flask, 4,4'-biindole (1.0 g, 4.31
mmol) was dissolved in 30.00 mL of acetic acid at room temperature.
To this solution 811.00 mg of sodium cyanoborohydride was added in
portions over 20 minutes at room temperature. The mixture was
stirred at room temperature for four hours. Crude was quenched with
2.0M NaOH and organic layer was extracted with ethyl acetate.
Organic layer was dried over sodium sulfate. Volatiles were removed
under reduced pressure and crude was dry-loaded to a silica gel
column and eluted with 80-100% ethyl acetate/hexanes to afford
4,4'-biindoline.
[1471] Step 3: In a round bottom flask, 4-formyl-3-methoxybenzoic
acid (97.00 mg, 0.54 mmol) was dissolved in 3.00 of THF at room
temperature. Solution was cooled down to 0.degree. C. and oxalyl
chloride (0.10 mL, 1.08 mmol) was added dropwise followed by one
drop of DMF. Gas evolution was observed. The mixture was warmed up
to room temperature and stirred for 45 minutes. Volatiles were
removed under reduced pressure and crude material was redissolved
in 3.00 of THF. On a separate vial, 4,4'-biindoline (51.00 mg, 0.22
mmol) was dissolved in 2.00 mL of THF at room temperature. The
4,4'-biindoline solution was added to the crude material at room
temperature followed by trimethylamine (0.15 mmol, 1.08 mmol). The
mixture was stirred at room temperature for 90 minutes. Solution
was quenched with saturated sodium bicarbonate and the organic
layer was extracted with ethyl acetate. Organic layer was dried
over sodium sulfate and volatiles were removed under reduced
pressure. Crude was dry-loaded to a silica gel column and eluted
with 20-100% ethyl acetate/hexanes to afford
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxybenzaldehyde).
Intermediate 36:
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)dibenzaldehyde
##STR00213##
[1473] 4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)dibenzaldehyde was
obtained in similar fashion as shown for Intermediate 35, using
4-formylbenzoic acid instead of 4-formyl-3-methoxybenzoic acid.
Intermediate 37:
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(3-(trifluoromethyl)benzaldehyde)
##STR00214##
[1475]
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(3-(trifluoromethyl)benzaldehyde) was prepared analogous to
Intermediate 11 starting from
4-hydroxy-3-(trifluoromethyl)benzaldehyde.
Intermediate 38:
5,5'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(6-formyl-3,1-phenylene))dinicotinonitrile
##STR00215##
[1477] To a 20 mL vial was added
4-((3-bromo-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde (300 mg, 0.94
mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(322 mg, 1.27 mmol, 1.35 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69 mg,
0.09 mmol, 10 mol %), potassium acetate (184 mg, 1.88 mmol, 2.0
equiv), and 1,4-dioxane (9.4 mL, 0.1M) at room temperature. The
vessel was sealed, and the mixture was sparged with nitrogen for 5
minutes before being heated to 90.degree. C. for 3 hours. The
reaction mixture was then cooled to room temperature, ethyl acetate
(10 mL) was added, and the contents of the vial were filtered
through celite. The filtrate was concentrated under vacuum, and the
crude
2-hydroxy-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)benzaldehyde was used without further purification.
[1478] To a 20 mL vial was added the crude
2-hydroxy-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)benzaldehyde,
4-((3-bromo-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde (300 mg, 0.94
mmol, 1.0 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69 mg,
0.09 mmol, 10 mol %), potassium carbonate (260 mg, 1.88 mmol, 2.0
equiv), N,N-dimethylformamide (9.4 mL, 0.1M), and water (0.9 mL) at
room temperature. The vessel was sealed, and the mixture was
sparged with nitrogen for 5 minutes before being heated to
90.degree. C. for 1 hours. The reaction mixture was then cooled to
room temperature, ethyl acetate (10 mL) was added, and the contents
of the vial were filtered through celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed once with water and once with
brine. The organic layer was then dried over magnesium sulfate,
filtered, and concentrated under vacuum. The crude material was
purified by silica gel column chromatography using a 0-10% methanol
in methylene chloride eluent gradient to provide
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-hydroxybenzaldehyde).
[1479] To a 20 mL vial was added
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-hydroxybenzaldehyde) (250 mg, 0.52 mmol) and methylene
chloride (5.2 mL, 0.1M) at room temperature under a nitrogen
atmosphere. The vessel was cooled to 0.degree. C., and triflic
anhydride (0.19 mL, 1.14 mmol, 2.2 equiv) was added dropwise. The
reaction mixture was stirred at 0.degree. C. for 1 hour before
slowly being warmed to room temperature. After 2 hours, the
reaction mixture was diluted with methylene chloride (10 mL), and
the contents of the vial were washed .times.1 with saturated
aqueous sodium bicarbonate, once with water, and once with brine.
The organic layer was then dried over magnesium sulfate, filtered,
and concentrated under vacuum. The crude material was purified by
silica gel column chromatography using a 0-10% methanol in
methylene chloride eluent gradient to provide
(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(6--
formyl-3,1-phenylene) bis(trifluoromethanesulfonate).
[1480] To a 20 mL vial was added
(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(6--
formyl-3,1-phenylene) bis(trifluoromethanesulfonate) (279 mg, 0.34
mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (188
mg, 0.82 mmol, 2.4 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg,
0.03 mmol, 10 mol %), potassium carbonate (113 mg, 0.82 mmol, 2.0
equiv), N,N-dimethylformamide (3.4 mL, 0.1M), and water (0.4 mL) at
room temperature. The vessel was sealed, and the mixture was
sparged with nitrogen for 5 minutes before being heated to
90.degree. C. for 1 hour. The reaction mixture was then cooled to
room temperature, ethyl acetate (10 mL) was added, and the contents
of the vial were filtered through celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed once with water and once with
brine. The organic layer was then dried over magnesium sulfate,
filtered, and concentrated under vacuum. The crude material was
purified by silica gel column chromatography using a 0-10% methanol
in methylene chloride eluent gradient to provide
5,5'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(6-formyl-3,1-phenylene))dinicotinonitrile.
Intermediate 39:
5,5'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(6-formyl-3,1-phenylene))bi-
s(oxy))bis(methylene))dinicotinonitrile
##STR00216##
[1482] To a 20 mL vial was added 4,4'-biindoline (500 mg, 2.1
mmol), 4-formyl-3-hydroxybenzoic acid (872 mg, 5.25 mmol, 2.5
equiv), N,N-diisopropylethylamine (1.83 mL, 10.5 mmol, 5.0 equiv)
and N,N-dimethylformamide (21.0 mL, 0.1M) at room temperature. To
the vessel was added
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-
ium 3-oxide hexafluorophosphate (1.76 g, 4.6 mmol, 2.2 equiv), and
the reaction mixture was stirred at room temperature for 1 hour
before being diluted with ethyl acetate (10 mL). The mixture was
acidified to pH=2 with 1N aqueous hydrochloric acid then washed
.times.1 with water and xl with brine. The organic layer was then
dried over magnesium sulfate, filtered, and concentrated under
vacuum. The crude material was purified by silica gel column
chromatography using a 0-10% methanol in methylene chloride eluent
gradient to provide
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-hydroxybenzaldehyde).
[1483] To a 20 mL vial was added
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-hydroxybenzaldehyde)
(492 mg, 0.92 mmol), 5-(chloromethyl)nicotinonitrile (309 mg, 2.0
mmol, 2.2 equiv), potassium carbonate (381 mg, 2.8 mmol, 3.0
equiv), sodium iodide (35 mg, 0.23 mmol, 25 mol %) and
N,N-dimethylformamide (9.2 mL, 0.1M) at room temperature. The
reaction mixture was stirred at 60.degree. C. for 1 hour before
being cooled to room temperature and diluted with ethyl acetate (30
m). The mixture was then washed .times.1 with water and .times.1
with brine. The organic layer was then dried over magnesium
sulfate, filtered, and concentrated under vacuum. The crude
material was purified by silica gel column chromatography using a
0-10% methanol in methylene chloride eluent gradient to provide
5,5'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(6-formyl-3,1-phenylene))bi-
s(oxy))bis(methylene))dinicotinonitrile.
Intermediate 40:
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(thiazol-2-ylmethoxy)benzaldehyde)
##STR00217##
[1485] To a 100 mL round bottom flask was added
4-((3-bromo-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde (750 mg, 2.3
mmol), 2-(chloromethyl)thiazole (374 mg, 3.5 mmol, 1.2 equiv),
potassium carbonate (336 mg, 2.0 mmol, 1.5 equiv), sodium iodide
(62 mg, 0.41 mmol, 25 mol %) and N,N-dimethylformamide (23.0 mL,
0.1M) at room temperature. The reaction mixture was stirred at
60.degree. C. for 1 hour before being cooled to room temperature
and diluted with ethyl acetate (40 mL). The mixture was washed once
with water and once with brine. The organic layer was then dried
over magnesium sulfate, filtered, and concentrated under vacuum.
The crude material was purified by silica gel column chromatography
using a 0-10% methanol in methylene chloride eluent gradient to
provide
4-((3-bromo-2-methylbenzyl)oxy)-2-(thiazol-2-ylmethoxy)benzaldehyde.
[1486] To a 20 mL vial was added
4-((3-bromo-2-methylbenzyl)oxy)-2-(thiazol-2-ylmethoxy)benzaldehyde
(460 mg, 1.1 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (377
mg, 1.49 mmol, 1.35 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg,
0.11 mmol, 10 mol %), potassium acetate (215 mg, 2.20 mmol, 2.0
equiv), and 1,4-dioxane (11.0 mL, 0.1 M) at room temperature. The
vessel was sealed, and the mixture was sparged with nitrogen for 5
minutes before being heated to 90.degree. C. for 3 hours. The
reaction mixture was then cooled to room temperature, ethyl acetate
(10 mL) was added, and the contents of the vial were filtered
through celite. The filtrate was concentrated under vacuum, and the
crude
4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-
-(thiazol-2-ylmethoxy)benzaldehyde was used without further
purification.
[1487] To a 20 mL vial was added the crude
4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-
-(thiazol-2-ylmethoxy)benzaldehyde,
4-((3-bromo-2-methylbenzyl)oxy)-2-(thiazol-2-ylmethoxy)benzaldehyde
(460 mg, 1.1 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg,
0.11 mmol, 10 mol %), potassium carbonate (304 mg, 2.2 mmol, 2.0
equiv), N,N-dimethylformamide (11.0 mL, 0.1 M), and water (1.1 mL)
at room temperature. The vessel was sealed, and the mixture was
sparged with nitrogen for 5 minutes before being heated to
90.degree. C. for 1 hours. The reaction mixture was then cooled to
room temperature, ethyl acetate (10 mL) was added, and the contents
of the vial were filtered through celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed once with water then brine.
The organic layer was then dried over magnesium sulfate, filtered,
and concentrated under vacuum. The crude material was purified by
silica gel column chromatography using a 0-10% methanol in
methylene chloride eluent gradient to provide
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile.
[1488] To a 20 mL vial was added
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-(thiazol-2-ylmethoxy)benzaldehyde) (413 mg, 0.61 mmol),
N-chlorosuccinimide (204 mg, 1.5 mmol, 2.5 equiv), and chloroform
(6.1 mL, 0.1M) at rt. To the mixture was added a drop of 4M
hydrochloric acid in dioxane. After 2 hours, 1M aqueous sodium
sulfite was added until the color disappeared. To this mixture was
added 1N aqueous sodium hydroxide until pH=7.
[1489] Finally, ethyl acetate (10 mL) and water (10 mL) were added,
and the organic layer was washed once with brine, dried over
magnesium sulfate, filtered, and concentrated under vacuum. The
crude residue of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(thiazol-2-ylmethoxy)benzaldehyde) was used without
further purification.
Intermediate 41:
2,2'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-formyl-6-methoxynicotinonitrile)
##STR00218##
[1491] To a 20 mL vial was added
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (150 mg, 0.29 mmol), N-iodosuccinimide
(144 mg, 0.64 mmol, 2.2 equiv), and methylene chloride (2.9 mL,
0.1M) at rt. To the vessel was added 1 drop oftrifluoroacetic acid.
After 2 hours, the mixture was diluted with methylene chloride 10
mL) and water (10 mL). The organic layer was washed once with
brine, dried over magnesium sulfate, filtered, and concentrated
under vacuum. The crude material was purified by silica gel column
chromatography using a 0-10% methanol in methylene chloride eluent
gradient to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-iodo-2-methoxynicotinaldehyde).
[1492] To a 2 dram vial was added
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-iodo-2-methoxynicotinaldehyde) (166 mg, 0.22 mmol), copper(I)
cyanide (59 mg, 0.66 mmol, 3.0 equiv), and acetonitrile (0.9 mL,
0.25M). The mixture was heated to reflux for 2 hours then cooled to
room temperature. The mixture was diluted with ethyl acetate (5 mL)
and filtered through celite. The filtrate of
2,2'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-formyl-6-methoxynicotinonitrile) was concentrated under vacuum
and used without further purification.
Intermediate 42:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxy-5-(methylsulfonyl)nicotinaldehyde)
##STR00219##
[1494] To a 2-dram vial was added
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-iodo-2-methoxynicotinaldehyde) (166 mg, 0.22 mmol), potassium
metabisulfite (196 mg, 0.88 mmol, 4.0 equiv), sodium formate (66
mg, 0.97 mmol, 4.4 equiv), tetrabutylammonium bromide (156 mg, 0.48
mmol, 2.2 equiv), palladium (II) acetate (5.0 mg, 0.02 mmol, 10 mol
%), triphenylphosphine (17 mg, 0.07 mmol, 30 mol %),
1,10-phenanthroline (12 mg, 0.07 mmol, 30 mol %), and DMSO (1.1 mL,
0.2M) at room temperature. The mixture was sparged for 5 minutes
with nitrogen and stirred overnight. Then, methyl iodide (0.041 mL,
0.66 mmol, 3.0 equiv) was added, and the mixture was stirred
overnight. The mixture was diluted with ethyl acetate (5 mL) and
washed once with water then brine. The organic layer was then dried
over magnesium sulfate, filtered, and concentrated under vacuum.
The crude material was purified by silica gel column chromatography
using a 0-10% methanol in methylene chloride eluent gradient to
provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxy-5-(methylsulfonyl)nicotinaldehyde).
Intermediate 43:
(S)-5-(((6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5--
chloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile
##STR00220## ##STR00221##
[1496] Step 1: To a solution of 4-hydroxy-indan-1-one in CH2Cl2
(500 mL) was added imidazole. The mixture was stirred for 5
minutes, to which was added portion wise tert-butyldimethylsilyl
chloride while cooling in an ice bath. The mixture was stirred for
16 hours at room temperature and was diluted with EtOAc. The
organic layer was washed with citric acid, water and brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude residue was purified by column
chromatography (Hex-EA) to give
4-(tert-butyl-dimethyl-silanyloxy)-indan-1-one (54 g, 101% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.27 (d, 1H, J=7.5 Hz),
7.15 (t, 1H, J=7.5 Hz), 6.89 (d, 1H, J=7.5 Hz), 2.93 (t, 2H, J=5.7
Hz), 2.57 (t, 2H, J=5.7 Hz), 0.81 (s, 9H), 0.15 (s, 6H).
[1497] Step 2: To a 3000 mL rbf was added
(R)-(+)-2-methyl-CBS-oxazaborolidine (8.397 g, 30.29 mmol), toluene
(30 mL) and borane-dimethylsulfide (105.35 mL, 1111 mmol) under N2.
The reaction was stirred at room temperature for 10 min then
diluted with DCM (240 mL) and cooled to -20.degree. C. A solution
of 4-bromo-2,3-dihydro-1H-inden-1-one (53.0 g, 202 mmol) in DCM
(240 mL) was added dropwise over 30 min while maintaining the
reaction temperature at -10.+-.5.degree. C. The reaction was
stirred for 2 h. Rxn quenched by the dropwise addition of MeOH (500
mL). Cooling bath was removed and reaction warmed to rt, then about
half the rxn volume was distilled off using a short-path
distillation apparatus. All remaining solvent was then evaporated
under reduced pressure to give a solid which was purified by silica
gel column chromatography eluting with EA-Hex to provide the
desired product (58 g, 109% yield) as an oil that crystallized on
standing. ES/MS m/z: [M-OH].sup.+=247. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.13 (dt, J=15.3, 0.8 Hz, 1H), 7.02 (d, J=7.4
Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 5.23 (t, J=6.0 Hz, 1H), 3.00 (ddd,
J=16.2, 8.6, 4.7 Hz, 1H), 2.79-2.66 (m, 1H), 2.46 (dddd, J=13.1,
8.3, 6.9, 4.7 Hz, 1H), 1.92 (dddd, J=13.6, 8.6, 6.3, 5.2 Hz, 1H),
1.00 (s, 9H), 0.20 (d, J=1.8 Hz, 6H).
[1498] Step 3: A solution of
(S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-ol (6.0
g, 22.7 mmol) and
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (11.7 g, 45.4
mmol), in toluene (40 mL) was degassed by vigorously bubbling
N.sub.2 thru solution for 10 min. Then Pd(OAc).sub.2 (1.02 g, 4.54
mmol), t-BuXPhos (3.85 g, 9.07 mmol) and cesium carbonate (29.5 g,
90.8 mmol) were added and the bubbling continued for 5 min more.
The reaction was then stirred at 35 C for 48 h under N.sub.2. Rxn
was cooled to rt and diluted with DCM. Filtered thru celite and
loaded directly on silica gel column, eluting with Hex-DCM to
provide
(S)-6-((4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)-2-
-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (9.51 g, 86% yield) as a
light oil that crystallized on standing. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 10.29 (d, J=0.8 Hz, 1H), 8.92 (d, J=2.1 Hz,
1H), 8.86 (d, J=2.0 Hz, 1H), 8.16-8.04 (m, 2H), 7.10 (s, 1H), 7.10
(dt, J=15.5, 0.8 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.79-6.72 (m,
1H), 6.50-6.41 (m, 2H), 5.68-5.53 (m, 2H), 4.12 (q, J=7.1 Hz, 1H),
3.07 (ddd, J=16.3, 8.8, 5.2 Hz, 1H), 2.86 (ddd, J=16.3, 8.6, 5.5
Hz, 1H), 2.51 (dddd, J=13.9, 8.6, 7.1, 5.3 Hz, 1H), 2.14 (dddd,
J=13.9, 8.7, 5.5, 4.4 Hz, 1H), 2.04 (s, 1H), 1.32-1.19 (m, 2H),
1.01 (s, 9H), 0.23 (s, 6H).
[1499] Step 4:
(S)-6-((4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)-2-
-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (4.69 g, 9.66 mmol) was
taken up in 50 mL THF and cooled to -78 C. TBAF (9.66 mL, 9.66
mmol) was added dropwise and the reaction allowed to warm up to 0 C
over 30 min, providing a dark orange solution. AcOH (0.552 mL,
9,655 mmol) was added dropwise, removing most of the color. Rxn was
then diluted with EtOAc and pH 5 citrate buffer. Organic layer was
dried (Na2SO4) and the reaction conc. Purification by silca gel
chromatography provided
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde (2.75 g, 77% yield) and an off-white solid.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 10.23 (d, J=0.8 Hz,
1H), 8.04 (d, J=8.4 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.07-6.96 (m,
1H), 6.78 (dd, J=7.9, 1.0 Hz, 1H), 6.53 (dd, J=7.1, 4.2 Hz, 1H),
6.34 (dd, J=8.4, 0.9 Hz, 1H), 5.20 (s, 1H), 4.66-4.57 (m, 2H), 3.10
(ddd, J=14.5, 8.7, 5.4 Hz, 1H), 2.89 (ddd, J=15.8, 8.7, 5.2 Hz,
1H), 2.66 (dddd, J=14.0, 8.6, 7.0, 5.4 Hz, 1H), 2.26 (dddd, J=13.9,
8.7, 5.2, 4.2 Hz, 1H), 0.91 (s, 2H), 0.08 (s, 9H).
[1500] Step 5: A solution of
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde (5.00 g, 13 mmol) in 55 mL DCM was treated with
pyridine (2.76 mL, 34 mmol), DMAP (164 mg, 1.3 mmol) and TEA (3.75
mL, 27 mmol) was cooled to -78 C and treated dropwise with Tf2O
(2.50 mL, 15 mmol). Stirred for 15 min, then allowed to warm to rt.
After 1 h the reaction was diluted with EtOAc, washed with citric
acid soln, dried with Na2SO4 and concentrated. Purification by
silica chromatography (hex-DCM) provided
(S)-1-((5-formyl-6-(2-(trimethylsilyl)ethoxy)pyridin-2-yl)oxy)-2-
,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (6.42 g, 94%
yield). [M+H]=503.7. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.25 (d, J=0.8 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.5 Hz,
1H), 7.33 (t, J=7.8 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.56 (dd,
J=7.1, 5.0 Hz, 1H), 6.37 (dd, J=8.4, 0.8 Hz, 1H), 4.60 (td, J=8.2,
1.2 Hz, 2H), 3.27 (ddd, J=16.6, 8.9, 5.1 Hz, 1H), 3.12-2.99 (m,
1H), 2.72 (dddd, J=13.7, 8.5, 7.1, 5.1 Hz, 1H), 2.29 (dddd, J=13.8,
8.8, 6.1, 4.9 Hz, 1H), 1.55 (s, 1H), 1.24-1.18 (m, 2H), 0.07 (s,
9H). 19F NMR .delta. -74.10.
[1501] Step 6: A solution of
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde (6.42 g, 0.13 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.89
g, 15 mmol), Pd-dppf (0.932 g, 1.27 mmol) and KOAc (3.75 g, 38
mmol) in 55 mL dioxane was stirred at 90 C overnight. Reaction was
diluted with EtOAc, filtered thru celite and conc. Purification of
the filtrate derived material by ISCO (DCM-hexanes) provided
(S)-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (4.89 g,
79% yield) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 10.24 (d, J=0.9 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.78 (dd,
J=7.3, 1.3 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.4 Hz, 1H),
6.51 (dd, J=7.1, 4.3 Hz, 1H), 6.33 (dd, J=8.3, 0.9 Hz, 1H),
4.66-4.57 (m, 2H), 3.36 (ddd, J=17.2, 8.7, 5.7 Hz, 1H), 3.15 (ddd,
J=17.2, 8.7, 5.6 Hz, 1H), 2.60 (dddd, J=14.1, 8.6, 7.1, 5.6 Hz,
1H), 2.26-2.13 (m, 1H), 1.34 (s, 12H), 1.31-1.18 (m, 2H), 0.07 (s,
9H).
[1502] Step 7: A solution of
(S)-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (3.60 g,
7.5 mmol), 2,6-dibromo-1-chlorobenzene (6.06 g, 22.4 mmol), Pd-dppf
(471 mg, 0.748 mmol) and K.sub.2CO.sub.3 (2.58 mg, 19 mmol) in 60
mL dioxane was treated with 10 mL water and heated to 90.degree. C.
for 2 h. The reaction was then cooled to rt, diluted with EtOAc and
dried with MgSO.sub.4. The mixture was filtered thru celite and
concentrated to provide a crude oil. Purification by column
chromatography (ISCO, elution with DCM-hexanes) provided
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde (3.05 g, 75% Yield). .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 10.25 (d, J=0.9 Hz, 1H), 8.06
(d, J=8.3 Hz, 1H), 7.66 (dd, J=7.7, 1.9 Hz, 1H), 7.50 (d, J=7.5 Hz,
1H), 7.39-7.28 (m, 2H), 7.31-7.13 (m, 2H), 6.61 (s, 1H), 6.47-6.31
(m, 1H), 4.67-4.57 (m, 2H), 2.99 (dd, J=15.6, 9.6 Hz, 1H),
2.90-2.74 (m, 1H), 2.65 (m, 1H), 2.21 (m, J=8.5 Hz, 1H), 1.34-1.18
(m, 2H), 0.07 (s, 9H).
[1503] Step 8: A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde (1.20 g, 2.20 mmol) in 6 mL
DCM and 3 mL DMF was treated with Palau-Cl (557 mg, 2.75 mmol) and
TFA (33.7 .mu.L, 0.44 mmol). The reaction was stirred for 16 h at
rt, then diluted with DCM and treated with 10 mL sat thiosulfate
and 20 mL NaHCO.sub.3. After stirring vigorously for 10 min, the
organic layer was separated, dried with MgSO.sub.4, filtered and
concentrated. Purification by column chromatography (ISCO, elution
with DCM-hexanes) provided
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (726 mg, 56% Yield).
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 10.20 (s, 1H), 8.09 (s,
1H), 7.66 (dd, J=7.7, 1.9 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.34 (t,
J=7.6 Hz, 1H), 7.29-7.14 (m, 1H), 7.20 (s, 2H), 6.58 (d, J=22.9 Hz,
1H), 4.61 (t, J=8.3 Hz, 2H), 2.94-2.77 (m, 2H), 2.69 (m, 2H),
2.28-2.20 (m, 1H), 1.27-1.17 (m, 2H), 0.07 (s, 9H).
[1504] Step 9: A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (303 mg, 0.523 mmol)
in 5 mL DMF was treated with CsF (318 mg, 2.1 mmol) and stirred for
1 h at 60.degree. C. K.sub.2CO.sub.3 (217 mg, 0.569 mmol) and
5-(chloromethyl)nicotinonitrile hydrochloride (148 mg, 0.784 mmol).
After 30 min the reaction was partitioned between EtOAc and 2.5%
LiCl. Organic layer was washed with 2% LiCl, dried with sodium
sulfate, filtered and conc. Purification by column chromatography
(ISCO, elution with EtOAc-hexanes) provided
(S)-5-(((6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5--
chloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile
(Intermediate 43). LCMS-ESI+ (m/z): [M+H]+ calcd for
C.sub.28H.sub.18BrCl.sub.2N.sub.3O.sub.3: 593.99; found:
593.79.
Intermediate 44: 6-bromo-1-naphthaldehyde
##STR00222##
[1506] Step 1: A 2 M solution of Borane dimethyl sulfide (4 equiv.)
was added dropwise to a slurry of 6-bromo-1-naphthoic acid (250 mg,
0.996 mmol) in THF (2.5 mL) at 0.degree. C. The reaction vessel was
then warmed to 35.degree. C. for 1 hour. LC/MS indicated full
consumption of starting material. The reaction vessel then cooled
to 0.degree. C. and methanol was added dropwise until gas evolution
was no longer observed. The reaction was then warmed to room
temperature, diluted with water (5 mL), and extracted 3.times.5 mL)
with ethyl acetate. The combined organic layers were dried over
sodium sulfate, concentrated in vacuo, and used without further
purification.
[1507] Step 2: (6-bromonaphthalen-1-yl)methanol from the previous
step was taken up in methylene chloride. At room temperature
Dess-Martin periodinane (1.2 equiv.) was added in a single portion.
The reaction was stirred at room temperature for 1 hour. LC/MS
indicated full consumption of starting material. The reaction was
concentrated in vacuo. The crude material was purified by column
chromatography (EtOAc/Hexanes) to afford
6-bromo-1-naphthaldehyde.
Intermediate 45:
5-((4-chloro-5-((2'-chloro-4''-((dimethylamino)methyl)-6'-fluoro-2-methyl-
-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitr-
ile
##STR00223##
[1509] Step 1. A stirred mixture of
N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)met-
hanamine hydrochloride (1.00 g, 3.36 mmol),
1-bromo-2-chloro-4-fluorobenzene (1.06 g, 5.04 mmol), aqueous
sodium carbonate solution (2.0 M, 8.4 mL, 16.8 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (79 mg, 0.10 mmol) in
1,4-dioxane was heated to 100.degree. C. After 50 min, the
resulting mixture was allowed to cool to room temperature, was
filtered through celite, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (0 to 20% methanol in dichloromethane) to give
1-(2'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-N,N-dimethylmethanamine.
[1510] Step 2. 2,2,6,6-Tetramethylpiperidinylmagnesium chloride
lithium chloride complex solution (1.0 M in tetrahydrofuran and
toluene, 6.46 mL, 6.5 mmol) was added via syringe to a stirred
solution of
1-(2'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-N,N-dimethylmethanamine
(775 mg, 2.94 mmol) in tetrahydrofuran (7.0 mL) at room
temperature. After 2 h, the resulting mixture was cooled to
0.degree. C., and iodine (1.12 g, 4.41 mmol) was added as a solid
under a nitrogen atmosphere. After 20 min, aqueous sodium
thiosulfate solution (1.0 M, 5 mL) was added, and the resulting
biphasic mixture was allowed to warm to room temperature with
vigorous stirring. Diethyl ether (200 mL) was added, and the
organic layer was washed sequentially with a mixture of water and
saturated aqueous sodium carbonate solution (10:1 v:v, 100 mL) and
water (100 mL), was dried over anhydrous magnesium sulfate, was
filtered, and was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (0 to 15%
methanol in dichloromethane) to give
1-(2'-chloro-4'-fluoro-3'-iodo-[1,1'-biphenyl]-4-yl)-N,N-dimethylmethanam-
ine.
[1511] Step 3. A stirred mixture of
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (292 mg, 0.565
mmol),
1-(2'-chloro-4'-fluoro-3'-iodo-[1,1'-biphenyl]-4-yl)-N,N-dimethylmethanam-
ine (200 mg, 0.513 mmol), aqueous sodium carbonate solution (2.0 M,
1.0 mL, 2.0 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.013 mmol) in
1,4-dioxane (5.0 mL) was heated to 105.degree. C. in a heating
block. After 60 min, the resulting mixture was allowed to cool to
room temperature, was filtered through celite, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 20% methanol in dichloromethane)
to give
5-((4-chloro-5-((2'-chloro-4''-((dimethylamino)methyl)-6'-fluoro-2-methyl-
-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitr-
ile.
Intermediate 46: 5-((4-chloro-5-((2,2'-dimethyl-4`
`-(quinuclidin-3-yloxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphe-
noxy)methyl)nicotinonitrile
##STR00224##
[1513] Step 1. Diisopropyl azodicarboxylate (464 mg, 2.29 mmol) was
added via syringe to a stirred mixture of quinuclidin-3-ol (117 mg,
0.918 mmol), 4-bromophenol (476 mg, 2.75 mmol), and
triphenylphosphine (650 mg, 2.48 mmol) in tetrahydrofuran (5.0 mL)
at room temperature. After 5 min, the resulting mixture was heated
to 50 C in a heating block. After 2 h, the resulting mixture was
allowed to cool to room temperature and was purified by flash
column chromatography on silica gel (0 to 100% ethyl acetate in
hexanes to 0 to 20% methanol in dichloromethane to 3% triethylamine
and 20% methanol in dichloromethane) to give
3-(4-bromophenoxy)quinuclidine.
[1514] Step 2. A stirred mixture of
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (30 mg, 0.049 mmol), 3-(4-bromophenoxy)quinuclidine (28 mg, 0.099
mmol), aqueous sodium carbonate solution (2.0 M, 200 .mu.L, 0.40
mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (2 mg, 0.002 mmol) in
1,4-dioxane (1.5 mL) was heated to 105.degree. C. in a heating
block. After 60 min, the resulting mixture was allowed to cool to
room temperature. Diethyl ether (20 mL) and ethyl acetate (10 mL)
were added, and the organic layer was washed with a mixture of
water and saturated aqueous sodium carbonate solution (10:1 v:v,
2.times.30 mL), was dried over magnesium sulfate, was filtered, and
was concentrated under reduced pressure to give
5-((4-chloro-5-((2,2'-dimethyl-4''-(quinuclidin-3-yloxy)-[1,1':3',1''-ter-
phenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
Intermediate 47:
5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,1':3'-
,1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)n-
icotinaldehyde 2,2,2-trifluoroacetate
##STR00225##
[1516] Step 1. A stirred mixture of
(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
(22.4 g, 83.3 mmol), 1,3-dibromo-2-chlorobenzene (33.8 g, 125
mmol), potassium carbonate (27.6 g, 200 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.83
g, 2.50 mmol) in 1,4-dioxane (150 mL) and water (40 mL) was heated
to 115.degree. C. in a heating block. After 90 min, the resulting
mixture was allowed to cool to room temperature and was filtered
through celite. Ethyl acetate (500 mL) was added, and the organic
layer was washed with a mixture of water and brine (1:1 v:v, 300
mL), was dried over anhydrous sodium sulfate, was filtered, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (0 to 30% ethyl acetate
in hexanes) to give
(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol.
[1517] Step 2. Sodium hydride (60% w/w dispersion in mineral oil,
1.70 g, 42.4 mmol) was added as a solid under a nitrogen atmosphere
to a stirred solution of
(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol (11.7 g, 35.3
mmol) in N,N-dimethylformamide (200 mL) at 0.degree. C. After 45
min, 6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (9.11 g,
35.3 mmol) was added as a solid under a nitrogen atmosphere. After
13.5 h, saturated aqueous ammonium chloride solution (20 mL) was
added, and the resulting mixture was concentrated under reduced
pressure. Ethyl acetate (267 mL), diethyl ether (400 mL), and
tetrahydrofuran (133 mL) were added, and the organic layer was
washed with water (800 mL), was dried over anhydrous magnesium
sulfate, was filtered, and was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (0 to 20% ethyl acetate in hexanes) to give
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-2-(2-(trimethyls-
ilyl)ethoxy)nicotinaldehyde.
[1518] Step 3. Hydrogen chloride solution (4.0 M in 1,4-dioxane,
5.46 mL, 22 mmol) was added via syringe over 5 min to a stirred
mixture of
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-2-(2-(trimethyls-
ilyl)ethoxy)nicotinaldehyde (11.0 g, 19.8 mmol) and
2-chloro-1,3-bis(methoxycarbonyl)guanidine (4.58 g, 21.8 mmol) in
acetonitrile (100 mL) and chloroform (50 mL) at room temperature.
After 30 min, saturated aqueous sodium bicarbonate solution (300
mL) and water (200 mL) were added, and the aqueous layer was
extracted with dichloromethane (2.times.250 mL). The combined
organic layers were dried over anhydrous sodium sulfate, were
filtered, and were concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (0 to 20%
ethyl acetate in hexanes) to give
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde.
[1519] Step 4. Cesium fluoride (1.55 g, 10.2 mmol) was added as a
solid under a nitrogen atmosphere to a stirred solution of
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde (1.50 g, 2.55 mmol) in
N,N-dimethylformamide (10 mL) at room temperature, and the
resulting mixture was heated to 70.degree. C. in a heating block.
After 45 min, 3-(chloromethyl)-5-(methylsulfonyl)pyridine (577 mg,
2.81 mmol) was added as a solid under a nitrogen atmosphere. After
75 min, the resulting mixture was allowed to cool to room
temperature. Ethyl acetate (83 mL) and diethyl ether (167 mL) were
added, and the organic layer was washed with water (2.times.250
mL), was dried over anhydrous magnesium sulfate, was filtered, and
was concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (0 to 100% ethyl
acetate in hexanes) to give
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-(-
methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde.
[1520] Step 5. A stirred mixture of
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-(-
methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde (500 mg, 0.761
mmol), 2-(trimethylsilyl)ethyl
(2-hydroxyethyl)(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenox-
y)ethyl)carbamate (412 mg, 0.914 mmol), saturated aqueous sodium
carbonate solution (2.0 M, 1.5 mL, 3.0 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg,
0.076 mmol) in 1,4-dioxane (8 mL) was heated to 105.degree. C. in a
heating block. After 5 h, the resulting mixture was purified by
flash column chromatography on silica gel (0 to 30% ethyl acetate
in hexanes) to give 2-(trimethylsilyl)ethyl
(2-((2',2''-dichloro-3''-(((3-chloro-5-formyl-6-((5-(methylsulfonyl)pyrid-
in-3-yl)methoxy)pyridin-2-yl)oxy)methyl)-[1,1':3',1''-terphenyl]-4-yl)oxy)-
ethyl)(2-hydroxyethyl)carbamate.
[1521] Step 6. Trifluoroacetic acid (2.0 mL) was added via syringe
to a stirred solution of 2-(trimethylsilyl)ethyl
(2-((2',2''-dichloro-3''-(((3-chloro-5-formyl-6-((5-(methylsulfonyl)pyrid-
in-3-yl)methoxy)pyridin-2-yl)oxy)methyl)-[1,1':3',1''-terphenyl]-4-yl)oxy)-
ethyl)(2-hydroxyethyl)carbamate (100 mg, 0.111 mmol) in
dichloromethane (5.0 mL) at room temperature. After 80 min, the
resulting mixture was concentrated under reduced pressured. The
residue was dried azeotropically by concentration of a toluene
solution under reduced pressure (2.times.3 mL) to give
5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,1':3'-
,1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)n-
icotinaldehyde 2,2,2-trifluoroacetate.
Intermediate 48:
5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,1':3'-
,1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)n-
icotinaldehyde 2,2,2-trifluoroacetate
##STR00226##
[1523] Step 1. A stirred mixture of
5-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.4 mmol),
(R)-2-methylpropane-2-sulfinamide (6.32 g, 52.2 mmol), and
tetraethoxytitanium (14.9 mL, 71.1 mmol) in toluene (50 mL) was
heated to 95.degree. C. in a heating block. After 15 h, the
resulting mixture was allowed to cool to room temperature and was
poured into vigorously stirred brine (50 mL). The resulting mixture
was filtered through celite, and the filter cake was extracted with
a mixture of diethyl ether and ethyl acetate (1:1 v:v, 100 mL). The
organic layer was washed with brine (50 mL), was dried over
anhydrous sodium sulfate, and was filtered through a short plug of
silica. The filter cake was extracted with a mixture of diethyl
ether and ethyl acetate (1:1 v:v, 100 mL), and the combined organic
layers were concentrated under reduced pressure, and the residue
was dried azeotropically by concentration of a toluene solution
under reduced pressure (2.times.50 mL). The residue was dissolved
in toluene (50 mL) and was stirred at room temperature. After 5
min, the resulting mixture was cooled to -78.degree. C. After 10
min, trimethylaluminum solution (2.0 M in toluene, 13.4 mL, 27
mmol) was added via syringe. In a separate reaction vessel,
tetravinylstannane (2.67 mL, 14.6 mmol) was added via syringe to a
stirred mixture of of methyllithium solution (1.6 M in diethyl
ether, 33.6 mL, 54 mmol) in toluene (100 mL) at 0.degree. C. After
15 min, the resulting mixture was cooled to -78.degree. C. After 15
min, the mixture of the dried residue from the first reaction and
trimethylaluminum in toluene was added via cannula over 10 min.
After 78 min, the resulting mixture was warmed to 0.degree. C.
After 100 min, vinylmagnesium bromide solution (1.0 M in
tetrahydrofuran, 48.8 mL, 49 mmol) was added via syringe. After 2
h, saturated aqueous sodium sulfate solution was added over 5 min,
and the resulting mixture was allowed to warm to room temperature
with vigorous stirring and was filtered through celite. The filter
cake was extracted with ethyl acetate (200 mL), and the combined
organic layers were washed with brine (100 mL), were dried over
anhydrous sodium sulfate, were filtered, and were concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 100% ethyl acetate in hexanes)
to give
(R)-N-((S)-5-bromo-1-vinyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-s-
ulfinamide.
[1524] Step 2. Ozone was bubbled through a stirred solution of
(R)-N-((S)-5-bromo-1-vinyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-s-
ulfinamide (667 mg, 1.95 mmol) in dichloromethane (20 mL) and
methanol (20 mL) at -78.degree. C. for 9 min, at which time a
persistently blue colored mixture was obtained. Nitrogen gas was
bubbled through the resulting mixture for 11 min, by which time the
blue color had dissipated. Sodium borohydride (442 mg, 11.7 mmol)
was added as a solid under a nitrogen atmosphere. After 15 min, the
resulting mixture was allowed to warm to room temperature over 15
min. After 30 min, aqueous sodium thiosulfate solution (1.0 M, 5
mL) was added, and the resulting mixture was concentrated under
reduced pressure. Ethyl acetate (100 mL) and saturated aqueous
ammonium chloride solution (20 mL) were added, and the organic
layer was washed with brine (50 mL), was dried over anhydrous
sodium sulfate, was filtered, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (0 to 10% methanol in dichloromethane) to give
(R)-N-((R)-5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-2-methylp-
ropane-2-sulfinamide.
[1525] Step 3. Hydrogen chloride solution (5.0 M in 2-propanol,
2.96 mL, 15 mmol) was added via syringe to a stirred solution of
(R)-N-((R)-5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-2-methylp-
ropane-2-sulfinamide (512 mg, 1.48 mmol) in 1,4-dioxane (5.3 mL) at
0.degree. C., and the resulting mixture was allowed to warm to room
temperature. After 30 min, the resulting mixture was concentrated
under reduced pressure. The residue was dried azeotropically by
concentration of a toluene solution under reduced pressure
(2.times.7 mL) to give
(R)-(1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)methanol
hydrochloride.
[1526] Step 4. Sodium triacetoxyborohydride (761 mg, 3.59 mmol) was
added as a solid to a vigorously stirred mixture of
(R)-(1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)methanol
hydrochloride (200 mg, 0.718 mmol), aqueous formaldehyde solution
(37% w/w, 267 .mu.L, 3.59 mmol) and potassium acetate (141 mg, 1.44
mmol) in dichloromethane (3.6 mL) and tetrahydrofuran (3.6 mL) at
room temperature. After 30 min, the resulting mixture was filtered
and was concentrated under reduced pressure. The residue was
purified by reverse phase preparative hplc (0.1% trifluoroacetic
acid in acetonitrile/water) to give
(R)-(5-bromo-1-(dimethylamino)-2,3-dihydro-1H-inden-1-yl)methanol
2,2,2-trifluoroacetate.
[1527] Step 5. A stirred mixture of
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (25 mg, 0.041 mmol),
(R)-(5-bromo-1-(dimethylamino)-2,3-dihydro-1H-inden-1-yl)methanol
2,2,2-trifluoroacetate (32 mg, 0.082 mmol), saturated aqueous
sodium carbonate solution (2.0 M, 164 .mu.L, 0.33 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (2 mg, 0.002 mmol) in
1,4-dioxane (1.5 mL) was heated to 105.degree. C. in a heating
block. After 60 min, the resulting mixture was purified by flash
column chromatography on silica gel (0 to 20% methanol in
dichloromethane) to give
(R)-5-(((5-chloro-6-((3'-(1-(dimethylamino)-1-(hydroxymethyl)-2,3-dihydro-
-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-3-formylpyridi-
n-2-yl)oxy)methyl)nicotinonitrile.
Intermediate 49:
2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane)
##STR00227##
[1529] A solution of 3-bromo-2-methylphenol (5 g, 26.7 mmol),
B.sub.2Pin.sub.2 (8.1 g 32.1 mmol), Pd(dppf)Cl.sub.2 (3.3 g, 4
mmol) and KOAc (6.9 g, 70 mmol) in dioxane (100 mL) was sparged
with argon for 15 min. The reaction mixture was heated at
90.degree. C. for 5 h under argon atmosphere. The reaction was
cooled to ambient temperatures followed by addition of a solution
of 3-bromo-2-methylphenol (5 g, 26.7 mmol) in 20 mL of dioxane and
K.sub.2CO.sub.3 (7.4 g, 53 mmol) in 25 mL H.sub.2O. The reaction
was heated at 90.degree. C. for an additional 16 h. The reaction
was cooled to ambient temperatures, and poured into a mixture of
sat. aq. NH.sub.4Cl and EtOAc. The layers were separated and the
aqueous layer was further extracted with EtOAc. The combined
organic layers were washed with brine, dried (over
Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
mixture was purified by SiO.sub.2 column chromatography (ISCO gold,
120 g column; 0-60% EtOAc/Hex) to afford 4.4 g (77%) of
2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diol as a white solid. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.28 (s, 1H), 6.97 (t, J=7.8 Hz,
1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 6.46 (dd, J=7.5, 1.2 Hz, 1H),
3.30 (s, 1H), 1.76 (s, 3H).
[1530] To a solution of 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diol
(824 mg, 3.85 mmol) in CH.sub.2Cl.sub.2 (20.0 mL) cooled in an
ice-water bath was added N,N-Diisopropylethylamine (2.68 mL, 15.4
mmol) followed by dropwise addition of Trifluoromethanesulfonic
Anhydride (1.58 mL, 9.61 mmol). The reaction mixture was maintained
in the bath allowing it warm to room temperature over 2 h. The
reaction mixture was quenched by the addition of sat NH.sub.4Cl and
EtOAc. The layers were separated and the aqueous layer was further
extracted with EtOAc. The combined organic layers were washed with
brine, dried (over Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The crude mixture was purified by SiO2 column chromatography
(ISCO gold, 40 g column; 0-100% EtOAc/Hex) to afford 1.6 g (87%)
2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl
bis(trifluoromethanesulfonate). .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 7.40-7.28 (m, 2H), 7.16 (dd, J=6.6, 2.2 Hz, 1H), 2.05 (s,
3H).
[1531] 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl
bis(trifluoromethanesulfonate) (1.6 g, 3.34 mmol), B.sub.2Pin.sub.2
(2.12 g, 8.36 mmol), KOAc (984 mg, 10.0 mmol) and Pd(dppf)Cl.sub.2
(553 mg, 0.67 mmol) were suspended in dioxane (32.0 mL) and sparged
with argon for 10 min. The reaction mixture was stirred at
90.degree. C. for 16 h. The mixture was cooled to ambient
temperatures and quenched by the addition of sat NH4Cl and EtOAc.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The combined organic layers were washed with
brine, dried (over Na2SO4), filtered and concentrated in vacuo. The
crude mixture was purified by SiO.sub.2 column chromatography (ISCO
gold, 40 g column; 0-100% EtOAc/Hex) to afford
2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane). .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.74
(dd, J=7.3, 1.6 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.12 (dd, J=7.6,
1.6 Hz, 1H), 2.20 (s, 3H), 1.35 (s, 12H).
Intermediate 50:
6,6'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(2-methoxynicotinaldehyd-
e)
##STR00228##
[1533]
2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolane) (200 mg, 0.46 mmol),
6-chloro-2-methoxynicotinaldehyde (205 mg, 1.2 mmol), Pd(PPh3)4 (80
mg, 0.07 mmol), and K2CO3 (254 mg, 1.84 mmol) were charged in a
vial and suspended in Dioxane (10 mL) and water (1 mL). The mixture
was sparged with argon for 5 min, and sealed with a teflon coated
cap. The mixture was stirred at 90.degree. C. for 8 h. After
cooling to room temperature, the reaction was diluted with ethyl
acetate and brine. The organic layer was separated, dried with
anhydrous sodium sulfate, concentrated, and purified by silica gel
chromatography to provide
6,6'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(2-methoxynicotinaldehyd-
e).
Intermediate 51:
(R)-1-((2',2''-dimethyl-3''-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-[1,1':3',1''-terphenyl]-4-yl)methyl)pyrrolidin-3-ol
##STR00229##
[1535] (4-Formylphenyl)boronic acid (2 g, 13.34 mmol),
1,3-dibromo-2-methylbenzene (6.67 g, 26.68 mmol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.55 g, 0.67 mmol) and potassium
carbonate (3.7 g, 26.7 mmol) were suspended in 20 mL dioxane and 2
mL water. The mixture was sparged for 10 min with argon and heated
to 90.degree. C. in a heating block for 4 h. After cooling to room
temperature, the reaction was diluted with EtOAc and brine. The
organic layer was separated, dried with Na.sub.2SO.sub.4 and
concentrated. Purified by silica gel chromatography (eluting with
EtOAc-Hex) to provide 2.46 g (67%) of
3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde.
[1536] 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (1.4 g,
5.09 mmol), bis(pinacolato)diboron (1.42 g, 5.6 mmol), KOAc (1.5 g,
15.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride (0.42 g, 0.51 mmol) were suspended in 10 mL dioxane and
argon was bubbled through the mixture for 5 min. The reaction was
heated to 90.degree. C. for 3 h, after which the reaction was
cooled to room temperature and diluted with 100 mL EtOAc. The
reaction mixture was filtered through a celite pad, concentrated
under reduced pressure, and purified by silica gel chromatography
to provide 1.32 g (80.5%) of
2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl-
]-4-carbaldehyde.
[1537]
2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-bi-
phenyl]-4-carbaldehyde (1 g, 3.1 mmol), 1,3-dibromo-2-methylbenzene
(1.57 g, 6.2 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.178 g, 0.22
mmol) and potassium carbonate (1.3 g, 9.3 mmol) were suspended in
10 mL dioxane and 1 mL water. The mixture was sparged for 10 min
with argon and heated to 90.degree. C. in a heating block for 4 h.
After cooling to room temperature, the reaction was diluted with
EtOAc and brine. The organic layer was separated, dried with
Na.sub.2SO.sub.4 and concentrated. Purified by silica gel
chromatography (eluting with EtOAc-Hex) to provide 0.72 g (63%) of
3''-bromo-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-carbaldehyde.
[1538]
3''-bromo-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-carbaldehyde
(0.720 g, 2.0 mmol), bis(pinacolato)diboron (0.55 g, 2.2 mmol),
KOAc (0.58 g, 5.9 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(0.16 g, 0.2 mmol) were suspended in 8 mL dioxane and argon was
bubbled through the mixture for 5 min. The reaction was heated to
90.degree. C. for 3 h, after which the reaction was cooled to room
temperature and diluted with 100 mL EtOAc. The reaction mixture was
filtered through a celite pad, concentrated under reduced pressure,
and purified by silica gel chromatography to provide 600 mg (74%)
of
2',2''-dimethyl-3''-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1':3-
',1''-terphenyl]-4-carbaldehyde.
[1539]
2',2''-dimethyl-3''-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[-
1,1':3',1''-terphenyl]-4-carbaldehyde (250 mg, 0.61 mmol), in DCM
(15 mL) was added a solution of (R)-pyrrolidin-3-ol (80 mg, 1.5 eq)
in DCM (10 mL). The resulting solution was allowed to stir for 1 h
at room temperature. Na(OAc).sub.3BH (192.75 mg, 0.91 mmol) was
added in one portion, and stirred for an additional 3 h. The
reaction was diluted with DCM, and washed with NaHCO.sub.3, and
Brine. The organic layer was dried over Na2SO4, and concentrated
and purified silica gel chromatography (20% MeOH in DCM) to provide
(R)-1-((2',2''-dimethyl-3''-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-[1,1':3',1''-terphenyl]-4-yl)methyl)pyrrolidin-3-ol.
Intermediate 52: tert-butyl
(S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
##STR00230##
[1541] Tert-butyl
(S)-2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
was synthesized following procedures in PCT Int. Appl. (2010), WO
2010/132601.
Intermediate 53:
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-hydroxybenzaldehyde
##STR00231##
[1543] Methyl-4-methylsalicylate (6300 mg, 37.91 mmol) and
n-chlorosuccinimide (5568.61 mg, 41.7 mmol) were stirred and heated
to 42.degree. C. overnight in acetonitrile (200 mL). Reaction was
diluted with EtAc and quenched with aqueous sodium thiosulfate.
Reaction was extracted with EtAc (3.times.) washed with
thiosulfate, water then brine, dried over sodium sulfate, filtered
and evaporated to dryness. Crude material was purified by silica
gel chromatography using Hex/DCM as the eluent to afford 6300 mg
(66.3%) of methyl 5-chloro-2-hydroxy-4-methylbenzoate.
[1544] Methyl 5-chloro-2-hydroxy-4-methylbenzoate (6300 mg, 31.4
mmol) was taken up in Pyridine (250 mL) and to this was added
Acetic Anhydride (5.94 mL, 62.81 mmol) and reaction allowed to stir
at room temperature overnight.
[1545] Next day solvents were removed under reduced pressure and
coevapped with DCM (2.times.) then placed under high vacuum. Crude
material was purified by silica gel chromatography using
Hexanes/EtAc as the eluent to provide 7.4 g (97%) of methyl
2-acetoxy-5-chloro-4-methylbenzoate.
[1546] To methyl 2-acetoxy-5-chloro-4-methylbenzoate (8300 mg, 34.2
mmol) and N-bromosuccinimide (5783.57 mg, 32.49 mmol) was added
CCl4 (400 mL) and reaction stirred at room temperature for 10
minutes then benzoyl peroxide (134.76 mg, 0.56 mmol) was added and
reaction was heated to 82.degree. C. overnight. Next day reaction
solvents were removed under reduced pressure and crude material was
purified by flash chromatography using Hex/DCM as the eluent to
obtain 8 g (58.2%) of methyl
2-acetoxy-4-(bromomethyl)-5-chlorobenzoate.
[1547] methyl 2-acetoxy-4-(bromomethyl)-5-chlorobenzoate (6500 mg,
20.21 mmol), 3-Bromo-2-methylphenol (7561.69 mg, 40.43 mmol),
sodium iodide (6060.08 mg, 40.43 mmol) and cesium carbonate
(19758.82 mg, 60.64 mmol) were stirred in DMF (400 mL) and heated
to 50.degree. C. under an argon atmosphere. After 60 minutes
starting material was consumed. Reaction was cooled on ice water
and to this was added 2-(trimethylsilyl)ethoxymethyl chloride (8.94
mL, 50.54 mmol) and reaction allowed to warm for 1 hour or until
intermediate is consumed
[1548] Reaction was diluted with EtAc, and LiCl (aq) extracted with
EtAc 3.times., washed with LiCl, water, brine, dried over sodium
sulfate, filtered and solvents removed under reduced pressure.
Crude material was purified by silica gel chromatography using
Hexanes/EtAc to afford 12.7 g (85.2%) of methyl
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl)ethoxy-
)methoxy)benzoate.
[1549] Methyl
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl)ethoxy-
)methoxy)benzoate (12.5 g, 16.96 mmol) was taken up in 300 mL THF
at room temperature and purged with argon. To this was added
lithium aluminum hydride (95%) (1.09 g, 27.29 mmol). Upon
consumption of starting materials sodium sulfate decahydrate (10 g)
was slowly added to the reaction and stirred overnight. The
following day solids were filtered off and mother liquor was
evaporated to dryness under reduced pressure. Crude material was
purified by silica gel chromatography using Hexanes/EtAc to afford
6.2 g (74.9%) of
(4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl)ethox-
y)methoxy)phenyl)methanol.
[1550]
(4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl-
)ethoxy)methoxy)phenyl)methanol (6.2 g, 12.71 mmol) was taken up in
DCM (250 mL) at room temperature under argon. To this was added
Dess-martin periodinane (6.47 g, 15.25 mmol) and the reaction was
stirred overnight. Upon completion reaction was stirred with sodium
thiosulfate (aq) for 30 minutes then extracted with DCM (3.times.),
dried over sodium sulfate, filtered and evaporated to dryness.
Crude material was purified by silica gel chromatography using
Hex/DCM as eluent to afford
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl)ethoxy-
)methoxy)benzaldehyde.
[1551]
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-((2-(trimethylsilyl)-
ethoxy)methoxy)benzaldehyde (5500 mg, 11.32 mmol) and magnesium
bromide etherate (5846.36 mg, 22.64 mmol) were stirred in DCM (250
mL) for 1 hour at room temperature or until starting materials were
consumed. To the reaction was ammonium chloride (aq.) and extracted
with DCM (3.times.)), dried over sodium sulfate, filtered and
evaporated to dryness. Crude material was taken up in DCM and
solids were sonicated and filtered off to provide product. Mother
liquor was purified by silica gel chromatography using Hex/DCM as
eluent to afford
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-hydroxybenzaldehyde.
Intermediate 54:
5-((4-chloro-5-(((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formyl-
phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-formylphe-
noxy)methyl)nicotinonitrile
##STR00232##
[1553]
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-hydroxybenzaldehyde
(520 mg, 1.46 mmol), 5-(chloromethyl)nicotinonitrile hydrochloride
(414.64 mg, 2.19 mmol), Sodium Iodide (657.56 mg, 4.39 mmol),
Potassium carbonate (1212.55 mg, 8.77 mmol) and
N,N-Dimethylformamide (50 mL) were placed in a round-bottomed flask
equipped with stir bar and heated to 65.degree. C. for 12 hours. A
t this point reaction was cooled to room temperature and diluted
with EtAc/aq. LiCl. Organics were extracted 3.times. with EtAc,
washed with aq. LiCl 3.times., water 1.times., brine, then dried
over sodium sulfate before filtering and evaporating organics under
reduced pressure to afford crude residue. Crude material was
purified by silica gel chromatography using Hexanes/EtAc as the
eluent 260 mg (37.7%) of
5-((5-((3-bromo-2-methylphenoxy)methyl)-4-chloro-2-formylphenoxy)methyl)n-
icotinonitrile.
[1554]
5-((5-((3-bromo-2-methylphenoxy)methyl)-4-chloro-2-formylphenoxy)me-
thyl)nicotinonitrile (50 mg, 0.11 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile,
Pd(dppf)Cl.sub.2 (10.85 mg, 0.01 mmol) and potassium carbonate
(43.95 mg, 0.32 mmol) were placed in a microwave vial equipped with
a stir bar and to this was added DMF (5 mL), water (1 mL) then the
reaction vessel was sealed and microwaved at 90.degree. C. for 45
minutes.
[1555] Reaction was diluted in EtAc/H.sub.2O and extracted with
EtAc (3.times.). Organics were then washed with lithium chloride,
water, brine, then dried over sodium sulfate before filtering and
evaporating organics under reduced pressure to afford crude
residue.
[1556] Crude material was purified by silica gel chromatography
using DCM/EtAc as the eluent to provide
5-((4-chloro-5-(((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formyl-
phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-formylphe-
noxy)methyl)nicotinonitrile.
Intermediate 55:
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxybenzyl)oxy)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
##STR00233##
[1558]
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-hydroxybenzaldehyde
(250 mg, 0.7 mmol) was taken up in DMF (25 mL) and to this was
added potassium carbonate (388.64 mg, 2.81 mmol) followed by
iodomethane (0.22 mL, 2.81 mmol) and the reaction was heated to
45.degree. C. for 3 hours with stirring. Reaction was cooled then
diluted in EtAc/aq. LiCl and extracted with EtAc (3.times.).
Organics were then washed with lithium chloride, water, brine, then
dried over sodium sulfate before filtering and evaporating organics
under reduced pressure to afford crude residue.
[1559] Crude material was purified by silica gel chromatography
using Hex/EtAc as the eluent to afford 210 mg (80.8%) of
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-methoxybenzaldehyde.
[M+1]=370.8
[1560]
4-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-methoxybenzaldehyde
(80 mg, 0.22 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (134.74 mg, 0.26
mmol), Pd(dppf)Cl.sub.2 (22.16 mg, 0.03 mmol) and potassium
carbonate (89.73 mg, 0.65 mmol) were placed in a microwave vial
equipped with a stir bar and to this was added DMF (6 mL), water (2
mL) then the reaction vessel was sealed and microwaved at
95.degree. C. for 45 minutes.
[1561] Reaction was diluted in EtAc/H2O and extracted 3.times. with
EtAc. Organics were then washed with ammonium chloride 1.times.,
water 1.times., brine, then dried over sodium sulfate before
filtering and evaporating organics under reduced pressure to afford
crude residue.
[1562] Crude material was purified by silica gel chromatography
using DCM/EtAc as the eluent to provide
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxybenzyl)oxy)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
Intermediate 56:
5-((4-chloro-2-formyl-5-((3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
##STR00234##
[1564] 3-bromo-2-methylphenol (0.36 mL, 2.86 mmol) was stirred in
DMF (15 mL) at room temperature under argon and to this was added
NaH (55%, 149.78 mg, 3.43 mmol) and suspension was stirred for 10
minutes. At this point methyl 6-(bromomethyl)nicotinate (723.88 mg,
3.15 mmol) was added and reaction was stirred until reaction was
complete. Reaction was diluted in EtAc and LiCl (aq) and extracted
with EtAc (3.times.). Organics were washed with LiCl (aq), water,
brine, dried over sodium sulfate, filtered and evaporated to
dryness to afford 990 mg of methyl
6-((3-bromo-2-methylphenoxy)methyl)nicotinate as crude.
[1565] methyl 6-((3-bromo-2-methylphenoxy)methyl)nicotinate (990
mg, 2.94 mmol) was dissolved in ether (100 mL) and to this was
added lithium aluminum hydride (134.12 mg, 3.53 mmol) and stirred
overnight. The next day LCMS shows complete consumption of starting
material. Reaction was poured into stirring solution of EtAc and
aqueous solution of Rochelle's salt and stirred for 3 hours.
Reaction was extracted 3.times. with EtAc, washed with water and
brine, dried over sodium sulfate, filtered and evaporated to
dryness to afford 850 mg (93.7%) of
(6-((3-bromo-2-methylphenoxy)methyl)pyridin-3-yl)methanol.
[M+1]=310.1.
[1566] (6-((3-bromo-2-methylphenoxy)methyl)pyridin-3-yl)methanol
(850 mg, 2.76 mmol)) was dissolved 100 mL DCM and to this was added
Dess-martin periodinane (1286.85 mg, 3.03 mmol) and stirred
overnight at room temperature. Reaction was quenched with stirring
sodium thiosulfate for 15 minutes the diluted with DCM. Organics
were extracted with DCM (3.times.) washed with water, dried over
sodium sulfate, filtered and evaporated to dryness.
[1567] Crude material was purified by silica gel chromatography
using Hexanes/EtAc as the eluent (to afford 830 mg (98.3%) of
6-((3-bromo-2-methylphenoxy)methyl)nicotinaldehyde.
[M+1]=308.0.
[1568]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (200 mg,
0.39 mmol), 6-((3-bromo-2-methylphenoxy)methyl)nicotinaldehyde
(129.83 mg, 0.42 mmol), Pd(dppf)Cl.sub.2 (39.47 mg, 0.0482 mmol),
K.sub.2CO.sub.3 (79.45 mg, 0.82 mmol), 1,4-Dioxane (8 mL) and water
(4 mL) were placed in a microwave vial equipped with stir bar and
heated in a microwave at 95.degree. C. for 30 minutes.
[1569] Reaction was diluted in EtAc/H.sub.2O and extracted with
EtAc (3.times.). Organics were then washed with ammonium chloride,
water, brine, then dried over sodium sulfate before filtering and
evaporating organics under reduced pressure to afford crude
residue.
[1570] Crude material was purified by silica gel chromatography
using Hex/EtAc as the eluent to afford
5-((4-chloro-2-formyl-5-((3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[M+1]=618.0.
Intermediate 57:
5-((4-chloro-5-(((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]-
-3-yl)oxy)methyl)-2-formylphenoxy)methyl)nicotinonitrile
##STR00235##
[1572]
5-((5-((3-bromo-2-methylphenoxy)methyl)-4-chloro-2-formylphenoxy)me-
thyl)nicotinonitrile (410 mg, 0.87 mmol), bis (pinacolato) diboron
(331.06 mg, 1.3 mmol),
(1,1'-Bis(diphenylphosphino)ferrocene)dichloropalladium(II),
complex with dichloromethane (60.84 mg, 0.09 mmol), potassium
acetate (156.58 mg, 2.61 mmol) and Dioxane (5 mL) were placed in a
sealed vial equipped with stir bar and stirred for 24 hours at
95.degree. C. Reaction was cooled, filtered and solvents removed
under reduced pressure. Crude material was purified by silica gel
chromatography using Hexanes/EtAc as the eluent to afford 210 mg
(46.6%) of
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenoxy)methyl)phenoxy)methyl)nicotinonitrile.
[1573]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenoxy)methyl)phenoxy)methyl)nicotinonitrile (120
mg, 0.23 mmol),
3-bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (105.28 mg,
0.28 mmol), Pd(dppf)Cl.sub.2 (23.68 mg, 0.03 mmol) and cesium
carbonate (158.26 mg, 0.49 mmol) were placed in a microwave vial
equipped with a stir bar and to this was added 1,4-Dioxane (8 mL),
water (4 mL) then the reaction vessel was sealed and microwaved at
95.degree. C. for 45 minutes. Reaction was diluted in EtAc/H.sub.2O
and extracted 3.times. with EtAc. Organics were then washed with
ammonium chloride, water, brine, then dried over sodium sulfate
before filtering and evaporating organics under reduced pressure to
afford crude residue. Crude material was purified by silica gel
chromatography using DCM/EtAc as the eluent to afford 100 mg
(62.5%) of
5-((4-chloro-5-(((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-ter-
phenyl]-3-yl)oxy)methyl)-2-formylphenoxy)methyl)nicotinonitrile.
[1574]
5-((4-chloro-5-(((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1-
''-terphenyl]-3-yl)oxy)methyl)-2-formylphenoxy)methyl)nicotinonitrile
(100 mg, 0.14 mmol) was dissolved in 1,4-dioxane (8 mL), 0.2 mL
(conc, aq) HCl and stirred for 1 hour at room temperature. Reaction
was quenched with saturated ammonium bicarbonate and extracted with
EtAc (3.times.), dried over sodium sulfate and evaporated to
dryness to afford
5-((4-chloro-5-(((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]-
-3-yl)oxy)methyl)-2-formylphenoxy)methyl)nicotinonitrile.
[1575] General Reductive Amination Procedures:
[1576] Procedure A--Reductive Amination with DMF/TEA;
NaBH(OAc).sub.3
[1577] Aldehyde (1 equiv) was suspended in DMF (0.025 M) and to
this was added (3S)-4-Amino-3-hydroxybutanoic acid (6 equiv)
followed by triethylamine (6 equiv) and the reaction stirred at
room temperature for 90 minutes. To this was added sodium
triacetoxyborohydride (6 equiv) and the reaction stirred an
additional 4 hours. At this point TFA was added slowly dropwise to
the reaction until the solution went clear. Reaction was diluted
with 2 mL of water, filtered and purified by reverse phase HPLC
(0.1% trifluoroacetic acid in acetonitrile/water) providing the
final compound upon lyophilization as the bis-TFA salt.
[1578] Procedure B--Reductive Amination with DMF/aq NaOH;
NaBH(OAc).sub.3
[1579] A solution of aldehyde (1 equiv) in DMF (0.014 M) was added
to a solution of the (S)-4-amino-3-hydroxybutanoic acid in 1N NaOH
(10 equiv). After 2 h sodium triacetoxyborohydride (10 equiv) was
added. After 30 min the reaction was complete and TFA was added.
Solids were removed by filtration and rinsed with MeOH. Organic
phase was removed under reduced pressure, and the crude subjected
to purification by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt.
[1580] Procedure C--Reductive amination with DMF/AcOH;
NaCNBH.sub.3+NaBH(OAc).sub.3
[1581] To a stirred mixture of aldehyde (1 equiv) and
(S)-3-aminobutanoic acid (15 equiv) in a 6:1 mixture of DMF/AcOH
(0.02 M) at room temperature was added sequentially sodium
cyanoborohydride (9 equiv) and sodium triacetoxyborohydride (9
equiv). After 15 min, trifluoroacetic acid was added until the
solution went clear. The resulting mixture was purified by reverse
phase HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
providing the final compound upon lyophilization as the bis-TFA
salt.
[1582] Procedure D--Reductive amination with DMSO/AcOH;
NaBH(OAc).sub.3
[1583] To a stirred mixture of aldehyde (1 equiv) and
(1R,2R)-2-aminocyclopentane-1-carboxylic acid (15 equiv) in 5:1
mixture of DMSO/AcOH (0.008 M) at room temperature was added sodium
triacetoxyborohydride (9 equiv). After 1 h, TFA was added until the
solution went clear. The resulting homogeneous mixture was purified
by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt.
[1584] Procedure E--Reductive Amination with MeOH/AcOH;
2-methylpyridine borane
[1585] Aldehyde A (1 equiv) was suspended in a 10:1 mixture of
MeOH/AcOH (0.01M) and to this was added
(3S)-4-amino-3-hydroxybutyric acid (3 equiv) at room temperature.
Mixture was stirred at room temperature under argon for 1 hour. To
this solution was added 2-methylpyridine borane (3 equiv) at room
temperature and the reaction was stirred for an additional 2 hours.
At this point, TFA was added dropwise to the reaction mixture until
the solution went clear. Reaction was filtered and purified by
reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt.
[1586] Procedure F--Reductive Amination with DMF/MeOH/AcOH;
2-methylpyridine borane
[1587] Aldehyde (1 equiv) was suspended in a 6:3:1 mixture of
DMF/MeOH/AcOH (0.01 M) and to this was added
(3S)-4-amino-3-hydroxybutyric acid (10 equiv) at room temperature.
Mixture was stirred at room temperature under argon for 1 hour. To
this solution was added 2-methylpyridine borane (10 equiv) at room
temperature and the reaction was stirred for an additional 2 hours.
At this point, TFA was added dropwise to the reaction mixture until
the solution goes clear. Reaction was filtered and purified by
reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt.
[1588] Procedure G--Reductive Amination with DCM/EtOH/KOH;
Na(OAc).sub.3BH
[1589] To aldehyde in DCM (0.05M) was added a pre-sonicated 0.1M
solution of KOH (10 equiv) and (3S)-4-amino-3-hydroxybutanoic acid
(10 equiv) in EtOH. The reaction was stirred for 1 hour at rt
before Na(OAc).sub.3BH (10 equiv) and AcOH (10 equiv) were added.
The cloudy reaction was sonicated for 1 min, and stirred at rt for
2 h. The reaction was quenched with the addition of 1M HCl until
the solution clears. The solution was concentrated in-vacuo,
diluted with a mixture of MeCN/H.sub.2O/DMF (1:1:1), and purified
by purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt.
[1590] Procedure H--Reductive Amination with DCM/DMF/DIPEA;
Na(OAc).sub.3BH
[1591] The di aldehyde
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (50 mg, 1 equiv) was taken in
a vial and dissolved in DCM (1.5 mL). The
(2S,4R)-4-hydroxypiperidine-2-carboxylic acid (125 mg, 10 equiv)
was dissolved in mixture of DMF (3 mL), and DIPEA (0.15 mL, 10
equiv) in a another vial. These two solutions were mixed together
and sonicated for 5 min, and allowed to stir for 1 h at room
temperature. To well stirred mixture was added Na(OAc).sub.3BH at
once and sonicated for 5 min to bring everything in to solution and
allowed to stirred for overnight. The solution was concentrated
under reduced pressure. The crude product was diluted with a
mixture of MeCN/H.sub.2O/(2:1, with 0.1% TFA), solids were removed
by filtration and purified by reverse phase HPLC (0.1%
trifluoroacetic acid in acetonitrile/water) providing the final
compound as the bis-TFA salt.
Example 1:
((6-(((1S,1'S)-1'-((5-(((carboxymethyl)amino)methyl)-3-chloro-6-
-methoxypyridin-2-yl)oxy)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biinden]-1-yl)-
oxy)-2-methoxypyridin-3-yl)methyl)glycine
##STR00236##
[1593] A solution of Intermediate 6 (65 mg, 0.11 mmol) was treated
using Method E, substituting glycine for
(S)-4-amino-3-hydroxybutanoic acid. Purification by prep RP-HPLC
(10-75% acetonitrile in water, 0.1% trifluoroacetic acid) furnished
5-(2-(4-morpholinophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-y-
l)-2-((tetrahydro-2H-pyran-3-yl)oxy)benzonitrile. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.09 (s, 4H), 7.92 (s, 1H), 7.72 (d,
J=8.1 Hz, 1H), 7.42 (d, J=6.8 Hz, 2H), 7.36-7.27 (m, 4H), 6.59 (dd,
J=6.8, 5.3 Hz, 1H), 6.53 (dd, J=6.9, 4.7 Hz, 1H), 6.45 (d, J=8.1
Hz, 1H), 4.09 (s, 4H), 3.97 (d, J=6.2 Hz, 6H), 3.84 (d, J=9.3 Hz,
4H), 2.95-2.85 (m, 2H), 2.81-2.54 (m, 4H), 2.15-2.00 (m, 2H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.37ClN.sub.4O.sub.8: 688.2; found: 688.0.
Example 2:
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]--
1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene)-
)bis(azanediyl))diacetic acid (or
2,2'-(((6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'--
diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
azanediyl))diacetic acid)
##STR00237##
[1595] A solution of Intermediate 5 (65 mg, 0.11 mmol) was treated
using general reductive amination procedure E, substituting glycine
for(S)-4-amino-3-hydroxybutanoic acid. Purification by prep RP-HPLC
(10-75% acetonitrile in water, 0.1% trifluoroacetic acid) furnished
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))diacetic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.16 (s, 4H), 7.92 (s, 2H), 7.43 (dd, J=6.8, 1.9 Hz, 2H), 7.38-7.29
(m, 4H), 6.60 (dd, J=6.9, 5.0 Hz, 2H), 4.09 (s, 4H), 3.98 (s, 6H),
3.84 (s, 4H), 2.91 (ddd, J=15.6, 8.4, 4.8 Hz, 2H), 2.78 (dt,
J=15.7, 7.1 Hz, 2H), 2.71-2.63 (m, 2H), 2.10 (dt, J=10.9, 5.6 Hz,
2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.36Cl.sub.2N.sub.4O.sub.8: 722.12; found: 721.99.
Example 3:
(3R,3'R)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-b-
iindene]-1,1'-diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(me-
thylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biinde-
ne]-1,1'-diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00238##
[1597] A solution of Intermediate 4 (17 mg, 0.025 mmol) was treated
using general reductive amination procedure B, substituting
(R)-4-amino-3-hydroxybutanoic acid for
(S)-4-amino-3-hydroxybutanoic acid. Purification by prep RP-HPLC
(10-75% acetonitrile in water, 0.1% trifluoroacetic acid) furnished
(3R,3'R)-4,4'-((((((1
S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis-
(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-h-
ydroxybutanoic acid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.09 (s, 4H), 7.92 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.42 (d, J=6.8
Hz, 2H), 7.36-7.27 (m, 4H), 6.59 (dd, J=6.8, 5.3 Hz, 1H), 6.53 (dd,
J=6.9, 4.7 Hz, 1H), 6.45 (d, J=8.1 Hz, 1H), 4.09 (s, 4H), 3.97 (d,
J=6.2 Hz, 6H), 3.84 (d, J=9.3 Hz, 4H), 2.95-2.85 (m, 2H), 2.81-2.54
(m, 4H), 2.15-2.00 (m, 2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.40H.sub.44Br.sub.2N.sub.4O.sub.10: 900.14;
found: 900.975.
Example 4:
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-b-
iindene]-1,1'-diyl)bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)py-
ridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid)
##STR00239##
[1599] A solution of Intermediate 2 (100 mg, 0.11 mmol) was treated
using general reductive amination procedure B. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1-
,1'-diyl)bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-
-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid).
.sup.1H NMR (400 MHz, Acetonitrile-d.sub.3/D.sub.2O-d.sub.2)
.delta. 8.88 (d, J=2.1 Hz, 2H), 8.78 (d, J=1.9 Hz, 2H), 8.24 (s,
2H), 7.95 (s, 2H), 7.26-7.24 (m, 4H), 6.42 (t, J=6.0 Hz, 2H), 5.57
(s, 4H), 4.26-4.23 (m, 4H), 4.21 (s, 4H), 3.16 (dd, J=12.8, 3.1 Hz,
4H), 3.02-2.95 m, 2H), 2.76-2.69 (m, 2H), 2.67-2.58 (m, 5H),
2.56-2.41 (m, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.52H.sub.48Br.sub.2N.sub.8O.sub.10: 1104.18; found:
1105.1.
Example 5:
((2S,2'S)-2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'--
biindene]-1,1'-diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)
##STR00240##
[1601] A solution of Intermediate 4 (30 mg, 0.043 mmol) was treated
using general reductive amination procedure B, substituting
(S)-2-amino-3-hydroxy-2-methylpropanoic acid for
(S)-4-amino-3-hydroxybutanoic acid. Purification by prep RP-HPLC
(10-75% acetonitrile in water, 0.1% trifluoroacetic acid) furnished
(2S,2'S)-2,2'-((((((1
S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis-
(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-h-
ydroxy-2-methylpropanoic acid). .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3/D.sub.2O-d.sub.2) .delta. 7.86 (d, J=4.5 Hz,
2H), 7.46 (d, J=7.7 Hz, 2H), 7.35-7.22 (m, 4H), 6.63-6.55 (m, 2H),
4.09 (d, J=4.2 Hz, 4H), 3.99 (d, J=4.1 Hz, 6H), 3.80-3.72 (m, 2H),
2.88 (d, J=6.7 Hz, 2H), 2.80-2.59 (m, 2H), 2.10 (s, 2H), 1.48 (d,
J=4.1 Hz, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.44Br.sub.2N.sub.4O.sub.10: 900.1; found: 900.2.
Example 6:
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-b-
iindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00241##
[1603] A solution of Intermediate 5 (75 mg, 0.124 mmol) was treated
using general reductive amination procedure B. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1-
,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxybutanoic acid). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.35 (s, 2H), 8.70 (s, 4H), 7.96 (s, 2H),
7.42 (dd, J=6.7, 1.9 Hz, 2H), 7.39-7.28 (m, 4H), 6.59 (t, J=6.0 Hz,
2H), 5.59 (s, 2H), 4.16 (s, 2H), 4.07 (s, 4H), 3.98 (s, 6H), 3.03
(s, 2H), 2.93-2.84 (m, 4H), 2.85-2.64 (m, 2H), 2.48-2.32 (m, 2H),
2.07 (dd, J=16.8, 5.6 Hz, 2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.40H.sub.44Cl.sub.2N.sub.4O.sub.10: 810.2;
found: 810.2.
Example 7:
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-b-
iindene]-1,1'-diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(me-
thylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00242##
[1605] A solution of Intermediate 4 (40 mg, 0.043 mmol) was treated
using general reductive amination procedure B. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1-
,1'-diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(3-hydroxybutanoic acid). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.35 (s, 2H), 8.64 (s, 4H), 8.08 (s, 2H),
7.46-7.39 (m, 2H), 7.39-7.27 (m, 4H), 6.57 (t, J=6.1 Hz, 2H), 5.57
(s, 2H), 4.16 (s, 2H), 4.07 (s, 4H), 3.98 (s, 6H), 3.03 (m, 2H),
2.89 (m, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 2.48-2.32 (m, 2H),
2.13-2.00 (m, 2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.44Br.sub.2N.sub.4O.sub.10: 900.14; found: 900.0.
Example 8:
(S)-4-(((5-bromo-6-(((1S,1'S)-1'-((3-bromo-5-(((2-hydroxyethyl)-
amino)methyl)-6-methoxypyridin-2-yl)oxy)-2,2',3,3'-tetrahydro-1H,1.sup.1H--
[4,4'-biinden]-1-yl)oxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybuta-
noic acid
##STR00243##
[1607] A solution of Intermediate 4 (126 mg, 0.181 mmol) in 2 mL
DCM and 5 mL DMSO was treated with ethanolamine (111 mg, 1.81 mmol)
and stirred for 2 h. Sodium triacetoxyborohydride (385 mg, 1.81
mmol) was added and the reaction stirred an additional hour.
Purification by prep RP-HPLC (10-75% acetonitrile in water, 0.1%
trifluoroacetic acid buffer) furnished the intermediate
5-bromo-6-(((1S,1'S)-1'-((3-bromo-5-(((2-hydroxyethyl)amino)methyl)-6-met-
hoxypyridin-2-yl)oxy)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biinden]-1-yl)oxy)-
-2-methoxynicotinaldehyde as a solid. This intermediate was treated
using general reductive amination procedure D and purified by
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(S)-4-(((5-bromo-6-(((1S,1'S)-1'-((3-bromo-5-(((2-hydroxyethyl)amino)meth-
yl)-6-methoxypyridin-2-yl)oxy)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biinden]--
1-yl)oxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.66 (s, 4H),
8.07 (d, J=1.0 Hz, 2H), 7.42 (dd, J=7.1, 1.7 Hz, 2H), 7.39-7.28 (m,
4H), 6.57 (t, J=6.1 Hz, 2H), 4.16 (s, 1H), 4.07 (s, 4H), 3.65 (t,
J=5.3 Hz, 2H), 3.06-2.95 (m, 2H), 2.95-2.84 (m, 2H), 2.84-2.74 (m,
2H), 2.74-2.64 (m, 2H), 2.42-2.29 (m, 2H), 2.11-2.00 (m, 2H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.38H.sub.42Br.sub.2N.sub.4O.sub.8: 842.13; found: 842.01.
Example 9:
(3S,3'S)-4,4'-(((((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]--
1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene)-
)bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00244##
[1609] A solution of Intermediate 6 (17 mg, 0.28 mmol) was treated
using general reductive amination procedure B. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(3S,3'S)-4,4'-(((((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))bis(3-hydroxybutanoic acid). .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3/D.sub.2O) .delta. 7.75 (s, 2H), 7.48 (d, J=7.5
Hz, 2H), 7.38-7.24 (m, 4H), 6.63 (dd, J=6.8, 4.4 Hz, 2H), 4.24 (t,
J=8.5 Hz, 3H), 4.13 (s, 4H), 4.09-3.91 (m, 9H), 3.96 (s, 23H), 3.12
(dd, J=13.0, 3.1 Hz, 2H), 3.01-2.92 (m, 2H), 2.92 (s, 2H), 2.71
(ddt, J=36.6, 13.4, 7.0 Hz, 4H), 2.50 (t, J=6.2 Hz, 4H), 2.16 (ddd,
J=13.4, 8.8, 4.4 Hz, 2H), 1.96 (t, J=2.5 Hz, 5H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.44Cl.sub.2N.sub.4O.sub.10: 810.2; found: 810.1.
Example 10:
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(ethan-1-ol) (or
2,2'-(((6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'--
diyl)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(a-
zanediyl))bis(ethan-1-ol))
##STR00245##
[1611] A solution of Intermediate 4 (33 mg, 0.045 mmol) was treated
using general reductive amination procedure B, substituting
ethanolamine for(S)-4-amino-3-hydroxybutanoic acid. Purification by
prep RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic
acid) furnished
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(ethan-1-ol). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.65 (s, 4H), 8.07 (s, 2H), 7.42 (dd, J=6.8, 1.7 Hz, 2H), 7.37-7.29
(m, 4H), 6.57 (dd, J=6.9, 5.3 Hz, 2H), 5.23 (s, 2H), 4.06 (d, J=5.1
Hz, 4H), 3.98 (s, 6H), 3.65 (s, 4H), 2.99 (s, 4H), 2.94-2.63 (m,
6H), 2.07 (dq, J=13.8, 7.6, 7.1 Hz, 2H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calculated for C.sub.36H.sub.40Br.sub.2N.sub.4O.sub.6:
784.1; found: 783.0.
Example 11:
(3S,3'S)-4,4'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1-
,1'-diyl)bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))bis(3-hydroxybutanoic acid)
##STR00246##
[1613] A solution of Intermediate 3 (15 mg, 0.028 mmol) was treated
using general reductive amination procedure B. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished the titled product. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.35 (s, 2H), 8.61 (s, 4H), 7.75 (d, J=8.1 Hz, 2H), 7.41
(dd, J=7.0, 1.6 Hz, 2H), 7.36-7.24 (m, 4H), 6.52 (dd, J=6.7, 4.9
Hz, 2H), 6.46 (d, J=8.0 Hz, 2H), 5.58 (s, 2H), 4.17 (s, 2H),
4.10-4.04 (m, 4H), 3.97 (s, 6H), 3.01 (m, 2H), 2.88 (m, 4H),
2.78-2.67 (m, 2H), 2.61 (dt, J=13.7, 7.1 Hz, 2H), 2.53-2.33 (m, 4H)
2.06 (m, 2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.46N.sub.4O.sub.10: 742.3; found: 742.2.
Example 12:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-((ethylamino)methyl)-3,1-phenylene))bis(oxy))bis(methylen-
e))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-((ethylamino)methyl)-5,1-phenylene))bis(oxy))bis(methylen-
e))dinicotinonitrile)
##STR00247##
[1615] A solution of Intermediate 12 (55 mg, 0.075 mmol) was
treated using general reductive amination procedure E substituting
ethylamine for(S)-4-amino-3-hydroxybutanoic acid. Purification by
prep RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic
acid) furnished
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-((ethylamino)methyl)-3,1-phenylene))bis(oxy))bis(methylen-
e))dinicotinonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.04 (d, J=2.0 Hz, 2H), 9.03 (d, J=2.1 Hz, 2H), 8.49 (t, J=2.1 Hz,
2H), 7.55 (s, 2H), 7.49 (dd, J=7.6, 1.4 Hz, 2H), 7.29 (t, J=7.6 Hz,
2H), 7.20 (s, 2H), 7.11 (dd, J=7.7, 1.3 Hz, 2H), 5.37 (s, 4H), 5.32
(d, J=2.9 Hz, 4H), 4.09 (t, J=5.8 Hz, 4H), 2.93 (h, J=7.0 Hz, 5H),
2.02 (s, 6H), 1.15 (t, J=7.2 Hz, 6H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calculated for C.sub.48H.sub.46Cl.sub.2N.sub.6O.sub.4:
840.3; found: 840.1.
Example 13:
(3S,3'S)-4,4'-(((((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis-
(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'--
diyl)bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl-
))bis(3-hydroxybutanoic acid))
##STR00248##
[1617] A solution of
6,6'-((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis-
(2-methoxynicotinaldehyde) (35 mg, 0.065 mmol) was treated using
general reductive amination procedure E. Purification by prep
RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic acid)
furnished
(3S,3'S)-4,4'-(((((2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis-
(3-hydroxybutanoic acid). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.56 (s, 4H), 7.70 (d, J=8.1 Hz, 2H), 7.42-7.32 (m, 2H),
7.30-7.19 (m, 4H), 6.47 (dd, J=6.8, 4.7 Hz, 2H), 6.41 (d, J=8.1 Hz,
2H), 5.54 (d, J=5.6 Hz, 2H), 4.12 (s, 2H), 4.02 (s, 4H), 3.92 (s,
6H), 2.95 (s, 2H), 2.91-2.75 (m, 4H), 2.69 (dd, J=16.1, 5.1 Hz,
2H), 2.62-2.47 (m, 2H), 2.38-2.23 (m, 2H), 2.10-1.92 (m, 2H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.46N.sub.4O.sub.10: 742.3; found: 742.2.
Example 14:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-hydroxypropanoic acid (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxypropanoic acid))
##STR00249##
[1619] A solution of Intermediate 10 (50 mg, 0.0975 mmol) was
treated using general reductive amination procedure E. Purification
by prep RP-HPLC (10-75% acetonitrile in water, 0.1% trifluoroacetic
acid) furnished
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(az-
anediyl))bis(3-hydroxypropanoic acid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.69 (d, J=8.1 Hz, 2H), 7.39 (d, J=7.4 Hz,
2H), 7.20 (t, J=7.6 Hz, 2H), 7.00 (dd, J=7.6, 1.4 Hz, 2H), 6.46 (d,
J=8.1 Hz, 2H), 5.38 (s, 4H), 4.12-3.98 (m, 4H), 3.87-3.71 (m, 6H),
3.83 (s, 6H), 1.95 (s, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.36H.sub.42N.sub.4O.sub.10: 690.3; found:
690.1.
Example 15:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(piperidin-1-ylmethyl)-3,1-phenylene))bis(oxy))bis(methyl-
ene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(piperidin-1-ylmethyl)-5,1-phenylene))bis(oxy))bis(methyl-
ene))dinicotinonitrile)
##STR00250##
[1621] A solution of Intermediate 12 (100 mg, 0.128 mmol) was
treated using general reductive amination procedure E, substituting
piperidine for(S)-4-amino-3-hydroxybutanoic acid and THF for DMF.
Purification by prep RP-HPLC (10-75% acetonitrile in water, 0.1%
trifluoroacetic acid) furnished
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylen-
e))bis(oxy))bis(4-chloro-6-(piperidin-1-ylmethyl)-3,1-phenylene))bis(oxy))-
bis(methylene))dinicotinonitrile. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.04 (dd, J=6.6, 2.1 Hz, 4H), 8.50 (t, J=2.1
Hz, 2H), 7.61 (s, 2H), 7.52 (dd, J=7.7, 1.4 Hz, 2H), 7.31 (t, J=7.6
Hz, 2H), 7.24 (s, 2H), 7.12 (dd, J=7.6, 1.3 Hz, 2H), 5.40-5.27 (m,
8H), 4.19 (d, J=4.7 Hz, 4H), 3.29 (d, J=11.9 Hz, 4H), 2.87 (q,
J=10.7 Hz, 4H), 2.03 (s, 6H), 1.76 (d, J=14.1 Hz, 4H), 1.59 (d,
J=15.5 Hz, 6H), 1.33 (d, J=12.4 Hz, 2H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calculated for C.sub.54H.sub.54Cl.sub.2N.sub.6O.sub.4:
920.4; found: 920.3.
Example 16:
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-dim-
ethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3--
yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00251##
[1623] To a clear solution of (S)-4-amino-3-hydroxybutanoic acid
(120 mg, 1 mmol) in 1N NaOH (1 mL) and EtOH (3 mL) was added a
solution of
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]--
3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (62 mg, 0.1
mmol, intermediate 16) in EtOH (1 mL) and dioxane (1 mL). The
resulting mixture was stirred at room temperature for 1 h, which
became cloudy. The mixture was then heated up to make a clear
solution. After cooling, sodium triacetoxyborohydride (280 mg, 1.3
mmol) was added. The mixture was stirred at room temperature for 16
h. A diluted HCl (1N, 1 mL) was added and concentrated.
Acetonitrile and methanol were added and concentrated again. DMSO
(.about.3 mL) was then added followed by a few drops of water,
which was filtered. The filtrate was loaded onto reverse-phase HPLC
and purified, affording
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-dim-
ethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3--
yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid as the bis-TFA
salt. [M+H] 823.1, .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.95 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.37 (t, J=2.1 Hz,
1H), 7.51 (s, 1H), 7.45 (dd, J=7.7, 1.4 Hz, 1H), 7.34-7.22 (m, 4H),
7.16 (ddd, J=17.3, 7.6, 1.5 Hz, 2H), 7.07 (td, J=7.9, 7.5, 1.8 Hz,
4H), 5.37 (s, 2H), 5.31 (s, 2H), 4.35 (dd, J=5.8, 4.3 Hz, 3H), 4.23
(s, 3H), 3.54 (dd, J=6.0, 4.1 Hz, 2H), 3.36 (dd, J=12.7, 3.0 Hz,
1H), 3.25-3.08 (m, 2H), 3.05-2.93 (m, 1H), 2.58 (d, J=6.3 Hz, 2H),
2.51 (dd, J=6.3, 1.0 Hz, 2H), 2.14 (s, 3H), 1.87 (s, 3H).
Example 17:
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00252##
[1625] To a solution of (3-bromo-2-methylphenyl)methanol (2.0 g, 10
mmol) and triethylamine (2.0 g, 20 mmol) in THF (80 mL) was
dropwise added methanesulfonyl chloride (1.38 g, 12 mmol). The
resulting mixture was stirred at room temperature for 16 h. The
mixture was then partitioned between ethyl acetate and water. The
ethyl acetate layer was washed with water, 5% sodium bicarbonate,
and then brine. After drying over sodium sulfate, the solution was
concentrated to dryness affording 3-bromo-2-methylbenzyl
methanesulfonate, which was used for the next reaction without
further purification.
[1626] To a solution of 4-hydroxybenzaldehyde (400 mg, 3.3 mmol)
and 3-bromo-2-methylbenzyl methanesulfonate (920 mg, 3.3 mmol) in
DMF (5 mL) was added cesium carbonate (1.4 g, 4.3 mmol) and stirred
at room temperature for 16 h. The mixture was then partitioned
between ethyl acetate and 3% LiCl in water. The ethyl acetate layer
was taken and concentrated. The residue was purified by Combiflash,
affording 4-((3-bromo-2-methylbenzyl)oxy)benzaldehyde. [M+H].sup.+
305.1.
[1627] A mixture of 4-((3-bromo-2-methylbenzyl)oxy)benzaldehyde (31
mg, 0.1 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (52 mg, 0.1
mmol), DMF (1.5 mL) and 2N potassium carbonate (0.2 mL) was purged
with argon for 10 min.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (8 mg, 0.01 mmol) was then added. The
resulting mixture was stirred at 80.degree. C. for 20 min. After
cooling, the mixture was partitioned between ethyl acetate and 3%
LiCl in water. The ethyl acetate layer was taken and concentrated.
The residue was purified by Combiflash, affording
5-((4-chloro-2-formyl-5-((3'-((4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[M+H].sup.+ 617.0.
[1628] Following general reductive amination procedure A,
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]--
3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (44 mg, 0.071
mmol) was converted to
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid as the
bis-TFA salt. [M+H] 823.1, .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.96 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.38 (t,
J=2.1 Hz, 1H), 7.51 (s, 1H), 7.50-7.37 (m, 4H), 7.26 (t, J=7.6 Hz,
2H), 7.16-7.04 (m, 5H), 5.38 (s, 2H), 5.31 (s, 2H), 5.17 (s, 2H),
4.36-4.18 (m, 2H), 4.24 (s, 2H), 4.18 (s, 2H), 3.18 (ddd, J=12.6,
11.3, 3.1 Hz, 2H), 3.04-2.92 (m, 2H), 2.52 (dd, J=6.3, 4.2 Hz, 4H),
2.09 (s, 3H), 2.03 (d, J=5.7 Hz, 4H).
Example 18:
N,N'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-
e-2,1-diyl))diacetamide (or
N,N'-((((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(-
ethane-2,1-diyl))diacetamide)
##STR00253##
[1630] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (80 mg, 0.16 mmol) in DMF (3.0 mL) was
added the N-(2-aminoethyl)acetamide (128 mg, 1.25 mmol), sodium
cyanoborohydride (78 mg, 1.25 mmol) and acetic acid (0.30 mL) and
the mixture was stirred at rt. After 18 h, the reaction mixture was
concentrated and purified by reverse phase chromatography to give
the title compound as TFA salt. LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.38H.sub.48N.sub.6O.sub.6: 685.3; found: 685.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.61 (brs), 8.08 (t,
J=5.8 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.44 (dd, J=7.7, 1.3 Hz,
2H), 7.25 (t, J=7.6 Hz, 2H), 7.05 (dd, J=7.6, 1.3 Hz, 2H), 6.53 (d,
J=8.1 Hz, 2H), 5.44 (s, 4H), 4.04-4.02 (m, 4H), 3.92 (s, 6H),
3.41-3.33 (m, 4H), 3.34-3.25 (m, 4H), 2.96-2.92 (m, 4H), 2.00 (s,
6H), 1.82 (s, 6H).
Example 19:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid))
##STR00254##
[1632] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (36 mg, 0.07 mmol) in DMF (2.0 mL) was
added the (S)-4-amino-3-hydroxybutanoic acid (67 mg, 0.56 mmol),
sodium cyanoborohydride (35 mg, 0.56 mmol) and acetic acid (0.20
mL) and the mixture was stirred at rt. After 18 h, the reaction
mixture was concentrated and purified by reverse phase
chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.38H.sub.46N.sub.4O.sub.10: 719.3; found: 719.2. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.65-8.52 (m, 4H), 7.75 (d, J=8.1
Hz, 2H), 7.44 (dd, J=7.5, 1.3 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.05
(dd, J=7.4, 1.3 Hz, 2H), 6.52 (d, J=8.1 Hz, 2H), 5.57 (brs, 2H),
5.43 (s, 4H), 4.20-3.97 (m, 6H), 3.91 (s, 6H), 2.98-2.86 (m, 4H),
2.39-2.26 (m, 4H), 2.00 (s, 6H).
Example 20:
5,5'-((((((2-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis-
(4-chloro-6-(((2-hydroxyethyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(me-
thylene))dinicotinonitrile (or
5,5'-((((((2-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis-
(4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5,1-phenylene))bis(oxy))bis(me-
thylene))dinicotinonitrile)
##STR00255##
[1634] Step 1: To a solution of 5-chloro-2,4-dihydroxybenzaldehyde
(227 mg, 1.32 mmol) in DMF (6 mL) and NaHCO.sub.3 (109 mg, 1.76
mmol), a separate solution of 1-bromo-3-(chloromethyl)benzene (180
mg, 0.87 mmol) in THF (6 mL) was added after 15 min at rt, followed
by the addition of NaI (131 mg, 0.87 mmol) at once. After 16 h, the
reaction mixture was diluted with EtOAc and brine solution. The
organic layer was then separated and the aqueous layer was back
extracted with EtOAc and the combined organic layers were dried
(MgSO.sub.4). Filtration, concentration and followed by
purification by column chromatography (SiO.sub.2, 0% EtOAc/hexanes
to 50% EtOAc/hexanes) gave
4-((3-bromobenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde.
[1635] Step 2: To a solution of
4-((3-bromobenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (800 mg, 2.34
mmol) in DMF (3 mL) and Cs.sub.2CO.sub.3 (2.3 g, 7.02 mmol), a
separate solution of 3-(chloromethyl)pyridine hydrogen chloride
(885 mg, 4.68 mmol) in DMF (7 mL) was added followed by the
addition of NaI (351 mg, 2.34 mmol) at once. The reaction mixture
was heated at 75.degree. C. After 16 h, the reaction mixture was
diluted with CH.sub.2Cl.sub.2 and brine solution. The organic layer
was then separated and the aqueous layer was back extracted with
CH.sub.2Cl.sub.2 and the combined organic layers were dried
(MgSO.sub.4). Filtration, concentration and followed by
purification by column chromatography (SiO.sub.2, 0% EtOAc/hexanes
to 100% EtOAc/hexanes) gave
5-((5-((3-bromobenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitril-
e.
[1636] Step 3: To a mixture
5-((5-((3-bromobenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitril-
e (53 mg, 0.12 mmol) and
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (50 mg, 0.10
mmol) in 1,4-Dioxane/water (3 mL, 2:1) was added K.sub.2CO.sub.3
(20 mg, 0.20 mmol) and Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol) and the
reaction mixture was heated at 85.degree. C. for 16 h. After
cooling to room temperature, the reaction mixture was diluted with
EtOAc and water. The organic layer was then separated and the
aqueous layer was back extracted with EtOAc and the combined
organic layers were dried (MgSO.sub.4). Filtration, concentration
and followed by purification by column chromatography (SiO.sub.2,
0% MeOH/EtOAc to 5% MeOH/EtOAc) gave
5,5'-((((((2-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis-
(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitril-
e.
[1637] Step 4: To a solution of
5,5'-((((((2-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis-
(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitril-
e (36 mg, 0.05 mmol) in DMF (2.0 mL) was added ethanolamine (17 mg,
0.28 mmol), sodium cyanoborohydride (35 mg, 0.56 mmol) and acetic
acid (0.20 mL) and the mixture was stirred at 45.degree. C. After
18 h, the reaction mixture was concentrated and purified by reverse
phase chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.47H.sub.44Cl.sub.2N.sub.6O.sub.6: 859.2; found: 859.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.05 (dd, J=5.1, 2.1
Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.56 (s, 2H), 8.48 (d, J=13.7 Hz,
1H), 7.58 (s, 1H), 7.51 (d, J=6.8 Hz, 1H), 7.46 (d, J=9.7 Hz, 1H),
7.31 (d, J=7.5 Hz, 1H), 7.22 (d, J=14.9 Hz, 1H), 7.15 (s, 1H), 5.38
(d, J=7.4 Hz, 2H), 5.33 (s, 2H), 5.22 (s, 1H), 4.14 (s, 2H), 3.63
(s, 2H), 2.95 (s, 2H), 2.69-2.65 (m, 1H), 2.35-2.31 (m, 1H), 2.25
(s, 1H).
Example 21:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan--
1-ol) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(ethan-1-ol))
##STR00256##
[1639] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (39 mg, 0.08 mmol) in DMF (2.0 mL) was
added ethanolamine (0.04 mL, 0.61 mmol), sodium cyanoborohydride
(38 mg, 0.61 mmol) and acetic acid (0.20 mL) and the mixture was
stirred at rt. After 45 min, the reaction mixture was concentrated
and purified by reverse phase chromatography to give the title
compound as TFA salt. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated
for C.sub.34H.sub.42N.sub.4O.sub.6: 603.3; found: 603.1. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.68-8.62 (s, 4H), 7.75 (d, J=8.1
Hz, 2H), 7.44 (dd, J=7.6, 1.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.05
(dd, J=7.7, 1.3 Hz, 2H), 6.53 (d, J=8.1 Hz, 2H), 5.44 (s, 4H),
4.12-4.05 (m, 4H), 3.92 (s, 6H), 3.68-3.60 (m, 4H), 2.99-2.92 (m,
4H), 2.00 (s, 6H).
Example 22:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-(pyridin-3-ylmethoxy)-4,1-phenylene))bis(methylene))bis(a-
zanediyl))bis(ethan-1-ol)
##STR00257##
[1641] Step 1: To a solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxybenzaldehyde) (85 mg, 0.15 mmol) in DMF (5 mL)
and Cs.sub.2CO.sub.3 (121 mg, 0.37 mmol), a separate solution of
3-(chloromethyl)pyridine (47 mg, 0.15 mmol) in DMF (2 mL) was added
followed by the addition of NaI (277 mg, 1.85 mmol) at once. The
reaction mixture was heated at 75.degree. C. After 16 h, the
reaction mixture was diluted with CH.sub.2Cl.sub.2 and brine
solution. The organic layer was then separated and the aqueous
layer was back extracted with CH.sub.2Cl.sub.2 and the combined
organic layers were dried (MgSO.sub.4). Filtration, concentration
and followed by purification by column chromatography (SiO.sub.2,
1% EtOAc/hexanes to 100% EtOAc/hexanes) gave
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde).
[1642] Step 2: To a solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde) (42 mg, 0.05 mmol)
in DMF (2.0 mL) was added ethanolamine (21 mg, 0.34 mmol), sodium
cyanoborohydride (43 mg, 0.6 mmol) and acetic acid (0.20 mL) and
the mixture was stirred at 45.degree. C. After 18 h, the reaction
mixture was concentrated and purified by reverse phase
chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.46H.sub.48Cl.sub.2N.sub.4O.sub.6: 823.2; found: 823.2.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.78 (s, 1H), 8.60 (d, J=4.9
Hz, 1H), 7.57 (s, 1H), 7.50 (d, J=10.9 Hz, 2H), 7.32 (t, J=7.6 Hz,
1H), 7.25 (s, 1H), 7.13 (d, J=7.0 Hz, 1H), 5.33 (d, J=7.6 Hz, 4H),
3.62 (s, 1H), 2.93 (s, 2H), 2.67 (t, J=1.8 Hz, 2H), 2.35-2.29 (m,
2H), 2.05 (s, 3H).
Example 23:
(2S,2'S)-1,1'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(propan-2-ol) (or
(2S,2'S)-1,1'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(propan-2-ol))
##STR00258##
[1644] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (39 mg, 0.08 mmol) in DMF (2.0 mL) was
added (S)-1-aminopropan-2-ol (46 mg, 0.61 mmol), sodium
cyanoborohydride (38 mg, 0.61 mmol) and acetic acid (0.20 mL) and
the mixture was stirred at 45.degree. C. After 4 h, the reaction
mixture was concentrated and purified by reverse phase
chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.34H.sub.46N.sub.4O.sub.6: 631.3; found: 631.1. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.53 (brs, 4H), 7.75 (d, J=8.1 Hz, 2H),
7.47-7.39 (m, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.05 (dd, J=7.6, 1.4 Hz,
2H), 6.52 (d, J=8.1 Hz, 2H), 5.43 (s, 4H), 5.32 (brs), 4.10-3.98
(m, 4H), 3.93 (s, 6H), 2.90-2.80 (m, 2H), 2.75-2.62 (m, 4H), 2.88
(d, J=4.9 Hz, 2H), 2.75-2.61 (m, 4H), 2.00 (s, 6H), 1.09 (d, J=6.3
Hz, 6H).
Example 24:
(2R,2'R)-1,1'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(propan-2-ol) (or
(2R,2'R)-1,1'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl)bis(propan-2-ol))
##STR00259##
[1646] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (39 mg, 0.08 mmol) in DMF (2.0 mL) was
added (R)-1-aminopropan-2-ol (46 mg, 0.61 mmol), sodium
cyanoborohydride (38 mg, 0.61 mmol) and acetic acid (0.20 mL) and
the mixture was stirred at 45.degree. C. After 4 h, the reaction
mixture was concentrated and purified by reverse phase
chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.34H.sub.46N.sub.4O.sub.6: 631.3; found: 631.2. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.53 (brs, 4H), 7.75 (d, J=8.1 Hz, 2H),
7.44 (dd, J=7.6, 1.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.05 (dd,
J=7.7, 1.4 Hz, 2H), 6.52 (d, J=8.1 Hz, 2H), 5.43 (s, 4H), 5.31
(brs), 4.08-3.99 (m, 4H), 3.91 (s, 6H), 2.90-2.80 (m, 2H),
2.75-2.62 (m, 4H), 2.00 (s, 6H), 1.09 (d, J=6.3 Hz, 6H).
Example 25:
5,5'-((((([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(oxy))bis(4-chloro-6-
-(((2-hydroxyethyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))di-
nicotinonitrile (or
5,5'-((((([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(oxy))bis(4-chloro-2-
-(((2-hydroxyethyl)amino)methyl)-5,1-phenylene))bis(oxy))bis(methylene))di-
nicotinonitrile)
##STR00260##
[1648] Step 1: To a mixture of
5-((5-((3-bromobenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitril-
e (100 mg, 0.22 mmol), potassium acetate (32 mg, 0.33 mmol),
4,4,5,5,-tetramethyl-2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-
,2-dioxaborolane (72 mg, 0.28 mmol) and
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride
dichloromethane adduct (20 mg, 0.03 mmol) was added 1,4-dioxane (2
mL). The mixture was heated in a heating block in microwave vial at
95.degree. C. for 1 h. After cooling to room temperature, the
reaction mixture was diluted with EtOAc and water. The organic
layer was then separated and the aqueous layer was back extracted
with EtOAc and the combined organic layers were dried (MgSO.sub.4).
Filtration, concentration gave
5-((4-chloro-2-formyl-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzyl)oxy)phenoxy)methyl)nicotinonitrile which was used further
without purification.
[1649] Step 2: To a mixture
5,5'-((((([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(oxy))bis(4-chloro-6-
-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile
(75 mg, 0.15 mmol) and
5-((5-((3-bromobenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitril-
e (113 mg, 0.25 mmol) in 1,4-Dioxane/water (6 mL, 2:1) was added
Cs.sub.2CO.sub.3 (96 mg, 0.30 mmol) and PEPSI-iPr (5 mg, 0.007
mmol) and the reaction mixture was heated at 95.degree. C. for 30
min. After cooling to room temperature, the reaction mixture was
diluted with EtOAc and water. The organic layer was then separated
and the aqueous layer was back extracted with EtOAc and the
combined organic layers were dried (MgSO.sub.4). Filtration,
concentration and followed by purification by column chromatography
(SiO.sub.2, 0% MeOH/EtOAc to 5% MeOH/EtOAc) gave
5,5'-((((([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(oxy))bis(4-chloro-6-
-formyl-3,1-phenylene))bis(oxy))bis(methylene))
dinicotinonitrile.
[1650] Step 3: To a solution of
5,5'-((5-((((([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(oxy))bis(4-chlo-
ro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))
dinicotinonitrile (29 mg, 0.04 mmol) in DMF (2.0 mL) was added
ethanolamine (14 mg, 0.23 mmol), sodium cyanoborohydride (30 mg,
0.46 mmol) and acetic acid (0.20 mL) and the mixture was stirred at
45.degree. C. After 18 h, the reaction mixture was concentrated and
purified by reverse phase chromatography to give the title compound
as TFA salt. LCMS-ESI+(m/z): [M+H].sup.+ calculated for
C.sub.46H.sub.42Cl.sub.2N.sub.6O.sub.6: 845.2; found: 845.2.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.02 (d, J=2.1 Hz, 1H), 8.99
(d, J=2.1 Hz, 1H), 8.44 (s, 1H), 7.79 (s, 1H), 7.65 (d, J=8.0 Hz,
1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.15 (s,
1H), 5.37 (s, 2H), 5.34 (s, 2H), 4.13 (s, 2H), 2.68-2.65 (m, 3H),
2.35-2.29 (m, 3H), 2.08 (s, 1H).
Example 26:
(S)-3-hydroxy-4-(((6-((3'-(((5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methy-
l)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)me-
thoxy)-2-methoxypyridin-3-yl)methyl)amino)butanoic acid
##STR00261##
[1652] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (28 mg, 0.06 mmol) in DMF (2.0 mL) was
added (S)-4-amino-3-hydroxybutanoic acid (52 mg, 0.43 mmol), sodium
cyanoborohydride (27 mg, 0.44 mmol) and acetic acid (0.20 mL) and
the mixture was stirred at rt. After 36 h, the reaction mixture was
concentrated and purified by reverse phase chromatography to give
the title compound as TFA salt. LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.38H.sub.44N.sub.4O.sub.9: 701.3; found: 701.3.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.19 (d, J=8.1 Hz, 1H),
8.07-7.96 (m, 3H), 7.81 (td, J=7.6, 3.9 Hz, 2H), 7.63 (td, J=7.5,
1.4 Hz, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H),
6.08-5.98 (m, 4H), 4.94-4.75 (m, 4H), 4.68 (s, 2H), 4.54 (s, 3H),
4.48 (s, 3H), 4.09-4.04 (m, 1H), 3.72-3.67 (m, 3H), 3.55-3.49 (m,
2H), 3.17-2.90 (m, 4H), 2.59 (s, 6H).
Example 27:
(S)-4-(((6-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-meth-
oxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methoxypy-
ridin-3-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00262##
[1654] Step 1: To a solution of 4-hydroxy-2-methoxybenzaldehyde
(341 mg, 2.24 mmol), (3-bromo-2-methylphenyl)methanol (410 mg, 2.04
mmol), PPh.sub.3 (801 mg, 3.06 mmol) in 2-MeTHF (7.0 mL) at
0.degree. C. was added Diisopropyl azodicarboxylate (0.6 mL, 3.06
mmol). The ice bath was removed and the reaction mixture was then
stirred at rt. After 4 h, the reaction mixture was directly
purified by column chromatography (SiO.sub.2, 1% EtOAc/hexanes to
50% EtOAc/hexanes) to give
4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde
[1655] Step 2: To a mixture
2-methoxy-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)nicotinaldehyde (70 mg, 0.18 mmol) and
4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde (70 mg, 0.21
mmol) in DME/water (3 mL, 2:1) was added Cs.sub.2CO.sub.3 (94 mg,
0.29 mmol), KOAc (11 mg, 0.19 mmol) and PEPSI-iPr (7 mg, 0.01 mmol)
and the reaction mixture was heated in microwave at 110.degree. C.
for 20 min. After cooling to room temperature, the reaction mixture
was directly purified by column chromatography (SiO.sub.2, 1%
EtOAc/hexanes to 50% EtOAc/hexanes) to give
6-((3'-((4-formyl-3-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-methoxynicotinaldehyde
[1656] Step 3: To a solution of
6-((3'-((4-formyl-3-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-methoxynicotinaldehyde (15 mg, 0.03 mmol) in DMF
(2.0 mL) was added (S)-4-amino-3-hydroxybutanoic acid (40 mg, 0.34
mmol), sodium cyanoborohydride (30 mg, 0.48 mmol) and acetic acid
(0.20 mL) and the mixture was stirred at rt. After 18 h, the
reaction mixture was concentrated and purified by reverse phase
chromatography to give the title compound as TFA salt.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.39H.sub.47N.sub.3O.sub.10: 718.3; found: 718.2. .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 7.68 (d, J=8.1 Hz, 1H), 7.44 (dt,
J=7.7, 1.4 Hz, 2H), 7.35-7.19 (m, 3H), 7.07 (ddd, J=7.7, 5.1, 1.4
Hz, 2H), 6.75 (d, J=2.3 Hz, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 6.48
(d, J=8.1 Hz, 1H), 5.49 (s, 2H), 5.18 (s, 2H), 4.32-4.28 (m, 2H),
4.19-4.17 (m, 5H), 4.03 (s, 3H), 3.91 (s, 3H), 3.22-3.08 (m, 3H),
3.02-2.83 (m, 3H), 2.57-2.50 (m, 6H), 2.07 (s, 3H), 2.05 (s,
3H).
Example 28:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-(2-morpholinoethoxy)-4,1-phenylene))bis(methylene))bis(az-
anediyl))bis(ethan-1-ol)
##STR00263##
[1658] Step 1: To a solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxybenzaldehyde) (86 mg, 0.16 mmol) in DMF (3 mL)
was added Cs.sub.2CO.sub.3 (254 mg, 0.78 mmol),
4-(2-chloroethyl)morpholine (93 mg, 0.62 mmol) and NaI (47 mg, 0.31
mmol). The reaction mixture was heated at 75.degree. C. After 16 h,
the reaction mixture was diluted with EtOAc and brine solution. The
organic layer was then separated and the aqueous layer was back
extracted with EtOAc and the combined organic layers were dried
(MgSO.sub.4). Filtration, concentration gave
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(2-morpholinoethoxy)benzaldehyde) which was used
further without purification.
[1659] Step 2: To a solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde) in DMF (2.0 mL)
was added ethanolamine (21 mg, 0.34 mmol), sodium cyanoborohydride
(43 mg, 0.6 mmol) and acetic acid (0.20 mL) and the mixture was
stirred at 45.degree. C. After 1 h, 2 more equiv. of ethanolamine
and sodium cyanoborohydride was added and heated at 45.degree. C.
After 16 h, Sodium triacetoxyborohydride was added and heated at
45.degree. C. for 3 h. The reaction mixture was concentrated and
purified by reverse phase chromatography to give the title compound
as TFA salt. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.46H.sub.60Cl.sub.2N.sub.4O.sub.8: 868.2; found: 868.3.
Example 29:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid))
##STR00264##
[1661]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxynicotinaldehyde) (6 mg, 0.01 mmol) was
converted to the title compound using general reductive amination
procedure F. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.38H.sub.44Cl.sub.2N.sub.4O.sub.10: 787.3; found: 787.2.
.sup.1H NMR (400 MHz, Methanol-d4) .delta. 7.81 (s, 2H), 7.47 (dd,
J=7.7, 1.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.3
Hz, 2H), 5.59 (s, 4H), 4.29 (dtd, J=9.4, 6.2, 3.0 Hz, 2H), 4.16 (s,
4H), 4.05 (s, 6H), 3.21 (dd, J=12.8, 3.0 Hz, 2H), 3.00 (dd, J=12.7,
9.8 Hz, 2H), 2.54 (d, J=6.3 Hz, 4H), 2.09 (s, 6H).
Example 30:
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxypyridine)
##STR00265##
[1663] To a stirred solution of Intermediate 18 (1 equiv) and
ethylenediamine (2.5 equiv) at 0.degree. C., was added NBS (2.5
equiv) in a single portion. The reaction was allowed to slowly warm
to room temperature. After 18 hours at room temperature full
conversion was observed by LCMS. The reaction mixture was then
diluted with 5:1 DMF/H.sub.2O to a total volume of 4.5 mL and
purified by reverse phase HPLC to afford after lyophilization
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxypyridine) as
the bis TFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.25 (s, 1H), 7.51 (dd, J=7.6, 1.3 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H),
7.13 (dd, J=7.6, 1.4 Hz, 1H), 5.70 (s, 2H), 4.19 (s, 3H), 4.03 (s,
4H), 2.11 (s, 3H). LCMS found 661.276.
Example 31:
(S)-4-(((6-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)naphthalen-2-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00266##
[1665] A vial was charged with 6-bromo-2-naphthaldehyde (500 mg,
2.12 mmol, 1 equiv), bis(pinacolato)diboron (648 mg, 2.55 mmol, 1.2
equiv), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(87 mg, 0.1 mmol) 5 mol %), and KOAc (420 mg, 4.24 mmol, 2 equiv).
The vial was sealed and dry dioxane was added via syringe. The
mixture was then degassed by sparging with argon for 10 minutes.
The vessel was then heated to 100 C for 2 hours. The reaction was
diluted with ethyl acetate and filtered through celites. The filter
cake was extracted with ethyl acetate (3.times.3 mL). The filtrate
was concentrate in vacuo. The crude material was purified by silica
gel chromatography (Hex/EtOAc, 100:0 to 0:100) to afford
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthaldehyde.
[1666] A vial was charged with Intermediate 19 (1 equiv),
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthaldehyde
(1.5 equiv),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mol
%), and K.sub.2CO.sub.3 (2 equiv). After the vial was sealed dry
dioxane (2 mL) and water (0.4 mL) were added via syringe. The
mixture was then degassed by sparging with argon for 10 minutes.
The vessel was then heated to 100 C for 2 hours. The reaction was
diluted with ethyl acetate and filtered through celites. The filter
cake was extracted with ethyl acetate (3.times.3 mL). The filtrate
was concentrate in vacuo. The crude material was purified by silica
gel chromatography (Hex/EtOAc, 100:0 to 0:100) to afford
5-((4-chloro-2-formyl-5-((3'-(6-formylnaphthalen-2-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[1667]
5-((4-chloro-2-formyl-5-((3'-(6-formylnaphthalen-2-yl)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (1
equiv) was suspended in DMF (0.025 M) and to this was added (3
S)-4-Amino-3-hydroxybutanoic acid (6 equiv) followed by
triethylamine (6 equiv) and the reaction stirred at room
temperature for 90 minutes. To this was added sodium
triacetoxyborohydride (6 equiv) and the reaction stirred an
additional 4 hours. At this point TFA was added slowly dropwise to
the reaction until the solution went clear. The reaction mixture
was then diluted with DMF to a total volume of 4.5 mL and purified
by reverse phase HPLC to afford after lyophilization
(S)-4-(((6-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)naphthalen-2-yl)methyl)amino)-3-hydroxybutanoic acid as
the bis TFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.96 (d, J=2.1 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.38 (s, 1H), 8.07
(s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.89 (s,
1H), 7.62 (dd, J=8.5, 1.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.52 (s, 1H),
7.48 (d, J=7.6 Hz, 1H), 7.40-7.25 (m, 4H), 7.19 (d, J=7.5 Hz, 1H),
7.17-7.14 (m, 1H), 7.09 (s, 1H), 5.39 (s, 2H), 5.33 (s, 2H), 4.45
(s, 2H), 4.34 (dt, J=6.8, 3.3 Hz, 0H), 4.24 (s, 3H), 3.27-3.16 (m,
2H), 3.07 (dd, J=12.7, 9.8 Hz, 1H), 3.02-2.94 (m, 1H), 2.56 (d,
J=6.3 Hz, 2H), 2.54-2.51 (m, 2H), 2.19 (s, 3H), 1.94 (d, J=0.9 Hz,
4H). LCMS found 843.231.
Example 32:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl)-
)bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00267##
[1669] To a stirred mixture of Intermediate 20 (1 equiv) and
(S)-3-aminobutanoic acid (5 equiv) in a 6:1 mixture of DMF/AcOH
(0.02 M) at room temperature was added sequentially sodium
cyanoborohydride (9 equiv) and sodium triacetoxyborohydride (9
equiv). After 4 hours at room temperature the reaction mixture was
diluted with DMF/H.sub.2O (5:1) to a total volumne of 4.5 mL. The
resulting mixture was purified by reverse phase HPLC (0.1%
trifluoroacetic acid in acetonitrile/water) providing the title
compound upon lyophilization as the bis-TFA salt. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.94 (d, J=2.1 Hz, 1H), 8.87 (d,
J=2.0 Hz, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.39 (d, J=7.6 Hz, 1H),
7.23 (t, J=7.6 Hz, 1H), 7.11-7.06 (m, 1H), 5.60 (s, 2H), 5.49 (d,
J=4.1 Hz, 2H), 4.31-4.21 (m, 3H), 3.24 (dd, J=12.7, 3.1 Hz, 1H),
3.03 (dd, J=12.7, 9.8 Hz, 1H), 2.54 (d, J=6.3 Hz, 2H), 2.03 (s,
3H). LCMS found 991.141 (M+1).
Example 33:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00268##
[1671] To a stirred mixture of Intermediate 21 (1 equiv) and
(S)-3-aminobutanoic acid (5 equiv) in a 6:1 mixture of DMF/AcOH
(0.02 M) at room temperature was added sequentially sodium
cyanoborohydride (9 equiv) and sodium triacetoxyborohydride (9
equiv). After 4 hours at room temperature the reaction mixture was
diluted with DMF/H.sub.2O (5:1) to a total volumne of 4.5 mL. The
resulting mixture was purified by reverse phase HPLC (0.1%
trifluoroacetic acid in acetonitrile/water) providing the title
compound upon lyophilization as the bis-TFA salt. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.04 (dd, J=5.1, 2.0 Hz, 4H), 8.58 (s, 4H),
8.48 (t, J=2.1 Hz, 2H), 7.72 (s, 2H), 7.53 (d, J=7.4 Hz, 2H), 7.31
(t, J=7.6 Hz, 2H), 7.17 (s, 2H), 7.12 (d, J=7.3 Hz, 2H), 5.39 (s,
4H), 5.33 (s, 4H), 4.15 (s, 6H), 2.85 (s, 2H), 2.44 (d, J=5.3 Hz,
2H), 2.37 (dd, J=15.9, 7.2 Hz, 2H), 2.05 (s, 6H). LCMS found 1077.1
(M+1).
Example 34:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl)-
)bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00269##
[1673] To a stirred mixture of Intermediate 20 (1 equiv) and
(S)-3-aminobutanoic acid (5 equiv) in a 6:1 mixture of DMF/AcOH
(0.02 M) at room temperature was added sequentially sodium
cyanoborohydride (9 equiv) and sodium triacetoxyborohydride (9
equiv). After 4 hours at room temperature the reaction mixture was
diluted with DMF/H.sub.2O (5:1) to a total volumne of 4.5 mL. The
resulting mixture was purified by reverse phase HPLC (0.1%
trifluoroacetic acid in acetonitrile/water) providing the title
compound upon lyophilization as the bis-TFA salt. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.88 (d, J=2.0
Hz, 1H), 8.34 (t, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.42-7.38 (m, 1H),
7.24 (t, J=7.6 Hz, 1H), 7.11-7.06 (m, 1H), 5.61 (t, J=2.3 Hz, 1H),
5.52-5.48 (m, 1H), 4.25 (s, 3H), 3.25 (dd, J=12.7, 3.1 Hz, 1H),
3.04 (dd, J=12.7, 9.8 Hz, 1H), 2.55 (d, J=6.3 Hz, 2H), 2.04 (s,
3H). LCMS found 991.178 (M+1).
Example 35:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-3-(((2-hydroxyethyl)amino)methyl)pyridine-6,2-diyl))bis(oxy-
))bis(methylene))dinicotinonitrile (or
5,5'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-3-(((2-hydroxyethyl)amino)methyl)pyridine-6,2
diyl))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00270##
[1675] To a stirred mixture of Intermediate 20 (1 equiv) and
ethanolamine (5 equiv) in a 6:1 mixture of DMF/AcOH (0.02 M) at
room temperature was added sequentially sodium cyanoborohydride (9
equiv) and sodium triacetoxyborohydride (9 equiv). After 4 hours at
room temperature the reaction mixture was diluted with DMF/H.sub.2O
(5:1) to a total volumne of 4.5 mL. The resulting mixture was
purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the title compound upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.88 (d, J=1.9
Hz, 1H), 8.34 (t, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.40 (dd, J=7.3, 1.3
Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.13-7.05 (m, 1H), 5.50 (d, J=3.8
Hz, 2H), 4.25 (s, 2H), 3.85-3.77 (m, 2H), 3.20-3.13 (m, 2H), 2.04
(s, 3H). LCMS found 875.120 (M+1).
Example 36:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-(((2-hydroxyethyl)amino)methyl)-4-vinyl-3,1-phenylene))bis(oxy))bi-
s(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-(((2-hydroxyethyl)amino)methyl)-4-vinyl-5,1-phenylene))bis(oxy))bi-
s(methylene))dinicotinonitrile)
##STR00271##
[1677] A vial was charged with Intermediate 23 (1 equiv), vinyl
potassium trifluoroborate (4.0 equiv),
Tetrakis(triphenylphosphine)palladium(0) (10 mol %), and
K.sub.2CO.sub.3 (3 equiv). After the vial was sealed dry DMF (2 mL)
and water (0.2 mL) were added via syringe. The mixture was then
degassed by sparging with argon for 10 minutes. The vessel was then
heated to 100 C for 2 hours. The reaction was diluted with ethyl
acetate and filtered through celites. The filter cake was extracted
with ethyl acetate (3.times.3 mL). The filtrate was concentrate in
vacuo. The crude material was used without further purification.
LCMS found 767.076 (M+1).
[1678] To a stirred mixture of bis-aldehyde (1 equiv) and
ethanolamine (5 equiv) in a 6:1 mixture of DMF/AcOH (0.02 M) at
room temperature was added sequentially sodium cyanoborohydride (9
equiv) and sodium triacetoxyborohydride (9 equiv). After 4 hours at
room temperature the reaction mixture was diluted with DMF/H.sub.2O
(5:1) to a total volumne of 4.5 mL. The resulting mixture was
purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the title compound upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.04 (t, J=1.9 Hz, 2H), 8.56 (s, 2H), 8.50
(t, J=2.1 Hz, 1H), 7.66 (s, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.13 (d,
J=7.7 Hz, 1H), 7.05 (s, 1H), 6.89 (dd, J=17.7, 11.2 Hz, 1H), 5.69
(dd, J=17.7, 1.6 Hz, 1H), 5.38 (s, 2H), 5.27 (s, 2H), 5.24-5.14 (m,
2H), 4.16 (s, 2H), 3.65 (d, J=5.2 Hz, 2H), 2.97 (s, 2H), 2.55 (t,
J=5.5 Hz, 5H), 2.02 (s, 3H). LCMS found 857.083 (M+1).
Example 37:
N,N'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidine-1,-
3-diyl))diacetamide (or
N,N'-(1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylen-
e))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(az-
etidine-3,1-diyl))diacetamide)
##STR00272##
[1680] Intermediate 18 (1 equiv) was suspended in DMF (0.025 M) and
to this was added (3S)-4-Amino-3-hydroxybutanoic acid (6 equiv)
followed by triethylamine (6 equiv) and the reaction stirred at
room temperature for 90 minutes. To this was added sodium
triacetoxyborohydride (6 equiv) and the reaction stirred an
additional 4 hours. At this point TFA was added slowly dropwise to
the reaction until the solution went clear. The reaction mixture
was then diluted with DMF to a total volume of 4.5 mL and purified
by reverse phase HPLC to afford, after lyophilization,
N,N'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidine-1,-
3-diyl))diacetamide as the bis TFA salt. .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.83 (s, 1H), 7.48 (dd, J=7.6, 1.4 Hz, 1H),
7.25 (t, J=7.6 Hz, 1H), 7.09 (dd, J=7.7, 1.4 Hz, 1H), 5.60 (s, 2H),
4.53 (d, J=9.8 Hz, 1H), 4.41-4.33 (m, 4H), 4.28-4.20 (m, 2H), 4.06
(s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). LCMS found 777.178 (M+1).
Example 38:
(S)-4-((5-bromo-4-((3'-((2-bromo-5-((5-cyanopyridin-3-yl)methoxy)-4-(((S)-
-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-h-
ydroxybutanoic acid
##STR00273##
[1682] To a stirred mixture of Intermediate 23 (1 equiv) and
ethanolamine (5 equiv) in a 6:1 mixture of DMF/AcOH (0.02 M) at
room temperature was added sequentially sodium cyanoborohydride (9
equiv) and sodium triacetoxyborohydride (9 equiv). After 4 hours at
room temperature the reaction mixture was diluted with DMF/H.sub.2O
(5:1) to a total volumne of 4.5 mL. The resulting mixture was
purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the title compound upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.05-8.94 (m, 3H), 8.55 (s, 1H), 8.51-8.39
(m, 2H), 7.70 (s, 1H), 7.64-7.47 (m, 2H), 7.39-7.24 (m, 2H),
7.18-7.06 (m, 3H), 5.31 (t, J=19.1 Hz, 6H), 4.39 (d, J=15.0 Hz,
1H), 4.25 (d, J=15.4 Hz, 1H), 4.13 (dq, J=10.7, 6.5 Hz, 2H), 4.03
(s, 1H), 3.01 (d, J=1.8 Hz, 1H), 2.98 (s, 1H), 2.83 (s, 1H),
2.48-2.30 (m, 2H), 2.02 (d, J=11.1 Hz, 7H). LCMS found 1059.0
(M+1).
Example 39:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-(((2-hydroxyethyl)amino)methyl)-4-propyl-3,1-phenylene))bis(oxy))b-
is(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-(((2-hydroxyethyl)amino)methyl)-4-propyl-5,1-phenylene))bis(oxy))b-
is(methylene))dinicotinonitrile)
##STR00274##
[1684] A vial was charged with Intermediate 23 (1 equiv),
n-propylboronic acid (10.0 equiv), SPhos Pd G3 (10 mol %), and
K.sub.3PO.sub.4 (6 equiv). After the vial was sealed dry toluene (2
mL) and water (0.2 mL) were added via syringe. The mixture was then
degassed by sparging with argon for 10 minutes. The vessel was then
heated to 100.degree. C. for 1 hour. The reaction was diluted with
ethyl acetate and filtered through celites. The filter cake was
extracted with ethyl acetate (3.times.3 mL). The filtrate was
concentrate in vacuo. The crude material was used without further
purification.
[1685] To a stirred mixture of bis-aldehyde (1 equiv) and
ethanolamine (5 equiv) in a 6:1 mixture of DMF/AcOH (0.02 M) at
room temperature was added sequentially sodium cyanoborohydride (9
equiv) and sodium triacetoxyborohydride (9 equiv). After 4 hours at
room temperature the reaction mixture was diluted with DMF/H.sub.2O
(5:1) to a total volumne of 4.5 mL. The resulting mixture was
purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing the title compound upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.04 (t, J=1.6 Hz, 2H), 8.49 (t, J=2.1 Hz,
3H), 7.50-7.45 (m, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.23 (s, 1H),
7.13-7.09 (m, 1H), 7.02 (d, J=2.8 Hz, 1H), 5.34 (d, J=3.0 Hz, 2H),
5.22 (d, J=4.1 Hz, 2H), 4.12 (s, 2H), 3.64 (t, J=5.4 Hz, 3H),
3.00-2.89 (m, 2H), 2.03 (s, 3H), 1.51 (q, J=7.5 Hz, 2H), 0.90-0.81
(m, 4H). LCMS found 889.059 (M+1).
Example 40
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methox-
y)pyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylp-
ropanoic acid) (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyr-
idine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropan-
oic acid))
##STR00275##
[1687] Step-1: To a mix of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-hydroxynicotinaldehyde) (20 mg, 0.031 mmol),
(5-(methylsulfonyl)pyridin-3-yl)methanol (14.6 mg, 0.078 mmol),
PPh3 (20.4 mg, 0.078 mmol), in THF (2 mL) under argon was added
DIAD (15.8 mg, 0.078 mmol) at once and stirred at RT for 3 h. The
solvent was concentrated and purified by column chromatography to
afford product
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde).
LC/MS calculated for (M+H).sup.+: 980.8, found: 980.7.
[1688] Step-2: Fine powder of NaOH (4.08 mg, 0.1 mmol),
(R)-2-amino-3-hydroxy-2-methylpropanoic acid (12.1 mg, 0.102 mmol)
were taken in a 8 mL Vial, added Ethanol (1 mL), flushed with argon
and sonicated for 10 min. To well stirred mix was added solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde)
(10 mg, 0.01 mmol) in DCM (0.25 mL) at once and stirred at RT for 1
h. The reaction mixture was added NaBH(OAc).sub.3 (21.6 mg, 0.102
mmol) at once followed by AcOH (20 uL), sonicated to mix well and
stirred at room temperature overnight. The solvent was concentrated
and purified by reverse phase HPLC to afford
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyridine-
-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.04 (dd,
J=4.7, 2.0 Hz, 4H), 8.53 (t, J=2.1 Hz, 2H), 8.06 (s, 2H), 7.42 (d,
J=7.8 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.12-7.04 (m, 2H), 5.64 (t,
J=3.1 Hz, 4H), 5.52 (d, J=2.1 Hz, 4H), 4.27 (s, 4H), 4.04 (d,
J=12.1 Hz, 2H), 3.83 (d, J=12.1 Hz, 2H), 3.20 (s, 6H), 2.04 (s,
6H), 1.56 (s, 6H). LC/MS calculated for (M+H).sup.+: 1185.1, found:
1187.3.
Example 41:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyridine-
-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diy-
l)bis(methylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)m-
ethoxy)pyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-me-
thylpropanoic acid))
##STR00276##
[1690]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)py-
ridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropa-
noic acid) was synthesized following the procedure shown in the
Example 40. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.04
(dd, J=4.7, 2.0 Hz, 4H), 8.53 (t, J=2.1 Hz, 2H), 8.06 (s, 2H), 7.42
(d, J=7.8 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.12-7.04 (m, 2H), 5.64
(t, J=3.1 Hz, 4H), 5.52 (d, J=2.1 Hz, 4H), 4.27 (s, 4H), 4.04 (d,
J=12.1 Hz, 2H), 3.83 (d, J=12.1 Hz, 2H), 3.20 (s, 6H), 2.04 (s,
6H), 1.56 (s, 6H). LC/MS calculated for (M+H).sup.+: 1185.1, found:
1187.3.
Example 42:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyridine-
-6,3 diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyr-
idine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00277##
[1692]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-bromo-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)py-
ridine-6,3
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) was
synthesized following procedure shown in Example 40. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.33 (s, 2H), 9.05 (dd, J=6.1, 2.0
Hz, 4H), 8.67 (s, 4H), 8.47 (d, J=2.3 Hz, 2H), 8.12 (s, 2H), 7.42
(d, J=7.6 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H),
5.58 (d, J=22.6 Hz, 6H), 5.47 (d, J=4.2 Hz, 4H), 4.12 (s, 8H), 3.94
(s, 2H), 3.15 (s, 2H), 3.04 (s, 2H), 2.88 (s, 2H), 2.47-2.25 (m,
6H), 1.99 (s, 6H). LC/MS calculated for (M+H).sup.+: 1185.1, found:
1187.3.
Example 43:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxy-2-methylpropanoic acid) (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxy-2-methylpropanoic acid))
##STR00278##
[1694]
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.83 (s, 2H), 7.51-7.42 (m, 2H), 7.23 (t,
J=7.6 Hz, 2H), 7.06 (dd, J=7.7, 1.4 Hz, 2H), 5.59 (s, 4H),
4.26-4.13 (m, 4H), 4.04 (d, J=2.2 Hz, 7H), 4.03-3.95 (m, 2H), 3.83
(d, J=12.1 Hz, 2H), 2.08 (s, 6H), 1.58 (s, 6H). LC/MS calculated
for (M+H).sup.+: 787.2, found: 788.3.
Example 44:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxy-2-methylpropanoic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxy-2-methylpropanoic acid))
##STR00279##
[1696]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.83 (s, 2H), 7.47 (dd, J=7.9, 1.4 Hz,
2H), 7.23 (t, J=7.6 Hz, 2H), 7.06 (dd, J=7.6, 1.4 Hz, 2H), 5.59 (s,
4H), 4.24-4.10 (m, 4H), 4.02 (d, J=14.9 Hz, 8H), 3.81 (d, J=12.1
Hz, 2H), 2.08 (s, 5H), 1.56 (s, 6H). LC/MS calculated for
(M+H).sup.+: 787.2, found: 788.0.
Example 45:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxy-2-methylpropanoic acid)
##STR00280##
[1698]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) was synthesized
following the procedure shown in Example 40. LC/MS calculated for
(M+H).sup.+: 875.1, found: 877.1.
Example 46:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxy-2-methylpropanoic acid)
##STR00281##
[1700]
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) was synthesized
following the procedure shown in Example 40. LC/MS calculated for
(M+H).sup.+: 875.1, found: 877.1.
Example 47:
(2S,2'S,4R,4'R)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(4-hydroxypiperidine-2-carboxylic acid) (or
(2S,2'S,4R,4'R)-1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bi-
s(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(4-hydroxypiperidine-2-carboxylic acid))
##STR00282##
[1702]
(2S,2'S,4R,4'R)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(4-hydroxypiperidine-2-carboxylic acid) was synthesized
following the general reductive amination procedure H. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.97 (s, 1H), 7.85 (s, 2H),
7.48 (dd, J=7.7, 1.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.09 (dd,
J=7.7, 1.3 Hz, 2H), 5.60 (s, 4H), 4.52-4.21 (m, 4H), 4.02 (s, 6H),
3.93-3.39 (m, 4H), 3.22-3.04 (m, 2H), 2.98 (s, 2H), 2.85 (d, J=0.7
Hz, 2H), 2.46 (d, J=13.5 Hz, 2H), 2.09 (s, 8H), 1.88-1.15 (m, 5H).
LC/MS calculated for (M+H).sup.+: 839.3, found: 839.5.
Example 48:
(2S,2'S,4S,4'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(4-hydroxypyrrolidine-2-carboxylic acid) (or
(2S,2'S,4S,4'S)-1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bi-
s(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(4-hydroxypyrrolidine-2-carboxylic acid))
##STR00283##
[1704]
(2S,2'S,4S,4'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(4-hydroxypyrrolidine-2-carboxylic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.87 (s, 2H), 7.52-7.43 (m, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.09 (dd, J=7.6, 1.4 Hz, 2H), 5.59 (s, 4H),
4.56-4.25 (m, 8H), 4.06 (s, 6H), 3.56 (d, J=11.7 Hz, 2H), 3.35 (dd,
J=11.8, 3.8 Hz, 2H), 2.71 (ddd, J=13.9, 10.9, 4.7 Hz, 2H),
2.28-2.18 (m, 2H), 2.09 (s, 6H). LC/MS calculated for (M+H).sup.+:
811.2, found: 812.2.
Example 49:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid))
##STR00284##
[1706]
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(3-hydroxybutanoic acid) was synthesized following
the procedure shown in Example 40. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.34 (s, 2H), 8.62 (s, 4H), 7.95 (s, 2H),
7.46 (d, J=7.6 Hz, 2H), 7.27 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.2 Hz,
2H), 5.56 (s, 4H), 4.14 (s, 2H), 4.03 (s, 4H), 3.94 (s, 6H), 3.01
(s, 2H), 2.86 (s, 2H), 2.47-2.28 (m, 4H), 2.02 (s, 6H). LC/MS
calculated for (M+H).sup.+: 787.3, found: 787.2.
Example 50:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxypropanoic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxypropanoic acid))
##STR00285##
[1708]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(3-hydroxypropanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.90 (s, 2H), 7.46 (d, J=7.6 Hz, 2H), 7.26
(t, J=7.6 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 5.55 (s, 4H), 4.00 (s,
4H), 3.90 (s, 6H), 3.79 (s, 4H), 3.72 (d, J=19.1 Hz, 2H), 2.01 (s,
6H). LC/MS calculated for (M+H).sup.+: 759.3, found: 759.2.
Example 51:
(2S,2'S,3R,3'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(2S,2'S,3R,3'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00286##
[1710]
(2S,2'S,3R,3'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)-
bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.92 (s, 2H), 7.46 (d, J=7.6 Hz, 2H), 7.27
(t, J=7.6 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 5.55 (d, J=2.2 Hz, 4H),
3.98 (d, J=14.1 Hz, 6H), 3.90 (s, 6H), 3.42 (s, 2H), 2.01 (s, 6H),
1.17 (d, J=6.3 Hz, 6H). LC/MS calculated for (M+H).sup.+: 787.2,
found: 787.2.
Example 52:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(2-(2H-tetrazol-5-yl)ethan-1-ol) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(2-(2H-tetrazol-5-yl)ethan-1-ol))
##STR00287##
[1712]
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(2-(2H-tetrazol-5-yl)ethan-1-ol) was synthesized following
the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.74 (s, 2H), 7.45 (dd, J=7.7, 1.4 Hz,
2H), 7.23 (t, J=7.6 Hz, 2H), 7.06 (dd, J=7.7, 1.4 Hz, 2H), 5.57 (s,
4H), 4.85 (s, 2H), 4.24 (d, J=4.0 Hz, 4H), 4.10 (d, J=5.8 Hz, 4H),
3.96 (s, 6H), 2.07 (s, 6H). LC/MS calculated for (M+H).sup.+:
807.3, found: 807.2.
Example 53:
(2S,2'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis-
(methylene))bis(piperidine-2-carboxylic acid)
##STR00288##
[1714]
(2S,2'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylen-
e))bis(methylene))bis(piperidine-2-carboxylic acid) was synthesized
following the procedure shown in Example 40. LC/MS calculated for
(M+H).sup.+: 1009.3, found: 1009.6.
Example 54:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00289##
[1716] Step-1: To a mixture of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-methoxynicotinaldehyde) (100 mg, 0.15 mmol)
cyclopropylboronic acid (51.4 mg, 0.59 mmol), potassium phosphate
(140.4 mg, 1.04 mmol), and tricyclohexylphosphine (33.5 mg, 0.12
mmol) in toluene (5 mL) and water (0.25 mL) under a nitrogen
atmosphere was added palladium acetate (6.4 mg, 0.06 mmol). The
mixture was heated to 100.degree. C. for 3 h and then cooled to
room temperature. Water (10 mL) was added and the mixture extracted
with EtOAc (2.times.15 mL), the combined organics were washed with
brine (10 mL), dried over MgSO.sub.4 and concentrated in vacuo.
Purification by column chromatography (10% EtOAc in hexanes)
afforded the desired compound
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-cyclopropyl-2-methoxynicotinaldehyde). .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 10.18 (s, 2H), 7.65 (d, J=0.7 Hz, 2H), 7.49
(dd, J=7.6, 1.4 Hz, 2H), 7.32-7.21 (m, 2H), 7.14 (dd, J=7.7, 1.4
Hz, 2H), 5.57 (s, 4H), 4.04 (s, 6H), 2.11 (s, 6H), 1.95 (ttd,
J=8.4, 5.3, 0.7 Hz, 2H), 0.92-0.80 (m, 4H), 0.67-0.53 (m, 4H).
[1717] Step-2:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid) was synthesized following
the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.47 (dd, J=7.7, 1.3 Hz, 2H), 7.32 (s, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (dd, J=7.7, 1.4 Hz, 2H), 5.55 (s, 4H),
4.27 (dq, J=9.7, 3.3 Hz, 2H), 4.12 (s, 4H), 4.01 (s, 7H), 3.16 (dd,
J=12.8, 3.0 Hz, 2H), 2.95 (dd, J=12.8, 9.8 Hz, 2H), 2.53 (d, J=6.3
Hz, 4H), 2.10 (s, 6H), 1.97 (td, J=8.5, 4.3 Hz, 2H), 0.95-0.79 (m,
4H), 0.69-0.51 (m, 4H). LC/MS calculated for (M+H).sup.+: 799.4,
found: 799.2.
Example 55:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00290##
[1719]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.47 (d, J=7.6 Hz, 2H), 7.32 (s, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5 Hz, 2H), 5.55 (s, 4H), 4.27
(dq, J=9.7, 3.3 Hz, 2H), 4.12 (s, 4H), 4.01 (s, 6H), 3.33 (d, J=9.6
Hz, 2H), 3.16 (dd, J=12.7, 3.0 Hz, 2H), 2.95 (dd, J=12.7, 9.8 Hz,
2H), 2.53 (d, J=6.4 Hz, 4H), 2.10 (s, 6H), 1.97 (tq, J=10.4, 5.1
Hz, 2H), 0.87 (dt, J=8.6, 3.1 Hz, 4H), 0.75-0.45 (m, 4H). LC/MS
calculated for (M+H).sup.+: 799.4, found: 799.2.
Example 56:
(S)-4-(((5-cyclopropyl-6-((3'-(((3-cyclopropyl-5-((((S)-4-ethoxy-2-hydrox-
y-4-oxobutyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-
-[1,1'-biphenyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydro-
xybutanoic acid
##STR00291##
[1721]
(S)-4-(((5-cyclopropyl-6-((3'-(((3-cyclopropyl-5-((((S)-4-ethoxy-2--
hydroxy-4-oxobutyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-di-
methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-
-hydroxybutanoic acid was isolated as byproduct from Example 55.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.47 (dd, J=7.6,
1.4 Hz, 2H), 7.32 (s, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.06 (dd, J=7.6,
1.4 Hz, 2H), 5.55 (s, 4H), 4.28 (dp, J=9.6, 2.8 Hz, 2H), 4.14 (d,
J=9.7 Hz, 6H), 4.01 (s, 6H), 3.15 (ddd, J=12.9, 10.0, 3.0 Hz, 2H),
2.96 (dd, J=12.8, 9.8 Hz, 2H), 2.54 (t, J=6.2 Hz, 4H), 2.10 (s,
6H), 1.97 (ddt, J=12.6, 9.5, 4.7 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H),
0.95-0.76 (m, 4H), 0.67-0.53 (m, 4H). LC/MS calculated for
(M+H).sup.+: 827.4, found: 827.2.
Example 57:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3-(methylsulfonyl)benzyl)oxy)-4,1-phenylene))b-
is(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid)
##STR00292##
[1723]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((3-(methylsulfonyl)benzyl)oxy)-4,1-phenyl-
ene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid) was synthesized following the procedure shown in Example 40.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.14 (s, 2H), 7.93
(dd, J=18.1, 7.8 Hz, 4H), 7.67 (t, J=7.7 Hz, 2H), 7.52 (s, 2H),
7.44 (d, J=7.6 Hz, 2H), 7.25 (t, J=7.7 Hz, 2H), 7.10 (d, J=7.5 Hz,
2H), 7.03 (s, 2H), 5.33 (d, J=27.2 Hz, 8H), 4.34-4.17 (m, 4H), 3.98
(d, J=12.0 Hz, 2H), 3.79 (d, J=12.1 Hz, 2H), 3.14 (s, 6H), 3.02 (s,
2H), 2.06 (s, 6H), 1.48 (s, 6H). LC/MS calculated for (M+H).sup.+:
1093.3, found: 1093.2.
Example 58:
(2S,2'S,4S,4'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenyle-
ne))bis(methylene))bis(4-hydroxypyrrolidine-2-carboxylic acid)
##STR00293##
[1725]
(2S,2'S,4S,4'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-p-
henylene))bis(methylene))bis(4-hydroxypyrrolidine-2-carboxylic
acid) was synthesized following the procedure shown in Example 40.
.sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) .delta. 8.98-8.85 (m,
4H), 8.31 (s, 2H), 7.53 (d, J=7.6 Hz, 2H), 7.47 (s, 2H), 7.33 (t,
J=7.6 Hz, 3H), 7.18 (d, J=7.5 Hz, 3H), 6.97 (d, J=6.2 Hz, 2H),
5.45-5.12 (m, 10H), 4.44 (d, J=12.3 Hz, 4H), 4.32 (td, J=8.6, 7.4,
4.3 Hz, 4H), 3.57-3.14 (m, 4H), 2.57 (d, J=10.7 Hz, 0H), 2.25 (d,
J=14.2 Hz, 2H), 2.05 (d, J=7.8 Hz, 6H). LC/MS calculated for
(M+H).sup.+: 1013.3, found: 1013.4.
Example 59:
(2S,2'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azeti-
dine-2-carboxylic acid) (or
(2S,2'S)-1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
azetidine-2-carboxylic acid))
##STR00294##
[1727]
(2S,2'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azetidine-2-carboxylic acid) was synthesized following the
procedure shown in Example 40. LC/MS calculated for (M+H).sup.+:
841.6, found: 841.2.
Example 60:
(S)-1-((6-((3'-(((3-bromo-5-(((S)-2-carboxyazetidin-1-yl)methyl)-6-methox-
ypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-me-
thoxypyridin-3-yl)methyl)azetidine-2-carboxylic acid
##STR00295##
[1729]
(S)-1-((6-((3'-(((3-bromo-5-(((S)-2-carboxyazetidin-1-yl)methyl)-6--
methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy-
)-2-methoxypyridin-3-yl)methyl)azetidine-2-carboxylic acid was
isolated as side product of Example 59. LC/MS calculated for
(M+H).sup.+: 761.2, found: 760.1.
Example 61:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-hydroxy-2-methylpropanoic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxy-2-methylpropanoic acid)
##STR00296##
[1731]
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(3-hydroxy-2-methylpropanoic acid) was synthesized
following the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.72 (d, J=8.1 Hz, 2H), 7.43 (dd, J=7.8,
1.4 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H), 7.04 (dd, J=7.6, 1.4 Hz, 2H),
6.47 (d, J=8.1 Hz, 2H), 5.49 (s, 4H), 4.31-4.09 (m, 4H), 4.02 (s,
8H), 3.91-3.70 (m, 2H), 2.84 (s, 1H), 2.06 (d, J=1.7 Hz, 6H), 1.59
(s, 6H). LC/MS calculated for (M+H).sup.+: 719.3, found: 719.0.
Example 62:
5,5'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(4,5,6,7-tetra-
hydro-1H-imidazo[4,5-c]pyridine-4-carboxylic acid) (or
5,5'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(4,5,6,7--
tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylic acid))
##STR00297##
[1733]
5,5'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(4,5,6,7-
-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylic acid) was
synthesized following the procedure shown in Example 40. .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 8.78 (s, 2H), 7.86 (s, 2H),
7.54-7.38 (m, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.6, 1.4 Hz,
2H), 5.56 (s, 4H), 4.68 (s, 2H), 4.03 (d, J=2.3 Hz, 4H), 3.96 (s,
6H), 3.46 (ddd, J=13.7, 9.1, 5.3 Hz, 2H), 3.29 (s, 10H), 2.96 (dt,
J=15.6, 6.8 Hz, 2H), 2.87-2.70 (m, 2H), 2.09 (s, 6H). LC/MS
calculated for (M+H).sup.+: 883.4, found: 883.3.
Example 63:
5,5'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))-
bis(methylene))bis(isoxazol-3-ol) (or
5,5'-((((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(methylene))bis(isoxazol-3-ol))
##STR00298##
[1735]
5,5'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))bis(methylene))bis(isoxazol-3-ol) was synthesized following
the procedure shown in Example 40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.78 (s, 2H), 7.47 (dd, J=7.7, 1.4 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.4 Hz, 2H), 6.18 (s,
2H), 5.59 (s, 4H), 4.35 (s, 4H), 4.17 (s, 4H), 4.04 (s, 6H), 2.08
(s, 6H). LC/MS calculated for (M+H).sup.+: 777.2, found: 779.9.
Example 64:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid))
##STR00299##
[1737]
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-cyclopropyl-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) was
synthesized following the procedure shown in Example 40. LC/MS
calculated for (M+H).sup.+: 799.4, found: 799.2.
Example 65:
1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidine-2-c-
arboxamide) (or
1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidin-
e-2-carboxamide))
##STR00300##
[1739]
1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidi-
ne-2-carboxamide) was synthesized following the reductive amination
procedure H. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.78
(s, 2H), 7.46 (dd, J=7.4, 1.1 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.08
(dd, J=7.6, 1.4 Hz, 2H), 5.57 (s, 4H), 5.07 (t, J=9.4 Hz, 2H),
4.39-4.20 (m, 4H), 4.15 (q, J=9.6 Hz, 2H), 4.04 (s, 6H), 3.97 (td,
J=9.6, 3.8 Hz, 2H), 2.80-2.63 (m, 2H), 2.50 (dq, J=11.5, 9.5 Hz,
2H), 2.08 (s, 6H). LC/MS calculated for (M+H).sup.+: 749.3, found:
749.2.
Example 66:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00301##
[1741] The title compound was prepared from Intermediate 12
following reductive amination procedure C using sodium
cyanoborohydride as the reducing agent. purified via prep HPLC
(5-95% acetonitrile in water, 0.1% trifluoroacetic acid
buffer).sup.1H NMR (400 MHz, DMSO-d.sub.6).sup.1H NMR (400 MHz,
Methanol-d4) .delta. 8.94 (dd, J=16.2, 2.0 Hz, 4H), 8.39 (t, J=2.0
Hz, 2H), 7.56-7.42 (m, 4H), 7.27 (t, J=7.6 Hz, 2H), 7.16-7.05 (m,
4H), 5.38 (s, 4H), 5.31 (s, 4H), 4.30-4.15 (m, 6H), 3.20 (dd,
J=12.8, 3.1 Hz, 2H), 3.03-2.92 (m, 2H), 2.52 (d, J=6.3 Hz, 4H),
2.08 (s, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.52H.sub.50Cl.sub.2N.sub.6O.sub.10: 989.3; found: 989.3.
Example 67:
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzyl)amino)-3-hydroxybutanoic
acid
##STR00302##
[1743] The title compound was isolated as a by-product of the
synthesis of Example 66. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.95 (dd, J=12.8, 2.0 Hz, 2H), 8.4 (s, 1H), 7.51 (s, 1H),
7.47 (dt, J=7.7, 1.7 Hz, 2H), 7.37 (s, 1H), 7.27 (td, J=7.6, 3.2
Hz, 2H), 7.16-7.05 (m, 3H), 6.76 (s, 1H), 5.38 (s, 2H), 5.31 (s,
2H), 5.20 (s, 2H), 4.34-4.06 (m, 6H), 3.19 (ddd, J=12.7, 4.7, 3.0
Hz, 2H), 2.97 (dd, J=12.7, 9.9 Hz, 2H), 2.52 (dd, J=6.4, 4.1 Hz,
4H), 2.08 (d, J=8.8 Hz, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.45H.sub.46Cl.sub.2N.sub.4O.sub.10: 873.3;
found: 873.4.
Example 68:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(((2-hydroxyethyl)amino)methyl)-3,1-phenylene))bis(oxy))b-
is(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5,1-phenylene))bis(oxy))b-
is(methylene))dinicotinonitrile)
##STR00303##
[1745] The title compound was prepared from Intermediate 12
following reductive amination procedure C using sodium
cyanoborohydride as the reducing agent. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.93 (dd, J=8.3, 2.0 Hz, 4H), 8.30
(s, 2H), 8.17 (s, 4H), 7.52 (dd, J=7.6, 1.4 Hz, 2H), 7.47 (s, 2H),
7.33 (t, J=7.6 Hz, 2H), 7.18 (dd, J=7.7, 1.4 Hz, 2H), 6.95 (s, 2H),
5.29 (s, 8H), 4.19 (s, 4H), 3.76-3.65 (m, 4H), 3.08 (s, 4H), 2.06
(s, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.48H.sub.46Cl.sub.2N.sub.6O.sub.6: 873.3; found: 873.4.
Example 69:
5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-((4-(((2-hydroxyeth-
yl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy-
)phenoxy)methyl)nicotinonitrile
##STR00304##
[1747] The title compound was prepared from Intermediate 26 using
reductive amination procedure C. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 9.00 (d, J=7.7 Hz, 2H), 8.31 (s, 1H),
7.57-7.39 (m, 5H), 7.31 (td, J=7.6, 5.0 Hz, 2H), 7.15 (ddd, J=7.7,
6.3, 1.4 Hz, 2H), 7.12-7.05 (m, 2H), 6.96 (s, 1H), 5.30 (d, J=4.6
Hz, 4H), 5.18 (s, 2H), 4.28-4.10 (m, 4H), 3.82-3.67 (m, 4H), 3.09
(d, J=6.7 Hz, 2H), 2.64 (t, J=5.6 Hz, 2H), 2.06 (s, 3H), 2.03 (s,
3H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.41H.sub.43ClN.sub.4O.sub.5: 707.3; found: 707.2.
Example 70:
N,N'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methyl-
ene))bis(azanediyl))bis(ethane-2,1-diyl))diacetamide
##STR00305##
[1749] The title compound was prepared from Intermediate 12
following reductive amination procedure C using sodium
cyanoborohydride as the only reducing agent. .sup.1H NMR 1H NMR
(400 MHz, Acetonitrile-d3) .delta. 8.94 (dd, J=15.8, 2.0 Hz, 4H),
8.59 (s, 2H), 8.33 (t, J=2.1 Hz, 2H), 7.51 (dd, J=7.7, 1.4 Hz, 2H),
7.45 (s, 2H), 7.32 (t, J=7.6 Hz, 4H), 7.17 (dd, J=7.6, 1.4 Hz, 2H),
6.94 (s, 2H), 5.30 (d, J=7.5 Hz, 8H), 4.15 (s, 4H), 3.34 (d, J=5.4
Hz, 4H), 3.10 (s, 4H), 2.06 (s, 6H), 1.85 (s, 6H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for
C.sub.52H.sub.52Cl.sub.2N.sub.8O.sub.6: 955.3; found: 955.4.
Example 71:
5-((4-chloro-5-((3'-((2-chloro-4-(((2-hydroxyethyl)amino)methyl)phenoxy)m-
ethyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-(((2-hydroxyethyl)ami-
no)methyl)phenoxy)methyl)nicotinonitrile
##STR00306##
[1751] The title compound was prepared following the procedure
described in Example 69 using 3-chloro-4-hydroxybenzaldehyde.
.sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) .delta. 8.95 (s, 1H),
8.3 (s, 1H), 8.03 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.53 (dt, J=7.6,
1.8 Hz, 2H), 7.48-7.41 (m, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.27 (d,
J=8.5 Hz, 1H), 7.17 (d, J=7.6 Hz, 2H), 6.95 (s, 1H), 5.29 (d,
J=11.4 Hz, 6H), 4.18 (d, J=14.1 Hz, 4H), 3.75 (dt, J=22.9, 5.1 Hz,
4H), 3.10 (d, J=12.9 Hz, 4H), 2.07 (d, J=7.7 Hz, 6H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.41H.sub.42Cl.sub.2N.sub.4O.sub.5: 741.3; found: 741.2.
Example 72:
3,3'-bis(((5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)me-
thyl)-2'-methyl-[1,1'-biphenyl]-2-carbonitrile
##STR00307##
[1753] The title compound was prepared from Intermediate 27
following general reductive amination procedure E. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.77-7.65 (m, 4H), 7.57-7.50 (m,
1H), 7.38 (dd, J=6.8, 2.0 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.17
(dd, J=7.7, 1.4 Hz, 1H), 6.52 (dd, J=21.1, 8.0 Hz, 2H), 5.66 (d,
J=3.6 Hz, 2H), 5.60-5.46 (m, 2H), 4.16 (d, J=1.9 Hz, 4H), 4.01 (d,
J=5.6 Hz, 6H), 3.83-3.70 (m, 6H), 3.15-3.07 (m, 5H), 3.02 (t, J=5.3
Hz, 2H), 2.19 (s, 3H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated
for C.sub.34H.sub.39N.sub.5O.sub.6: 614.3; found: 614.3.
Example 73:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(((3-hydroxypropyl)amino)methyl)-3,1-phenylene))bis(oxy))-
bis(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(((3-hydroxypropyl)amino)methyl)-5,1-phenylene))bis(oxy))-
bis(methylene))dinicotinonitrile)
##STR00308##
[1755]
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinic-
otinonitrile (Intermediate 12, 500 mg, 0.64 mmol) was dissolved in
a mixture of THF and methanol (2:1) 12 mL and then sodium
borohydride (48 mg, 0.001 mol) was slowly added. Reaction mixture
was stirred at room temperature for 10 min, quenched by the
addition of water and then extracted with EtOAc. Organic layers
were dried over Mg.sub.2SO.sub.4 and evaporated under reduced
pressure to yield
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(hydroxymethyl)-3,1-phenylene))bis(oxy))bis(methylene))di-
nicotinonitrile.
[1756] To a solution of
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(hydroxymethyl)-3,1-phenylene))bis(oxy))bis(methylene))di-
nicotinonitrile (2.4 mmol) in dichloromethane (5 mL), kept at
0.degree. C., was added methanesulfonyl chloride (4.8 mmol) over a
period of 10 min. Mixture warmed up to room temperature and stirred
for 4 hrs. Reaction mixture was transferred to a separatory funnel
and was successively washed with water and dichloromethane. The
organic phase was dried with sodium sulfate and evaporated to
obtain
((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(5-
-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene)
dimethanesulfonate.
[1757] To a solution of
((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(5-
-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene)
dimethanesulfonate (752 mg, 1.36 mmol) in DMF was added
3-aminopropan-1-ol (1.6 gr, 5.4 mmol) under argon atmosphere and
stirred at room temperature for 1 hr. and purified via prep HPLC
(5-95% acetonitrile in water, 0.1% trifluoroacetic acid). .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=10.8, 2.1 Hz,
4H), 8.42-8.30 (m, 2H), 7.58-7.42 (m, 4H), 7.26 (t, J=7.6 Hz, 2H),
7.12 (d, J=7.8 Hz, 2H), 7.06 (d, J=6.6 Hz, 2H), 5.34 (dd, J=31.2,
3.2 Hz, 8H), 4.20 (s, 2H), 3.52-3.48 (m, 4H), 3.15 (t, J=7.0 Hz,
2H), 3.05 (t, J=7.2 Hz, 6H), 2.86 (d, J=0.7 Hz, 2H), 2.07 (s, 6H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.50H.sub.50Cl.sub.2N.sub.6O.sub.6: 901.3; found: 901.4.
Example 74:
(3S,3'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dibutyric acid
((3S,3'S)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))dibutyric acid)
##STR00309##
[1759] Sodium triacetoxyborohydride (9 equiv) and sodium
cyanoborohydride (9 equiv) were added sequentially to a stirred
mixture of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and (S)-3-aminobutanoic acid
(15 equiv) in N,N-dimethylformamide (40 mL per mmol substrate) and
acetic acid (7 mL per mmol substrate) at room temperature. After 15
min, trifluoroacetic acid (0.2 mL) was added. The resulting mixture
was purified by reverse phase preparative HPLC (0.1%
trifluoroacetic acid in acetonitrile/water) to give
(3S,3'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dibutyric acid. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.82 (s, 2H), 7.47 (dd, J=7.7, 1.4 Hz, 2H), 7.24 (t, J=7.6
Hz, 2H), 7.07 (dd, J=7.6, 1.4 Hz, 2H), 5.59 (s, 4H), 4.20 (d,
J=13.4 Hz, 2H), 4.14 (d, J=13.3 Hz, 2H), 4.06 (s, 6H), 3.64 (h,
J=6.6 Hz, 2H), 2.75 (d, J=6.3, 4H), 2.08 (s, 6H), 1.42 (d, J=6.7
Hz, 6H); LRMS: 755.2.
Example 75:
(1R,1'R,2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentane-1-carboxylic acid) (or
(1R,1'R,2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentane-1-carboxylic acid)
##STR00310##
[1761] Sodium triacetoxyborohydride (9 equiv) was added to a
stirred mixture of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and
(1R,2R)-2-aminocyclopentane-1-carboxylic acid (15 equiv) in
dimethylsulfoxide (100 mL per mmol substrate) and acetic acid (20
mL per mmol substrate) at room temperature. After 60 min,
trifluoroacetic acid (0.2 mL) was added. The resulting mixture was
purified by reverse phase preparative HPLC (0.1% trifluoroacetic
acid in acetonitrile/water) to give
(1R,1'R,2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentane-1-carboxylic acid). .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.47 (dd,
J=7.5, 1.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.6, 1.4
Hz, 2H), 5.59 (s, 4H), 4.15 (d, J=1.9 Hz, 4H), 4.06 (s, 6H), 3.91
(q, J=7.2 Hz, 2H), 2.94 (dt, J=9.4, 7.0 Hz, 2H), 2.32-2.13 (m, 4H),
2.08 (s, 6H), 2.02-1.67 (m, 8H); LRMS: 807.2.
Example 76:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(methylazaned-
iyl))diacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(methyla-
zanediyl))diacetic acid)
##STR00311##
[1763]
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(methyl-
azanediyl))diacetic acid was synthesized in a manner similar to
Procedure D using sarcosine in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid and with a reaction
temperature of 60.degree. C. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.86 (s, 2H), 7.49 (d, J=7.7 Hz, 2H),
7.26 (t, J=7.6 Hz, 2H), 7.09 (dd, J=7.7, 1.4 Hz, 2H), 5.60 (s, 4H),
4.35 (s, 4H), 4.05 (s, 6H), 4.04 (s, 4H), 2.89 (s, 6H), 2.10 (s,
6H); LRMS: 727.3.
Example 77:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(2,2-dimethylpropanoic acid) (or
3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(2,2-dimethylpropanoic acid))
##STR00312##
[1765]
3,3'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(2,2-dimethylpropanoic acid) was synthesized in a manner
similar to Procedure D using 3-amino-2,2-dimethylpropanoic acid in
place of (1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 7.80 (s, 2H), 7.48 (d, J=7.6 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.5 Hz, 2H), 5.59 (s, 4H),
4.16 (s, 4H), 4.07 (s, 6H), 3.09 (s, 4H), 2.09 (s, 6H), 1.29 (s,
12H); LRMS: 783.3.
Example 78:
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-(carboxymethyl)-N,N-dimethy-
lmethanaminium) (or
1,1'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-(carboxymethyl)-N,N-di-
methylmethanaminium))
##STR00313##
[1767] Iodomethane (0.029 mL, 0.47 mmol) was added via syringe to a
stirred solution of
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(methylazaned-
iyl))diacetic acid (17 mg, 0.023 mmol) in dimethylsulfoxide and
aqueous sodium hydroxide solution (2.0 M, 0.47 mL) at room
temperature. After 30 min, trifluoroacetic acid (0.1 mL) was added.
The resulting mixture was purified by reverse phase preparative
HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-(carboxymethyl)-N,N-dimethy-
lmethanaminium). .sup.1H NMR (400 MHz, Methanol-d4) .delta. 7.87
(s, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.26 (t, J=7.6 Hz, 2H), 7.10 (d,
J=7.8 Hz, 2H), 5.62 (s, 4H), 4.67 (s, 4H), 4.11 (s, 4H), 4.04 (s,
6H), 3.24 (s, 12H), 2.10 (s, 6H). LRMS: 378.1 ([M].sup.2+).
Example 79:
(1S,1'S,2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentane-1-carboxylic acid) (or
(1S,1'S,2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentane-1-carboxylic acid))
##STR00314##
[1769]
(1S,1'S,2R,2'R)-2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)-
bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(cyclopentane-1-carboxylic acid) was
synthesized using general reductive amination procedure D using
(1S,2R)-2-aminocyclopentane-1-carboxylic acid in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.81 (s, 2H), 7.52-7.43 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.11-7.03 (m, 2H), 5.59 (s, 4H), 4.23-4.19 (m, 4H),
4.06 (s, 6H), 3.66 (q, J=7.0 Hz, 2H), 3.17 (q, J=6.7 Hz, 2H),
2.26-1.64 (m, 12H), 2.09 (s, 6H); LRMS: 807.2.
Example 80:
(1S,1'S,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexane-1-carboxylic acid) (or
(1S,1'S,2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid))
##STR00315##
[1771]
(1S,1'S,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,12'-biphenyl]-3,3'-diyl-
)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid) was
synthesized using general reductive amination procedure D using
(1S,2S)-2-aminocyclohexane-1-carboxylic acid in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.81 (s, 2H), 7.47 (dd, J=7.3, 1.3 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.12-7.01 (m, 2H), 5.59 (s, 4H), 4.24
(d, J=13.3 Hz, 2H), 4.15 (d, J=13.3 Hz, 2H), 4.07 (s, 6H),
3.38-3.28 (m, 2H), 2.54 (td, J=11.3, 4.0 Hz, 2H), 2.35-2.25 (m,
4H), 2.09 (s, 6H), 1.95-1.87 (m, 2H), 1.85-1.77 (m, 2H), 1.58-1.30
(m, 8H); LRMS: 835.3.
Example 81:
(.+-.)-(1R,1'R,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl-
)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid) (or
(1R,1'R,2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid)) and
(1S,1'R,2R,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexane-1-carboxylic acid)
##STR00316##
[1773] A stereoisomeric mixture of
(.+-.)-(1R,1'R,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl-
)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid) and
(1S,1'R,2R,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexane-1-carboxylic acid) was synthesized
using general reductive amination procedure D using
(.+-.)-(1R,2S)-2-aminocyclohexane-1-carboxylic acid in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.79 (s, 2H), 7.47 (d, J=7.6 Hz, 2H),
7.24 (t, J=7.6 Hz, 2H), 7.14-7.00 (m, 2H), 5.59 (s, 4H), 4.21 (d,
J=13.4 Hz, 2H), 4.13 (d, J=13.3 Hz, 2H), 4.05 (s, 6H), 3.38-3.28
(m, 2H), 3.18 (q, J=4.4 Hz, 2H), 2.35-2.25 (m, 2H), 2.09 (s, 6H),
2.04-1.94 (m, 2H), 1.93-1.80 (m, 4H), 1.70-1.57 (m, 4H), 1.55-1.20
(m, 4H); LRMS: 835.3.
Example 82:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-methylbutanoic acid) (or
3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-methylbutanoic acid))
##STR00317##
[1775]
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(3-methylbutanoic acid) was synthesized using general
reductive amination procedure D using 3-amino-3-methylbutanoic acid
in place of (1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 7.81 (s, 2H), 7.46 (d, J=7.5 Hz,
2H), 7.23 (t, J=7.5 Hz, 2H), 7.06 (dd, J=7.5, 1.2 Hz, 2H), 5.59 (s,
4H), 4.14 (s, 4H), 4.06 (s, 6H), 2.82 (s, 4H), 2.09 (s, 6H), 1.50
(s, 12H); LRMS: 783.3.
Example 83:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(N,N-dimethylpropanamide) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(N,N-dimethylpropanamide))
##STR00318##
[1777]
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(N,N-dimethylpropanamide) was synthesized using general
reductive amination procedure D using
(+)-2-amino-N,N-dimethylpropanamide hydrochloride (15 equiv) and
N,N-diisopropylethylamine (17 equiv) in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.77 (s, 2H), 7.48 (d, J=7.4 Hz, 2H),
7.24 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.60 (s, 4H), 4.38
(q, J=6.9 Hz, 2H), 4.11 (d, J=13.3 Hz, 2H), 4.05 (s, 6H), 4.03 (d,
J=14.0 Hz, 2H), 3.02 (d, J=0.7 Hz, 6H), 2.92 (d, J=1.7 Hz, 6H),
2.09 (s, 6H), 1.46 (d, J=6.9 Hz, 6H); LRMS: 781.3.
Example 84:
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(2,2-di-
fluoro-3-hydroxybutanoic acid) (or
4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(2-
,2-difluoro-3-hydroxybutanoic acid))
##STR00319##
[1779]
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(-
2,2-difluoro-3-hydroxybutanoic acid) was synthesized using general
reductive amination procedure C using
3-carboxy-3,3-difluoro-2-hydroxypropan-1-aminium
2,2,2-trifluoroacetate (5 equiv) and triethylamine (10 equiv) in
place of (S)-3-aminobutanoic acid and using
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde). .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.68 (d, J=8.1 Hz, 2H), 7.43 (d, J=7.6 Hz,
2H), 7.22 (t, J=7.6 Hz, 2H), 7.05 (dd, J=7.7, 1.4 Hz, 2H), 6.47 (d,
J=8.1 Hz, 2H), 5.49 (s, 4H), 4.42-4.28 (m, 2H), 4.18 (s, 4H), 4.03
(s, 6H), 3.33-3.19 (m, 4H), 2.05 (S, 6H); LRMS: 791.1.
Example 85:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(bicyclo[1.1.1]pentane-1-carboxylic acid) (or
3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(bicyclo[1.1.1]pentane-1-carboxylic acid))
##STR00320##
[1781] Trifluoroacetic acid (0.8 mL) was added to a stirred
solution of
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
acid (87.9 mg, 0.387 mmol) in dichloromethane (2.0 mL) at room
temperature. After 25 min, the resulting mixture was concentrated
under reduced pressure.
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))-
bis(oxy))bis(5-chloro-2-methoxynicotinaldehyde) (15 mg, 0.026
mmol), N,N-diisopropylethylamine (0.135 mL, 0.774 mmol),
N,N-dimethylformamide (1.5 mL), and acetic acid (0.2 mL) were added
sequentially, and the resulting mixture was stirred at room
temperature. After 5 min, sodium triacetoxyborohydride (54.7, 0.258
mmol) was added. After 7 min, trifluoroacetic acid (0.2 mL) was
added. The resulting mixture was purified by reverse phase
preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
to give
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(bicyclo[1.1.1]pentane-1-carboxylic acid). .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.82 (s, 2H), 7.53-7.39 (m, 2H), 7.23 (t,
J=7.6 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 5.59 (s, 4H), 4.09 (s, 4H),
4.05 (s, 6H), 2.37 (s, 12H), 2.08 (s, 6H); LRMS: 803.1.
Example 86:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-phenylacetic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(2-phenylacetic acid))
##STR00321##
[1783] A solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (7.0 mg, 0.012 mmol) in
N,N-dimethylformamide (1.0 mL) was added via syringe to a stirred
mixture of (S)-2-amino-2-phenylacetic acid (18.2 mg, 0.120 mmol)
and aqueous sodium hydroxide solution (0.120 mL, 0.120 mmol) at
room temperature. After 30 min, sodium triacetoxyborohydride (25.5
mg, 0.120 mmol) was added. After 40 min, the resulting mixture was
heated to 85.degree. C. After 180 min, the reaction mixture was
cooled to room temperature and trifluoroacetic acid (0.2 mL) was
added. The resulting mixture was purified by reverse phase
preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
to give
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-phenylacetic acid). .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.70 (s, 2H), 7.47 (s, 14H), 7.23 (d, J=7.6
Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.57 (s, 4H), 4.87 (s, 2H), 4.12
(d, J=15.6 Hz, 2H), 4.09 (d, J=15.6 Hz, 2H), 3.98 (s, 6H), 2.08 (s,
6H); LRMS: 851.0.
Example 87:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(oxetane-3-carboxylic acid) (or
3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(oxetane-3-carboxylic acid))
##STR00322##
[1785]
3,3'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(oxetane-3-carboxylic acid) was synthesized using general
reductive amination procedure C using 3-aminooxetane-3-carboxylic
acid (6 equiv) and triethylamine (10 equiv) in place of
(S)-3-aminobutanoic acid. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.83 (s, 2H), 7.47 (d, J=7.3 Hz, 2H), 7.24 (t, J=7.6 Hz,
2H), 7.07 (dd, J=7.7, 1.4 Hz, 2H), 5.60 (s, 4H), 5.03 (d, J=7.9 Hz,
4H), 4.78 (d, J=7.9 Hz, 4H), 4.21 (s, 4H), 4.06 (s, 6H), 2.08 (s,
6H); LRMS: 805.2 ([M+Na].sup.+).
Example 88:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(N-methylpropanamide) (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(N-methylpropanamide))
##STR00323##
[1787]
(2S,2'S)-2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(N-methylpropanamide) was synthesized using
general reductive amination procedure D using
(S)-2-amino-N-methylpropanamide hydrochloride (15 equiv) and
N,N-diisopropylethylamine (17 equiv) in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.77 (s, 2H), 7.47 (d, J=7.6 Hz, 2H),
7.24 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.59 (s, 4H), 4.08
(d, J=3.4 Hz, 4H), 4.05 (s, 6H), 3.82 (q, J=7.0 Hz, 2H), 2.76 (s,
6H), 2.09 (s, 6H), 1.50 (d, J=7.0 Hz, 6H); LRMS: 753.3.
Example 89: Dimethyl
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2R,2'R)-dipropionate (or (2R,2'R)-dimethyl
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))dipropionate)
##STR00324##
[1789] Dimethyl
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2R,2'R)-dipropionate was synthesized using general reductive
amination procedure C using methyl D-alaninate hydrochloride (12.5
equiv) and N,N-diisopropylethylamine (20 equiv) in place of
(S)-3-aminobutanoic acid. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.80 (s, 2H), 7.47 (dd, J=7.5, 1.3 Hz, 2H), 7.24 (t, J=7.6
Hz, 2H), 7.10-7.04 (m, 2H), 5.60 (s, 4H), 4.18 (s, 4H), 4.14 (q,
J=7.2 Hz, 2H), 4.05 (s, 6H), 3.84 (s, 6H), 2.09 (s, 6H), 1.58 (d,
J=7.2 Hz, 6H); LRMS: 755.3.
Example 90:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dipropionic acid (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))dipropionic acid)
##STR00325##
[1791] Aqueous sodium hydroxide solution (1 M, 0.55 mL) was added
via syringe to a stirred solution of dimethyl
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2R,2'R)-dipropionate (17 mg, 0.023 mmol) in dimethylsulfoxide at
room temperature. After 120 min, trifluoroacetic acid (0.2 mL) was
added. The resulting mixture was purified by reverse phase
preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
to give
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dipropionic acid. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.80 (s, 2H), 7.47 (d, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz,
2H), 7.07 (d, J=7.5 Hz, 2H), 5.59 (s, 4H), 4.15 (s, 4H), 4.04 (s,
6H), 3.88 (q, J=7.2 Hz, 2H), 2.08 (s, 6H), 1.56 (d, J=7.2 Hz, 6H);
LRMS: 727.1.
Example 91:
1,1'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(cyclopropane-1-carboxylic acid) (or
1,1'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(cyclopropane-1-carboxylic acid))
##STR00326##
[1793]
1,1'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(cyclopropane-1-carboxylic acid) was synthesized as in
Example 89 using methyl 1-aminocyclopropane-1-carboxylate (12.5
equiv) in place of methyl D-alaninate hydrochloride (12.5 equiv)
and N,N-diisopropylethylamine (20 equiv). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.46 (d, J=7.6 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.3 Hz, 2H), 5.59 (s, 4H), 4.32
(s, 4H), 4.04 (s, 6H), 2.07 (s, 6H), 1.62-1.45 (m, 4H), 1.38-1.27
(m, 4H); LRMS: 749.3 ([M-H].sup.-).
Example 92:
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-dim-
ethyl-3'-nitro-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanop-
yridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00327##
[1795]
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,-
2'-dimethyl-3''-nitro-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-
-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
synthesized using general reductive amination procedure D using
5-((4-chloro-5-((2,2'-dimethyl-3''-nitro-4''-(2-oxoethoxy)-[1,1':3',1''-t-
erphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile in
place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(S)-4-amino-3-hydroxybutanoic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.93 (d,
J=1.9 Hz, 1H), 8.37 (s, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.66 (dd,
J=8.6, 2.2 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.42 (d,
J=8.7 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.26 (q, J=7.3 Hz, 2H),
7.19-7.12 (m, 2H), 7.08 (s, 1H), 5.37 (s, 2H), 5.31 (s, 2H), 4.55
(t, J=5.0 Hz, 2H), 4.38-4.30 (m, 1H), 4.26-4.18 (m, 3H), 3.60 (t,
J=5.0 Hz, 2H), 3.53-3.36 (m, 1H), 3.20 (ddd, J=12.6, 6.5, 3.4 Hz,
2H), 3.06-2.92 (m, 1H), 2.59 (dd, J=6.2, 2.4 Hz, 2H), 2.55-2.49 (m,
2H), 2.14 (s, 3H), 1.91 (s, 3H); LRMS: 868.3.
Example 93:
(4-((4''-(2-(((S)-1-carboxyethyl)amino)ethoxy)-2,2'-dimethyl-3''-nitro-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)metho-
xy)benzyl)-L-alanine
##STR00328##
[1797]
(4-((4''-(2-(((S)-1-carboxyethyl)amino)ethoxy)-2,2'-dimethyl-3''-ni-
tro-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl-
)methoxy)benzyl)-L-alanine was synthesized using general reductive
amination procedure D using
5-((4-chloro-5-((2,2'-dimethyl-3''-nitro-4''-(2-oxoethoxy)-[1,1':3',1''-t-
erphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile in
place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using L-alanine in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.97 (s, 1H), 8.92 (d, J=1.9 Hz,
1H), 8.40 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.70-7.63 (m, 1H), 7.51
(d, J=4.4 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H),
7.34 (t, J=7.6 Hz, 1H), 7.31-7.21 (m, 2H), 7.16 (s, 1H), 7.14 (s,
1H), 7.08 (s, 1H), 5.37 (s, 2H), 5.32 (s, 2H), 4.54 (t, J=4.9 Hz,
2H), 4.36-4.15 (m, 3H), 4.01 (d, J=7.3 Hz, 1H), 3.62 (d, J=5.1 Hz,
2H), 2.14 (s, 3H), 1.92 (d, J=5.9 Hz, 3H), 1.65 (d, J=7.2 Hz, 3H),
1.54 (d, J=7.2 Hz, 3H); LRMS: 808.3.
Example 94:
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-dim-
ethyl-3'-(trifluoromethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro--
2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid
##STR00329##
[1799]
(S)-4-((4-((4''-(2-(((S)-3-Carboxy-2-hydroxypropyl)amino)ethoxy)-2,-
2'-dimethyl-3''-(trifluoromethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5--
chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid was synthesized using general reductive amination procedure D
using
5-((4-chloro-5-((2,2'-dimethyl-3''-(trifluoromethyl)-4''-(2-oxoethoxy)-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(S)-4-amino-3-hydroxybutanoic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.95 (s, 1H), 8.93 (s, 1H), 8.37 (s,
1H), 7.61 (d, J=9.3 Hz, 1H), 7.58 (s, 1H), 7.53-7.44 (m, 3H),
7.41-7.06 (m, 6H), 5.37 (s, 2H), 5.33 (d, J=14.4 Hz, 2H), 4.49 (t,
J=5.1 Hz, 2H), 4.37-4.27 (m, 1H), 4.26-4.17 (m, 3H), 3.60 (t, J=5.0
Hz, 2H), 3.44-3.37 (m, 1H), 3.29-3.14 (m, 2H), 3.05-2.89 (m, 1H),
2.56 (d, J=6.3 Hz, 2H), 2.51 (d, J=6.2 Hz, 2H), 2.14 (s, 3H), 1.88
(s, 3H); LRMS: 891.2.
Example 95:
(4-((4''-(2-(((S)-1-carboxyethyl)amino)ethoxy)-2,2'-dimethyl-3''-(trifluo-
romethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridi-
n-3-yl)methoxy)benzyl)-L-alanine
##STR00330##
[1801]
(4-((4''-(2-(((S)-1-Carboxyethyl)amino)ethoxy)-2,2'-dimethyl-3''-(t-
rifluoromethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyano-
pyridin-3-yl)methoxy)benzyl)-L-alanine was synthesized using
general reductive amination procedure D using
5-((4-chloro-5-((2,2'-dimethyl-3''-(trifluoromethyl)-4''-(2-oxoethoxy)-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using L-alanine in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.97 (s, 1H), 8.92 (s, 1H), 8.40 (s,
1H), 7.97 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.51 (d,
J=4.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.42-7.06 (m, 6H), 5.37 (s,
2H), 5.33 (d, J=10.9 Hz, 2H), 4.49 (t, J=5.1 Hz, 2H), 4.38-4.16 (m,
3H), 4.01 (q, J=7.4 Hz, 1H), 3.62 (d, J=5.5 Hz, 2H), 2.14 (s, 3H),
1.88 (s, 3H), 1.65 (d, J=7.2 Hz, 3H), 1.55 (d, J=6.2 Hz, 3H); LRMS:
831.3.
Example 96:
2-(((6-((3'-(((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)oxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyridin-3-y-
l)methyl)amino)-2-methylpropanoic acid
##STR00331##
[1803] Trimethylsilyl trifluoromethanesulfonate (0.037 mL, 0.21
mmol) was added via syringe to a stirred mixture of
2-amino-2-methylpropanoic acid (18.6 mg, 0.181 mmol) and
N,N-diisopropylethylamine (0.052 mL, 0.30 mmol) in
N,N-dimethylformamide (1.0 mL) at room temperature. After 50 min,
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (7.0 mg, 0.012 mmol) was
added, and the resulting mixture was heated to reflux over 30
seconds and allowed to cool to room temperature. After 10 min,
acetic acid (0.15 mL), sodium cyanoborohydride (6.81 mg, 0.108
mmol), and sodium triacetoxyborohydride (23.0 mg, 0.108 mmol) were
added sequentially. After 90 min, trifluoroacetic acid (0.2 mL) was
added. The resulting mixture was purified by reverse phase
preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
to give
2-(((6-((3'-(((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)oxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyridin-3-y-
l)methyl)amino)-2-methylpropanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.84 (s, 1H), 7.81 (s, 1H), 7.53-7.43 (m,
2H), 7.28-7.22 (m, 2H), 7.11-7.04 (m, 2H), 5.60 (s, 4H), 4.21 (s,
2H), 4.13 (s, 2H), 4.06 (s, 3H), 4.05 (s, 3H), 2.09 (s, 3H), 2.09
(s, 3H), 1.65 (s, 6H); LRMS: 755.3.
Example 97:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(2-methylpropanoic acid) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(2-methylpropanoic acid))
##STR00332##
[1805]
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(2-methylpropanoic acid) was synthesized as described in
Example 89 using methyl 2-amino-2-methylpropanoate hydrochloride in
place of methyl D-alaninate hydrochloride. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.46 (d, J=7.6 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.3 Hz, 2H), 5.60 (s, 4H), 4.10
(s, 4H), 4.04 (s, 6H), 2.08 (s, 6H), 1.60 (s, 12H); LRMS:
755.2.
Example 98:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dipropionic acid (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))dipropionic acid)
##STR00333##
[1807]
(2S,2'S)-2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))dipropionic acid was synthesized as shown in Example
89 using methyl L-alaninate hydrochloride in place of methyl
D-alaninate hydrochloride. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.80 (s, 2H), 7.47 (d, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz,
2H), 7.07 (d, J=7.5 Hz, 2H), 5.59 (s, 4H), 4.15 (s, 4H), 4.04 (s,
6H), 3.86 (d, J=7.2 Hz, 2H), 2.08 (s, 6H), 1.55 (d, J=7.2 Hz, 6H);
LRMS: 727.0.
Example 99:
(2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dibutyric acid (or
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))dibutyric acid)
##STR00334##
[1809]
(2R,2'R)-2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))dibutyric acid was synthesized using general
reductive amination procedure D using (R)-2-aminobutanoic acid in
place of (1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.79 (s, 2H), 7.47 (d, J=7.6
Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.59 (s,
4H), 4.14 (d, J=1.5 Hz, 4H), 4.04 (s, 6H), 3.72 (t, J=5.8 Hz, 2H),
2.08 (s, 6H), 2.06-1.83 (m, 4H), 1.03 (t, J=7.5 Hz, 6H); LRMS:
755.2.
Example 100: Dimethyl
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2S,2'S)-dipropionate (or (2S,2'S)-dimethyl
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))dipropionate)
##STR00335##
[1811] Dimethyl
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2S,2'S)-dipropionate was synthesized using general reductive
amination procedure C using methyl L-alaninate hydrochloride in
place of methyl D-alaninate hydrochloride. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.77 (s, 2H), 7.47 (d, J=7.7 Hz, 2H),
7.24 (t, J=7.7 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.59 (s, 4H),
4.12-3.97 (m, 6H), 4.08 (s, 4H), 4.04 (s, 6H), 3.80 (s, 6H), 2.09
(s, 6H), 1.53 (d, J=7.1 Hz, 6H); LRMS: 755.2.
Example 101:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))dipropanamide
##STR00336##
[1813]
(2S,2'S)-2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))dipropanamide was synthesized using general reductive
amination procedure D using (S)-2-amino-propanamide hydrochloride
(15 equiv) and N,N-diisopropylethylamine (17 equiv) in place of
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.76 (s, 2H), 7.47 (d, J=7.6 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.58 (s, 4H),
4.04 (s, 10H), 3.83-3.73 (m, 2H), 2.08 (s, 6H), 1.50 (d, J=7.0 Hz,
6H); LRMS: 725.3.
Example 102:
(S)-((6-((4-(4'-(2-((2-hydroxyethyl)amino)ethoxy)-2-methyl-[1,1'-biphenyl-
]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxypyridin-3-yl)methyl)glycin-
e
##STR00337##
[1815] Lithium tetrafluoroborate (38.4 mg, 0.410 mmol) was added to
a stirred solution of tert-butyl
(S)-((6-((4-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-2,3-d-
ihydro-1H-inden-1-yl)oxy)-2-methoxypyridin-3-yl)methyl)glycinate
(28 mg, 0.041 mmol) in acetonitrile (1.5 mL) and water (0.1 mL) at
room temperature, and the resulting mixture was heated to
60.degree. C. After 65 min, the reaction mixture was heated to
79.degree. C. After 75 min, the reaction mixture was allowed to
cool to room temperature. Dimethylsulfoxide (0.5 mL), ethanolamine
(0.025 mL, 0.41 mmol), N,N-diisopropylethylamine (0.071 mL, 0.41
mmol), and acetic acid (0.15 mL) were added sequentially. After 15
min, sodium triacetoxyborohydride (212 mg, 0.41 mmol) was added.
After 30 min, trifluoroacetic acid (0.1 mL) was added. The
resulting mixture was purified by reverse phase preparative HPLC
(0.1% trifluoroacetic acid in acetonitrile/water) to give
tert-butyl
(S)-((6-((4-(4'-(2-((2-hydroxyethyl)amino)ethoxy)-2-methyl-[1,1'-biphenyl-
]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxypyridin-3-yl)methyl)glycin-
ate, which was immediately dissolved in dimethylsulfoxide (1.5 mL).
The resulting mixture was stirred at room temperature, and aqueous
sodium hydroxide solution (1 M, 0.5 mL) was added. After 30 min,
trifluoroacetic acid (0.1 mL) was added. The resulting mixture was
purified by reverse phase preparative HPLC (0.1% trifluoroacetic
acid in acetonitrile/water) to give
(S)-((6-((4-(4'-(2-((2-hydroxyethyl)amino)ethoxy)-2-methyl-[1,1'--
biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxypyridin-3-yl)methy-
l)glycine. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.67 (d,
J=8.2 Hz, 1H), 7.49-7.21 (m, 5H), 7.21-7.01 (m, 5H), 6.59 (t, J=5.6
Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 4.35 (t, J=5.0 Hz, 2H), 4.22 (s,
2H), 4.08 (s, 3H), 3.91-3.79 (m, 2H), 3.87 (s, 2H), 3.53 (t, J=5.0
Hz, 2H), 3.26 (t, J=5.3 Hz, 2H), 3.00-2.53 (m, 3H), 2.65 (s, 3H),
2.21-2.07 (m, 1H); LRMS: 620.2 ([M+Na].sup.+).
Example 103:
(S)-4-((2-((3'-((S)-1-((5-(((carboxymethyl)amino)methyl)-6-methoxypyridin-
-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)e-
thyl)amino)-3-hydroxybutanoic acid
##STR00338##
[1817]
(S)-4-((2-((3'-((S)-1-((5-(((Carboxymethyl)amino)methyl)-6-methoxyp-
yridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-2'-methyl-[1,1'-biphenyl]-4-yl-
)oxy)ethyl)amino)-3-hydroxybutanoic acid was synthesized in a
manner similar to Example 102 using (S)-4-amino-3-hydroxybutanoic
acid in place of ethanolamine. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.68 (d, J=8.1 Hz, 1H), 7.41 (t, J=9.7
Hz, 1H), 7.36-6.96 (m, 9H), 6.59 (d, J=6.0 Hz, 1H), 6.42 (d, J=8.0
Hz, 1H), 4.39-4.31 (m, 3H), 4.22 (s, 2H), 4.08 (s, 3H), 3.89 (s,
2H), 3.57-3.51 (m, 2H), 3.39-3.29 (m, 1H), 3.20-3.02 (m, 1H),
3.02-2.42 (m, 8H), 2.25-2.06 (m, 1H); LRMS: 656.2.
Example 104:
(2R,2'R,3S,3'S)-2,2'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(pyrrolidine-3-
-carboxylic acid) (or
(2R,2'R,3S,3'S)-2,2'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(pyrrolid-
ine-3-carboxylic acid))
##STR00339##
[1818] Example 105:
(2R,3S)-2-(6-((3'-(((5-((2R,3S)-3-((allyloxy)carbonyl)pyrrolidin-2-yl)-3--
chloro-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-y-
l)methoxy)-5-chloro-2-methoxypyridin-3-yl)pyrrolidine-3-carboxylic
acid
##STR00340##
[1820] Step 1: 4-Bromobutanoyl chloride (2.00 mL, 17.3 mmol) was
added via syringe to a stirred mixture of allyl alcohol (2.94 mL,
43.2 mmol) and 2,6-lutidine (3.02 mL, 25.9 mmol) in tetrahydrofuran
(35 mL) at 0.degree. C., and the resulting mixture was allowed to
warm to room temperature. After 90 min, diethyl ether (250 mL) was
added, and the organic layer was washed sequentially with aqueous
hydrogen chloride solution (2.times.150 mL), saturated aqueous
sodium bicarbonate solution (100 mL), and water (100 mL), was dried
over anhydrous magnesium sulfate, was filtered, and was
concentrated under reduced pressure to give allyl 4-bromobutanoate,
which was used in the next step without further purification.
[1821] Step 2: A stirred mixture of allyl 4-bromobutanoate (3.58 g,
17.3 mmol) and sodium azide (1.69 g, 25.9 mmol) in
dimethylsulfoxide (30 mL) was heated to 65.degree. C. After 20 h,
the reaction mixture was allowed to cool to room temperature, and
diethyl ether (600 mL) was added. The organic layer was washed with
water (2.times.500 mL), was dried over anhydrous magnesium sulfate,
was filtered, and was concentrated under reduced pressure. The
residue was purified by flash column chromatography (0 to 5% ethyl
acetate in hexanes) to give allyl 4-azidobutanoate.
[1822] Step 3: Allyl 4-azidobutanoate (0.086 mL, 0.516 mmol) was
added dropwise via syringe over 2 min to a solution of lithium
diisopropyl amide (2.0 M in tetrahydrofuran/heptane/ethylbenzene,
0.318 mL, 0.64 mmol) in tetrahydrofuran (3.0 mL) at -78.degree. C.
After 40 min, a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (100 mg, 0.172 mmol) in
tetrahydrofuran (3.0 mL). After 40 min, a mixture of acetic acid
(0.5 mL) and tetrahydrofuran (1.0) mL was added, and the resulting
mixture was allowed to warm to room temperature. Ethyl acetate (60
mL) was added, and the organic layer was washed sequentially with
saturated aqueous ammonium chloride solution (40 mL) and a 1:1
mixture of saturated aqueous sodium bicarbonate solution and brine
(1:1 v:v, 30 mL), was dried over sodium sulfate, was filtered, and
was concentrated under reduced pressure. The residue was purified
by flash column chromatography (0 to 50% ethyl acetate in hexanes)
to give diallyl
2,2'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(hydroxymethylene))bis(4-azid-
obutanoate).
[1823] Step 4: Dess-Martin periodinane (219 mg, 0.516 mmol) was
added to a stirred solution of diallyl
2,2'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(hydroxymethylene))bis(4-azid-
obutanoate) (158 mg, 0.172 mmol) in dichloromethane (2.0 mL) at
room temperature. After 150 min, aqueous sodium thiosulfate
solution (1 M, 1 mL), saturated aqueous sodium bicarbonate solution
(10 mL), and ethyl acetate (60 mL) were added sequentially. The
organic layer was washed with saturated aqueous sodium bicarbonate
solution (2.times.30 mL), was dried over sodium sulfate, was
filtered, and was concentrated under reduced pressure. The residue
was purified by flash column chromatography (0 to 50% ethyl acetate
in hexanes) to give diallyl
2,2'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxynicotinoyl))bis(4-azidobutanoate).
[1824] Step 5: Triphenylphosphine (99.2 mg, 0.378 mmol) was added
to a stirred solution of diallyl
2,2'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxynicotinoyl))bis(4-azidobutanoate) (158
mg, 0.172 mmol) in tetrahydrofuran (2.0 mL) and water (0.015 mL) at
room temperature, and the resulting mixture was heated to
65.degree. C. After 50 min, the reaction mixture was cooled to
0.degree. C. over 5 min. Acetonitrile (6.0 mL) and acetic acid (0.4
mL) were added sequentially. After 5 min, sodium
triacetoxyborohydride (365 mg, 1.72 mmol) was added, and the
resulting mixture was allowed to warm slowly to room temperature
over 14 h. Ethyl acetate (80 mL) was added, and the organic layer
was washed sequentially with a mixture of water and saturated
aqueous sodium carbonate solution (5:1 v:v, 60 mL), saturated
aqueous sodium bicarbonate solution (50 mL), and brine (50 mL), was
dried over anhydrous sodium sulfate, was filtered, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography (0 to 100% ethyl acetate in hexanes,
then 0 to 10% methanol in dichloromethane) to give di-allyl
2,2'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))(2R,2'R,3S,3'S)-bis(pyrr-
olidine-3-carboxylate) as a mixture of stereoisomers in which the
relative stereochemistry of vicinal substituents on all pyrrolidine
rings were cis.
[1825] Step 6: Tetrakis(triphenylphosphine)palladium(0) (20 mg,
0.017 mmol) was added to a stirred mixture of di-allyl
2,2'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))(2R,2'R,3S,3'S)-bis(pyrrolidine-3-
-carboxylate) (mixture of stereoisomers in which the relative
stereochemistry of vicinal substituents on all pyrrolidine rings
were cis, 143 mg, 0.172 mmol), triphenylphosphine (9.0 mg, 0.034
mmol), and pyrrolidine (0.287 mL, 3.44 mmol) in acetonitrile (5.0
mL) at 0 C. After 24 min, the reaction mixture was allowed to warm
to room temperature. After 136 min,
tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.051 mmol) was
added. After 45 min, tetrakis(triphenylphosphine)palladium(0) (60
mg, 0.051 mmol) was added. After 12 h, the reaction mixture was
concentrated under reduced pressure. N,N-dimethylformamide (1.0
mL), water (0.2 mL), and trifluoroacetic acid (0.2 mL) were added
sequentially, and the resulting mixture was purified by reverse
phase preparative HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) to give
(2R,2'R,3S,3'S)-2,2'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(pyrrolid-
ine-3-carboxylic acid) as a mixture of stereoisomers in which the
relative stereochemistry of vicinal substituents on all pyrrolidine
rings were cis (.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
7.77 (s, H), 7.46 (d, J=7.7 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.08
(d, J=7.6 Hz, 2H), 5.57 (s, 4H), 4.93 (d, J=7.1 Hz, 2H), 4.03 (s,
6H), 3.68 (dt, J=11.6, 7.8 Hz, 2H), 3.63-3.55 (m, 2H), 3.55-3.43
(m, 2H), 2.46 (q, J=7.8 Hz, 4H), 2.08 (s, 6H); LRMS: 751.2) and
(2R,3S)-2-(6-((3'-(((5-((2R,3S)-3-((allyloxy)carbonyl)pyrrolidin-2-yl)-3--
chloro-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-y-
l)methoxy)-5-chloro-2-methoxypyridin-3-yl)pyrrolidine-3-carboxylic
acid as a mixture of stereoisomers in which the relative
stereochemistry of vicinal substituents on all pyrrolidine rings
were cis. (.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.76 (d,
J=1.1 Hz, 2H), 7.72-6.89 (m, 6H), 6.26-6.15 (m, 1H), 5.68-5.53 (m,
6H), 4.93 (d, J=7.0 Hz, 2H), 4.05-3.97 (m, 7H), 3.80-3.38 (m, 6H),
2.54-2.40 (m, 2H), 2.09 (s, 6H); LRMS: 791.2).
Example 106:
(3S,3'S)-4,4'-((((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4-
'''-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxybutanoi-
c acid)
##STR00341##
[1827] 3-Bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (50
mg, 0.132 mmol) was dissolved in DMF (1 mL), treated with
bis(pinacolato)diboron (54 mg, 0.211 mmol), Pd(dppf)Cl.sub.2-DCM
(9.6 mg, 0.013 mmol) and potassium acetate (38.8 mg, 0.395 mmol).
The mixture was purged with argon and then heated at 85.degree. C.
for 1.5 h. After cooling to room temperature, the mixture was
diluted with EtOAc and water. The organic layer was concentrated
and the residue was purified by silica gel chromatography using
Hexanes/EtOAc as the eluent to afford
2-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolane.
[1828] 3-Bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (30
mg, 0.079 mmol) and
2-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolane (33 mg, 0.079 mmol) were suspended in
1,4-dioxane and H.sub.2O (1.8 mL, 5:1), added potassium carbonate
(55 mg, 0.395 mmol) and tetrakis(triphenylphosphine)palladium (18
mg, 0.015 mmol). The mixture was purged with argon and then heated
at 85.degree. C. After 1 h, the mixture was allowed to cool to room
temperature. EtOAc and water were added to the mixture. The organic
layer was concentrated under reduced pressure and the residue was
purified by silica gel chromatography using Hexanes/EtOAc as the
eluent to afford
4,4'''-bis(2,2-diethoxyethoxy)-2',2''-dimethyl-1,1':3',1'':3'',1'''-quate-
rphenyl.
[1829] 4,4'''-bis
(2,2-diethoxyethoxy)-2',2''-dimethyl-1,1':3',1'':3'',1'''-quaterphenyl
(21 mg, 0.035 mmol) was dissolved in 1,4-dioxane (1.8 mL). 37%
hydrochloric acid (0.2 mL) was added dropwise to the mixture. After
stirring at room temperature for 1 h, the reaction was quenched by
adding saturated aqueous NaHCO.sub.3. The mixture was extracted
with EtOAc. The organic layer was dried over sodium sulfate and
evaporated under reduced pressure to afford
2,2'-((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bi-
s(oxy))diacetaldehyde as the crude.
[1830]
(3S,3'S)-4,4'-((((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterpheny-
l]-4,4'''-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxyb-
utanoic acid) was synthesized from
2,2'-((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bi-
s(oxy))diacetaldehyde and (S)-4-amino-3-hydroxybutanoic acid using
reductive amination procedure G as the bis-TFA salt. MS (m/z)
657.402 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.39-7.22 (m, 6H), 7.17 (dd, J=7.3, 1.4 Hz, 2H), 7.10 (d, J=7.8 Hz,
2H), 7.04 (d, J=8.6 Hz, 4H), 5.60 (d, J=5.6 Hz, 2H), 4.29 (t, J=5.2
Hz, 4H), 4.20 (s, 2H), 3.39 (s, 2H), 3.21 (s, 2H), 2.99 (s, 2H),
2.45-2.23 (m, 4H), 1.90 (s, 6H).
Example 107:
(3R,3'R)-4,4'-((((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4-
'''-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxybutanoi-
c acid)
##STR00342##
[1832]
(3R,3'R)-4,4'-((((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterpheny-
l]-4,4'''-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxyb-
utanoic acid) was synthesized from
2,2'-((2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bi-
s(oxy))diacetaldehyde and (R)-4-amino-3-hydroxybutanoic acid using
reductive amination procedure G as the bis-TFA salt. MS (m/z)
657.329 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.38-7.23 (m, 6H), 7.17 (d, J=7.1 Hz, 2H), 7.10 (d, J=7.4 Hz, 2H),
7.04 (d, J=8.6 Hz, 4H), 5.60 (s, 2H), 4.29 (s, 4H), 4.19 (s, 2H),
3.38 (s, 2H), 3.16 (s, 2H), 2.99 (s, 2H), 2.45-2.24 (m, 4H), 1.90
(s, 6H).
Example 108:
(3S)-4-((4-((3-(3-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2,3-dihy-
drobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyrid-
in-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00343##
[1834] (7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol
(synthesized using Ref. European Journal of Medicinal Chemistry 120
(2016) 227e243) (100 mg, 0.408 mmol) and
2-(4'-(2,2-diethoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolane (275 mg, 0.53 mmol) were suspended in
1,4-dioxane and H.sub.2O (4.8 mL, 5:1), added potassium carbonate
(282 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (94
mg, 0.082 mmol). The mixture was purged with argon and then heated
at 85.degree. C. After 1.5 h, the mixture was allowed to cool to
room temperature. EtOAc and water were added to the mixture. The
organic layer was concentrated and the residue was purified by
silica gel chromatography using Hexanes/EtOAc as the eluent to
afford
5-((4-chloro-2-formyl-5-((4-(3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]di-
oxin-6-yl)-2-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile.
[1835]
5-((4-chloro-2-formyl-5-((4-(3-(hydroxymethyl)-2,3-dihydrobenzo[b][-
1,4]dioxin-6-yl)-2-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile
(140 mg, 251 mmol) was dissolved in dichloromethane (5 mL), added
Dess-Martin periodinane (213 mg, 503 mmol). The mixture was left
stirring at room temperature for 40 min and then filtered through a
short bed of Celite. The filtrated was diluted with EtOAc, washed
with saturated aqueous NaHCO.sub.3, followed by aqueous sodium
thiosulfate. The organic layer was evaporated under reduced
pressure to give
5-((4-chloro-2-formyl-5-((4-(3-formyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-
)-2-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile as the
crude.
[1836]
(3S)-4-((4-((3-(3-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2,-
3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyan-
opyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
synthesized from
5-((4-chloro-2-formyl-5-((4-(3-formyl-2,3-dihydrobenzo[b][1,4]dioxin-
-6-yl)-2-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile (used
crude) and (S)-4-amino-3-hydroxybutanoic acid using reductive
amination procedure G as the bis-TFA salt. MS (m/z) 761.068
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd,
J=6.0, 2.1 Hz, 2H), 8.81 (s, 2H), 8.56 (s, 2H), 8.45 (t, J=2.1 Hz,
1H), 7.57 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H),
7.17 (d, J=6.5 Hz, 2H), 6.98 (d, J=8.3 Hz, 1H), 6.90-6.69 (m, 2H),
5.36 (s, 2H), 5.28 (s, 2H), 4.68-4.38 (d, J=11.4 Hz, 1H), 4.13-4.02
(m, 6H), 3.12-2.72 (m, 6H), 2.45-2.31 (m, 4H), 2.23 (s, 3H).
Example 109:
(S)-4-(((6-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-di-
methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyridin-3-y-
l)methyl)amino)-3-hydroxybutanoic acid
##STR00344## ##STR00345##
[1838] 3-Bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (70
mg, 0.185 mmol) and
2-methoxy-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)nicotinaldehyde (99 mg, 0.258 mmol) were suspended in
1,4-dioxane and H.sub.2O (2.4 mL, 5:1), added potassium carbonate
(138 mg, 0.923 mmol) and tetrakis(triphenylphosphine)palladium (43
mg, 0.037 mmol). The mixture was purged with argon and then heated
at 85.degree. C. After 1 h, the mixture was allowed to cool to room
temperature. EtOAc and water were added to the mixture. The organic
layer was concentrated and the residue was purified by silica gel
chromatography using Hexanes/EtOAc as the eluent to afford
6-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)-2-methoxynicotinaldehyde.
6-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)-2-methoxynicotinaldehyde (41 mg, 0.074 mmol) was dissolved
in DMF/chloroform (2 mL, 1:1), added palau'chlor (29 mg, 0.139
mmol) in one portion. 4 N HCl in 1,4-dioxane (0.031 mL, 0.124 mmol)
was added dropwise. Complete conversion was observed after 30 min
stirring at room temperature. The mixture was then diluted with
EtOAc, washed with saturated aqueous NaHCO.sub.3. The organic layer
was evaporated under reduced pressure. The residue was purified by
silica gel chromatography using Hexanes/EtOAc as the eluent to
afford
5-chloro-6-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terpheny-
l]-3-yl)methoxy)-2-methoxynicotinaldehyde.
[1839]
5-chloro-6-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-te-
rphenyl]-3-yl)methoxy)-2-methoxynicotinaldehyde (35 mg, 0.059 mmol)
was dissolved in 1,4-dioxane (2 mL). 37% hydrochloric acid (0.2 mL)
was added dropwise to the mixture. After stirring at room
temperature for 2 h, the reaction was quenched by adding saturated
aqueous NaHCO.sub.3. The mixture was extracted with EtOAc. The
organic layer was dried over sodium sulfate and evaporated under
reduced pressure to afford
5-chloro-6-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]-3-yl-
)methoxy)-2-methoxynicotinaldehyde as the crude.
[1840]
(S)-4-(((6-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2-
,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyrid-
in-3-yl)methyl)amino)-3-hydroxybutanoic acid was synthesized from
5-chloro-6-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]-3-yl-
)methoxy)-2-methoxynicotinaldehyde (crude) and
(S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure G as the bis-TFA salt. MS (m/z) 722.115 [M+H].sup.+.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s, 1H), 7.46
(dd, J=7.7, 1.4 Hz, 1H), 7.38-6.97 (m, 9H), 5.59 (s, 2H), 4.43-4.21
(m, 4H), 4.16 (s, 2H), 4.05 (s, 3H), 3.58-3.47 (m, 2H), 3.35 (dd,
J=12.7, 3.1 Hz, 1H), 3.24-3.09 (m, 2H), 3.00 (dd, J=12.8, 9.8 Hz,
1H), 2.56 (dd, J=16.1, 6.3 Hz, 4H), 2.15 (s, 3H), 1.87 (s, 3H).
Example 110:
(R)-4-(((6-((4''-(2-(((R)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2,2'-di-
methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyridin-3-y-
l)methyl)amino)-3-hydroxybutanoic acid
##STR00346##
[1842]
(R)-4-(((6-((4''-(2-(((R)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2-
,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-methoxypyrid-
in-3-yl)methyl)amino)-3-hydroxybutanoic acid was synthesized from
5-chloro-6-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphenyl]-3-yl-
)methoxy)-2-methoxynicotinaldehyde (crude) and
(R)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure G as the bis-TFA salt. MS (m/z) 722.066 [M+H].sup.+.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s, 1H), 7.46
(dd, J=7.7, 1.4 Hz, 1H), 7.36-6.96 (m, 9H), 5.59 (s, 2H), 4.44-4.22
(m, 4H), 4.16 (s, 2H), 4.05 (s, 3H), 3.54 (t, J=5.1 Hz, 2H), 3.35
(dd, J=12.7, 3.0 Hz, 1H), 3.26-3.05 (m, 2H), 3.00 (dd, J=12.8, 9.8
Hz, 1H), 2.56 (dd, J=16.2, 6.3 Hz, 4H), 2.15 (s, 3H), 1.87 (s,
3H).
Example 111:
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2''-fluo-
ro-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyan-
opyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid (or
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2''-fluo-
ro-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyan-
opyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid)
##STR00347##
[1844] 4-bromo-3-fluorophenol (200 mg, 1.05 mmol) was dissolved in
DMF (2 mL), added 2-bromo-1,1-diethoxyethane (495 mg, 2.5 mmol),
followed by addition of cesium carbonate (1.70 g, 5.25 mmol). The
mixture was heated to 85.degree. C. Clean complete conversion was
observed after 3 h, EtOAc and water were added to the mixture, and
the organic layer was evaporated under reduced pressure. The
residue was purified by silica gel chromatography using
Hexanes/EtOAc as the eluent to afford
1-bromo-4-(2,2-diethoxyethoxy)-2-fluorobenzene.
[1845] 1-bromo-4-(2,2-diethoxyethoxy)-2-fluorobenzene (38 mg, 0.128
mmol) and
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinoni-
trile (25 mg, 0.041 mmol) were suspended in 1,4-dioxane and
H.sub.2O (1.44 mL, 5:1), added potassium carbonate (22.7 mg, 0.164
mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol).
The mixture was purged with argon and then heated at 85.degree. C.
After 1 h, the mixture was allowed to cool to room temperature.
EtOAc and water were added to the mixture. The organic layer was
concentrated and the residue was purified by silica gel
chromatography using Hexanes/EtOAc as the eluent to afford
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2''-fluoro-2,2'-dimet-
hyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinon-
itrile.
[1846]
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2''-fluoro-2,2'-dimethyl--
[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitri-
le (18 mg, 0.025 mmol) was dissolved in 1,4-dioxane (1 mL). 37%
hydrochloric acid (0.1 mL) was added dropwise to the mixture. After
stirring at room temperature for 18 h, the reaction was quenched by
adding saturated aqueous NaHCO.sub.3. The mixture was extracted
with EtOAc. The organic layer was dried over sodium sulfate and
evaporated under reduced pressure to afford
5-((4-chloro-5-((2''-fluoro-2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''--
terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile as
the crude.
[1847]
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2'-
'-fluoro-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((-
5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
was synthesized from
5-((4-chloro-5-((2''-fluoro-2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''--
terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(crude) and (S)-4-amino-3-hydroxybutanoic acid using reductive
amination procedure G as the bis-TFA salt. MS (m/z) 841.044
[M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94
(dd, J=12.0, 2.1 Hz, 2H), 8.37 (d, J=2.2 Hz, 1H), 7.51 (s, 1H),
7.46 (d, J=7.4 Hz, 1H), 7.37-7.02 (m, 7H), 6.99-6.80 (m, 2H), 5.37
(s, 2H), 5.31 (s, 2H), 4.36 (t, J=5.0 Hz, 3H), 4.23 (s, 3H), 3.54
(t, J=5.1 Hz, 2H), 3.41-3.32 (m, 1H), 3.26-3.07 (m, 2H), 2.97 (dd,
J=12.7, 9.8 Hz, 1H), 2.58 (d, J=6.3 Hz, 2H), 2.56-2.46 (m, 2H),
2.13 (s, 3H), 1.81 (d, J=1.2 Hz, 3H).
Example 112:
(S)-4-((4-((3'-(5-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)pyridin-
-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyr-
idin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00348##
[1849] 6-Bromopyridin-3-ol (200 mg, 1.15 mmol) was dissolved in DMF
(2 mL), added 2-bromo-1,1-diethoxyethane (566 mg, 2.87 mmol), and
followed by addition of cesium carbonate (1.87 g, 5.75 mmol). The
mixture was heated to 85.degree. C. Clean complete conversion was
observed after 1 h. EtOAc and water were added to the mixture, and
the organic layer was evaporated under reduced pressure. The
residue was purified by silica gel chromatography using
Hexanes/EtOAc as the eluent to afford
2-bromo-5-(2,2-diethoxyethoxy)pyridine.
[1850] 2-bromo-5-(2,2-diethoxyethoxy)pyridine (43 mg, 0.148 mmol)
and
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (30 mg, 0.049 mmol) were suspended in 1,4-dioxane and H.sub.2O
(1.44 mL, 5:1), added potassium carbonate (27 mg, 0.197 mmol) and
tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol). The
mixture was purged with argon and then heated at 85.degree. C.
After 1 h, the mixture was allowed to cool to room temperature.
EtOAc and water were added to the mixture. The organic layer was
concentrated and the residue was purified by silica gel
chromatography using Hexanes/EtOAc as the eluent to afford
5-((4-chloro-5-((3'-(5-(2,2-diethoxyethoxy)pyridin-2-yl)-2,2'-d-
imethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitri-
le.
[1851]
5-((4-chloro-5-((3'-(5-(2,2-diethoxyethoxy)pyridin-2-yl)-2,2'-dimet-
hyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(15.9 mg, 0.023 mmol) was dissolved in 1,4-dioxane (1 mL). 37%
hydrochloric acid (0.1 mL) was added dropwise to the mixture. After
stirring at room temperature for 18 h, the reaction was quenched by
adding saturated aqueous NaHCO.sub.3. The mixture was extracted
with EtOAc. The organic layer was dried over sodium sulfate and
evaporated under reduced pressure to afford
5-((4-chloro-5-((2,2'-dimethyl-3'-(5-(2-oxoethoxy)pyridin-2-yl)-[1,1'-bip-
henyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile as the
crude.
[1852]
(S)-4-((4-((3'-(5-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)p-
yridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cy-
anopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
synthesized from
5-((4-chloro-5-((2,2'-dimethyl-3'-(5-(2-oxoethoxy)pyridin-2-yl)-[1,1'-bip-
henyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (crude)
and (S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure G as the bis-TFA salt. MS (m/z) 824.129 [M+H].sup.+.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=13.2,
2.0 Hz, 2H), 8.48-8.26 (m, 2H), 7.72 (dd, J=8.7, 2.9 Hz, 1H), 7.60
(d, J=8.7 Hz, 1H), 7.52-7.42 (m, 2H), 7.42-7.31 (m, 2H), 7.27 (t,
J=7.6 Hz, 1H), 7.20 (dd, J=7.0, 2.0 Hz, 1H), 7.14 (dd, J=7.7, 1.4
Hz, 1H), 7.08 (s, 1H), 5.37 (s, 2H), 5.31 (s, 2H), 4.48 (t, J=5.0
Hz, 2H), 4.35 (dp, J=9.4, 3.2 Hz, 1H), 4.27-4.12 (m, 3H), 3.59 (t,
J=5.0 Hz, 2H), 3.37 (dd, J=12.7, 3.0 Hz, 1H), 3.25-3.08 (m, 2H),
2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.59 (d, J=6.3 Hz, 2H), 2.51 (dd,
J=6.3, 1.1 Hz, 2H), 2.15 (s, 3H), 1.91 (s, 3H).
Example 113:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid))
##STR00349##
[1854] The title compound was prepared from Intermediate 25
following reductive amination procedure G. .sup.1H NMR (400 MHz,
Methanol-d) .delta. 7.95 (s, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.09 (d, J=7.6 Hz, 2H), 5.59 (s, 4H), 4.38-4.23 (m,
2H), 4.16 (s, 4H), 4.07 (s, 6H), 3.21 (dd, J=12.8, 3.1 Hz, 2H),
3.01 (dd, J=12.8, 9.8 Hz, 2H), 2.55 (d, J=6.3 Hz, 4H), 2.11 (s,
6H). MS (m/z) 876.890 (M+H)+.
Example 114:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid))
##STR00350##
[1856] The title compound was prepared from Intermediate 25
following reductive amination procedure G using
(3R)-4-amino-3-hydroxybutanoic acid in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.94 (s, 2H), 7.48 (dd, J=7.5, 1.3 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.8, 1.4 Hz, 2H), 5.58 (s,
4H), 4.28 (dtd, J=9.4, 6.3, 3.0 Hz, 2H), 4.15 (s, 4H), 4.05 (s,
6H), 3.20 (dd, J=12.8, 3.1 Hz, 2H), 3.00 (dd, J=12.8, 9.8 Hz, 2H),
2.54 (d J=6.3 Hz, 4H), 2.09 (s, 6H). MS (m/z) 876.849 (M+H)+.
Example 115:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(5-amino-5-oxopentanoic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(5-amino-5-oxopentanoic acid))
##STR00351##
[1858] The title compound was prepared from Intermediate 25
following reductive amination procedure G using L-glutamine in
place of (3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.92 (s, 2H), 7.52-7.42 (m, 2H), 7.23 (q,
J=7.8 Hz, 2H), 7.08 (d, J=7.2 Hz, 2H), 5.58 (s, 4H), 4.16 (d, J=1.5
Hz, 4H), 4.05 (s, 6H), 3.93-3.87 (m, 2H), 2.63-2.50 (m, 4H),
2.31-2.04 (m, 10H). MS (m/z) 930.8887 (M+H)+.
Example 116:
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))di-
butanamide (or
4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediy-
l))dibutanamide)
##STR00352##
[1860] The title compound was prepared from Intermediate 25
following reductive amination procedure G using 4-aminobutanoic
acid hydrochloride in place of (3S)-4-amino-3-hydroxybutanoic acid.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.93 (s, 2H), 7.47
(d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.11-7.04 (m, 2H), 5.58
(s, 4H), 4.10 (s, 4H), 4.05 (s, 6H), 3.08 (t, J=7.1 Hz, 4H), 2.41
(t, J=6.7 Hz, 4H), 2.09 (s, 6H), 2.00-1.88 (m, 4H). MS (m/z)
842.933 (M+H)+.
Example 117:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis((4-amino-4-ox-
obutyl)azanediyl))diacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis((4-amino-
-4-oxobutyl)azanediyl))diacetic acid)
##STR00353##
[1862] To Intermediate 25 (50 mg, 0.075 mmol) in methylene chloride
(1.5 mL) was added a 3 mL solution of ethanol containing
4-aminobutanoic acid hydrochloride (62 mg, 0.45 mmol) and potassium
hydroxide (25 mg, 0.45 mmol). The reaction was stirred for 1 hour
at room temperature before Na(OAc).sub.3BH (156 mg, 0.75 mmol) and
AcOH (45 mg, 0.75 mmol) were added. The cloudy reaction was
sonicated for 1 min and stirred at room temperature for 2 h.
Glyoxalic acid monohydrate (137 mg, 1.5 mmol) was added, and the
reaction was stirred for an additional 0.5 h before additional
Na(OAc).sub.3BH (156 mg, 0.75 mmol) was added. After 1 h, the
reaction was quenched with the addition of 1M HCl until the
solution clears. The solution was concentrated in vacuo, diluted
with a mixture of MeCN/H.sub.2O/DMF (1:1:1), and purified by
purified by reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) providing 9 mg of the title compound upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.03 (s, 2H), 7.55-7.33 (m, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.16-7.00 (m, 2H), 5.58 (s, 4H), 4.39 (s, 4H), 4.05
(s, 6H), 3.98 (s, 4H), 2.46 (t, J=6.4 Hz, 4H), 2.10 (s, 6H), 2.05
(q, J=6.6 Hz, 4H). MS (m/z) 958.931 (M+H)+.
Example 118:
N-(4-amino-4-oxobutyl)-N-((6-((3'-(((5-(((4-amino-4-oxobutyl)amino)methyl-
)-3-bromo-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-5-bromo-2-methoxypyridin-3-yl)methyl)glycine
##STR00354##
[1864] 6 mg of the title compound was isolated as a byproduct from
Example 117. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.03
(s, 1H), 7.93 (s, 1H), 7.55-7.40 (m, 2H), 7.32-7.15 (m, 2H),
7.15-7.00 (m, 2H), 5.58 (s, 4H), 4.38 (s, 2H), 4.10 (s, 2H), 4.05
(d, J=2.4 Hz, 6H), 3.95 (d, J=3.8 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H),
2.50-2.34 (m, 4H), 2.16-2.06 (m, 6H), 2.08-1.98 (m, 2H), 2.01-1.86
(m, 2H). MS (m/z) 900.996 (M+H)+.
Example 119:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxy-5-methylpyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(3-hydroxybutanoic acid)
##STR00355##
[1866] Intermediate 25 (25 mg, 0.037 mmol), potassium carbonate
(20.6 mg, 0.15 mmol), trimethylboroxine (18.7 mg, 0.15 mmol), and
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg,
0.007 mmol) were suspended in dioxane (1 mL) and water (0.1 mL) in
a 2 dram vial. The suspension was sparged with nitrogen gas for 5
minutes, sealed, and heated to 90.degree. C. for 1 h. The reaction
was diluted with ethyl acetate and washed with brine. The organic
phase was dried over anhydrous sodium sulfate, and concentrated to
provide the crude product which was used directly in the next step
following reductive amination procedure G to provide 6 mg of the
title compound as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.51 (s, 2H), 7.44 (d, J=7.4 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.6 Hz, 2H), 5.53 (s, 4H), 4.28
(d, J=6.3 Hz, 2H), 4.14 (s, 4H), 4.01 (s, 6H), 3.18 (dd, J=12.8,
3.1 Hz, 2H), 2.97 (dd, J=12.7, 9.8 Hz, 2H), 2.53 (d, J=6.3 Hz, 4H),
2.16 (s, 6H), 2.08 (s, 6H). MS (m/z) 747.073 (M+H)+.
Example 120:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxy-5-vinylpyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxy-5-vinylpyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid))
##STR00356##
[1868] The title compound was synthesized analogously to Example
119 using potassium vinyltrifluoroborate in place of
trimethylboroxine, and following reductive amination procedure G.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.89 (s, 2H), 7.44
(d, J=7.7 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.7 Hz, 2H),
6.83 (dd, J=17.8, 11.3 Hz, 2H), 5.76 (dd, J=17.8, 1.3 Hz, 2H), 5.57
(s, 4H), 5.31-5.14 (m, 2H), 4.35-4.23 (m, 2H), 4.18 (s, 4H), 4.05
(s, 4H), 3.20 (dd, J=12.8, 3.1 Hz, 2H), 2.99 (dd, J=12.7, 9.8 Hz,
2H), 2.54 (d, J=6.3 Hz, 4H), 2.07 (s, 6H). MS (m/z) 771.103
(M+H)+.
Example 121:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(me-
thylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))b-
is(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00357##
[1870] Intermediate 24 (24 mg, 0.037 mmol),
5-(hydroxymethyl)isophthalonitrile (17.7 mg, 0.11 mmol), and
triphenylphosphine (29.4 mg, 0.11 mmol) were charged into a 2 dram
vial. The contents was dissolved in tetrahydrofuran (1 mL) and
stirred, while diisopropyl azodicarboxylate (22.7 mg, 0.11 mmol) in
THF (0.3 mL) was added dropwise. After stirring for 2 h at room
temperature, the reaction was concentrated in vacuo, and the crude
product was used directly in the next step following reductive
amination procedure G to provide 11 mg of the title compound as the
bis-TFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.19-8.15 (m, 4H), 8.16-8.12 (m, 2H), 8.04 (s, 2H), 7.38 (d, J=7.0
Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.5, 1.3 Hz, 2H), 5.58
(t, J=2.7 Hz, 4H), 5.51-5.37 (m, 4H), 4.36-4.21 (m, 6H), 3.26 (dd,
J=12.7, 3.1 Hz, 2H), 3.04 (dd, J=12.7, 9.8 Hz, 2H), 2.55 (dd,
J=6.2, 0.8 Hz, 4H), 2.02 (s, 6H). MS (m/z) 1128.910 (M+H)+.
Example 122:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00358##
[1872] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.17 (d, J=1.5 Hz, 4H), 8.15
(d, J=1.5 Hz, 2H), 7.90 (s, 2H), 7.45-7.32 (m, 2H), 7.23 (t, J=7.6
Hz, 2H), 7.16-7.02 (m, 2H), 5.58 (s, 4H), 5.51-5.41 (m, 4H),
4.33-4.19 (m, 6H), 3.26 (dd, J=12.7, 3.1 Hz, 2H), 3.04 (dd, J=12.7,
9.8 Hz, 2H), 2.55 (dd, J=6.3, 1.0 Hz, 4H), 2.02 (s, 6H). MS (m/z)
1038.8985 (M+H)+.
Example 123:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid))
##STR00359##
[1874] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24 and following
reductive amination procedure G using (S)-2-methylserine in place
of (3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.20 (d, J=1.5 Hz, 4H), 8.14 (d, J=1.5
Hz, 2H), 7.93 (s, 2H), 7.38 (d, J=7.6 Hz, 2H), 7.22 (t, J=7.6 Hz,
2H), 7.07 (d, J=7.3 Hz, 2H), 5.62-5.53 (m, 4H), 5.53-5.43 (m, 4H),
4.29 (s, 4H), 4.06 (d, J=12.1 Hz, 2H), 3.84 (d, J=12.2 Hz, 2H),
2.02 (s, 6H), 1.58 (s, 6H). MS (m/z) 1039.058 (M+H)+.
Example 124:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxypropanoic acid)
##STR00360##
[1876] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24 and following
reductive amination procedure G using (L)-serine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.18 (s, 4H), 8.14 (d, J=1.6 Hz, 2H),
7.91 (s, 2H), 7.38 (d, J=7.5 Hz, 2H), 7.23 (t, J=7.7 Hz, 2H), 7.07
(d, J=7.5 Hz, 2H), 5.65-5.51 (m, 4H), 5.47 (d, J=3.1 Hz, 4H), 4.33
(q, J=13.5 Hz, 4H), 4.09-3.93 (m, 6H), 2.02 (s, 6H). MS (m/z)
1010.992 (M+H)+.
Example 125:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(methylene)-
)bis(azanediyl))diacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))diacetic acid)
##STR00361##
[1878] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24 and following
reductive amination procedure G using glycine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.18 (d, J=1.5 Hz, 4H), 8.14 (t, J=1.6
Hz, 2H), 7.89 (s, 2H), 7.45-7.29 (m, 2H), 7.23 (t, J=7.6 Hz, 2H),
7.14-7.03 (m, 2H), 5.65-5.53 (m, 4H), 5.53-5.42 (m, 4H), 4.28 (s,
4H), 3.92 (s, 4H), 2.02 (s, 6H). MS (m/z) 950.991 (M+H)+.
Example 126:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(pyrimidin-5-ylmethoxy)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(pyrimidin-5-ylmethoxy)pyridine-6,3-diyl))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00362##
[1880] The title compound was synthesized analogously to Example
121 using pyrimidin-5-ylmethanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 9.13 (s, 2H), 8.94 (s, 4H), 8.03 (s, 2H), 7.43 (d, J=7.8
Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.3 Hz, 2H), 5.55 (m,
8H), 4.36-4.18 (m, 6H), 3.23 (dd, J=12.7, 3.1 Hz, 2H), 3.01 (dd,
J=12.7, 9.8 Hz, 2H), 2.53 (d, J=6.3 Hz, 4H), 2.06 (s, 6H). MS (m/z)
517.059 (M+2H)2+.
Example 127:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(2-(pyrimidin-5-yl)ethoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(2-(pyrimidin-5-yl)ethoxy)pyridine-6,3-diyl)-
)bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00363##
[1882] The title compound was synthesized analogously to Example
121 using 2-(pyrimidin-5-yl)ethan-1-ol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d4) .delta.
9.03 (s, 2H), 8.77 (s, 4H), 7.96 (s, 2H), 7.44 (d, J=7.2 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.05 (dd, J=7.7, 1.4 Hz, 2H), 5.54 (s, 4H),
4.71 (t, J=6.4 Hz, 4H), 4.24 (dtd, J=9.4, 6.3, 3.0 Hz, 2H),
4.18-4.04 (m, 6H), 3.25-3.13 (m, 6H), 2.97 (dd, J=12.7, 9.8 Hz,
2H), 2.55 (d, J=6.3 Hz, 4H), 2.06 (s, 6H). MS (m/z) 1060.991
(M+H)+.
Example 128:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(2-(4-cyanopyridin-2-yl)ethoxy)pyridine-6,3-diyl)-
)bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(2-(4-cyanopyridin-2-yl)ethoxy)pyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00364##
[1884] The title compound was synthesized analogously to Example
121 using 2-(2-hydroxyethyl)isonicotinonitrile in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.76-8.68 (m, 2H), 7.94 (s, 2H), 7.76 (s, 2H), 7.59 (dd,
J=5.1, 1.5 Hz, 2H), 7.45 (d, J=7.4 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H),
7.04 (d, J=7.5 Hz, 2H), 5.57-5.50 (m, 4H), 4.26 (dd, J=9.3, 6.6 Hz,
2H), 4.09 (d, J=2.6 Hz, 4H), 3.38 (t, J=6.3 Hz, 5H), 3.20 (dd,
J=12.7, 3.1 Hz, 2H), 2.99 (dd, J=12.7, 9.9 Hz, 2H), 2.54 (d, J=6.3
Hz, 4H), 2.06 (s, 6H). MS (m/z) 1108.987 (M+H)+.
Example 129:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-2-(((R)-5-oxopyrrolidin-2-yl)methoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))diacetic acid
##STR00365##
[1886] The title compound was synthesized analogously to Example
121 using (S)-5-(hydroxymethyl)pyrrolidin-2-one in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G using glycine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.98 (d, J=0.7 Hz, 2H), 7.45 (d, J=7.6
Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 5.57 (m,
4H), 4.60-4.43 (m, 2H), 4.35-4.26 (m, 2H), 4.26-4.10 (m, 6H), 3.93
(s, 4H), 2.55-2.29 (m, 6H), 2.09 (s, 6H), 2.00-1.89 (m, 2H). MS
(m/z) 954.980 (M+H)+.
Example 130:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-2-(((S)-5-oxopyrrolidin-2-yl)methoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))diacetic acid
##STR00366##
[1888] The title compound was synthesized analogously to Example
121 using (R)-5-(hydroxymethyl)pyrrolidin-2-one in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G using glycine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.98 (d, J=0.7 Hz, 2H), 7.45 (d, J=7.7
Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.61-5.51
(m, 4H), 4.55-4.46 (m, 2H), 4.39-4.26 (m, 2H), 4.26-4.09 (m, 6H),
3.91 (s, 4H), 2.50-2.26 (m, 6H), 2.09 (s, 6H), 1.95 (m, 2H). MS
(m/z) 955.025 (M+H)+.
Example 131:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(oxetan-2-ylmethoxy)pyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(oxetan-2-ylmethoxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00367##
[1890] The title compound was synthesized analogously to Example
121 using oxetan-2-ylmethanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.99 (s, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.25 (t, J=7.6 Hz,
2H), 7.08 (d, J=7.5 Hz, 2H), 5.68-5.49 (m, 4H), 5.33-5.14 (m, 2H),
4.80-4.72 (m, 2H), 4.69-4.60 (m, 4H), 4.56 (dt, J=11.9, 3.0 Hz,
2H), 4.33-4.23 (m, 2H), 4.23-4.12 (m, 4H), 3.23 (dd, J=12.7, 3.0
Hz, 2H), 3.02 (dd, J=12.7, 10.0 Hz, 2H), 2.78 (q, J=8.5, 6.6 Hz,
2H), 2.65 (p, J=8.3 Hz, 2H), 2.54 (d, J=6.2 Hz, 4H), 2.10 (s, 6H).
MS (m/z) 988.919 (M+H)+.
Example 132:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(oxetan-3-ylmethoxy)pyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(oxetan-3-ylmethoxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00368##
[1892] The title compound was synthesized analogously to Example
121 using oxetan-3-ylmethanolin place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.98 (s, 2H), 7.45 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz,
2H), 7.08 (d, J=7.6 Hz, 2H), 5.57 (s, 4H), 4.94-4.87 (m, 4H),
4.72-4.63 (m, 4H), 4.58 (q, J=6.4 Hz, 4H), 4.35-4.21 (m, 2H), 4.19
(s, 4H), 3.54-3.40 (m, 2H), 3.24 (dd, J=12.6, 3.0 Hz, 2H), 3.02
(dd, J=12.7, 9.8 Hz, 2H), 2.54 (d, J=6.3 Hz, 4H), 2.09 (s, 6H). MS
(m/z) 988.93 (M+H)+.
Example 133:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-(2-(pyrimidin-5-yl)ethoxy)pyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))diacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-(2-(pyrimidin-5-yl)ethoxy)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))diacetic acid)
##STR00369##
[1894] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24, using
2-(pyrimidin-5-yl)ethan-1-ol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G using glycine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.02 (s, 2H), 8.77 (s, 4H), 7.82 (s, 2H),
7.44 (d, J=7.4 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.05 (d, J=7.1 Hz,
2H), 5.55 (s, 4H), 4.70 (t, J=6.0 Hz, 4H), 4.14 (s, 4H), 3.84 (s,
4H), 3.20 (t, J=6.3 Hz, 4H), 2.05 (s, 6H). MS (m/z) 883.010
(M+H)+.
Example 134:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-(3-(methylamino)-3-oxopropoxy)pyridine-6,3-diyl)-
)bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-(3-(methylamino)-3-oxopropoxy)pyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00370##
[1896] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24, using
3-hydroxy-N-methylpropanamide in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.81 (s, 2H), 7.46 (dd, J=7.7, 1.4 Hz, 2H), 7.25 (t, J=7.6
Hz, 2H), 7.08 (dd, J=7.7, 1.4 Hz, 2H), 5.57 (d, J=1.7 Hz, 4H), 4.67
(t, J=5.8 Hz, 4H), 4.36 (dtd, J=9.4, 6.3, 2.9 Hz, 2H), 4.14 (s,
4H), 3.20 (dd, J=12.8, 3.0 Hz, 2H), 3.00 (dd, J=12.7, 9.9 Hz, 2H),
2.74 (s, 6H), 2.69 (t, J=5.8 Hz, 4H), 2.55 (dd, J=6.3, 2.2 Hz, 4H),
2.08 (s, 6H). MS (m/z) 929.116 (M+H)+.
Example 135:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(3-(dimethylamino)-3-oxopropoxy)pyridine-6,3-diyl-
))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(3-(dimethylamino)-3-oxopropoxy)pyridine-6,3-
-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00371##
[1898] The title compound was synthesized analogously to Example
121 using 3-hydroxy-N,N-dimethylpropanamide in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.94 (s, 2H), 7.52-7.43 (m, 2H), 7.24 (t, J=7.6 Hz, 2H),
7.08 (d, J=7.2 Hz, 2H), 5.62-5.50 (m, 4H), 4.72-4.62 (m, 4H),
4.40-4.26 (m, 2H), 4.13 (s, 4H), 3.19 (dd, J=12.7, 3.0 Hz, 2H),
3.08 (s, 6H), 3.03-2.98 (m, 2H), 2.96 (s, 6H), 2.92 (t, J=5.8 Hz,
4H), 2.54 (dd, J=6.3, 1.8 Hz, 4H), 2.09 (s, 6H). MS (m/z) 524.252
(M+2H)2+.
Example 136:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridine-
-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00372##
[1900] The title compound was synthesized analogously to Example
121 using intermediate 32 in place of intermediate 24, using
(1-methyl-1H-pyrazol-4-yl)methanolin place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.83 (s, 2H), 7.59 (s, 2H), 7.51 (s, 2H), 7.45 (d, J=7.4
Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.05 (d, J=7.6 Hz, 2H), 5.72-5.53
(m, 4H), 5.50-5.31 (m, 4H), 4.20 (dp, J=9.6, 3.2 Hz, 2H), 4.12 (s,
4H), 3.83 (s, 6H), 3.13 (dd, J=12.7, 3.1 Hz, 2H), 2.92 (dd, J=12.7,
9.8 Hz, 2H), 2.47 (dd, J=6.3, 2.6 Hz, 4H), 2.07 (s, 6H). MS (m/z)
947.046 (M+H)+.
Example 137:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(pyridin-3-ylmethoxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(pyridin-3-ylmethoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00373##
[1902] The title compound was synthesized analogously to Example
121 using pyridin-3-ylmethanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.74 (s, 2H), 8.60-8.50 (m, 2H), 8.07 (d, J=7.8 Hz, 2H),
8.02 (s, 2H), 7.54 (dd, J=8.0, 5.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.7 Hz, 2H), 5.60 (s, 4H), 5.50
(s, 4H), 4.33-4.13 (m, 6H), 3.22 (dd, J=12.7, 3.0 Hz, 2H), 3.01
(dd, J=12.7, 9.8 Hz, 2H), 2.52 (d, J=6.3 Hz, 4H), 2.05 (s, 6H). MS
(m/z) 1030.966 (M+H)+.
Example 138:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(thiazol-5-ylmethoxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(thiazol-5-ylmethoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00374##
[1904] The title compound was synthesized analogously to Example
121 using thiazol-5-ylmethanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 9.00 (d, J=0.8 Hz, 2H), 8.07-7.91 (m, 4H), 7.49-7.40 (m,
2H), 7.26 (t, J=7.6 Hz, 2H), 7.09 (dd, J=7.8, 1.4 Hz, 2H),
5.96-5.72 (m, 4H), 5.62 (s, 4H), 4.35-3.88 (m, 6H), 3.17 (dd,
J=12.7, 3.1 Hz, 2H), 2.96 (dd, J=12.7, 9.8 Hz, 2H), 2.49 (dd,
J=6.3, 1.7 Hz, 4H), 2.08 (s, 6H). MS (m/z) 1042.936 (M+H)+.
Example 139:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((1-benzyl-1H-1,2,3-triazol-5-yl)methoxy)-5-bromopyridine-
-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-((1-benzyl-1H-1,2,3-triazol-5-yl)methoxy)-5-bromopyr-
idine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00375##
[1906] The title compound was synthesized analogously to Example
121 using (1-benzyl-1H-1,2,3-triazol-5-yl)methanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.98 (d, J=0.9 Hz, 4H), 7.40 (d, J=7.3 Hz, 2H), 7.35-7.25
(m, 10H), 7.20 (t, J=7.6 Hz, 2H), 7.08-6.98 (m, 2H), 5.57 (d, J=2.7
Hz, 8H), 5.47 (s, 4H), 4.27 (dtd, J=9.5, 6.3, 3.0 Hz, 2H), 4.16 (s,
4H), 3.17 (dd, J=12.8, 3.0 Hz, 2H), 2.97 (dd, J=12.7, 9.9 Hz, 2H),
2.50 (d, J=6.2 Hz, 4H), 2.00 (s, 6H). MS (m/z) 1191.132 (M+H)+.
Example 140:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((3-cyano-4-fluorobenzyl)oxy)pyridine-6,3-diyl))b-
is(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((3-cyano-4-fluorobenzyl)oxy)pyridine-6,3-di-
yl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00376##
[1908] The title compound was synthesized analogously to Example
121 using 2-fluoro-5-(hydroxymethyl)benzonitrile in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.01 (s, 2H), 7.89 (dd, J=6.0, 2.2 Hz, 2H), 7.83 (ddd,
J=7.9, 5.1, 2.3 Hz, 2H), 7.44-7.29 (m, 4H), 7.23 (t, J=7.6 Hz, 2H),
7.13-7.01 (m, 2H), 5.62-5.37 (m, 8H), 4.34-4.11 (m, 6H), 3.22 (dd,
J=12.7, 3.1 Hz, 2H), 3.01 (dd, J=12.7, 9.8 Hz, 2H), 2.53 (dd,
J=6.3, 1.4 Hz, 4H), 2.04 (s, 6H). MS (m/z) 1114.939 (M+H)+.
Example 141:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(cyclopropylmethoxy)pyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(cyclopropylmethoxy)pyridine-6,3-diyl))bis(m-
ethylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00377##
[1910] The title compound was synthesized analogously to Example
121 using cyclopropylmethanol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.95 (s, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.23 (t, J=7.6 Hz,
2H), 7.06 (d, J=7.3 Hz, 2H), 5.54 (s, 4H), 4.34-4.21 (m, 6H), 4.18
(s, 4H), 3.24 (dd, J=12.7, 3.1 Hz, 2H), 3.02 (dd, J=12.7, 9.8 Hz,
2H), 2.55 (d, J=6.3 Hz, 4H), 2.08 (s, 6H), 1.32 (td, J=7.8, 4.3 Hz,
2H), 0.67-0.49 (m, 4H), 0.45-0.30 (m, 4H). MS (m/z) 956.889
(M+H)+.
Example 142:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(2-(1H-pyrazol-3-yl)ethoxy)-5-bromopyridine-6,3-diyl))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(2-(1H-pyrazol-3-yl)ethoxy)-5-bromopyridine-6,3-diyl-
))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00378##
[1912] The title compound was synthesized analogously to Example
121 using 2-(1H-pyrazol-3-yl)ethan-1-ol in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.94 (s, 2H), 7.57 (d, J=2.2 Hz, 2H), 7.44 (d, J=7.6 Hz,
2H), 7.22 (t, J=7.5 Hz, 2H), 7.09-6.97 (m, 2H), 6.23 (d, J=2.2 Hz,
2H), 5.54 (s, 4H), 4.74-4.59 (m, 4H), 4.41-4.20 (m, 2H), 4.12 (s,
4H), 3.20-3.12 (m, 6H), 2.99 (dd, J=12.8, 9.9 Hz, 2H), 2.54 (d,
J=6.3 Hz, 4H), 2.07 (s, 6H). MS (m/z) 1037.019 (M+H)+.
Example 143:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(4-cyanobutoxy)pyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(4-cyanobutoxy)pyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00379##
[1914] Intermediate 24 (24 mg, 0.037 mmol), 5-bromopentanenitrile
(24.2 mg, 0.15 mmol), and potassium carbonate (20.7 mg, 0.15 mmol)
were charged into a 2 dram vial. The contents were suspended in
N,N-dimethylformamide (0.5 mL) and stirred at 70.degree. C. After 4
h, the reaction was concentrated in vacuo, diluted with methylene
chloride, filtered to remove insoluble salts, and concentrated to
provide the crude product which was used directly in the next step
following reductive amination procedure G to provide 15 mg of the
title compound as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.96 (s, 2H), 7.45 (d, J=7.2 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.6, 1.4 Hz, 2H), 5.56 (s, 4H),
4.60-4.38 (m, 4H), 4.27 (dtd, J=9.4, 6.3, 3.0 Hz, 2H), 4.17 (s,
4H), 3.24 (dd, J=12.7, 3.1 Hz, 2H), 3.03 (dd, J=12.7, 9.8 Hz, 2H),
2.59-2.50 (m, 8H), 2.09 (s, 6H), 2.06-1.91 (m, 4H), 1.91-1.71 (m,
4H). MS (m/z) 1011.002 (M+H)+.
Example 144:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(3-cyanopropoxy)pyridine-6,3-diyl))bis(methylene)-
)bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(3-cyanopropoxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00380##
[1916] The title compound was synthesized analogously to Example
143 using 4-bromobutanenitrile in place of 5-bromopentanenitrile,
and following reductive amination procedure G. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 7.98 (s, 2H), 7.46 (dd, J=7.6, 1.4 Hz,
2H), 7.25 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.7, 1.4 Hz, 2H), 5.57 (s,
4H), 4.56 (td, J=5.6, 5.0, 2.8 Hz, 4H), 4.28 (dtd, J=9.5, 6.3, 3.1
Hz, 2H), 4.21 (s, 4H), 3.25 (dd, J=12.7, 3.1 Hz, 2H), 3.04 (dd,
J=12.7, 9.7 Hz, 2H), 2.66 (t, J=6.8 Hz, 4H), 2.17 (p, J=6.4 Hz,
4H), 2.09 (s, 6H). MS (m/z) 982.991 (M+H)+.
Example 145:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(3-amino-3-oxopropoxy)-5-bromopyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(3-amino-3-oxopropoxy)-5-bromopyridine-6,3-diyl))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00381##
[1918] The title compound was synthesized analogously to Example
143 using 3-bromopropanamide in place of 5-bromopentanenitrile, and
following reductive amination procedure G. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.95 (s, 2H), 7.47 (d, J=7.5 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.5 Hz, 2H), 5.56 (s, 4H), 4.68
(t, J=5.7 Hz, 4H), 4.32 (d, J=5.4 Hz, 2H), 4.14 (s, 4H), 3.19 (dd,
J=12.8, 2.9 Hz, 2H), 3.00 (dd, J=12.8, 9.9 Hz, 2H), 2.74 (t, J=5.8
Hz, 4H), 2.55 (dd, J=6.4, 2.5 Hz, 4H), 2.10 (s, 6H). MS (m/z)
990.943 (M+H)+.
Example 146:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-(3-amino-3-oxopropoxy)-5-chloropyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))diacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(2-(3-amino-3-oxopropoxy)-5-chloropyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))diacetic acid)
##STR00382##
[1920] The title compound was synthesized analogously to Example
143 using intermediate 32 in place of intermediate 24, using
3-bromopropanamide in place of 5-bromopentanenitrile, and following
reductive amination procedure G using glycine in place of
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.54-7.37 (m, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.11-7.03 (m, 2H), 5.58 (m, 4H), 4.68 (t, J=5.9 Hz,
4H), 4.17 (s, 4H), 3.87 (s, 4H), 2.74 (t, J=5.8 Hz, 4H), 2.09 (s,
6H). MS (m/z) 813.011 (M+H)+.
Example 147:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(2-(methylamino)-2-oxoethoxy)pyridine-6,3-diyl))b-
is(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(2-(methylamino)-2-oxoethoxy)pyridine-6,3-di-
yl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00383##
[1922] The title compound was synthesized analogously to Example
143 using 2-bromo-N-methylacetamide in place of
5-bromopentanenitrile, and following reductive amination procedure
G. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.02 (s, 2H),
7.45 (d, J=7.3 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.10 (d, J=7.4 Hz,
2H), 5.55-5.40 (m, 4H), 4.96 (s, 4H), 4.40-4.29 (m, 2H), 4.23 (d,
J=1.7 Hz, 4H), 3.28-3.23 (m, 2H), 3.07 (dd, J=12.7, 9.9 Hz, 2H),
2.77 (s, 6H), 2.56 (dd, J=6.3, 2.3 Hz, 4H), 2.07 (s, 6H). MS (m/z)
510.251 (M+2H)2+
Example 148:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((4-cyanopyridin-2-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((4-cyanopyridin-2-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00384##
[1924] The title compound was synthesized analogously to Example
143 using 2-(bromomethyl)isonicotinonitrile in place of
5-bromopentanenitrile, and following reductive amination procedure
G. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.76 (dd, J=5.1,
0.9 Hz, 2H), 7.97 (s, 2H), 7.93-7.89 (m, 2H), 7.67 (dd, J=5.2, 1.5
Hz, 2H), 7.39-7.28 (m, 2H), 7.19 (t, J=7.6 Hz, 2H), 7.05 (dd,
J=7.7, 1.4 Hz, 2H), 5.78-5.57 (m, 4H), 5.44-5.23 (m, 4H), 4.40-4.19
(m, 6H), 3.32-3.28 (m, 2H), 3.10 (dd, J=12.7, 9.9 Hz, 2H), 2.56 (d,
J=6.3 Hz, 4H), 1.99 (s, 6H). MS (m/z) 541.107 (M+2H)2+.
Example 149:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(3-methoxypropoxy)pyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(3-methoxypropoxy)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00385##
[1926] The title compound was synthesized analogously to Example
143 using 1-bromo-3-methoxypropane in place of
5-bromopentanenitrile, and following reductive amination procedure
G. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.94 (s, 2H),
7.56-7.34 (m, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.4 Hz,
2H), 5.56 (d, J=1.8 Hz, 4H), 4.57-4.44 (m, 4H), 4.27 (dtd, J=9.4,
6.3, 2.9 Hz, 2H), 4.16 (s, 4H), 3.57 (t, J=5.9 Hz, 4H), 3.33 (s,
6H), 3.23 (dd, J=12.7, 3.0 Hz, 2H), 3.01 (dd, J=12.7, 9.8 Hz, 2H),
2.55 (d, J=6.3 Hz, 4H), 2.09 (m, 10H). MS (m/z) 993.001 (M+H)+.
Example 150:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(2-methoxy-2-oxoethoxy)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(2-methoxy-2-oxoethoxy)pyridine-6,3-diyl))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00386##
[1928] The title compound was synthesized analogously to Example
143 using methyl 2-bromoacetate in place of 5-bromopentanenitrile,
and following reductive amination procedure G. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.04 (s, 2H), 7.41 (d, J=7.2 Hz,
2H), 7.25 (t, J=7.6 Hz, 2H), 7.09 (dd, J=7.6, 1.3 Hz, 2H),
5.67-5.34 (m, 4H), 5.19-4.97 (m, 4H), 4.42-4.16 (m, 6H), 3.75 (s,
6H), 3.26 (dd, J=12.7, 3.1 Hz, 2H), 3.05 (dd, J=12.7, 9.9 Hz, 2H),
2.68-2.46 (m, 4H), 2.07 (s, 6H). MS (m/z) 992.861 (M+H)+.
Example 151:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(allyloxy)-5-bromopyridine-6,3-diyl))bis(methylene))bis(a-
zanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(allyloxy)-5-bromopyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00387##
[1930] The title compound was synthesized analogously to Example
143 using 3-bromoprop-1-ene in place of 5-bromopentanenitrile, and
following reductive amination procedure G. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.97 (s, 2H), 7.51-7.38 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.16-6.99 (m, 2H), 6.22-5.96 (m, 2H), 5.55 (s, 4H),
5.50-5.34 (m, 2H), 5.28 (dd, J=10.6, 1.4 Hz, 2H), 4.95 (dd, J=5.9,
1.5 Hz, 4H), 4.33-4.21 (m, 2H), 4.18 (s, 4H), 3.22 (dd, J=12.7, 3.1
Hz, 2H), 3.01 (dd, J=12.8, 9.8 Hz, 2H), 2.54 (d, J=6.3 Hz, 4H),
2.09 (s, 6H). MS (m/z) 928.882 (M+H)+.
Example 152:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((6-cyanopyridin-2-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((6-cyanopyridin-2-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00388##
[1932] The title compound was synthesized analogously to Example
143 using 6-(bromomethyl)picolinonitrile in place of
5-bromopentanenitrile, and following reductive amination procedure
G. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.07-7.93 (m,
6H), 7.81 (d, J=7.8 Hz, 4H), 7.31 (dd, J=7.7, 1.3 Hz, 2H), 7.19 (t,
J=7.6 Hz, 2H), 7.10-6.95 (m, 2H), 5.63 (d, J=2.6 Hz, 4H), 5.35 (d,
J=1.7 Hz, 4H), 4.47-4.18 (m, 6H), 3.09 (dd, J=12.8, 9.9 Hz, 2H),
2.56 (d, J=6.3 Hz, 4H), 1.99 (s, 6H). MS (m/z) 541.155 (M+2H)2+
Example 153:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3-cyanobenzyl)oxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-((3-cyanobenzyl)oxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00389##
[1934] The title compound was synthesized analogously to Example
143 using intermediate 32 in place of intermediate 24, using
3-(bromomethyl)benzonitrile in place of 5-bromopentanenitrile, and
following reductive amination procedure G. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.87 (d, J=9.3 Hz, 4H), 7.78 (d, J=7.9
Hz, 2H), 7.68 (d, J=7.9 Hz, 2H), 7.55 (t, J=7.7 Hz, 2H), 7.40-7.30
(m, 2H), 7.22 (t, J=7.6 Hz, 2H), 7.05 (d, J=7.4 Hz, 2H), 5.63-5.41
(m, 8H), 4.34-4.19 (m, 6H), 3.23 (dd, J=12.7, 3.1 Hz, 2H), 3.01
(dd, J=12.7, 9.8 Hz, 2H), 2.53 (dd, J=6.3, 1.2 Hz, 4H), 2.01 (s,
6H). MS (m/z) 989.001 (M+H)+.
Example 154:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(2,2,2-trifluoroethoxy)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-(2,2,2-trifluoroethoxy)pyridine-6,3-diyl))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00390##
[1936] The title compound was synthesized analogously to Example
143 using 2,2,2-trifluoroethyl trifluoromethanesulfonate in place
of 5-bromopentanenitrile, and following reductive amination
procedure G. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.08
(s, 2H), 7.45 (dd, J=7.7, 1.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.09
(dd, J=7.7, 1.4 Hz, 2H), 5.57 (s, 4H), 5.02-4.94 (m, 4H), 4.41-4.08
(m, 6H), 3.23 (dd, J=12.7, 3.0 Hz, 2H), 3.02 (dd, J=12.7, 9.9 Hz,
2H), 2.53 (d, J=6.3 Hz, 4H), 2.09 (s, 6H). MS (m/z) 507.070
(M+2H)2+.
Example 155:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(2-amino-2-oxoethoxy)-5-bromopyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(2-amino-2-oxoethoxy)-5-bromopyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00391##
[1938] The title compound was synthesized analogously to Example
143 using 2-bromoacetamide in place of 5-bromopentanenitrile, and
following reductive amination procedure G. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.01 (s, 2H), 7.48 (d, J=7.5 Hz, 2H),
7.26 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.3 Hz, 2H), 5.51 (s, 4H), 5.00
(d, J=3.5 Hz, 4H), 4.32 (s, 2H), 4.28-4.17 (m, 4H), 3.27-3.22 (m,
2H), 3.06 (dd, J=12.7, 9.9 Hz, 2H), 2.55 (dd, J=6.3, 3.0 Hz, 4H),
2.08 (s, 6H). MS (m/z) 962.931 (M+H)+.
Example 156:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bi-
s(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methylpyridine-6,3-diyl))bis(methylene))bis(azanediy-
l))bis(3-hydroxybutanoic acid))
##STR00392##
[1940] (2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol (60.6
mg, 0.25 mmol) and 6-chloro-2-methylnicotinaldehyde (86 mg, 0.55
mmol) were reacted according to the general palladium arylation
reaction using t-ButylXantphos in place of t-ButylXPhos to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methylnicotinaldehyde). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 10.24-10.01 (m, 2H), 8.14-7.99 (m, 2H),
7.52-7.34 (m, 2H), 7.34-7.19 (m, 2H), 7.14-7.00 (m, 2H), 6.90-6.71
(m, 2H), 5.64-5.43 (m, 4H), 2.85-2.69 (m, 6H), 2.15-1.94 (m,
6H).
[1941]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-methylnicotinaldehyde) (12 mg, 0.025 mmol) was reacted
according to reductive amination procedure E to provide the title
compound as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.72 (d, J=8.5 Hz, 2H), 7.47-7.39 (m,
2H), 7.22 (t, J=7.6 Hz, 2H), 7.05 (dd, J=7.8, 1.4 Hz, 2H), 6.77 (d,
J=8.4 Hz, 2H), 5.45 (d, J=1.3 Hz, 4H), 4.33 (dtd, J=9.3, 6.3, 3.1
Hz, 2H), 4.27 (s, 4H), 3.28-3.24 (m, 2H), 3.08 (dd, J=12.8, 10.0
Hz, 2H), 2.60-2.52 (m, 10H), 2.06 (s, 6H). MS (m/z) 687.157
(M+H)+
Example 157:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(pyrimidin-5-ylmethoxy)pyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(pyrimidin-5-ylmethoxy)pyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00393##
[1943] 2-Chloro-6-hydroxynicotinic acid (2.3 g, 12 mmol) was
pulverized into a fine powder and charged into 200 mL flask.
Borane-dimethyl sulfide in THF (2M, 50 mL) was added dropwise and
the resulting suspension was stirred for 16 h. The reaction was
quenched by slow addition of methanol (50 mL) and refluxed for 1 h.
The solution was cooled to room temperature, concentrated, and
triturated with diethyl ether. The solids were filtered to provide
6-chloro-5-(hydroxymethyl)pyridin-2-ol. A second batch was obtained
from the mother liquor. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.23 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 5.27
(t, J=5.6 Hz, 1H), 4.41 (d, J=5.5 Hz, 2H).
[1944] 6-Chloro-5-(hydroxymethyl)pyridin-2-ol (1.22 g, 7.63 mmol),
3,3'-bis(chloromethyl)-2,2'-dimethyl-1,1'-biphenyl (888 mg, 3.18
mmol), potassium carbonate (879 mg, 6.36 mmol), and sodium iodide
(45 mg, 0.3 mmol) were suspended in acetone (20 mL). The suspension
was heated to 65.degree. C. for 4 h. The resulting purple
suspension was diluted with saturated aqueous sodium bicarbonate
and extracted with methylene chloride (3.times.). The organic layer
was separated, dried with anhydrous sodium sulfate, concentrated,
and to provide
((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(2-
-chloropyridine-6,3-diyl))dimethanol. The crude material was
suspended in methylene chloride (25 mL) and stirred vigorously at
room temperature. Dess-Martin periodinane (2.7 g, 6.36 mmol) was
added in one portion and allowed to stir for 10 minutes before
water (114 mg, 6.36 mmol) was added dropwise. After 14 h, 1M
aqueous sodium hydroxide (30 mL) was added and the reaction was
stirred vigorously for 30 min. The organic layer was separated,
dried over anhydrous sodium sulfate, concentrated, and purified by
column chromatography to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-chloronicotinaldehyde). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.16 (d, J=0.8 Hz, 2H), 8.15 (d, J=8.4 Hz, 2H), 7.47 (dd,
J=7.5, 1.3 Hz, 2H), 7.27 (t, J=7.6 Hz, 2H), 7.08 (ddd, J=8.5, 7.1,
1.1 Hz, 4H), 5.50 (s, 4H), 2.02 (s, 6H).
[1945] Pyrimidin-5-ylmethanol (19.4 mg, 0.176 mmol) in
N,N-dimethylformamide (0.5 mL) was treated with sodium hydride (7
mg, 0.176 mmol) at room temperature. After stirring for 15 min, the
cloudy alkoxide solution was added dropwise to a suspension of
(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(2-chloronicotinaldehyde) (40 mg, 0.077 mmol) in
N,N-dimethylformamide (0.5 mL). After stirring for 15 min at room
temperature, the reaction with diluted with saturated aqueous
ammonium chloride and ethyl acetate. The organic layer was washed
with brine, dried over anhydrous sodium sulfate, and concentrated
to provide the crude product which as used directly in the next
step following reductive amination procedure A to provide the title
compound as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.11 (s, 2H), 8.93 (s, 4H), 7.76 (d,
J=8.2 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H), 7.06
(d, J=7.7 Hz, 2H), 6.56 (d, J=8.1 Hz, 2H), 5.58 (d, J=2.5 Hz, 4H),
5.50-5.36 (m, 4H), 4.23 (s, 6H), 3.22 (dd, J=12.7, 3.1 Hz, 2H),
3.00 (dd, J=12.7, 9.8 Hz, 2H), 2.53 (d, J=6.3 Hz, 4H), 2.01 (s,
6H). MS (m/z) 875.153 (M+H)+.
Example 158:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(2-morpholinoethoxy)pyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-(2-morpholinoethoxy)pyridine-6,3-diyl))bis(methylene-
))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00394##
[1947] Sodium hydride (300 mg, 7.5 mmol) was charged in a 200 mL RB
and THF was added (40 mL). 2-morpholinoethan-1-ol (0.911 mL, 7.5
mmol) was added dropwise, and allowed to stir for 15 min.
2,6-dichloronicotinic acid (576 mg, 3 mmol) was added dropwise as a
solution in THF (10 mL) and stirred for 2 h. Borane dimethyl
sulfide complex in THF (10.5 mL, 21 mmol, 2M) added dropwise at
room temperature. After stirring for 16 h, the reaction was
quenched by slow addition of methanol (20 mL) and refluxed for 1 h.
The solution was cooled to room temperature, concentrated, and
purified by column chromatography to provide
(6-chloro-2-(2-morpholinoethoxy)pyridin-3-yl)methanol. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.70 (dt, J=7.7, 0.9 Hz, 1H),
6.97 (d, J=7.6 Hz, 1H), 4.55 (d, J=0.9 Hz, 2H), 4.50 (t, J=5.6 Hz,
2H), 3.75-3.64 (m, 4H), 2.79 (t, J=5.6 Hz, 2H), 2.65-2.49 (m,
4H).
[1948] (6-Chloro-2-(2-morpholinoethoxy)pyridin-3-yl)methanol (200
mg, 0.73 mmol) was dissolved in methylene chloride and Dess-Martin
periodinane (373 mg, 0.88 mmol) was added in one portion. After
stirring for 5 minutes, water (12 mg, 0.88 mmol.) was added. After
1.5 h, the reaction was poured into 15 mL of 1N aqueous sodium
hydroxide, and extracted with methylene chloride (3.times.). The
combined organics were dried over anhydrous sodium sulfate,
concentrated, and purified by column chromatography to provide
6-chloro-2-(2-morpholinoethoxy)nicotinaldehyde (184 mg, 93%) as an
orange oil. .sup.1H NMR displayed as a mixture of aldehyde to
acetal in methanol-d.sub.4 .sup.1H NMR for aldehyde: (400 MHz,
Methanol-d.sub.4) .delta. 10.27 (d, J=0.8 Hz, 1H), 8.11 (d, J=7.9
Hz, 1H), 7.14 (dd, J=7.9, 0.8 Hz, 1H), 4.70-4.55 (m, 2H), 3.69 (m,
4H), 2.86 (t, J=5.6 Hz, 2H), 2.61 (m, 4H).
[1949] (2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol (72.5
mg, 0.30 mmol) and 6-chloro-2-(2-morpholinoethoxy)nicotinaldehyde
(180 mg, 0.66 mmol) were reacted according to the general palladium
arylation reaction to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-(2-morpholinoethoxy)nicotinaldehyde) (120 mg, 25%) as an oil.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 10.16 (d, J=0.8 Hz,
2H), 8.07 (d, J=8.4 Hz, 2H), 7.49-7.32 (m, 2H), 7.25 (t, J=7.6 Hz,
2H), 7.09 (dd, J=7.6, 1.4 Hz, 2H), 6.53 (dd, J=8.4, 0.9 Hz, 2H),
5.56 (s, 4H), 4.71-4.55 (m, 4H), 3.73-3.62 (m, 8H), 2.84 (t, J=5.6
Hz, 4H), 2.57 (t, J=4.8 Hz, 8H).
[1950]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-(2-morpholinoethoxy)nicotinaldehyde) (30 mg, 0.042 mmol)
was reacted according to reductive amination procedure G to provide
17 mg of the title compound as the bis-TFA salt. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.76 (d, J=8.2 Hz, 2H), 7.42 (dd,
J=7.7, 1.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.6, 1.4
Hz, 2H), 6.57 (d, J=8.1 Hz, 2H), 5.55-5.31 (m, 4H), 4.33 (dtd,
J=9.3, 6.2, 3.1 Hz, 2H), 4.23 (q, J=13.3 Hz, 4H), 3.94 (s, 8H),
3.69 (t, J=4.8 Hz, 4H), 3.45 (s, 8H), 3.26 (d, J=3.1 Hz, 2H), 3.08
(dd, J=12.8, 9.7 Hz, 2H), 2.58 (d, J=6.2 Hz, 4H), 2.05 (s, 6H). MS
(m/z) 917.263 (M+H)+.
Example 159:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-(2-morpholinoethoxy)pyridine-6,3-diyl))bis(methy-
lene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-(2-morpholinoethoxy)pyridine-6,3-diyl))bis(-
methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00395##
[1952]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-(2-morpholinoethoxy)nicotinaldehyde) (46 mg, 0.065 mmol)
and N-chlorosuccinimide (60 mg, 0.45 mmol) was dissolved in 1 mL of
CDCl.sub.3. The resulting clear solution was heated at 50.degree.
C. for 1.5 h. The reaction was cooled to room temperature, and
concentrated in vacuo to provide the crude product which was used
directly in the next step following reductive amination procedure G
to provide the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.88 (s, 2H), 7.47 (dd, J=7.0, 1.4 Hz,
2H), 7.27 (t, J=7.6 Hz, 2H), 7.10 (dd, J=7.6, 1.4 Hz, 2H),
5.67-5.42 (m, 4H), 4.43-4.31 (m, 2H), 4.31-4.18 (m, 4H), 4.09-3.82
(m, 8H), 3.80-3.63 (m, 6H), 3.43 (s, 8H), 3.29-3.26 (m, 2H), 3.22
(q, J=7.4 Hz, 2H), 3.09 (dd, J=12.8, 9.5 Hz, 2H), 2.61-2.56 (m,
4H), 2.08 (s, 6H). MS (m/z) 985.234 (M+H)+.
Example 160:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxy-5-(trifluoromethyl)pyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxy-5-(trifluoromethyl)pyridine-6,3-diyl))bis(me-
thylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00396##
[1954] To a stirred solution of
2-chloro-6-methoxy-3-(trifluoromethyl)pyridine (255 mg, 1.2 mmol)
in tetrahydrofuran (3 mL) was added t-BuLi (1.7 M solution in
n-heptane, 0.9 mL, 1.57 mmol) at -78.degree. C. After 1 h at this
temperature, N,N-dimethylformamide (264 mg, 3.6 mmol) was added
dropwise. After stirring for 15 min, the reaction was allowed to
warm slowly to room temperature. The resulting mixture was quenched
with aqueous 1M HCl, brine, and extracted with diethyl ether
(3.times.). The combined organic layer was dried over anhydrous
magnesium sulfate, concentrated and purified by column
chromatography to provide
6-chloro-2-methoxy-5-(trifluoromethyl)nicotinaldehyde as a clear
oil (183 mg, 63%). .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.30 (s, 1H), 8.39 (s, 1H), 4.16 (s, 3H).
[1955] (3-bromo-2-methylphenyl)methanol (184 mg, 0.92 mmol) in
N,N-dimethylformamide (0.5 mL) was treated with sodium hydride (37
mg, 0.92 mmol) at room temperature. After stirring for 15 min, the
cloudy alkoxide solution was added dropwise to a solution of
6-chloro-2-methoxy-5-(trifluoromethyl)nicotinaldehyde (183 mg,
0.764 mmol) in N,N-dimethylformamide (0.5 mL). After stirring at
room temperature for 30 min, the reaction with diluted with
saturated aqueous ammonium chloride and ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate,
concentrated, and purified by column chromatography to provide
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxy-5-(trifluoromethyl)nicotinaldeh-
yde (43 mg, 14%) as a solid. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 10.20 (s, 1H), 8.40-8.24 (m, 1H), 7.56 (d, J=8.0 Hz, 1H),
7.38 (d, J=7.6 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 5.58 (s, 2H), 4.11
(s, 3H), 2.47 (s, 3H).
[1956]
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxy-5-(trifluoromethyl)nicoti-
naldehyde (15 mg, 0.037 mmol)
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3 mg,
0.004 mmol), potassium acetate (11 mg, 0.11 mmol), and
bis(pinacolato)diboron (9.5 mg, 0.037 mmol) were suspended in
dioxane (0.3 mL). The suspension was sparged with nitrogen gas for
1 minute and then heated at 90.degree. C. for 2 h. After cooling to
room temperature, the reaction was diluted with ethyl acetate and
water. The organic layer was separated, dried with anhydrous sodium
sulfate, concentrated and used directly in the next step. Crude
2-methoxy-6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zyl)oxy)-5-(trifluoromethyl)nicotinaldehyde (16 mg, 0.36 mmol),
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxy-5-(trifluoromethyl)nicotinaldeh-
yde (15 mg, 0.38 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3 mg,
0.004 mmol), and potassium carbonate (15.6 mg, 0.11 mmol) were
suspended in dioxane (0.7 mL) and water (0.07 mL). The suspension
was sparged with nitrogen gas for 5 minutes and then heated at
95.degree. C. for 3 h. After cooling to room temperature, the
reaction was diluted with ethyl acetate and water. The organic
layer was separated, dried with anhydrous sodium sulfate,
concentrated, and purified by silica gel chromatography to provide
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxy-5-(trifluoromethyl)nicotinaldehyde) (20 mg, 82%).
[1957]
6,6'-(((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-methoxy-5-(trifluoromethyl)nicotinaldehyde) (20 mg,
0.031 mmol) was reacted according to reductive amination procedure
G to provide 9 mg of the title compound as the bis-TFA salt.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.04 (s, 2H), 7.47
(dd, J=7.8, 1.3 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7,
1.4 Hz, 2H), 5.65 (s, 4H), 4.29 (dtd, J=9.4, 6.3, 3.0 Hz, 2H), 4.21
(s, 4H), 4.13 (s, 6H), 3.23 (dd, J=12.7, 3.1 Hz, 2H), 3.02 (dd,
J=12.7, 9.8 Hz, 2H), 2.55 (d, J=6.3 Hz, 4H), 2.06 (s, 6H). MS (m/z)
854.996 (M+H)+.
Example 161:
(2R,2'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(2-hydroxypropanoic acid)
##STR00397##
[1959]
(2R,2'R)-3,3'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenyle-
ne))bis(methylene))bis(azanediyl))bis(2-hydroxypropanoic acid) was
prepared using general reductive amination procedure B substituting
(R)-3-amino-2-hydroxypropanoic acid for
(S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.96 (d, J=2.0 Hz, 2H), 8.92 (d, J=2.0
Hz, 2H), 8.37 (t, J=2.0 Hz, 2H), 7.51 (s, 2H), 7.47 (d, J=7.5 Hz,
2H), 7.26 (t, J=7.5 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.08 (s, 2H),
5.38 (s, 4H), 5.31 (s, 4H), 4.40 (dd, J=8.7, 4.0 Hz, 2H), 4.26 (d,
J=1.7 Hz, 4H), 3.36 (dd, J=12.9, 4.0 Hz, 2H), 3.17 (dd, J=12.9, 8.7
Hz, 2H), 2.08 (s, 6H). ES/MS (M+1): 961.4
Example 162:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00398##
[1961]
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenyle-
ne))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) was
prepared using general reductive amination procedure A substituting
(R)-4-amino-3-hydroxybutanoic acid for
(S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (d, J=2.1 Hz, 2H), 8.92 (d, J=2.0
Hz, 2H), 8.37 (t, J=2.0 Hz, 2H), 7.51 (s, 2H), 7.47 (d, J=7.6 Hz,
2H), 7.27 (t, J=7.6 Hz, 2H), 7.15-7.09 (m, 2H), 7.07 (s, 2H), 5.37
(s, 4H), 5.31 (s, 4H), 4.23 (m, 5H), 3.20 (dd, J=12.7, 3.1 Hz, 2H),
2.97 (dd, J=12.7, 9.8 Hz, 2H), 2.52 (dd, J=6.3, 1.2 Hz, 4H), 2.08
(s, 6H). ES/MS (M+1): 989.1.
Example 163:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-((((1H-tetrazol-5-yl)methyl)amino)methyl)-4-chloro-3,1-phenylene))-
bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-((((1H-tetrazol-5-yl)methyl)amino)methyl)-4-chloro-5,1-phenylene))-
bis(oxy))bis(methylene))dinicotinonitrile)
##STR00399##
[1963]
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(6-((((1H-tetrazol-5-yl)methyl)amino)methyl)-4-chloro-3,1-pheny-
lene))bis(oxy))bis(methylene))dinicotinonitrile was prepared using
general reductive amination procedure A substituting
(1H-tetrazol-5-yl)methanamine for (3S)-4-amino-3-hydroxybutanoic
acid and omitting triethylamine. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.92 (dd, J=5.8, 2.0 Hz, 4H), 8.34 (d,
J=2.0 Hz, 2H), 7.52 (s, 2H), 7.46 (dd, J=7.6, 1.4 Hz, 2H), 7.26 (t,
J=7.6 Hz, 2H), 7.12 (dd, J=7.7, 1.4 Hz, 2H), 7.06 (s, 2H), 5.34 (s,
4H), 5.31 (s, 4H), 4.58 (s, 4H), 4.37 (s, 4H), 2.07 (s, 6H). ES/MS
(M+1): 948.9.
Example 164:
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-p-
henylene))bis(methylene))bis(azanediyl))dibutyric acid
##STR00400##
[1965]
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(m-
ethylene))bis(azanediyl))dibutyric acid was prepared using general
reductive amination procedure G substituting 4-aminobutanoic acid
for (3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.96 (d, J=2.1 Hz, 2H), 8.92 (d, J=2.0
Hz, 2H), 8.36 (t, J=2.1 Hz, 2H), 7.50 (s, 2H), 7.46 (dd, J=7.6, 1.3
Hz, 2H), 7.26 (t, J=7.6 Hz, 2H), 7.12 (dd, J=7.6, 1.3 Hz, 2H), 7.06
(s, 2H), 5.38 (s, 4H), 5.31 (s, 4H), 4.20 (s, 4H), 3.12-3.03 (m,
4H), 2.41 (t, J=6.9 Hz, 4H), 2.07 (s, 6H), 1.97-1.86 (m, 4H). ES/MS
(M+1): 957.2.
Example 165:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanamide)
##STR00401##
[1967]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenyle-
ne))bis(methylene))bis(azanediyl))bis(3-hydroxybutanamide) was
prepared using general reductive amination procedure G substituting
(S)-4-amino-3-hydroxybutanamide for (3S)-4-amino-3-hydroxybutanoic
acid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.96 (d,
J=2.1 Hz, 2H), 8.92 (d, J=2.0 Hz, 2H), 8.39 (t, J=2.1 Hz, 2H), 7.50
(s, 2H), 7.47 (d, J=7.6 Hz, 2H), 7.30-7.23 (m, 2H), 7.12 (d, J=7.3
Hz, 2H), 7.07 (s, 2H), 5.37 (s, 43H), 5.31 (s, 4H), 4.28-4.14 (m,
6H), 3.22-3.17 (m, 1H), 3.04-2.93 (m, 2H), 2.45 (dd, J=6.0, 2.2 Hz,
4H), 2.08 (s, 6H). ES/MS (M+1): 987.1.
Example 166:
(2S,2'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-hydroxypropanoic acid) (or
(2S,2'S)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(2-hydroxypropanoic acid))
##STR00402##
[1969]
(2S,2'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(2-hydroxypropanoic acid) was prepared using
general reductive amination procedure G substituting l-isoserine
for (3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.51-7.44 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.12-7.04 (m, 2H), 5.59 (s, 4H), 4.42 (dd, J=8.7,
4.0 Hz, 2H), 4.18 (s, 4H), 4.05 (s, 6H), 3.38 (dd, J=12.9, 4.0 Hz,
2H), 3.19 (dd, J=12.9, 8.7 Hz, 2H), 2.09 (s, 6H). ES/MS (M+1):
759.0.
Example 167:
(2R,2'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-hydroxypropanoic acid) (or
(2R,2'R)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(2-hydroxypropanoic acid))
##STR00403##
[1971]
(2R,2'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(2-hydroxypropanoic acid) was prepared using
general reductive amination procedure G substituting d-isoserine
for (3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.51-7.44 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.3 Hz, 2H), 5.59 (s, 4H), 4.44
(dd, J=8.8, 3.9 Hz, 2H), 4.18 (s, 4H), 4.05 (s, 6H), 3.39 (dd,
J=12.9, 3.9 Hz, 2H), 3.19 (dd, J=12.9, 8.8 Hz, 2H), 2.09 (s, 6H).
ES/MS (M+1): 758.9.
Example 168:
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(N-(methylsulfonyl)acetamide) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(N-(methylsulfonyl)acetamide))
##STR00404##
[1973] Benzyl (2-(methylsulfonamido)-2-oxoethyl)carbamate:
Carbonyldiimidazole (1.55 g, 956 mmol) was added to a solution of
((benzyloxy)carbonyl)glycine (2.00 g, 9.56 mmol) in tetrahydrofuran
(40 mL). Mild gas evolution was observed. After 30 min the solution
was heated at reflux for 1.5 h. The solution was cooled to RT and
methylsulfonamide (0.909 g, 9.56 mmol) was added. The solution was
stirred at room temperature for 15 min. A solution of
1,8-Diazabicyclo[5.4.0]undec-7-ene in tetrahydrofuran (5 mL) was
added. After 22 h the reaction was poured into ice cold 0.75 N
hydrochloric acid (100 mL). A solid gradually formed. The solid was
isolated by filtration with water washing. The solid was dried
under vacuum, providing benzyl
(2-(methylsulfonamido)-2-oxoethyl)carbamate.
[1974] 2-Amino-N-(methylsulfonyl)acetamide: 10% Palladium on carbon
(746 mg, 0.701 mmol) was added to a solution of benzyl
(2-(methylsulfonamido)-2-oxoethyl)carbamate (2.008 g, 7.01 mmol) in
ethanol (30 mL). The atmosphere was exchanged with hydrogen
(balloon). After stirring for 1 h a solid had precipitated. The
hydrogen was removed. The solid was removed by filtration through
celite (along with the catalyst). The solid was washed with water
(30 mL). The aqueous phase was filtered through a syringe filter
and subjected to lyophilization providing
2-amino-N-(methylsulfonyl)acetamide.
[1975]
2,2'-((((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(N-(methylsulfonyl)acetamide) was prepared using general
reductive amination procedure G substituting
2-amino-N-(methylsulfonyl)acetamide for
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.47 (dd, J=7.6, 1.4 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.6, 1.4 Hz, 2H), 5.60 (s,
4H), 4.19 (s, 4H), 4.06 (s, 6H), 3.90 (s, 4H), 3.24 (s, 6H), 2.09
(s, 6H). ES/MS (M+1): 853.1.
Example 169:
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-tetrazol-5-yl)methyl)m-
ethanamine) (or
1,1'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-tetrazol-5-yl)met-
hyl)methanamine))
##STR00405##
[1977]
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-tetrazol-5-yl)me-
thyl)methanamine) was prepared using general reductive amination
procedure A substituting (1H-tetrazol-5-yl)methanamine for
(3S)-4-amino-3-hydroxybutanoic acid, omitting triethylamine and
adding dichloromethane in equal proportion to dimethylformamide
(0.0125 M). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81
(s, 2H), 7.50-7.44 (m, 2H), 7.24 (td, J=7.6, 0.7 Hz, 2H), 7.07 (dd,
J=7.7, 1.4 Hz, 2H), 5.59 (s, 4H), 4.57 (s, 4H), 4.27 (s, 4H), 4.03
(s, 6H), 2.08 (s, 6H). ES/MS (M+1): 747.3.
Example 170:
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((5-methyl-1,3,4-oxadiazol--
2-yl)methyl)methanamine) (or
1,1'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((5-methyl-1,3,4-oxadi-
azol-2-yl)methyl)methanamine))
##STR00406##
[1979]
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((5-methyl-1,3,4-oxad-
iazol-2-yl)methyl)methanamine) was prepared using general reductive
amination procedure A substituting
(5-methyl-1,3,4-oxadiazol-2-yl)methanamine for
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.47 (dd, J=7.5, 1.3 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.7, 1.4 Hz, 2H), 5.60 (s,
4H), 4.56 (s, 4H), 4.30 (s, 4H), 4.05 (s, 6H), 2.56 (s, 6H), 2.09
(s, 6H). ES/MS (M+1): 775.2.
Example 171:
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-1,2,3-triazol-4-yl)met-
hyl)methanamine) (or
1,1'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-1,2,3-triazol-4-y-
l)methyl)methanamine))
##STR00407##
[1981]
1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-((1H-1,2,3-triazol-4--
yl)methyl)methanamine) was prepared using general reductive
amination procedure A substituting
(1H-1,2,3-triazol-4-yl)methanamine hydrochloride for
(3S)-4-amino-3-hydroxybutanoic acid, and adding dichloromethane in
equal proportion to dimethylformamide (0.0125 M). .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.79 (s, 2H), 7.47 (d, J=7.7 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.6, 1.4 Hz, 2H), 5.59 (s,
4H), 4.39 (s, 4H), 4.18 (s, 4H), 4.03 (s, 6H), 2.08 (s, 6H). ES/MS
(M+1): 745.0.
Example 172:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))d-
ipropionic acid
##STR00408##
[1983]
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))dipropionic acid was prepared using general reductive
amination procedure G substituting 3-aminopropanoic acid for
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.47 (dd, J=7.7, 1.4 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.4 Hz, 2H), 5.59 (s,
4H), 4.15 (s, 4H), 4.06 (s, 6H), 3.27 (t, J=6.5 Hz, 4H), 2.75 (t,
J=6.5 Hz, 4H), 2.09 (s, 6H). ES/MS (M+1): 726.9.
Example 173:
(4R,4'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(isoxazolidin-3-one) (or
(4R,4'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(isoxazolidin-3-one))
##STR00409##
[1985]
(4R,4'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))b-
is(azanediyl))bis(isoxazolidin-3-one) was prepared using general
reductive amination procedure A substituting
(R)-4-aminoisoxazolidin-3-one for (3S)-4-amino-3-hydroxybutanoic
acid, and adding dichloromethane in equal proportion to
dimethylformamide (0.0125 M). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.47 (dd, J=7.7, 1.4 Hz,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.6, 1.4 Hz, 2H), 5.60 (s,
4H), 4.70 (dd, J=9.7, 8.0 Hz, 2H), 4.51 (t, J=8.1 Hz, 2H),
4.45-4.32 (m, 4H), 4.21 (d, J=13.3 Hz, 2H), 4.05 (s, 6H), 2.08 (s,
6H). ES/MS (M+1): 752.8.
Example 174:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(N--(N,N-dimethylsulfamoyl)acetamide)-2-amino-N--(N,N-dimethylsulfamoyl)-
acetamide (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(N--(N,N-dimethylsulfamoyl)acetamide))
##STR00410##
[1987] Benzyl
(2-((N,N-dimethylsulfamoyl)amino)-2-oxoethyl)carbamate:
Carbonyldiimidazole (1.55 g, 956 mmol) was added to a solution of
((benzyloxy)carbonyl)glycine (2.00 g, 9.56 mmol) in tetrahydrofuran
(40 mL). Mild gas evolution was observed. After 30 min the solution
was heated at reflux for 1.5 h. The solution was cooled to RT and
N,N-dimethylsulfamide (1.18 g, 9.56 mmol) was added. The solution
was stirred at room temperature for 15 min. A solution of
1,8-Diazabicyclo[5.4.0]undec-7-ene in tetrahydrofuran (5 mL) was
added. After 22 h the reaction was poured into ice-cold 0.75 N
hydrochloric acid (100 mL). The aqueous phase was extracted with
ethyl acetate (3.times.50 mL). The combined organic phases were
washed with brine (50 mL) and dried over sodium sulfate. The
solvent was removed under reduced pressure. The residue was
subjected to flash chromatography (0-100% ethyl acetate/hexanes).
The fractions containing product were combined and the solvent was
removed under reduced pressure, providing benzyl
(2-((N,N-dimethylsulfamoyl)amino)-2-oxoethyl)carbamate.
[1988] 2-amino-N--(N,N-dimethylsulfamoyl)acetamide: 10% Palladium
on carbon (628 mg, 0.590 mmol) was added to a solution of benzyl
(2-(methylsulfonamido)-2-oxoethyl)carbamate (1.86 g, 5.90 mmol) in
ethanol (30 mL). The atmosphere was exchanged with hydrogen
(balloon). After stirring for 1 h a solid had precipitated. The
hydrogen was removed. The solid was removed by filtration through
celite (along with the catalyst). The solid was washed with water
(30 mL). The aqueous phase was filtered through a syringe filter
and subjected to lyophilization providing
2-amino-N--(N,N-dimethylsulfamoyl)acetamide.
##STR00411##
[1989]
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(N--(N,N-dimethylsulfamoyl)acetamide) was prepared using
general reductive amination procedure G substituting
2-amino-N--(N,N-dimethylsulfamoyl)acetamide for
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.51-7.44 (m, 2H), 7.25 (t,
J=7.6 Hz, 2H), 7.08 (dd, J=7.6, 1.4 Hz, 2H), 5.60 (s, 4H), 4.19 (s,
4H), 4.06 (s, 6H), 3.90 (s, 4H), 2.90 (s, 12H), 2.09 (s, 6H). ES/MS
(M+1): 910.9.
Example 175:
1,1'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))-
bis(methylene))bis(cyclopropan-1-ol) (or
1,1'-((((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(methylene))bis(cyclopropan-1-ol))
##STR00412##
[1991]
1,1'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))bis(methylene))bis(cyclopropan-1-ol) was prepared using
general reductive amination procedure G substituting
1-(aminomethyl)cyclopropan-1-ol for (3S)-4-amino-3-hydroxybutanoic
acid, methanol for ethanol and omitting potassium hydroxide.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s, 2H),
7.51-7.44 (m, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.11-7.04 (m, 2H), 5.59
(s, 4H), 4.21 (s, 4H), 4.05 (s, 6H), 3.12 (s, 5H), 2.09 (s, 6H),
0.93-0.85 (m, 4H), 0.74-0.66 (m, 4H). ES/MS (M+1): 722.9.
Example 176:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(1,1-difluoropropan-2-ol) (or
3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(1,1-difluoropropan-2-ol))
##STR00413##
[1993]
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))bis(1,1-difluoropropan-2-ol) was prepared using general
reductive amination procedure A substituting
3-amino-1,1-difluoropropan-2-ol hydrochloride for
(3S)-4-amino-3-hydroxybutanoic acid, diisopropylethylamine for
triethylamine and adding ethanol in equal proportion to
dimethylformamide (0.0125 M). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.51-7.44 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.07 (dd, J=7.6, 1.4 Hz, 2H), 5.98-5.66 (m, 2H),
5.59 (s, 4H), 4.18 (d, J=1.3 Hz, 4H), 4.17-4.05 (m, 2H), 4.05 (s,
6H), 3.24 (dd, J=12.8, 3.3 Hz, 2H), 3.12 (dd, J=13.0, 9.9 Hz, 2H),
2.09 (s, 6H). ES/MS (M+1): 770.8.
Example 177:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(3-cyano-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3--
hydroxybutanoic acid)
##STR00414##
[1995] A suspension of
3,3'-bis(chloromethyl)-2,2'-dimethyl-1,1'-biphenyl (100 mg, 0.358
mmol), 4-hydroxy-3-iodobenzaldehyde (266 mg, 1.07 mmol), cesium
carbonate (350 mg, 1.07 mmol), and sodium iodide (161 mg, 1.07
mmol) in dimethylformamide (3 mL) was stirred at 20.degree. C. for
20 h. The mixture was diluted with ethyl acetate (30 mL) and washed
with water (2.times.10 mL) and brine (10 mL). The organic phase was
dried over sodium sulfate and the solvent was removed under reduced
pressure. The residue was subjected to flash chromatography (0-50%
ethyl acetate/hexanes). The fractions containing product were
combined and the solvent was removed under reduced pressure,
providing
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(3-iodobenzaldehyde).
[1996]
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(3-iodobenzaldehyde) (75 mg, 0.107 mmol), and copper (I)
cyanide (24 mg, 0.267 mmol) were combined with dimethylformamide (2
mL) and heated at 140.degree. C. for 20 min in a microwave reactor.
The reaction had mono CN and desired material. The reaction was
diluted with ethyl acetate (10 mL) and water (10 mL). A solid
formed which was removed by filtration. The organic phase was
washed with water (2.times.10 mL) and brine (10 mL). The organic
phase was dried over sodium sulfate and the solvent was removed
under reduced pressure. The residue was subjected to flash
chromatography (0-100% ethyl acetate/hexanes). The fractions
containing product were combined and the solvent was removed under
reduced pressure, providing
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(3-formylbenzonitrile).
[1997]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(3-cyano-4,1-phenylene))bis(methylene))bis(azanediyl))-
bis(3-hydroxybutanoic acid) was prepared following reductive
amination procedure A substituting glycine (10 equiv) for
(3S)-4-Amino-3-hydroxybutanoic acid (6 equiv) and using 10 eq
trimethylamine rather than 6 eq. for a reaction time of 16 h.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.80 (d, J=2.3 Hz,
2H), 7.77 (dd, J=8.8, 2.3 Hz, 2H), 7.52-7.47 (m, 2H), 7.44 (d,
J=8.8 Hz, 2H), 7.28 (t, J=7.6 Hz, 2H), 7.16-7.09 (m, 2H), 5.36 (s,
4H), 4.33-4.24 (m, 1H), 4.23 (s, 4H), 3.20 (dd, J=12.6, 3.1 Hz,
2H), 3.01 (dd, J=12.4, 9.5 Hz, 2H), 2.54 (d, J=6.3 Hz, 4H), 2.09
(s, 6H). ES/MS (M+1): 707.1.
Example 178:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))d-
iacetic acid (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))diacetic acid)
##STR00415##
[1999]
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azaned-
iyl))diacetic acid was prepared following reductive amination
procedure G, substituting glycine for
(3S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.51-7.44 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.08 (dd, J=7.8, 1.4 Hz, 2H), 5.59 (s, 4H), 4.18 (s,
4H), 4.05 (s, 6H), 3.87 (s, 4H), 2.09 (s, 6H). ES/MS (M+1):
698.8.
Example 179:
(2R,2'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-fluoropropanoic acid) (or
(2R,2'R)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(2-fluoropropanoic acid))
##STR00416##
[2001] Diethyl
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2R,2'R)-bis(2-fluoropropanoate) bis trifluoroacetic acid salt was
prepared following reductive amination procedure G, substituting
ethyl (R)-3-amino-2-fluoropropanoate hydrochloride for
(3S)-4-amino-3-hydroxybutanoic acid.
[2002] A solution of lithium hydroxide (4.57 mg, 0.191 mmol) in
water (0.5 mL) was added to a solution of diethyl
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))(-
2R,2'R)-bis(2-fluoropropanoate) bis trifluoroacetic acid salt (20
mg, 0.0191 mmol) in methanol. After 1 h trifluoroacetic acid (0.2
mL) was added and .about. half the solvent was removed under
reduced pressure. The solution was subjected to preparative HPLC
(eluent: 0.1% trifluoroacetic acid/0.1 acetonitrile). The clean
fractions containing product were combined and subjected to
lyophilization, providing
(2R,2'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(aza-
nediyl))bis(2-fluoropropanoic acid). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.50-7.43 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.07 (dd, J=7.7, 1.4 Hz, 2H), 5.60 (s, 4H), 5.36
(dd, J=8.4, 3.2 Hz, 1H), 5.24 (dd, J=8.3, 3.4 Hz, 1H), 4.21 (s,
4H), 4.06 (s, 6H), 3.69-3.45 (m, 4H), 2.08 (s, 6H). .sup.19F NMR
(400 MHz, Methanol-d4) .delta. -195.66. ES/MS (M+1): 762.9.
Example 180:
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxy-4,1-phe-
nylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid)
##STR00417##
[2004] In a round bottom flask,
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxybenzaldehyde)
(27.00 mg, 0.048 mmol) was dissolved in a mixture of 12.00 mL of
methanol and 1.20 mL of acetic acid. To this solution was added
(3S)-4-amino-3-hydroxybutyric acid (18.00 mg, 0.151 mmol) at room
temperature. The flask was capped and the solution was stirred at
room temperature for 30 min. To this solution, 2-methylpyridine
borane (16.00 mg, 0.150 mmol) was added at room temperature. The
flask was capped and the mixture was stirred at room temperature
for an additional 2 hours. Reaction was filtered and purified by
reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) to afford
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxy-4,1-phe-
nylene))bis(azanediyl))bis-(3-hydroxybutanoic acid) upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.16 (s, 1H), 7.60-7.46 (m, 1H),
7.36-7.18 (m, 3H), 7.02 (s, 1H), 4.41-4.23 (m, 3H), 4.07 (s, 2H),
4.03-3.87 (m, 3H), 3.26-3.16 (m, 1H), 3.01 (dq, J=22.1, 9.0, 7.1
Hz, 3H), 2.55 (q, J=5.4 Hz, 2H). ES/MS M.sup.+1: 767.33.
Example 181:
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00418##
[2006] In a round bottom flask,
4,4'-([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxybenzaldehyde)
(22.00 mg, 0.044 mmol) was dissolved in a mixture of 5.00 mL of
methanol and 5.50 mL of acetic acid. To this solution was added
(3S)-4-amino-3-hydroxybutyric acid (16.00 mg, 0.13 mmol) at room
temperature. The flask was capped and the solution was stirred at
room temperature for 30 min. To this solution, 2-methylpyridine
borane (14.00 mg, 0.013 mmol) was added at room temperature. The
flask was capped and the mixture was stirred at room temperature
for an additional 2 hours. Reaction was filtered and purified by
reverse phase HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) to afford
(3S,3'S)-4,4'-((([4,4'-biindoline]-1,1'-dicarbonyl)bis(4,1-phenylene))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.65-8.51 (m, 1H), 8.27 (td, J=7.9, 1.7
Hz, 1H), 7.77-7.57 (m, 5H), 4.25 (s, 3H), 4.03 (s, 2H), 3.17 (dd,
J=12.6, 3.0 Hz, 1H), 3.03-2.90 (m, 3H), 2.52 (t, J=6.2 Hz, 2H).
ES/MS M.sup.+1: 707.31.
Example 182:
(3S,3'S,4R,4'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(3-hydroxypentanoic acid) (or
(3S,3'S,4R,4'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(3-hydroxypentanoic acid))
##STR00419##
[2008] In a round bottom flask,
(3S)-4-amino-3-hydroxy-4-methylbutyric acid HCl salt (183.77 mg,
1.08 mmol) was dissolved in 6.0 mL of DMF at room temperature and
the solution was stirred for 5 min at room temperature. To this
solution,
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (63.00 mg, 0.108 mmol) was
added at room temperature followed by triethylamine (0.100 mL).
Flask was capped and solution was stirred at room temperature.
After 30 min, sodium cyanoborohydride (68.00 mg, 1.08 mmol) and
sodium triacetoxyborohydride (230.00 mg, 1.08 mmol) were added to
the mixture at room temperature and the solution was stirred for an
additional 4 hours. Reaction was filtered and purified by reverse
phase HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to
afford
(3S,3'S,4R,4'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(me-
thylene))bis(azanediyl))bis(3-hydroxypentanoic acid) upon
lyophilization as the bis-TFA salt. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 1H), 7.47 (dd, J=7.7, 1.4 Hz,
1H), 7.24 (t, J=7.6 Hz, 1H), 7.07 (dd, J=7.6, 1.4 Hz, 1H), 5.58 (s,
2H), 4.43 (td, J=6.6, 2.8 Hz, 1H), 4.17 (d, J=2.6 Hz, 2H), 4.04 (s,
3H), 3.39 (qd, J=6.7, 2.7 Hz, 1H), 2.53 (d, J=6.6 Hz, 2H), 2.08 (s,
3H), 1.31 (d, J=6.8 Hz, 3H). ES/MS M.sup.+1: 815.28.
Example 183:
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))d-
ibutyric acid (or
4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))dibutyric acid)
##STR00420##
[2010] In a round bottom flask,
(3S)-4-amino-3-hydroxy-4-methylbutyric acid (124.15 mg, 1.20 mmol)
was dissolved in 6.0 mL of DMF at room temperature and the solution
was stirred for 5 min at room temperature. To this solution,
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (70.00 mg, 0.120 mmol) was
added at room temperature. Following general reductive amination
procedure C,
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))d-
ibutyric acid (8.00, 0.01 mmol) was obtained upon lyophilization as
the bis-TFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
7.80 (s, 1H), 7.47 (dd, J=7.7, 1.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H),
7.07 (dd, J=7.6, 1.4 Hz, 1H), 5.59 (s, 2H), 4.12 (s, 2H), 4.05 (s,
3H), 3.19-3.03 (m, 2H), 2.98 (s, 1H), 2.85 (t, J=1.1 Hz, 1H), 2.46
(t, J=6.9 Hz, 2H), 2.08 (s, 3H), 1.96 (dt, J=14.8, 7.2 Hz, 2H).
ES/MS M.sup.+1: 755.26.
Example 184:
(1R,1'R,3S,3'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexane-1-carboxylic acid) (or
(1R,1'R,3S,3'S)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclohexane-1-carboxylic acid))
##STR00421##
[2012] In a round bottom flask,
(3S)-4-amino-3-hydroxy-4-methylbutyric acid (123.15 mg, 0.86 mmol)
was dissolved in 3.0 mL of DMF at room temperature and the solution
was stirred for 5 min at room temperature. To this solution,
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (50.00 mg, 0.086 mmol) was
added at room temperature. Following general reductive amination
procedure C,
(1R,1'R,3S,3'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexane-1-carboxylic acid) (20.00 mg, 0.02
mmol) was obtained upon lyophilization as the bis-TFA salt. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s, 1H), 7.47 (dd,
J=7.7, 1.4 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.06 (dd, J=7.5, 1.4
Hz, 1H), 5.60 (s, 2H), 4.15 (s, 2H), 4.05 (s, 3H), 3.30-3.11 (m,
1H), 2.53-2.35 (m, 2H), 2.18 (d, J=11.9 Hz, 1H), 2.11-1.87 (m, 5H),
1.67-1.16 (m, 4H). ES/MS M.sup.+1: 835.32.
Example 185:
(1S,1'S,3R,3'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentane-1-carboxylic acid) (or
(1S,1'S,3R,3'R)-3,3'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentane-1-carboxylic acid))
##STR00422##
[2014] In a round bottom flask,
(3S)-4-amino-3-hydroxy-4-methylbutyric acid (37.00 mg, 0.28 mmol)
was dissolved in 3.0 mL of DMF at room temperature and the solution
was stirred for 5 min at room temperature. To this solution,
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (50.00 mg, 0.086 mmol) was
added at room temperature. Following general reductive amination
procedure C,
(1S,1'S,3R,3'R)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentane-1-carboxylic acid) (35.00 mg, 0.04
mmol) was obtained upon lyophilization as the bis-TFA salt. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s, 1H), 7.47 (dd,
J=7.7, 1.4 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.07 (dd, J=7.6, 1.4
Hz, 1H), 5.59 (s, 2H), 4.12 (s, 2H), 4.05 (s, 3H), 3.74-3.60 (m,
1H), 2.98 (s, 3H), 2.85 (d, J=0.7 Hz, 2H), 2.38 (dt, J=13.6, 7.7
Hz, 1H), 2.22 (dd, J=13.6, 6.9 Hz, 1H), 2.12-1.95 (m, 7H), 1.83
(dd, J=13.8, 7.0 Hz, 1H). ES/MS M.sup.+1: 807.29.
Example 186:
2,2'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan--
1-ol) (or
2,2'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(ethan-1-ol))
##STR00423##
[2016] Step 1: (3-Bromo-2-chlorophenyl)methanol: To a solution of
3-bromo-2-chlorobenzoic acid (4.128 g, 17.5 mmol) in anhydrous THF
(30 mL) under nitrogen was added dropwise a borane-dimethyl
sulphide complex (1.6 mL) at 0.degree. C. After the addition was
complete the mixture was heated to reflux for 3 h. The mixture was
cooled to room temperature and poured slowly into water. The
aqueous layer was extracted with DCM and the combined organic
layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in
vacuum to give the product.
[2017] Step 2:
(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol:
Dioxane (30 mL) was charged to a round-bottom flask and nitrogen
was bubbled through for 10 minutes.
(3-bromo-2-chlorophenyl)methanol (2 g, 9.03 mmol) was added and
nitrogen was bubbled through for a while. Potassium acetate (2.66
g, 27.1 mmol) was added. Bis(pinacolato)diboron (3.67 g, 23.87
mmol) was added and then PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.66 g,
1.94 mmol) was added. The reaction was heated at 80.degree. C.
overnight. The reaction was diluted with ethyl acetate, filtered
through a celite bed and the bed washed with ethyl acetate. The
combined organic portions were concentrated under vacuum to provide
a black pasty residue. This crude residue was purified by silica
gel column with 5-30% EtOAc in hexanes to give the product as a
solid.
[2018] Step 3: (2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)dimethanol:
A solution of (3-bromo-2-chlorophenyl)methanol (600 mg, 2.71 mmol),
(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
(728 mg, 2.71 mmol), K.sub.2CO.sub.3 (936 mg, 6.77 mmol) in
1,4-dioxane (9 mL) and water (2.3 mL) was purged with nitrogen for
5 min. Pd(dppf)Cl.sub.2.DCM (198 mg, 0.27 mmol) was added and the
reaction mixture was heated at 100.degree. C. for 12 h. The
reaction mixture was filtered through a pad of celite and the pad
was washed with MeOH. The filtrate was concentrated to dryness and
the residue was purified by silica gel column with 0-30% EtOAc in
hexanes to give a product.
[2019] Step 4:
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde): A mixture of cesium carbonate (1.3 g,
4.04 mmol), palladium (II) acetate (46 mg, 0.20 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos)(171 mg, 0.40 mmol), 6-chloro-2-methoxynicotinaldehyde (434
mg, 2.53 mmol) and
(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)dimethanol (286 mg, 1.01
mmol) in Toluene (6 mL) was heated at 85.degree. C. for 4 h. The
reaction mixture was cooled down and purified by column
chromatography (1% ethyl acetate/hexanes-50% ethyl acetate/hexanes)
to give the product as a solid.
[2020] Step 5:
2,2'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan--
1-ol): The compound was prepared using reductive amination
procedure E. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.83-8.59
(m, 4H), 7.77 (d, 2H), 7.61 (dd, 2H), 7.44 (t, 2H), 7.30 (dd, 2H),
6.56 (d, 2H), 5.58-5.44 (m, 4H), 4.04 (d, 4H), 3.87 (s, 6H), 3.64
(t, 4H), 2.95 (t, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated
for C.sub.32H.sub.36Cl.sub.2N.sub.4O.sub.6: 643.2; found:
643.1.
Example 187:
(3S,3'S)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid))
##STR00424##
[2022] Reductive amination of
6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde with (S)-4-amino-3-hydroxybutanoic acid
using reductive amination procedure E gave the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.77-8.49 (m, 4H), 7.77
(d, 2H), 7.71-7.53 (m, 4H), 7.45 (t, 2H), 7.30 (dd, 2H), 6.56 (d,
2H), 5.65-5.40 (m, 4H), 4.15 (d, 2H), 4.04 (d, 4H), 3.87 (s, 6H),
2.98 (s, 2H), 2.86 (d, 2H), 2.60 (s, 2H), 2.46-2.27 (m, 4H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.40Cl.sub.2N.sub.4O.sub.10: 759.2.2; found: 759.1.
Example 188:
(3R,3'R)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid))
##STR00425##
[2024] Reductive amination of
6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde with (R)-4-amino-3-hydroxybutanoic acid
using reductive amination procedure E gave the title compound.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.71 (d, 2H), 7.58
(dd, 2H), 7.38 (t, 2H), 7.23 (dd, 2H), 6.55 (d, 2H), 5.59 (d, 4H),
4.28 (m, 2H), 4.17 (s, 4H), 3.97 (d, 6H), 3.19 (dd, 2H), 2.98 (dd,
2H), 2.54 (d, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.40Cl.sub.2N.sub.4O.sub.10: 759.2; found: 759.0.
Example 189:
(3S,3'S)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid))
##STR00426##
[2026] Step 1.
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde) (60 mg, 0.11 mmol), was weighted into
a small flask and DCM (1.5 mL) added until all solid dissolved. The
reaction mixture was diluted with 1.5 mL DMF and treated with NBS
(43 mg, 0.24 mmol) and 10 mol % TFA (0.085 mL, 1% solution in DMF).
After 5 h, the reaction mixture was diluted with DCM and washed
with 5% sodium thiosulfate. The organic layer was dried with
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
as crude in next step without further purification.
[2027] Step 2: Reductive amination of
6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde with (S)-4-amino-3-hydroxybutanoic acid
using reductive amination procedure G gave the title compound.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.99 (s, 2H), 7.63
(dd, 2H), 7.41 (t, 2H), 7.26 (dd, 2H), 5.67 (d, 4H), 4.28 (m, 2H),
4.16 (s, 4H), 3.99 (s, 6H), 3.21 (dd, 2H), 3.00 (dd, 2H), 2.54 (d,
4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.38Br.sub.2Cl.sub.2N.sub.4O.sub.10: 915.0; found:
916.7.
Example 190:
(S)-4-(((6-((3'-(((3-Bromo-5-((((S)-3-carboxy-2-hydroxypropyl)amino)methy-
l)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)me-
thoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00427##
[2029] The title compound was isolated as a by-product from Example
189. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.98 (s, 1H),
7.71 (d, 1H), 7.66-7.55 (m, 2H), 7.40 (m, 2H), 7.30-7.20 (m, 2H),
6.55 (d, 1H), 5.67 (d, 2H), 5.63-5.54 (m, 2H), 4.37-4.22 (m, 2H),
4.16 (d, 4H), 3.98 (d, 6H), 3.20 (m, 2H), 2.99 (m, 2H), 2.54 (m,
4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.39BrCl.sub.2N.sub.4O.sub.10: 837.1; found: 838.8.
Example 191:
(3R,3'R)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxybutanoic acid))
##STR00428##
[2031] Reductive amination of
6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-methoxynicotinaldehyde with (R)-4-amino-3-hydroxybutanoic acid
using reductive amination procedure G gave the title compound.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.98 (s, 2H), 7.63
(dd, 2H), 7.41 (t, 2H), 7.26 (dd, 2H), 5.77-5.53 (m, 4H), 4.40-4.23
(m, 2H), 4.16 (s, 4H), 3.21 (dd, 2H), 3.00 (dd, 2H), 2.54 (d, 4H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.38Br.sub.2Cl.sub.2N.sub.4O.sub.10: 915.0; found:
917.0.
Example 192:
(R)-4-(((6-((3'-(((3-Bromo-5-((((R)-3-carboxy-2-hydroxypropyl)amino)methy-
l)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)me-
thoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00429##
[2033] The title compound was isolated as a byproduct from Example
191. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.98 (s, 1H),
7.71 (d, J=8.1 Hz, 1H), 7.60 (m, 2H), 7.40 (dt, 2H), 7.24 (dt, 2H),
6.55 (d, 1H), 5.67 (d, 2H), 5.63-5.53 (m, 2H), 4.28 (m, 2H), 4.16
(d, 4H), 3.98 (d, 6H), 3.20 (m, 2H), 2.99 (m, 2H), 2.54 (dd, 4H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.36H.sub.39BrCl.sub.2N.sub.4O.sub.10: 837.1; found: 839.0.
Example 193:
(3S,3'S)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00430## ##STR00431##
[2035] Step 1:
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde): A mixture of
cesium carbonate (2.75 g, 8.47 mmol), palladium (II) acetate (95
mg, 0.42 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos) (225 mg, 0.53 mmol),
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (1.256 g, 4.87
mmol) and (2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)dimethanol (600
mg, 2.12 mmol) in toluene (6 mL) was heated at 95.degree. C. in a
sealed tube. After 3 h, reaction mixture was cooled down and
filtered through a pad a celite and rinsed with DCM. The filtrate
is concentrated and the residue was purified by column
chromatography with 10% to 20% ethyl acetate in hexanes to give the
product.
[2036] Step 2:
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde):
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (726 mg) was
suspended in 4.5 mL AcOH, and sonicated for 10 min. Sodium acetate
(205 mg) and bromine (400 mg, 0.13 mL) in 0.6 mL of AcOH were
added. After 40 min, the reaction was diluted with 30 mL DCM and 45
mL of 2M NaOH. After stirring for 10 min, the organic layer was
separated, and the aqueous layer extracted with DCM (20 mL). The
organic layer was dried, and concentrated to afford a crude
product.
[2037] Step 3:
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-hydroxynicotinaldehyde): A mixture of
6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde) (550 mg)
and CsF (390 mg) in DMF (4 mL) was stirred at 60.degree. C. for 90
minutes. The reaction mixture was then quenched with aq.
NH.sub.4Cl, and extracted with CH.sub.2Cl.sub.2. The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was used for next step.
[2038] Step 4:
5,5'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile:
6,6'-(((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-bromo-2-hydroxynicotinaldehyde) (385 mg),
5-(chloromethyl)nicotinonitrile (258 mg) and K.sub.2CO.sub.3 (390
mg) is dissolved in 5 mL DMF. NaI (190 mg) was added. The solution
is then heated to 60.degree. C. The reaction mixture was diluted
with DCM and water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was used
for next step.
[2039] Step 5: Reductive amination of
5,5'-((((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile with (S)-4-amino-3-hydroxybutanoic acid using reductive
amination procedure G gave the title compound. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.86 (dd, 4H), 8.27 (t, 2H), 8.07
(s, 2H), 7.57 (dd, 2H), 7.41 (t, 2H), 7.32-7.24 (m, 2H), 5.71-5.41
(m, 8H), 4.34-4.20 (m, 6H), 3.25 (dd, 2H), 3.03 (dd, 2H), 2.54 (dd,
4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.48H.sub.42Br.sub.2Cl.sub.2N.sub.8O.sub.10: 1119.1; found:
1121.1.
Example 194:
(S)-4-(((6-((3'-(((3-Bromo-5-((((S)-3-carboxy-2-hydroxypropyl)amino)methy-
l)-6-((5-cyanopyridin-3-yl)methoxy)pyridin-2-yl)oxy)methyl)-2,2'-dichloro--
[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)pyridin-3-yl-
)methyl)amino)-3-hydroxybutanoic acid
##STR00432##
[2041] The title compound was isolated as a by-product from Example
193. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.93-8.72 (m,
4H), 8.32-8.18 (m, 2H), 7.84-7.70 (m, 2H), 7.66-7.43 (m, 2H), 7.36
(m, 2H), 7.30-7.13 (m, 2H), 6.68-6.53 (m, 1H), 5.73-5.36 (m, 8H),
4.37-4.09 (m, 6H), 3.27-2.93 (m, 4H), 2.53 (m, 4H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for
C.sub.48H.sub.43BrCl.sub.2N.sub.8O.sub.10: 1041.2; found:
1042.9.
Example 195:
(3S,3'S)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00433##
[2043] Reductive amination of
5,5'-((((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotinonitrile
with (S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure G gave the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.88 (d, 2H), 8.86-8.75 (m, 2H), 8.25 (t,
2H), 7.80 (d, 2H), 7.60-7.45 (m, 2H), 7.43-7.32 (m, 2H), 7.25 (m,
2H), 6.63 (dd, 2H), 5.53 (m, 8H), 4.26 (d, 6H), 3.23 (dd, 2H),
3.13-2.95 (m, 2H), 2.54 (dd, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calculated for C.sub.48H.sub.44Cl.sub.2N.sub.8O.sub.10: 963.3;
found: 963.2.
Example 196:
(3R,3'R)-4,4'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00434##
[2045] Reductive amination of
5,5'-((((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile with (R)-4-amino-3-hydroxybutanoic acid using reductive
amination procedure G gave the title compound. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.89 (d, 2H), 8.84 (dd, 2H), 8.26
(t, 2H), 8.07 (s, 2H), 7.57 (d, 2H), 7.41 (t, 2H), 7.27 (dd, 2H),
5.71-5.30 (m, 8H), 4.26 (m, 6H), 3.25 (dd, 1H), 3.13-2.93 (m, 2H),
2.54 (dd, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.48H.sub.42Br.sub.2Cl.sub.2N.sub.8O.sub.10: 1119.1; found:
1120.9.
Example 197:
(2S,2'S)-2,2'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)
(or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid))
##STR00435##
[2047] Reductive amination of
5,5'-((((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile with (S)-2-amino-3-hydroxy-2-methylpropanoic acid using
reductive amination procedure G gave the title compound. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.90 (d, 2H), 8.87-8.76 (m,
2H), 8.29 (t, 2H), 8.15-8.07 (m, 2H), 7.63-7.50 (m, 2H), 7.40 (t,
2H), 7.27 (dd, 2H), 5.66-5.43 (m, 8H), 4.25 (s, 4H), 4.00 (d, 2H),
3.80 (d, 2H), 1.54 (d, J=9.9 Hz, 6H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calculated for
C.sub.48H.sub.42Br.sub.2Cl.sub.2N.sub.8O.sub.10: 1119.1; found:
1120.8.
Example 198:
(2R,2'R)-2,2'-((((((2,2'-Dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid)
##STR00436##
[2049] Reductive amination of
5,5'-((((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-bromo-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotin-
onitrile with (R)-2-amino-3-hydroxy-2-methylpropanoic acid using
reductive amination procedure G gave the title compound. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.90 (s, 2H), 8.81 (d, 2H),
8.29 (t, 2H), 8.10 (s, 2H), 7.62-7.51 (m, 2H), 7.40 (t, 2H), 7.27
(dd, 2H), 5.69-5.41 (m, 8H), 4.25 (s, 4H), 4.01 (d, 2H), 3.80 (d,
2H), 1.54 (d, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.48H.sub.42Br.sub.2Cl.sub.2NO.sub.10: 1119.1; found:
1120.9.
Example 199:
5-((4-Chloro-5-((3'-((2-chloro-5-(cyclopropylmethoxy)-4-(((2-hydroxyethyl-
)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)--
2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
##STR00437## ##STR00438##
[2051] Step 1:
1-Bromo-3-(((4-methoxybenzyl)oxy)methyl-2-methylbenzene: To a
stirred solution of (3-bromo-2-methylphenyl)methanol (2 g, 9.95
mmol) in dry DMF (16 mL) was added 60% NaH (418 mg, 10.44 mmol).
After the reaction mixture was stirred for 30 minutes,
1-(chloromethyl)-4-methoxybenzene (1.636 g, 10.44 mmol) was added
at 0.degree. C. and the reaction mixture was stirred for another 2
h at room temperature. The reaction was then diluted with Et.sub.2O
and water. The organic phase was washed with brine and dried with
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified via silica gel column chromatography with
0-15% EtOAc in hexanes to give the product.
[2052] Step 2:
(3'-(((4-Methoxybenzyl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)met-
hanol: A solution of
1-bromo-3-(((4-methoxybenzyl)oxy)methyl)-2-methylbenzene (400 mg,
1.245 mmol),
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)me-
thanol (340 mg, 1.37 mmol), K.sub.2CO.sub.3 (516 mg, 3.74 mmol) in
1,4-dioxane (6 mL) and water (1.5 mL) was purged with nitrogen for
30 min. Pd(dppf)Cl.sub.2.DCM (102 mg, 0.125 mmol) was added and the
reaction mixture was heated at 100.degree. C. for 12 h. The
reaction mixture was filtered through a pad of Celite and the pad
was washed with MeOH. The filtrate was concentrated to dryness and
the residue was purified by silica gel column chromatography with
0-30% EtOAc in hexanes to give a product.
[2053] Step 3:
5-Chloro-2-hydroxy-4-((3'-(((4-methoxybenzyl)oxy)methyl)-2,2'-dimethyl-[1-
,1'-biphenyl]-3-yl)methoxy)benzaldehyde: Diisopropyl
azodicarboxylate (176 mg, 0.87 mmol) in tetrahydrofuran (1.4 mL)
was added dropwise to a cooled (0.degree. C.) solution of
5-chloro-2,4-dihydroxybenzaldehyde (136 mg, 0.79 mmol),
triphenylphosphine (217 mg, 0.88 mmol) and
(3'-(((4-methoxybenzyl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)met-
hanol (315 mg, 0.87 mmol) in dry tetrahydrofuran (2.6 mL). The
resulting reaction mixture was allowed to slowly warm to room
temperature with stirring overnight. The reaction mixture was
concentrated and the residue was purified by silica gel column
chromatography with 0-20% EtOAc in hexanes to give the product.
[2054] Step 4:
5-((4-Chloro-2-formyl-5-((3'-(((4-methoxybenzyl)oxy)methyl)-2,2'-dimethyl-
-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile:
Cesium carbonate (291 mg, 0.89 mmol),
5-chloro-2-hydroxy-4-((3'-(((4-methoxybenzyl)oxy)methyl)-2,2'-dimethyl-[1-
,1'-biphenyl]-3-yl)methoxy)benzaldehyde (234 mg, 0.45 mmol) were
combined in dimethylformamide (2.2 mL). Added
5-(chloromethyl)nicotinonitrile (138 mg, 0.91 mmol) and stirred at
75.degree. C. overnight. The mixture was treated with
CH.sub.2Cl.sub.2 and water. The organic phase was separated, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
by silica gel column chromatography with 0-20% EtOAc in hexanes to
give the product as a solid.
[2055] Step 5:
5-((4-Chloro-2-formyl-5-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl-
]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile:
2,3-Dichloro-5,6-dicyanobenzoquinone (263 mg, 1.16 mM) was added to
a vigorously stirring, biphasic solution of
5-((4-chloro-2-formyl-5-((3'-(((4-methoxybenzyl)oxy)methyl)-2,2'-dimethyl-
-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (612
mg, 0.967 mM) in CH.sub.2Cl.sub.2 (20 mL) and water (4 mL) at room
temperature. The reaction flask was covered with aluminum foil to
exclude light. The reaction mixture was stirred at room temperature
for 3 h. The crude material was diluted with CH.sub.2Cl.sub.2 and
water. The organic layer was separated, dried with
Na.sub.2SO.sub.4, concentrated. The residue was purified via silica
gel column chromatography with 0-5% MeOH in CH.sub.2Cl.sub.2 to
give the product as a solid.
[2056] Step 6:
5-((4-Chloro-5-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile-
: Diisopropyl azodicarboxylate (116 mg, 0.57 mmol) in
tetrahydrofuran (1.1 mL) was added dropwise to a cooled (0.degree.
C.) solution of 5-chloro-2,4-dihydroxybenzaldehyde (90 mg, 0.522
mmol), triphenylphosphine (143 mg, 0.58 mmol) and
5-((4-chloro-2-formyl-5-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl-
]-3-yl)methoxy)phenoxy)methyl) nicotinonitrile (200 mg, 0.39 mmol)
in dry tetrahydrofuran (14 mL). The resulting reaction mixture was
allowed to slowly warm to room temperature with stirring overnight.
The reaction mixture was concentrated and the residue was purified
by silica gel column with 0-20% EtOAc in hexanes to give the
product.
[2057] Step 7:
5-((4-Chloro-5-((3'-((2-chloro-5-(cyclopropylmethoxy)-4-formylphenoxy)met-
hyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)ni-
cotinonitrile:
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(22 mg, 0.033 mmol) was suspended in dimethylformamide (0.3 mL),
cesium carbonate (16 mg, 0.042 mmol) was added and the reaction
stirred for approximately 5 minutes in which it appeared to exhibit
improved solubility. (Bromomethyl)cyclopropane (9 mg, 0.066 mmol)
was added to the reaction. The reaction was capped and stirred at
65.degree. C. for 1.5 h. The mixture was treated with
CH.sub.2Cl.sub.2 and water. The organic phase was separated, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
by silica gel column with 0-20% EtOAc in hexanes to give the
product.
[2058] Step 8:
5-((4-Chloro-5-((3'-((2-chloro-5-(cyclopropylmethoxy)-4-(((2-hydroxyethyl-
)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)--
2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile:
Reductive amination of
5-((4-chloro-5-((3'-((2-chloro-5-(cyclopropylmethoxy)-4-formylphenoxy)met-
hyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)ni-
cotinonitrile with 2-aminoethan-1-ol using reductive amination
procedure C gave the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.03 (m, 2H), 8.57 (s, 3H), 8.51-8.43 (m,
1H), 7.61-7.53 (m, 1H), 7.49 (m, 3H), 7.35-7.25 (m, 2H), 7.21 (d,
1H), 7.10 (d, J=7.4 Hz, 2H), 7.01 (s, 1H), 5.36 (d, 2H), 5.35-5.22
(m, 4H), 4.10 (d, 4H), 3.96 (d, 2H), 3.62 (m, 4H), 2.94 (d, 4H),
2.01 (d, 6H), 1.24 (m, 1H), 0.66-0.50 (m, 2H), 0.42-0.27 (m, 2H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.45H.sub.48Cl.sub.2N.sub.4O.sub.6: 811.3; found: 811.2.
Example 200:
5-((4-Chloro-5-((3'-((2-chloro-5-((3-cyano-4-fluorobenzyl)oxy)-4-(((2-hyd-
roxyethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-
methoxy)-2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
##STR00439##
[2060] Step 1:
5-((4-Chloro-5-((3'-((2-chloro-5-((3-cyano-4-fluorobenzyl)oxy)-4-formylph-
enoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)-
methyl)nicotinonitrile:
5-((4-Chloro-5-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(22 mg, 0.033 mmol) was suspended in dimethylformamide (0.4 mL),
cesium carbonate (13.5 mg, 0.042 mmol) was added and the reaction
stirred for approximately 5 minutes in which it appeared to exhibit
improved solubility. 5-(Bromomethyl)-2-fluorobenzonitrile (8 mg,
0.036 mmol) was added to the reaction. The reaction was capped and
stirred at room temperature overnight. The mixture was treated with
CH.sub.2Cl.sub.2 and water. The organic phase was separated, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
by silica gel column chromatography with 0-5% MeOH in
CH.sub.2Cl.sub.2 to give the product.
[2061] Step 2: Reductive amination of
5-((4-chloro-5-((3'-((2-chloro-5-((3-cyano-4-fluorobenzyl)oxy)-4-formylph-
enoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)-
methyl)nicotinonitrile with 2-aminoethan-1-ol using reductive
amination procedure C gave the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.02 (dd, 2H), 8.57 (d, 4H), 8.48 (t,
1H), 8.10 (dd, 1H), 7.93 (m, 1H), 7.62-7.52 (m, 3H), 7.49 (m, 2H),
7.29 (t, m 2H), 7.19 (s, 1H), 7.15 (s, 1H), 7.10 (m, 2H), 5.42-5.22
(m, 8H), 4.12 (m, 4H), 3.62 (m, 4H), 2.94 (s, 4H), 2.02 (s, 6H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.49H.sub.46Cl.sub.2FN.sub.5O.sub.6: 890.3; found: 890.1.
Example 201:
5-((4-Chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(((5-(((2-hydroxyet-
hyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methy)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
##STR00440##
[2063] Step 1: tert-Butyl
(2-((tert-butyldimethylsilyl)oxy)ethyl)((6-((3'-((2-chloro-5-((5-cyanopyr-
idin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-
-yl)methoxy)-2-methoxypyridin-3-yl)methyl)carbamate: Cesium
carbonate (121 mg, 0.37 mmol), palladium (II) acetate (8.4 mg,
0.037 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos) (16 mg, 0.037 mmol), tert-butyl
(2-((tert-butyldimethylsilyl)oxy)ethyl)((6-chloro-2-methoxypyridin-3-yl)m-
ethyl)carbamate (80 mg, 0.186 mmol), and
5-((4-chloro-2-formyl-5-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl-
]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (95 mg, 185.6
.mu.mol) were combined. Toluene (1.2 mL) was added. Toluene (2 mL)
was added and the mixture purged with a stream of argon for 5
minutes. The reaction was sealed and heated at 80.degree. C.
overnight. The reaction mixture was filtered and the filtrate was
concentrated to dryness. The residue was purified chromatography
with 0-60% ethyl acetate in hexanes to give a product.
[2064] Step 2:
5-((4-Chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(((5-(((2-hydroxyet-
hyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile: Reductive
amination of with 2-aminoethan-1-ol using reductive amination
procedure C, followed by deprotection with trifluoroacetic acid
gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.01 (m, 2H), 8.57 (s, 4H), 8.51-8.43 (m, 1H), 7.74 (d,
1H), 7.56 (s, 1H), 7.46 (dd, 2H), 7.27 (m, 2H), 7.18 (s, 1H), 7.07
(t, 2H), 6.52 (d, 1H), 5.44 (s, 2H), 5.40-5.12 (m, 6H), 4.12 (t,
2H), 4.03 (t, 2H), 3.91 (s, 3H), 3.62 (q, 4H), 2.94 (s, 4H),
2.11-1.90 (m, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.41H.sub.44ClN.sub.5O.sub.6: 738.3; found: 738.1.
Example 202:
(S)-4-((5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(((5-(((2-hydrox-
yethyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00441##
[2066] Step 1:
(S)-4-((4-((3'-(((5-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)o-
xy)ethyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,-
1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl-
)amino)-3-hydroxybutanoic acid: Reductive amination of tert-butyl
(2-((tert-butyldimethylsilyl)oxy)ethyl)((6-((3'-((2-chloro-5-((5-cyanopyr-
idin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-
-yl)methoxy)-2-methoxypyridin-3-yl)methyl)carbamate with
(S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure C gave the intermediate.
[2067] Step 2:
(S)-4-((5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(((5-(((2-hydrox-
yethyl)amino)methyl)-6-methoxypyridin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid: A
solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M,
0.03 mL, 0.03 mmol) was added to the above intermediate in
tetrahydrofuran (1.5 mL) at 0.degree. C. The solution was allowed
to warm to room temperature and stirred for one hour. The mixture
was then cooled to 0.degree. C. and quenched with water. The
mixture was extracted with CH.sub.2Cl.sub.2 and washed with brine.
The organic phase was dried over sodium sulfate and concentrated
under reduced pressure to give a residue. The above residue was
stirred in a mixture of CH.sub.2Cl.sub.2/TFA (1.25 mL, 4:1) for 2
hrs. Prep-HPLC separation gave the title compound. .sup.1H NMR (400
MHz, Acetonitrile-d.sub.3) .delta. 8.93 (s, 2H), 8.28 (s, 1H), 8.08
(m, 1H), 7.66 (d, 1H), 7.49 (d, 3H), 7.30 (d, 3H), 7.14 (d, 2H),
6.93 (d, 1H), 6.57-6.28 (m, 1H), 5.50 (s, 2H), 5.28 (d, 4H), 4.17
(m, 4H), 3.99 (m, 3H), 3.77 (s, 2H), 3.08 (d, 4H), 2.50 (m, 2H),
2.05 (d, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.43H.sub.46ClN.sub.5O.sub.8: 796.3; found: 796.2.
Example 203:
(S)-4-(((6-((3'-((4-((((S)-3-Carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00442##
[2069] Step 1:
5-((4-Chloro-2-formyl-5-((3'-(((5-formyl-6-methoxypyridin-2-yl)oxy)methyl-
)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitril-
e: Cesium carbonate (46 mg, 0.14 mmol), palladium (II) acetate (2
mg, 0.007 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos) (6 mg, 0.014 mmol), 6-chloro-2-methoxynicotinaldehyde (12
mg, 0.07 mmol), and
5-((4-chloro-2-formyl-5-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (34 mg, 66
.quadrature.mol) were combined. Toluene (0.4 mL) was added. The
reaction was sealed and heated at 80.degree. C. overnight. The
reaction mixture was filtered and the filtrate was concentrated to
dryness. The residue was purified by silica gel column with 0-50
percent ethyl acetate in hexanes to give the product.
[2070] Step 2:
(S)-4-(((6-((3'-((4-((((S)-3-Carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid: Reductive amination of
5-((4-chloro-2-formyl-5-((3'-(((5-formyl-6-methoxypyridin-2-yl)oxy)methyl-
)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitril-
e with (S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure C gave the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (d, 2H), 8.37 (s, 1H), 7.97 (s, 2H),
7.68 (d, 1H), 7.51 (s, 1H), 7.45 (t, 2H), 7.24 (m, 2H), 7.14-7.01
(m, 3H), 6.48 (d, 1H), 5.49 (s, 2H), 5.38 (s, 2H), 5.30 (s, 2H),
4.36-4.19 (m, 2H), 4.17 (s, 2H), 4.03 (s, 3H), 3.25-2.98 (m, 4H),
2.85 (m, 4H), 2.63-2.41 (m, 4H), 2.07 (d, 6H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for
C.sub.45H.sub.48ClN.sub.5O.sub.10: 854.3; found: 854.2.
Example 204:
5-((4-Chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-((4-(((2-hydroxyeth-
yl)amino)methyl)-2-(trifluoromethyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
##STR00443##
[2072] Step 1:
5-((4-Chloro-2-formyl-5-((3'-((4-formyl-2-(trifluoromethyl)phenoxy)methyl-
)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitril-
e: Diisopropyl azodicarboxylate (50 mg) in tetrahydrofuran (0.4 mL)
was added dropwise to a cooled (0.degree. C.) solution of
4-hydroxy-3-(trifluoromethyl)benzaldehyde (43 mg),
triphenylphosphine (61.5 mg) and
(5-((4-chloro-2-formyl-5-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (115 mg) in dry
tetrahydrofuran (0.75 mL). The resulting reaction mixture was
allowed to slowly warm to room temperature with stirring overnight.
The reaction mixture was concentrated and the residue was purified
by silica gel column chromatography with 20-90% EtOAc in hexanes to
give the product.
[2073] Step 2:
5-((4-Chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-((4-(((2-hydroxyeth-
yl)amino)methyl)-2-(trifluoromethyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile: Reductive
amination of
5-((4-chloro-2-formyl-5-((3'-((4-formyl-2-(trifluoromethyl)phenoxy)met-
hyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonit-
rile with 2-aminoethan-1-ol using reductive amination procedure C
gave the title compound. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.95 (s, 2H), 8.45 (s, 2H), 8.29 (s,
1H), 7.93 (s, 2H), 7.83 (s, 1H), 7.75 (d, 1H), 7.57-7.49 (m, 2H),
7.47 (s, 1H), 7.41-7.28 (m, 3H), 7.17 (d, 2H), 6.96 (s, 1H), 5.30
(d, 6H), 4.21 (d, 4H), 3.75 (m, 4H), 3.10 (m, 4H), 2.07 (s, 3H),
2.03 (s, 3H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.42H.sub.42ClF.sub.3N.sub.4O.sub.5: 775.3; found: 775.2.
Example 205:
5-((4-Chloro-5-((3-(1-(3-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyeth-
yl)amino)methyl)benzoyl)indolin-4-yl)-2-methylbenzyl)oxy)-2-(((2-hydroxyet-
hyl)amino)methyl)phenoxy)methyl)nicotinonitrile
##STR00444## ##STR00445##
[2075] Step 1:
4-(4-Bromoindoline-1-carbonyl)-2-hydroxybenzaldehyde:
4-Formyl-3-hydroxybenzoic acid (830 mg, 5 mmol) was combined with
4-bromoindoline (1089 mg, 5.5 mmol), triethylamine (0.77 mL, 5.5
mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyBOP, 2.86 g, 5.5 mmol) in CH.sub.2Cl.sub.2
(10 mL). The mixture was stirred at room temperature overnight,
then concentrated and purified by silica gel column chromatography
(0-5% MeOH in CH.sub.2Cl.sub.2) to afford the product.
[2076] Step 2:
5-((4-Chloro-2-formyl-5-((3-(1-(4-formyl-3-hydroxybenzoyl)indolin-4-yl)-2-
-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile: To a solution of
4-(4-bromoindoline-1-carbonyl)-2-hydroxybenzaldehyde (150 mg, 0.433
mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (220 mg,
0.424 mmol), NaHCO.sub.3 (117 mg, 0.85 mmol) in DMF (12 mL) and
water (3 mL) was added Pd(PPh.sub.3).sub.4 (61 mg, 0.12 equiv). The
reaction mixture was heated at 80.degree. C. for 1 h. Water and
EtOAc were added to the reaction mixture. The organic layer was
dried, and concentrated. The residue was purified by silica gel
column chromatography with 0-10% MeOH in CH.sub.2Cl.sub.2 to give
the product.
[2077] Step 3:
5-((4-Chloro-5-((3-(1-(3-((5-cyanopyridin-3-yl)methoxy)-4-formylbenzoyl)i-
ndolin-4-yl)-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile:
Cesium carbonate (248 mg, 0.76 mmol),
5-((4-chloro-2-formyl-5-((3-(1-(4-formyl-3-hydroxybenzoyl)indolin-4-yl)-2-
-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile (250 mg, 0.38
mmol) and 5-(chloromethyl)nicotinonitrile (116 mg, 0.76 mmol) and
NaI (12 mg) were stirred at 75.degree. C. for 45 minutes in
dimethyl formamide (2.5 mL). The reaction was extracted with
CH.sub.2Cl.sub.2 and water. The organic phase was dried, filtered
and concentrated. The residue was purified silica gel column
chromatography with 0-10% MeOH in CH.sub.2Cl.sub.2 to give the
product.
[2078] Step 4:
5-((4-Chloro-5-((3-(1-(3-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyeth-
yl)amino)methyl)benzoyl)indolin-4-yl)-2-methylbenzyl)oxy)-2-(((2-hydroxyet-
hyl)amino)methyl)phenoxy)methyl)nicotinonitrile: Reductive
amination of
5-((4-chloro-5-((3-(1-(3-((5-cyanopyridin-3-yl)methoxy)-4-formylbenzoyl)i-
ndolin-4-yl)-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile
with 2-aminoethan-1-ol using reductive amination procedure E gave
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.06-8.96 (m, 4H), 8.78 (s, 2H), 8.74-8.58 (m, 4H), 8.47 (m, 2H),
8.27 (m, 2H), 7.75 (d, 2H), 7.70 (m, 2H), 7.60-7.53 (m, 2H), 7.49
(d, 2H), 7.27 (m, 2H), 7.21-7.10 (m, 2H), 6.96-6.81 (m, 1H),
5.42-5.24 (m, 6H), 4.27 (s, 2H), 4.13 (s, 2H), 3.89 (s, 2H), 3.63
(m, 4H), 2.97 (d, 4H), 2.64 (s, 4H), 2.12 (s, 3H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for C.sub.49H.sub.46ClN.sub.7O.sub.6:
864.3; found: 864.2.
Example 206:
(S)-4-((4-(4-(3-((4-((((S)-3-Carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2-methylphenyl)indoline-
-1-carbonyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutano-
ic acid
##STR00446##
[2080] Reductive amination of
5-((4-chloro-5-((3-(1-(3-((5-cyanopyridin-3-yl)methoxy)-4-formylbenzoyl)i-
ndolin-4-yl)-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile
with (S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure E gave the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.00-8.85 (m, 4H), 8.44-8.34 (m, 2H),
7.60 (d, 1H), 7.51 (s, 1H), 7.50-7.44 (m, 1H), 7.40 (s, 1H),
7.35-7.23 (m, 2H), 7.18 (dd, 1H), 7.08 (s, 1H), 6.94 (s, 1H),
5.45-5.37 (m, 4H), 5.30 (s, 2H), 4.39 (s, 2H), 4.32-4.12 (m, 4H),
3.99 (s, 2H), 3.26-2.70 (m, 6H), 2.61-2.44 (m, 4H), 2.18 (s, 3H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.53H.sub.50ClN.sub.7O.sub.10: 980.3; found: 980.3.
Example 207:
(S)-4-((5-Chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((-
2-hydroxyethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutan-
oic acid
##STR00447## ##STR00448##
[2082] Step 1:
5-((5-((3-Bromo-2-methylbenzyl)oxy)-4-chloro-2-(((2-hydroxyethyl)amino)me-
thyl)phenoxy)methyl)nicotinonitrile: Reductive amination of
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicot-
inonitrile with 2-aminoethan-1-ol using reductive amination
procedure E gave the product.
[2083] Step 2:
5-((4-Chloro-5-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hy-
droxyethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl-
)methoxy)-2-formylphenoxy)methyl)nicotinonitrile: To a solution of
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-(((2-hydroxyethyl)amino)me-
thyl)phenoxy)methyl)nicotinonitrile (86 mg, 0.166 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (98 mg, 0.189
mmol), NaHCO.sub.3 (65 mg, 0.47 mmol) in DMF (4 mL) and water (1
mL) was added Pd(PPh.sub.3).sub.4 (40 mg). The reaction mixture was
heated at 80.degree. C. for 1 h. The reaction mixture was filtered
and the filtrate purified by prep-HPLC to give the product.
[2084] Step 3:
(S)-4-((5-Chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((-
2-hydroxyethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutan-
oic acid: Reductive amination of
5-((4-chloro-5-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hy-
droxyethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl-
)methoxy)-2-formylphenoxy)methyl)nicotinonitrile with
(S)-4-amino-3-hydroxybutanoic acid using reductive amination
procedure E gave the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.01-8.87 (m, 4H), 8.38 (q, 2H), 7.51 (s,
2H), 7.50-7.41 (m, 2H), 7.27 (t, 2H), 7.12 (dd, 2H), 7.08 (s, 2H),
5.37 (s, 4H), 5.31 (s, 4H), 4.23 (m, 5H), 3.86-3.68 (m, 2H),
3.25-2.87 (m, 4H), 2.51 (d, 2H), 2.08 (s, 6H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calculated for
C.sub.50H.sub.48Cl.sub.2N.sub.6O.sub.8: 931.3; found: 931.2.
Example 208:
(S)-4-((4-((5-(3-((4-((((S)-3-Carboxy-2-hydroxypropyl)amino)methyl)-2-chl-
oro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2-methylphenyl)pyridin-
-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hy-
droxybutanoic acid
##STR00449##
[2086] Step 1:
(5-(3-(Hydroxymethyl)-2-methylphenyl)pyridin-3-yl)methanol: A
solution of (3-iodo-2-methylphenyl)methanol (200 mg, 0.806 mmol),
(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanol
(199 mg, 0.847 mmol), K.sub.2CO.sub.3 (334 mg, 2.42 mmol) in
1,4-dioxane (4 mL) and water (1 mL) was purged with nitrogen for 30
min. Pd(dppf)Cl.sub.2:DCM (66 mg, 0.081 mmol) was added and the
reaction mixture was heated under microwave at 100.degree. C. for 1
h. The reaction mixture was filtered through a pad of celite and
the pad was washed with MeOH. The filtrate was concentrated to
dryness and the residue was purified by silica gel column with 1-5%
MeOH in CH.sub.2Cl.sub.2 to give a product.
[2087] Step 2:
5-Chloro-4-((5-(3-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2-methylph-
enyl)pyridin-3-yl)methoxy)-2-hydroxybenzaldehyde: Diisopropyl
azodicarboxylate (387 mg, 1.9 mmol) in tetrahydrofuran (3.7 mL) was
added dropwise to a cooled (0.degree. C.) solution of
5-chloro-2,4-dihydroxybenzaldehyde (300 mg, 1.738 mmol),
triphenylphosphine (477 mg, 1.93 mmol) and
(5-(3-(hydroxymethyl)-2-methylphenyl)pyridin-3-yl)methanol (200 mg,
0.86 mmol) in dry tetrahydrofuran (7.5 mL). The resulting reaction
mixture was allowed to slowly warm to room temperature with
stirring overnight. The reaction mixture was concentrated and the
residue was purified by silica gel column with 20-60% EtOAc in
hexanes to give the product.
[2088] Step 3:
5-((4-Chloro-5-((3-(5-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formy-
lphenoxy)methyl)pyridin-3-yl)-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)n-
icotinonitrile: Cesium carbonate (138 mg, 0.42 mmol),
5-chloro-4-((5-(3-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2-methylph-
enyl)pyridin-3-yl)methoxy)-2-hydroxybenzaldehyde (58 mg, 0.411
mmol) were combined in dimethylformamide (1 mL).
5-(Chloromethyl)nicotinonitrile (138 mg, 0.91 mmol) and NaI (0.1
equiv) were added and the mixture was stirred at 75.degree. C.
overnight. The mixture was treated with CH.sub.2Cl.sub.2 and water.
The organic phase was separated, dried over Na.sub.2SO.sub.4, and
concentrated. The residue was purified by prep-HPLC to give the
product.
[2089] Step 4:
(S)-4-((4-((5-(3-((4-((((S)-3-Carboxy-2-hydroxypropyl)amino)methyl)-2-chl-
oro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2-methylphenyl)pyridin-
-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hy-
droxybutanoic acid: Reductive amination of
5-((4-chloro-5-((3-(5-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formy-
lphenoxy)methyl)pyridin-3-yl)-2-methylbenzyl)oxy)-2-formylphenoxy)methyl)n-
icotinonitrile with (S)-4-amino-3-hydroxybutanoic acid using
reductive amination procedure C gave the title compound. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.99-8.86 (m, 4H), 8.70 (s,
1H), 8.54 (s, 1H), 8.36 (d, 2H), 8.01 (s, 1H), 7.53 (dd, 3H),
7.36-7.24 (m, 2H), 7.08 (d, 2H), 5.38 (m, 8H), 4.24 (m, 6H),
3.27-3.09 (m, 2H), 3.06-2.92 (m, 2H), 2.52 (m, 4H), 2.29 (s, 3H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.50H.sub.47Cl.sub.2N.sub.7O.sub.10: 976.3; found: 976.2.
Example 209:
(S)-4-((4-((3'-(1-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)-1H-inda-
zol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyano-
pyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00450## ##STR00451##
[2091] Step 1: To a solution of 5-bromo-1H-indazole (820 mg, 4.16
mmol), bromoacetaldehyde dimethyl acetal (0.980 mL, 8.32 mmol) in
DMSO (8.00 mL) was added cesium carbonate (5.42 g, 16.7 mmol). The
reaction mixture was stirred at 40.degree. C. for 24 h. Analysis by
tlc/LCMS indicated formation of the desired product, and a
significant amount of the starting material remaining. The reaction
mixture was cooled to rt, and quenched by the addition of sat
NH.sub.4Cl and EtOAc. The layers were separated and the aqueous
layer was further extracted with EtOAc. The organic layers were
combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo. The crude mixture was purified
by SiO.sub.2 column chromatography (ISCO gold, 40 g column; 0-100%
EtOAc/Hex) to afford 5-bromo-1-(2,2-dimethoxyethyl)indazole.
[2092] Step 2: 5-bromo-1-(2,2-dimethoxyethyl)indazole (300 mg, 1.05
mmol), (3-Bromo-2-methylphenyl)boronic acid (283 mg, 1.32 mmol),
potassium carbonate (436 mg, 3.16 mmol) and
tetrakis(triphenylphosphine)palladium (122 mg, 0.105 mmol) were
combined in a reaction vessel. Dioxane (10.0 mL) and water (2.0 mL)
were injected and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 90.degree. C. for 5 h. Analysis by tlc/LCMS
indicated consumption of the bromide starting material and
formation of the desired product. The reaction mixture was cooled
to rt, and quenched by the addition of sat NH.sub.4Cl and EtOAc.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO.sub.2 column
chromatography (ISCO gold, 24 g column; 0-50% EtOAc/Hex) to afford
5-(3-bromo-2-methylphenyl)-1-(2,2-dimethoxyethyl)-1H-indazole.
(M+1=375.08, 377.05).
[2093] Step 3:
5-[[4-chloro-2-formyl-5-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]methoxy]phenoxy]methyl]pyridine-3-carbonitrile (120
mg, 0.23 mmol),
5-(3-bromo-2-methylphenyl)-1-(2,2-dimethoxyethyl)-1H-indazole (80%
purity, 160 mg, 0.35 mmol), potassium carbonate (110 mg, 0.81 mmol)
and tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol) were
combined in a sealed vial. Dioxane (3.0 mL) and water (0.75 mL)
were injected and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 95.degree. C. for 5 h. Analysis by tlc/LCMS
indicated consumption of the boronate starting material and
formation of the desired product. The reaction mixture was cooled
to rt, and quenched by the addition of sat NH.sub.4Cl and EtOAc.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO2 column chromatography
(ISCO gold, 12 g column; 0-50% EtOAc/Hex) to afford
5-((4-chloro-5-((3'-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
(M+1=688.09).
[2094] Step 4: To a solution of
5-((4-chloro-5-((3'-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in THF (1.0 mL) was added (0.50 mL) of 4N HCl then 10 drops of
conc. HCl. The mixture was stirred at rt overnight. Analysis by
LCMS indicated formation of the desired product (a mixture of the
desired product, and the hydrate and hemiacetal derivatives were
observed in the LCMS chromatogram). The reaction mixture was poured
into a mixture of brine and EtOAc. The layers were separated and
the aqueous layer was further extracted with EtOAc. The organic
layers were combined, washed with brine, dried (over
Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The crude
mixture was processed in the next step immediately (M+1=641.35; the
1H NMR of the crude material indicated formation of the desired
aldehyde product).
[2095] Step 5:
5-((4-chloro-5-((2,2'-dimethyl-3'-(1-(2-oxoethyl)-1H-indazol-5-yl)-[1,1'--
biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (85
mg, 0.13 mmol) was transformed to the desired product with
(3S)-4-amino-3-hydroxy-butanoic acid (160 mg, 1.3 mmol) via
reductive amination using a modified version of Procedure G
(modification of the work-up as described). The crude mixture was
concentrated in vacuo, and then re-dissolved in DMF (3 mL) and TFA
(0.1 mL). The resulting solution was purified by reverse-phase HPLC
(10-90% MeCN/H2O+0.1% TFA) to afford
(S)-4-((4-((3'-(1-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)-1H-inda-
zol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyano-
pyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid as the
bis-TFA salt: .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.95
(d, J=2.1 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.37 (t, J=2.1 Hz, 1H),
8.16 (d, J=0.9 Hz, 1H), 7.74 (t, J=1.1 Hz, 1H), 7.70-7.63 (m, 1H),
7.51 (s, 1H), 7.49-7.43 (m, 2H), 7.34-7.22 (m, 3H), 7.17 (dd,
J=7.7, 1.4 Hz, 1H), 7.11 (dd, J=7.4, 1.6 Hz, 1H), 7.07 (s, 1H),
5.37 (s, 2H), 5.32 (s, 2H), 4.83-4.74 (m, 2H), 4.31 (dtd, J=9.5,
6.3, 3.1 Hz, 1H), 4.26-4.15 (m, 3H), 3.82-3.59 (m, 2H), 3.37-3.31
(m, 1H), 3.24-3.07 (m, 2H), 3.06-2.92 (m, 1H), 2.56 (d, J=6.3 Hz,
2H), 2.51 (d, J=6.3 Hz, 2H), 2.16 (s, 3H), 1.88 (s, 3H); 19F NMR
(400 MHz, Methanol-d4) .delta. -77.6; ES/MS: M+1=847.12.
Example 210:
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzofuran-2-yl)methyl)amino)-3-hydroxybutanoic acid (or
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzofuran-2-yl)methyl)amino)-3-hydroxybutanoic
acid)
##STR00452##
[2097] Step 1: To a solution of methyl
5-bromobenzofuran-2-carboxylate (250 mg, 0.98 mmol) in THF (20 mL)
cooled in an ice-water bath was added 2M lithium borohydride (0.98
mL) then methanol (79 .mu.L, 2.0 mmol). The reaction mixture was
allowed to slowly warm to rt. Analysis by tlc indicated consumption
of the starting material. The reaction mixture was quenched by the
addition of sat NaHCO.sub.3 and EtOAc. After stirring for 5 min
(significant evolution of gas was observed), the layers were
separated and the aqueous layer was further extracted with EtOAc.
The organic layers were combined, washed with brine, dried (over
Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The crude
mixture was processed in the next step immediately.
[2098] Step 2: To a solution of intermediate from the preceding
step in dichloromethane (20 mL) cooled in an ice-water bath was
added Dess-Martin periodinane (620 mg, 1.5 mmol). The reaction
mixture was allowed to slowly warm to rt and left overnight.
Analysis by TLC indicated consumption of the starting material. The
reaction mixture was quenched by the addition of sat NH.sub.4Cl and
EtOAc. The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO.sub.2 column
chromatography (ISCO gold, 12 g column; 0-50% EtOAc/Hex) to afford
5-bromobenzofuran-2-carbaldehyde.
[2099] Step 3: 5-bromobenzofuran-2-carbaldehyde (180 mg, 0.78
mmol), (3-Bromo-2-methylphenyl)boronic acid (210 mg, 0.97 mmol),
potassium carbonate (320 mg, 2.3 mmol) and
tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were
combined in a sealed vial. Dioxane (2.0 mL) and water (0.50 mL)
were injected and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 90.degree. C. overnight. Analysis by tlc
indicated consumption of the bromide starting material. The
reaction mixture was cooled to rt, and quenched by the addition of
sat NH.sub.4Cl and EtOAc. The layers were separated and the aqueous
layer was further extracted with EtOAc. The organic layers were
combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo. The crude mixture was purified
by SiO.sub.2 column chromatography (ISCO gold, 12 g column; 0-50%
EtOAc/Hex) to afford
5-(3-bromo-2-methyl-phenyl)benzofuran-2-carbaldehyde (as a 2:1
mixture with the protodebromination by-product. .sup.1H NMR signal
of the CH.sub.3 group: 2.30 and 2.19 ppm, respectively).
[2100] Step 4: 5-(3-bromo-2-methyl-phenyl)benzofuran-2-carbaldehyde
(66%, 210 mg, 0.43 mmol),
5-[[4-chloro-2-formyl-5-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]methoxy]phenoxy]methyl]pyridine-3-carbonitrile (150
mg, 0.29 mmol), potassium carbonate (140 mg, 1.0 mmol) and
tetrakis(triphenylphosphine)palladium (84 mg, 0.072 mmol) were
combined in a sealed vial. Dioxane (2.0 mL) and water (0.50 mL)
were injected and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 100.degree. C. for 2 h. Analysis by tlc/LCMS
indicated consumption of the boronate starting material and
formation of the desired product. The reaction mixture was cooled
to rt, and quenched by the addition of sat NH.sub.4Cl and EtOAc.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO.sub.2 column
chromatography (ISCO gold, 12 g column; 0-50% EtOAc/Hex) to afford
5-((4-chloro-2-formyl-5-((3'-(2-formylbenzofuran-5-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
(M+1=627).
[2101] Step 5:
5-((4-chloro-2-formyl-5-((3'-(2-formylbenzofuran-5-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (35 mg,
0.056 mmol) from the preceding step was transformed to the desired
product with (3S)-4-amino-3-hydroxy-butanoic acid (31 mg, 0.56
mmol) via reductive amination using a modified version of Procedure
G (modification of the work-up as described). The crude mixture was
concentrated in vacuo, then re-dissolved in DMF (2 mL) and TFA (0.1
mL). The resulting solution was purified by reverse-phase HPLC
(10-90% MeCN/H2O+0.1% TFA) to afford
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzofuran-2-yl)methyl)amino)-3-hydroxybutanoic acid as
the bis-TFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.95 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.37 (t, J=2.1 Hz,
1H), 7.65-7.55 (m, 2H), 7.51 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.35
(dd, J=8.6, 1.7 Hz, 1H), 7.35-7.20 (m, 3H), 7.16 (d, J=7.6 Hz, 1H),
7.14-7.05 (m, 3H), 5.37 (s, 2H), 5.31 (s, 2H), 4.53 (d, J=15.0 Hz,
1H), 4.49 (d, J=14.1 Hz, 1H), 4.32 (ddt, J=12.8, 6.4, 3.0 Hz, 1H),
4.28-4.17 (m, 3H), 3.20 (dd, J=12.8, 3.1 Hz, 1H), 3.10 (dd, J=12.6,
9.9 Hz, 1H), 2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.56 (d, J=6.3 Hz, 2H),
2.51 (dd, J=6.3, 1.2 Hz, 2H), 2.16 (s, 3H), 1.88 (s, 3H) (note: a
proton coincided with the methanol (solvent) peak or was not
detected and is thus not listed); .sup.19F NMR (400 MHz,
Methanol-d4) .delta. -77.7; ES/MS: M+1=833.02.
Example 211:
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-((5-c-
yanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[biphenyl]-3-yl)ben-
zo[b]thiophen-[1,1'-biphenyl]-3-yl)benzo[b]thiophen-2-yl)methyl)amino)-3-h-
ydroxybutanoic acid 3.2
##STR00453##
[2103]
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-
-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)benzo[b]thiophen-2-yl)methyl)amino)-3-hydroxybutanoic acid
was prepared as the bis-TFA salt by a sequence identical to the
route used to prepare Example 210 starting with methyl
5-bromobenzo[b]thiophene-2-carboxylate instead of
5-bromobenzofuran-2-carboxylate: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0
Hz, 1H), 8.37 (t, J=2.1 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.82 (d,
J=1.6 Hz, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.46 (d, J=7.5 Hz, 1H),
7.40 (dd, J=8.3, 1.7 Hz, 1H), 7.36-7.24 (m, 3H), 7.17 (dd, J=7.7,
1.4 Hz, 1H), 7.12 (dd, J=7.4, 1.6 Hz, 1H), 7.08 (s, 1H), 5.37 (s,
2H), 5.32 (s, 2H), 4.60 (s, 2H), 4.32 (dtd, J=9.5, 6.3, 3.0 Hz,
1H), 4.28-4.17 (m, 3H), 3.29-3.26 (m, 1H), 3.20 (dd, J=12.7, 3.1
Hz, 1H), 3.08 (dd, J=12.7, 9.9 Hz, 1H), 3.00-2.93 (m, 1H), 2.55 (d,
J=6.3 Hz, 2H), 2.51 (dd, J=6.3, 1.1 Hz, 2H), 2.16 (s, 3H), 1.90 (s,
3H); 19F NMR (400 MHz, Methanol-d4) .delta. -77.7; ES/MS:
M+1=849.29.
Example 212:
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((6-cyanopyridin-2-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)-3-hydroxybutanoic
acid
##STR00454##
[2105] A solution of
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (750
mg, 2.1 mmol) in 5 mL DMF under N2 was treated with K2CO3 (585 mg,
2.5 mmol, 2 equiv) and the mixture stirred under N.sub.2 at rt for
15 min. Iodomethane (0.39 mL, 6.3 mmol, 3 equiv) was added and the
reaction stirred under N.sub.2 at 40.degree. C. for 4 h. The
mixture was diluted with water and extracted with EtOAc (2.times.),
then washed with saturated NH.sub.4Cl solution, dried over MgSO4,
filtered and concentrated under reduced pressure to yield.
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzaldehyde as a
solid. [M+H]=370.88.
[2106] A mixture of
3-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)benzonitrile (280 mg, 0.54
mmol),
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzaldehyde (200
mg, 0.54 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (55 mg, 0.068
mmol, 0.125 equiv) and potassium carbonate (80 mg, 0.81 mmol, 1.5
equiv) were placed in a microwave vial along with DMF (9 mL) and
water (1 mL) and heated to 100.degree. C. in a microwave for 30
min. After cooling to room temperature, the reaction was diluted
with EtOAc and water. The organic layer was separated, dried with
Na.sub.2SO.sub.4 and concentrated. Purified by silica gel
chromatography (eluting with DCM-MeOH) to provide
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile-
. [M+H]=681.04.
[2107] The title compound was synthesized from
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in a manner similar to general reductive amination procedure A.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=14.7,
2.0 Hz, 2H), 8.38 (t, J=2.1 Hz, 1H), 7.56-7.37 (m, 4H), 7.27 (q,
J=7.4 Hz, 2H), 7.18-7.02 (m, 3H), 6.95 (s, 1H), 5.37 (s, 2H), 5.31
(s, 3H), 4.39-4.13 (m, 7H), 3.96 (s, 3H), 3.19 (ddd, J=12.2, 8.8,
3.1 Hz, 2H), 2.97 (ddd, J=12.7, 9.8, 2.7 Hz, 2H), 2.52 (dd, J=7.8,
6.2 Hz, 4H), 2.08 (d, J=1.9 Hz, 6H).
Example 213:
(2S,2'S)-3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(2-hydroxypropanoic acid)
##STR00455##
[2109] The title compound was synthesized from Intermediate 12 in a
manner similar to general reductive amination procedure A. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=15.1, 2.0 Hz,
4H), 8.37 (t, J=2.1 Hz, 2H), 7.48 (d, J=21.4 Hz, 4H), 7.26 (t,
J=7.6 Hz, 2H), 7.16-7.05 (m, 4H), 5.38 (s, 4H), 5.31 (s, 4H), 4.40
(dd, J=8.7, 3.9 Hz, 2H), 4.26 (d, J=1.8 Hz, 4H), 3.36 (dd, J=12.9,
4.0 Hz, 4H), 3.17 (dd, J=12.9, 8.8 Hz, 4H), 2.08 (s, 6H). 19F NMR
(376 MHz, Methanol-d4) .delta. -77.68 (d, J=7.6 Hz).
[M+H]=961.15.
Example 214:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azaned-
iyl))bis(3-hydroxybutanoic acid)
##STR00456##
[2111] A solution of
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-hydroxybenzaldehyde) (550 mg, 0.99 mmol) in 5 mL DMF
under N.sub.2 was treated with CS2CO3 (975 mg, 2.99 mmol, 3 equiv)
and the mixture stirred under N.sub.2 at rt for 15 min. Iodomethane
(0.25 mL, 3.99 mmol, 4 equiv) was added and the reaction stirred
under N.sub.2 at 40.degree. C. for 6 h. The mixture was diluted
with water and extracted with EtOAc (2.times.), then washed with
saturated NH4Cl solution, dried over MgSO4, filtered and
concentrated under reduced pressure. Purification was carried out
with by ISCO (Hex/EtOAc) provided
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxybenzaldehyde) as a solid. [M+H]=580.62.
[2112] The title compound was synthesized from
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxybenzaldehyde) in a manner similar to general
reductive amination procedure A. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.56-7.47 (m, 2H), 7.30 (t, J=7.6 Hz, 1H),
7.14-7.07 (m, 1H), 7.04 (s, 1H), 5.33 (d, J=2.2 Hz, 2H), 4.14 (s,
1H), 4.02 (s, 2H), 3.88 (s, 3H), 3.37 (s, 2H), 2.95 (d, J=12.7 Hz,
1H), 2.85-2.75 (m, 1H), 2.35 (dd, J=15.8, 7.2 Hz, 1H), 2.02 (s,
3H). 19F NMR (376 MHz, DMSO-d6) .delta. -73.95. [M+H]=785.18
Example 215:
(2S,2'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(2-hydroxybutanoic acid)
##STR00457##
[2114] The title compound was synthesized from Intermediate 12 in a
manner similar to general reductive amination procedure A. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (t, J=2.4 Hz, 2H),
8.63-8.34 (m, 4H), 7.56 (s, 2H), 7.48 (d, J=7.4 Hz, 2H), 7.28 (t,
J=7.6 Hz, 2H), 7.19 (s, 2H), 7.10 (d, J=7.2 Hz, 2H), 5.56 (s, 2H),
5.44-5.18 (m, 8H), 4.13 (s, 6H), 4.04 (dd, J=8.5, 4.0 Hz, 4H), 2.99
(s, 6H), 2.02 (s, 8H). .sup.19F NMR (376 MHz, DMSO-d6) .delta.
-74.33. [M+H]=989.50.
Example 216:
(S)-3-((4-((3'-((4-((((S)-2-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-
-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphe-
nyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)-2-hydroxypropanoic
acid
##STR00458##
[2116] The title compound was synthesized from
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in a manner similar to general reductive amination procedure A.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.95 (d, J=15.3 Hz,
4H), 7.56-7.35 (m, 4H), 7.27 (q, J=7.3 Hz, 2H), 7.19-7.05 (m, 2H),
6.96 (s, 2H), 5.38 (s, 2H), 5.32 (s, 3H), 4.43 (ddd, J=19.4, 8.8,
3.9 Hz, 2H), 4.30-4.15 (m, 4H), 3.97 (s, 3H), 3.44-3.35 (m, 3H),
3.17 (ddd, J=12.9, 8.9, 3.9 Hz, 3H), 2.09 (d, J=2.2 Hz, 6H). 19F
NMR (376 MHz, Methanol-d4) .delta. -77.74. [M+H]=859.26.
Example 217:
(4-((3'-((4-(((carboxymethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3--
yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-c-
hloro-2-methoxybenzyl)glycine
##STR00459##
[2118] The title compound was synthesized from
5-((4-chloro-5-((3'-((2-chloro-4-formyl-5-methoxyphenoxy)methyl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
in a manner similar to general reductive amination procedure A.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (d, J=16.3 Hz,
4H), 8.39 (t, J=2.1 Hz, 2H), 7.59-7.45 (m, 2H), 7.42 (s, 2H), 7.27
(q, J=7.3 Hz, 4H), 7.17-7.04 (m, 2H), 5.38 (s, 2H), 5.32 (s, 3H),
4.27 (s, 1H), 4.20 (s, 2H), 3.96 (s, 2H), 3.84 (d, J=8.6 Hz, 3H),
2.09 (d, J=1.6 Hz, 6H). 19F NMR (376 MHz, Methanol-d4) .delta.
-77.71. [M+H]=799.11.
Example 218:
4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxy-3-methylbutanoic acid)
##STR00460##
[2120] The title compound was synthesized from Intermediate 12 in a
manner similar to general reductive amination procedure A. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.95 (dd, J=16.2, 2.0 Hz,
6H), 8.38 (t, J=2.1 Hz, 4H), 7.48 (d, J=15.8 Hz, 4H), 7.27 (t,
J=7.6 Hz, 2H), 7.17-6.95 (m, 4H), 5.38 (s, 2H), 5.31 (s, 2H),
4.40-4.05 (m, 4H), 3.25 (d, J=12.7 Hz, 2H), 3.08 (d, J=12.7 Hz,
2H), 2.67-2.49 (m, 4H), 2.09 (s, 6H), 1.31 (s, 6H). 19F NMR (376
MHz, Methanol-d4) .delta. -77.67. [M+H]=1017.32.
Example 219:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((2-cyanopyridin-4-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00461##
[2122] The title compound was synthesized in analogy to Example
214, using 4-(chloromethyl)picolinonitrile instead of methyl
iodide. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.71 (ddd,
J=12.2, 5.1, 0.8 Hz, 2H), 8.01 (dd, J=1.7, 0.8 Hz, 2H), 7.79 (dd,
J=5.1, 1.6 Hz, 2H), 7.52 (s, 2H), 7.40 (dd, J=7.7, 1.4 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.09 (dd, J=7.7, 1.4 Hz, 2H), 6.97 (s, 2H),
5.40 (s, 4H), 5.33 (s, 2H), 5.28 (s, 4H), 4.41-4.24 (m, 6H), 3.25
(dd, J=12.7, 3.0 Hz, 2H), 3.03 (dd, J=12.7, 9.8 Hz, 2H), 2.54 (d,
J=6.3 Hz, 4H), 2.09 (s, 6H). .sup.19F NMR (376 MHz, Methanol-d4)
.delta. -77.74. [M+H]=989.35.
Example 220:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((3,5-dicyanobenzyl)oxy)-4,1-phenylene))bis(meth-
ylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00462##
[2124] Into a flask containing 3,5-Dicyanotoluene (0.5 g, 3.52
mmol, obtained from Alfa-Aeser, Ward Hill, Mass., USA) was added
NBS (0.75 g, 4.22 mmol, 1.1 equiv), 2,2'-Azobisisobutyronitrile,
98% (0.12 g, 0.7 mmol, 0.2 equiv. and CCl.sub.4 (10 mL). The
solution was heated to 85 C for 16 hr. After cooling, the mixture
was filtered and the filtrate concentrated under reduced pressure.
Purification was carried out with by ISCO (Hex/EtOAc) provided of
5-(bromomethyl)isophthalonitrile. .sup.1H NMR (400 MHz, CDCl3)
.delta. 7.87 (s, 2H), 7.69 (s, 1H), 4.48 (s, 2H).
[2125] The title compound was synthesized in analogy to Example
214. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.20 (s, 2H),
7.51 (s, 2H), 7.45 (d, J=7.4 Hz, 2H), 7.26 (t, J=7.6 Hz, 2H), 7.11
(dd, J=7.7, 1.4 Hz, 2H), 7.01 (s, 2H), 5.36 (s, 4H), 5.29 (s, 4H),
4.26 (s, 4H), 3.21 (dd, J=12.8, 3.0 Hz, 4H), 2.99 (dd, J=12.7, 9.8
Hz, 4H), 2.53 (dd, J=6.3, 1.5 Hz, 6H), 2.07 (s, 6H). .sup.19F NMR
(376 MHz, Methanol-d.sub.4) .delta. -77.65. [M+H]=1037.18.
Example 221:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((6-cyanopyridin-2-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00463##
[2127] The title compound was synthesized in analogy to Example 214
using 6-(bromomethyl)picolinonitrile instead of methyl iodide.
.sup.1HNMR (400 MHz, Methanol-d4) .delta. 8.07 (t, J=7.9 Hz, 2H),
7.87 (dd, J=7.9, 3.7 Hz, 4H), 7.51-7.40 (m, 2H), 7.24 (t, J=7.6 Hz,
4H), 7.13-7.02 (m, 4H), 5.44 (s, 4H), 5.27 (s, 4H), 4.30 (dd,
J=10.4, 5.0 Hz, 4H), 3.26 (d, J=3.0 Hz, 2H), 3.06 (dd, J=12.8, 9.9
Hz, 2H), 2.54 (d, J=6.3 Hz, 2H), 2.07 (s, 6H). .sup.19F NMR (376
MHz, Methanol-d.sub.4) .delta. -77.54. [M+H]=989.18.
Example 222:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-carbamoylpyridin-3-yl)methoxy)-5-chloro-4,1-phenylene-
))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00464##
[2129] Into a flask containing compound of Example 66
((S)-4-((4-((3'-((4-((((R)-2-carboxy-2-hydroxyethyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-
-3-hydroxybutanoic acid (20 mg, 0.020 mmol) was added DMSO (3 mL),
Hydrogen peroxide (0.01 mL, 0.05 mmol) and Potassium carbonate
(5.66 mg, 0.04 mmol). The reaction was allowed to stir for several
hours after which reaction was complete. It was directly purified
by RP-HPLC to furnish the titled compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.05 (s, 2H), 8.87 (s, 2H), 8.50 (q,
J=3.3, 2.1 Hz, 2H), 7.52-7.43 (m, 3H), 7.26 (t, J=7.6 Hz, 2H), 7.12
(d, J=1.3 Hz, 2H), 7.10 (d, J=3.3 Hz, 2H), 5.40 (s, 4H), 5.31 (s,
4H), 4.30-4.18 (m, 6H), 3.21 (dd, J=12.8, 3.1 Hz, 2H), 2.99 (dd,
J=12.7, 9.8 Hz, 2H), 2.52 (d, J=6.3 Hz, 4H), 2.08 (s, 6H). .sup.19F
NMR (376 MHz, Methanol-d.sub.4) .delta. -78.03. bis TFA salt.
[M+H]=1025.2.
Example 223:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(3-(trifluoromethyl)-4,1-phenylene))bis(methylene))bis(azanediyl))bis-
(ethan-1-ol)
##STR00465##
[2131] The title compound was synthesized from Intermediate 37 in a
manner similar to general reductive amination procedure A. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.34 (s, 2H), 8.80 (s, 2H),
7.85 (d, J=2.1 Hz, 2H), 7.77 (dd, J=8.4, 2.2 Hz, 2H), 7.61-7.44 (m,
4H), 7.29 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.8, 1.4 Hz, 2H), 5.58 (s,
2H), 5.32 (d, J=2.4 Hz, 4H), 4.17 (s, 2H), 3.02 (s, 2H), 2.86 (d,
J=10.2 Hz, 2H), 2.44-2.27 (m, 2H), 1.97 (s, 6H). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -61.48, -74.03 (d, J=4.2 Hz).
[M+H]=677.2.
Example 224:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(3-(trifluoromethyl)-4,1-phenylene))bis(methylene))bis(azane-
diyl))bis(3-hydroxybutanoic acid)
##STR00466##
[2133] The title compound was synthesized from Intermediate 37 in a
manner similar to general reductive amination procedure A. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.34 (s, 2H), 8.80 (s, 2H),
7.85 (d, J=2.1 Hz, 2H), 7.77 (dd, J=8.4, 2.2 Hz, 2H), 7.61-7.44 (m,
2H), 7.29 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.8, 1.4 Hz, 2H), 5.58 (s,
4H), 5.32 (d, J=2.4 Hz, 4H), 4.17 (s, 4H), 3.02 (s, 2H), 2.86 (d,
J=10.2 Hz, 2H), 2.44-2.27 (m, 4H), 1.97 (s, 6H). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -61.48, -74.03 (d, J=4.2 Hz).
[M+H]=793.32.
Example 225:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((4-cyanopyridin-2-yl)methoxy)-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00467##
[2135] The title compound was synthesized in analogy to Example 214
using 2-(chloromethyl)isonicotinonitrile instead of methyl iodide.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.82 (dd, J=5.1,
0.9 Hz, 2H), 7.92 (t, J=1.2 Hz, 2H), 7.71 (dd, J=5.1, 1.5 Hz, 2H),
7.48 (s, 2H), 7.42 (dd, J=7.6, 1.4 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H),
7.13-7.04 (m, 3H), 5.49 (s, 4H), 5.26 (s, 4H), 4.33 (td, J=6.5, 3.1
Hz, 2H), 4.28 (s, 4H), 3.34 (s, 3H), 3.26 (dd, J=12.7, 3.0 Hz, 2H),
3.07 (dd, J=12.7, 9.9 Hz, 2H), 2.55 (d, J=6.3 Hz, 4H), 2.05 (s,
6H). [M+H]=989.30.
Example 226:
(1R,1'R,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentan-1-ol) (or
(1R,1'R,2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentan-1-ol))
##STR00468##
[2137] To a solution of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (60 mg, 0.10 mmol) in DMF (1
mL) was added (1R,2S)-2-aminocyclopentan-1-ol (142 mg, 1.03 mmol).
The mixture was stirred at rt for 1 h, then NaBH(OAc).sub.3 (219
mg, 1.03 mmol) was added. The mixture was stirred for an additional
2 h, then TFA was added until the reaction mixture reached pH 5
(ca. 0.1 mL). The mixture was filtered and purified via preparative
reverse-phase HPLC (5-95% MeCN in H.sub.2O) to yield the product as
a solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.81 (s,
2H), 7.46 (d, J=7.5 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5
Hz, 2H), 5.58 (s, 4H), 4.40-4.29 (m, 2H), 4.13 (q, J=13.3 Hz, 4H),
4.03 (s, 6H), 3.42 (td, J=8.8, 4.8 Hz, 2H), 3.30 (dt, J=3.3, 1.6
Hz, 2H), 2.08 (s, 6H), 2.00-1.73 (m, 8H), 1.65 (td, J=15.9, 15.4,
6.2 Hz, 2H). LCMS-ESI+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.49Cl.sub.2N.sub.4O.sub.6: 751.30; found: 751.22.
Example 227:
(1S,1'S,2R,2'R)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentan-1-ol) (or
(1S,1'S,2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentan-1-ol))
##STR00469##
[2139] Prepared in a similar manner to Example 226, using
(1S,2R)-2-aminocyclopentan-1-ol in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.46 (d, J=7.5 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5 Hz, 2H), 5.58 (s, 4H),
4.40-4.29 (m, 2H), 4.13 (q, J=13.3 Hz, 4H), 4.03 (s, 6H), 3.42 (td,
J=8.8, 4.8 Hz, 2H), 3.30 (dt, J=3.3, 1.6 Hz, 2H), 2.08 (s, 6H),
2.00-1.73 (m, 8H), 1.65 (td, J=15.9, 15.4, 6.2 Hz, 2H). LCMS-ESI+
(m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.49Cl.sub.2N.sub.4O.sub.6: 751.30; found: 751.16.
Example 228:
(1R,1'R,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexan-1-ol)
##STR00470##
[2141] Prepared in a similar manner to Example 226, using
(1R,2S)-2-aminocyclohexan-1-ol in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.80 (s, 2H), 7.46 (d, J=7.4 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5 Hz, 2H), 5.58 (s, 4H),
4.22-4.04 (m, 6H), 4.03 (s, 6H), 3.15 (dt, J=10.6, 4.1 Hz, 2H),
2.07 (s, 6H), 1.98-1.68 (m, 8H), 1.71-1.18 (m, 8H). LCMS-ESI+
(m/z): [M+H].sup.+ calculated for
C.sub.42H.sub.53Cl.sub.2N.sub.4O.sub.6: 779.33; found: 779.22.
Example 229:
(1S,1'S,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclohexan-1-ol)
##STR00471##
[2143] Prepared in a similar manner to Example 226, using
(1S,2S)-2-aminocyclohexan-1-ol in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.47 (d, J=7.6 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5 Hz, 2H), 5.58 (s, 4H), 4.18
(d, J=1.8 Hz, 4H), 4.04 (s, 6H), 3.54 (td, J=9.8, 4.9 Hz, 2H),
2.91-2.80 (m, 2H), 2.22 (d, J=13.1 Hz, 2H), 2.14-2.02 (m, 8H),
1.90-1.72 (m, 4H), 1.54-1.22 (m, 8H). LCMS-ESI+ (m/z): [M+H].sup.+
calculated for C.sub.42H.sub.53Cl.sub.2N.sub.4O.sub.6: 779.33;
found: 779.24.
Example 230:
(1S,1'S,2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(me-
thylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))-
bis(azanediyl))bis(cyclopentan-1-ol) (or
(1S,1'S,2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)b-
is(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyl-
ene))bis(azanediyl))bis(cyclopentan-1-ol))
##STR00472##
[2145] Prepared in a similar manner to Example 226, using
(1S,2S)-2-aminocyclopentan-1-ol in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.82 (s, 2H), 7.47 (d, J=7.3 Hz, 2H),
7.23 (t, J=7.6 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 5.59 (s, 4H), 4.27
(d, J=13.4 Hz, 2H), 4.20 (q, J=6.7 Hz, 2H), 4.14 (d, J=13.4 Hz,
2H), 4.05 (s, 6H), 3.38-3.31 (m, 2H), 2.23 (dt, J=13.5, 6.7 Hz,
2H), 2.08 (s, 6H), 2.04-1.99 (m, 2H), 1.79 (dq, J=15.2, 7.5 Hz,
4H), 1.65 (ddd, J=13.1, 9.8, 5.9 Hz, 4H). LCMS-ESI+ (m/z):
[M+H].sup.+ calculated for C.sub.40H.sub.49Cl.sub.2N.sub.4O.sub.6:
751.30; found: 751.10.
Example 231:
1,1'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(cyclobutane-1-carbonitrile) (or
1,1'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(cyclobutane-1-carbonitrile))
##STR00473##
[2147] Prepared in a similar manner to Example 226, using
1-aminocyclobutane-1-carbonitrile in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.81 (s, 2H), 7.46 (d, J=7.5 Hz, 2H),
7.22 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.5 Hz, 2H), 5.58 (s, 4H), 4.11
(s, 3H), 4.04 (s, 6H), 2.96-2.43 (m, 8H), 2.33-2.20 (m, 2H),
2.20-2.10 (m, 2H), 2.07 (s, 6H). LCMS-ESI+ (m/z): [M+Na].sup.+
calculated for C.sub.40H.sub.42Cl.sub.2N.sub.6NaO.sub.4: 763.2;
found: 762.9.
Example 232:
(2'S)-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))di-L-proline
(or
(2'S)-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))di-L-prolin-
e)
##STR00474##
[2149] Prepared in a similar manner to Example 226, using L-proline
in place of (1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.84 (s, 2H), 7.47 (d, J=7.5 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.09 (d, J=6.7 Hz, 2H), 5.59 (s, 4H), 4.38
(q, J=13.9 Hz, 4H), 4.32-4.26 (m, 2H), 4.05 (s, 6H), 3.61 (ddd,
J=11.0, 7.5, 3.9 Hz, 2H), 3.41-3.31 (m, 2H), 2.62-2.51 (m, 2H),
2.25-2.11 (m, 4H), 2.09 (s, 6H), 2.06-1.96 (m, 2H). LCMS-ESI+
(m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.45Cl.sub.2N.sub.4O.sub.8: 779.26; found: 779.10.
Example 233:
(3S,3'S)-4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(morp-
holine-3-carboxylic acid) (or
(3S,3'S)-4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(morpholine-3-carboxylic acid))
##STR00475##
[2151] Prepared in a similar manner to Example 226, using
(S)-morpholine-3-carboxylic acid in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.86 (s, 2H), 7.48 (d, J=7.1 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.1 Hz, 2H), 5.60 (s, 4H),
4.52-4.33 (m, 4H), 4.30-4.14 (m, 4H), 4.13-3.90 (m, 8H), 3.87-3.70
(m, 4H), 3.55-3.43 (m, 2H), 3.28-3.18 (m, 2H), 2.09 (s, 6H).
LCMS-ESI+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.45Cl.sub.2N.sub.4O.sub.10: 811.25; found: 810.97.
Example 234:
(2'R)-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))di-D-proline
(or
(2'R)-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bi-
s(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))di-D-prolin-
e)
##STR00476##
[2153] Prepared in a similar manner to Example 226, using D-proline
in place of (1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.84 (s, 2H), 7.47 (d, J=7.5 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.09 (d, J=6.7 Hz, 2H), 5.59 (s, 4H), 4.38
(q, J=13.9 Hz, 4H), 4.32-4.26 (m, 2H), 4.05 (s, 6H), 3.61 (ddd,
J=11.0, 7.5, 3.9 Hz, 2H), 3.41-3.31 (m, 2H), 2.62-2.51 (m, 2H),
2.25-2.11 (m, 4H), 2.09 (s, 6H), 2.06-1.96 (m, 2H). LCMS-ESI+
(m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.45Cl.sub.2N.sub.4O.sub.8: 779.26; found: 779.09.
Example 235:
4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(morpholine-2--
carboxylic acid) (or
4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(morpholi-
ne-2-carboxylic acid))
##STR00477##
[2155] Prepared in a similar manner to Example 226, using
morpholine-2-carboxylic acid in place of
(1R,2S)-2-aminocyclopentan-1-ol: .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.86 (s, 2H), 7.48 (d, J=7.9 Hz, 2H),
7.24 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.4 Hz, 2H), 5.60 (s, 4H), 4.43
(d, J=6.6 Hz, 2H), 4.29 (s, 4H), 4.12 (dt, J=12.4, 2.8 Hz, 2H),
4.05 (s, 6H), 3.90-3.81 (m, 2H), 3.65 (d, J=12.8 Hz, 2H), 3.43-3.31
(m, 4H), 3.23-3.15 (m, 2H), 2.08 (s, 6H). LCMS-ESI+ (m/z):
[M+H].sup.+ calculated for C.sub.40H.sub.45Cl.sub.2N.sub.4O.sub.10:
811.25; found: 811.00.
Example 236:
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylamino)propanoic
acid) (or
3,3'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylami-
no)propanoic acid))
##STR00478##
[2157] To a solution of methyl 2-(dimethoxyphosphoryl)acetate
(0.083 mL, 0.52 mmol) in THF (3 mL) at 0.degree. C. was added
n-BuLi (1.94 M in hexane, 0.27 mL, 0.52 mmol) dropwise. The mixture
was allowed to warm to rt and stir 20 min.
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (100 mg, 0.172 mmol) was then
added as a solid in one portion, and the mixture was allowed to
stir at rt for an additional 30 min. The mixture was poured over
H.sub.2O, and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(3.times.5 mL). The combined organics were dried (MgSO.sub.4) and
concentrated, and the residue purified via column chromatography
(SiO.sub.2, 0-30% EtOAc in hexane) to yield dimethyl
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))(2E,2'E)-diacrylate as a
solid.
[2158] To a solution of dimethylamine (2.0 M in THF, 0.43 mL, 0.87
mmol) at -78.degree. C. was added n-BuLi (1.94 M in hexane, 0.45
mL, 0.87 mmol) dropwise. The mixture was stirred at -78.degree. C.
for 1 h, then a solution of dimethyl
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))(2E,2'E)-diacrylate (60
mg, 0.087 mmol) in THF (1 mL) was added dropwise. The mixture was
stirred at -78.degree. C. for an additional 1 h, then MeOH (1 mL)
was added dropwise. The mixture was warmed to room temperature,
concentrated, and purified via preparative reverse-phase HPLC
(25-95% MeCN in H.sub.2O) to yield dimethyl
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylamino)propanoate)
as a solid.
[2159] To a solution of dimethyl
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylamino)propanoate)
(65 mg, 0.083 mmol) in THF/H.sub.2O/DMSO (1:1:1 by volume, 3 mL)
was added LiOH (14 mg, 0.33 mmol). The mixture was stirred
vigorously for 30 min, then purified via preparative reverse-phase
HPLC (25-98% MeCN in H.sub.2O) to yield
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylamino)propanoic
acid), as an inseparable mixture of diastereomers. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.91 (d, J=1.7 Hz, 2H), 7.47 (t,
J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.12-7.06 (m, 2H), 5.60 (s,
4H), 4.95-4.91 (m, 2H), 4.07 (d, J=2.7 Hz, 6H), 3.26-3.10 (m, 4H),
2.82 (s, 12H), 2.09 (d, J=4.0 Hz, 6H). LCMS-ESI+ (m/z): [M+H].sup.+
calculated for C.sub.38H.sub.45Cl.sub.2N.sub.4O.sub.8: 755.26;
found: 755.33.
Example 237:
(3S,3'S)-4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-chloro-2-methoxynicotinoyl))bis(azanediyl))bis(3-hydr-
oxybutanoic acid)
##STR00479##
[2161] To a slurry of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) (390 mg, 0.67 mmol) and
2-methyl-2-butene (1.28 mL, 12.1 mmol) in tBuOH/THF (2:3 v/v, 50
mL) was added a solution of NaClO.sub.2 (728 mg, 8.05 mmol) and
NaH.sub.2PO.sub.4 (1.21 g, 10.1 mmol) in H.sub.2O (20 mL). The
mixture was stirred at rt for 16 h, then diluted with EtOAc (50
mL), washed with NH.sub.4Cl (3.times.50 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
column chromatography (SiO.sub.2, 0-13% MeOH in CH.sub.2Cl.sub.2)
to yield
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinic acid) as a solid.
[2162]
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-chloro-2-methoxynicotinic acid) (389 mg, 0.63 mmol),
methyl (S)-4-amino-3-hydroxybutanoate (253 mg, 2 mmol), HATU (579
mg, 2 mmol), and DIPEA (0.74 mL, 3 mmol) were stirred in DMF (20
mL) for 15 min. The mixture was concentrated and the residue
purified by preparative reverse-phase HPLC (35-98% MeCN in
H.sub.2O) to yield dimethyl
4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxynicotinoyl))bis(azanediyl))(3S,3'S)-bis(3-hydr-
oxybutanoate) as a solid.
[2163]
(3S,3'S)-4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(5-chloro-2-methoxynicotinoyl))bis(azanediyl))bis(-
3-hydroxybutanoic acid) was prepared in a similar manner to Example
36, using dimethyl
4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-chloro-2-methoxynicotinoyl))bis(azanediyl))(3S,3'S)-bis(3-hydr-
oxybutanoate) in place of dimethyl
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(3-(dimethylamino)propanoate).
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 8.35 (s, 2H), 7.54
(d, J=7.6 Hz, 2H), 7.30 (t, J=7.6 Hz, 2H), 7.13 (d, J=7.3 Hz, 2H),
5.68 (s, 4H), 4.21 (s, 2H), 4.14 (s, 6H), 3.66-3.55 (m, 2H),
3.50-3.39 (m, 2H), 2.56 (dd, J=15.6, 4.7 Hz, 2H), 2.46 (dd, J=15.7,
7.9 Hz, 2H), 2.12 (s, 6H). LCMS-ESI+ (m/z): [M+H].sup.+ calculated
for C.sub.38H.sub.41Cl.sub.2N.sub.4O.sub.12: 815.21; found:
815.31.
Example 238:
(3S,3'S)-4,4'-(((((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(e-
thene-2,1-diyl))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)-
bis(ethene-2,1-diyl))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(az-
anediyl))bis(3-hydroxybutanoic acid))
##STR00480##
[2165] 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-dicarbaldehyde: To a
solution of (2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)dimethanol
(150 mg, 0.62 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added
Dess-Martin periodinane (630 mg, 1.55 mmol). The mixture was
stirred at rt for 15 min, then diluted with CH.sub.2Cl.sub.2 (10
mL), poured over Na.sub.2S.sub.2O.sub.3 (1 M aq., 10 mL), and
washed with NaHCO.sub.3 (saturated aq., 2.times.10 mL). The
organics were dried (MgSO.sub.4) and concentrated, and the residue
purified via column chromatography (SiO.sub.2, 0-25% EtOAc in
hexane) to yield the product as a solid.
[2166] 2,2'-dimethyl-3,3'-divinyl-1,1'-biphenyl: To a slurry of
methyl triphenylphosphonium bromide (19.9 g, 53 mmol) in THF (50
mL) at 0.degree. C. was added n-BuLi (1.8 M in hexane, 29 mL, 53
mmol) dropwise. The mixture was stirred for 30 min, then
2,2'-dimethyl-[1,1'-biphenyl]-3,3'-dicarbaldehyde (4.85 g, 20 mmol)
in THF (25 mL) was added dropwise. The mixture was allowed to warm
to rt and stirred 12 h, then diluted with Et.sub.2O (400 mL),
washed with NH.sub.4Cl (saturated aq., 300 mL). The organics were
dried (MgSO.sub.4) and concentrated, and the residue purified via
column chromatography (SiO.sub.2, hexane) to yield the product as a
solid.
[2167] 2-methoxy-6-vinylnicotinaldehyde: A mixture of
6-chloro-2-methoxynicotinaldehyde (2.69 g, 16 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.22 mL, 39 mmol),
palladium tetrakis(triphenylphosphine) (287 mg, 0.78 mmol), and
Na.sub.2CO.sub.3 (4.99 g, 47 mmol) in dioxane (20 mL) and H.sub.2O
(4 mL) were subjected to 3 vacuum/argon cycles, and then heated to
80.degree. C. for 12 h. The mixture was cooled to rt, filtered over
Celite, and concentrated. The residue was purified via column
chromatography (SiO.sub.2, 0-15% EtOAc in hexane) to yield the
product as an oil.
[2168]
6,6'-((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(ethene--
2,1-diyl))bis(2-methoxynicotinaldehyde): A mixture of
2,2'-dimethyl-3,3'-divinyl-1,1'-biphenyl (500 mg, 2 mmol) and
2-methoxy-6-vinylnicotinaldehyde (870 mg, 5 mmol) in
1,2-dichloroethane (20 mL) was sparged with argon for 15 min. Then,
Hoveyda-Grubbs Second Generation Metathesis Catalyst (267 mg, 0.427
mmol) was added, and the mixture was heated to reflux for 20 h. The
mixture was concentrated and the residue purified by column
chromatography (SiO.sub.2, 0-30% EtOAc in hexane) to yield the
product as a solid.
[2169]
(3S,3'S)-4,4'-(((((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl-
)bis(ethene-2,1-diyl))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(a-
zanediyl))bis(3-hydroxybutanoic acid) was prepared in a similar
manner to Example 226, using (S)-4-amino-3-hydroxybutanoic acid in
place of (1R,2S)-2-aminocyclopentan-1-ol, and using
6,6'-((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(ethene-2,1-di-
yl))bis(2-methoxynicotinaldehyde) in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde): .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.14 (d, J=15.7 Hz, 1H), 7.75 (d, J=7.5
Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 7.12 (d,
J=5.1 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.25 (s,
2H), 4.10 (s, 3H), 3.24 (dd, J=12.7, 3.0 Hz, 1H), 3.03 (dd, J=12.7,
9.8 Hz, 1H), 2.56 (d, J=6.3 Hz, 2H), 2.15 (s, 3H). LCMS-ESI+ (m/z):
[M+H].sup.+ calculated for C.sub.40H.sub.47N.sub.4O.sub.8: 711.34;
found: 711.03.
Example 239:
(3S,3'S)-4,4'-(((((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(e-
thene-2,1-diyl))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bi-
s(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)-
bis(ethene-2,1-diyl))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00481##
[2171] 5-chloro-2-methoxy-6-vinylnicotinaldehyde: A mixture of
5,6-dichloro-2-methoxynicotinaldehyde (1.4 g, 6.7 mmol),
tributyl(vinyl)tin (2.2 mL, 7.4 mmol), LiCl (346 mg, 8.04 mmol),
and palladium tetrakis(triphenylphosphine) (550 mg, 0.48 mmol) in
dioxane (30 mL) was sparged with argon for 15 min. The mixture was
heated to 95.degree. C. for 24 h, then cooled to rt, filtered over
celite, and concentrated. The residue was taken up in
CH.sub.2Cl.sub.2 (30 mL) and washed with KF (saturated aq.,
3.times.20 mL). The organics were dried (MgSO.sub.4), concentrated,
and the residue purified via column chromatography (SiO.sub.2,
0-30% EtOAc in hexane) to yield the product as a solid.
[2172]
(3S,3'S)-4,4'-(((((1E,1'E)-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl-
)bis(ethene-2,1-diyl))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid) was prepared in a
similar manner to Example 238, using
5-chloro-2-methoxy-6-vinylnicotinaldehyde instead of
2-methoxy-6-vinylnicotinaldehyde. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.32 (d, J=15.4 Hz, 2H), 7.86 (s, 2H),
7.73 (d, J=7.9 Hz, 2H), 7.49 (d, J=15.4 Hz, 2H), 7.32 (t, J=7.7 Hz,
2H), 7.12 (d, J=7.2 Hz, 2H), 4.32 (dtd, J=8.0, 5.7, 5.0, 2.4 Hz,
2H), 4.25 (s, 4H), 4.11 (s, 6H), 3.26 (dd, J=12.8, 2.9 Hz, 2H),
3.05 (dd, J=12.7, 9.8 Hz, 2H), 2.56 (d, J=6.3 Hz, 4H), 2.17 (s,
6H). LCMS-ESI+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.45Cl.sub.2N.sub.4O.sub.8: 779.26; found: 779.01.
Example 240:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00482##
[2174] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1081.8. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.91 (dd, J=28.7, 2.1 Hz, 5H), 8.33
(s, 2H), 7.40 (d, J=7.6 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.08 (d,
J=7.5 Hz, 2H), 5.61 (s, 2H), 5.48 (s, 6H), 4.24 (s, 4H), 3.47 (s,
2H), 3.26-3.21 (m, 2H), 3.12 (s, 2H), 3.04 (d, J=10.0 Hz, 2H), 2.54
(d, J=6.3 Hz, 4H), 2.04 (s, 4H).
Example 241:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-iodo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-iodo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
azanediyl))bis(3-hydroxybutanoic acid))
##STR00483##
[2176] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=971.6. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.09 (s, 2H), 7.49 (d, J=7.5 Hz, 2H),
7.24 (t, J=7.6 Hz, 2H), 7.11-7.05 (m, 2H), 5.55 (s, 4H), 4.31-4.22
(m, 2H), 4.14 (s, 4H), 4.05 (s, 6H), 3.20 (dd, J=12.7, 3.1 Hz, 2H),
2.99 (dd, J=12.7, 9.9 Hz, 2H), 2.54 (d, J=6.3 Hz, 4H), 2.12 (s,
6H).
Example 242:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))bis(meth-
ylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))bis-
(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00484##
[2178] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=769.8. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.06 (s, 2H), 7.50 (d, J=7.8 Hz, 2H),
7.27 (t, J=7.77 (dd,J=8.1, 5.8 Hz, 2H), 7.38 (dd,J=17.4, 7.6
Hz,2H), 7.28-7.20(m, 2H), 7.0-7.03 (m, 2H), 6.58 (dd. J=15.5. 8.1
Hz. 2H), 5.63-5.55 (m, 1H), 5.54-5.35 (m, 3H), 4.30-4.20 (m, 4H).
3.49-3.46 (m, 2H), 3.25-2.80 (m, 9H), 2.54 (d,J=6.4 Hz, 2HO,
2.49-2.45 (m, 2H), 2.01 (d, J=16.2 Hz, 6H).
Example 243:
(3S,3'S)-4,4,-((((((2,2',-dimethyl-[1,1'-biphenyl]-3,3'-diyl)
bis(methylene))bis(oxy))bis(5-cyano-2-methoxypyridine-6,3-diyl))
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,
1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(5-cyano-2-methoxypyrid-
ine-6,3-diyl)) bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00485##
[2180] The title compound was synthesized according to general
reductive animation procedure C. [M+1]=769.8. .sup.1H NMR (400 MHz,
Methanool-ds).delta.8.06 (s, 2H), 7.50 (d, J=7.8 Hz, 2H). 7.27 (t,
J=7.6 Hz, 2H), 7.10 (dd, J=7.5, 1.3 Hz, 2H), 5.67 (s, 4H),
4.33-4.25 (m, 2H), 4.18 (s, 4H), 4.14 (s, 6H), 3.23 (dd, J=12.8,
3.0 Hz, 2H), 3.02 (dd, J=12.8, 9.9 Hz, 2H), 2.55 (d, J=6.3 Hz, 4H),
2.11 (s, 6H).
Example 244:
(3S,3'S)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(pyrro-
lidin-3-ol) (or
(3S,3'S)-1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
pyrrolidin-3-ol))
##STR00486##
[2182] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=813.6. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.00 (s, 2H), 7.49 (d, J=7.6 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.6 Hz, 2H), 5.59 (s, 4H),
4.55-4.50 (m, 2H), 4.33 (d, J=37.0 Hz, 4H), 4.06 (d, J=3.3 Hz, 6H),
3.74-3.40 (m, 7H) 3.25-3.10 (m, 4H), 2.10 (s, 7H).
Example 245:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)-6-methoxy-4,1-phenylene))b-
is(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00487##
[2184] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=982.1. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.91 (dd, J=13.5, 2.0 Hz, 4H), 8.35 (t,
J=2.1 Hz, 2H), 7.44 (d, J=7.6 Hz, 2H), 7.26 (t, J=7.6 Hz, 2H),
7.17-7.01 (m, 2H), 6.65-6.34 (m, 4H), 5.25 (d, J=35.1 Hz, 6H), 4.28
(s, 4H), 3.91 (s, 6H), 3.14 (dd, J=12.9, 3.1 Hz, 2H), 2.93 (dd,
J=12.8, 10.0 Hz, 2H), 2.50 (dd, J=6.3, 1.7 Hz, 4H), 2.05 (s,
6H).
Example 246:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)-6-methyl-4,1-phenylene))bi-
s(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00488##
[2186] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=950.1. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.91 (dd, J=13.5, 2.0 Hz, 4H), 8.35 (t,
J=2.1 Hz, 2H), 7.44 (d, J=7.6 Hz, 2H), 7.26 (t, J=7.6 Hz, 2H),
7.14-7.03 (m, 2H), 6.58-6.40 (m, 4H), 5.24 (d, J=35.1 Hz, 6H), 4.28
(s, 4H), 3.95 (s, 6H), 3.14 (dd, J=12.9, 3.1 Hz, 2H), 2.90 (dd,
J=12.8, 10.0 Hz, 2H), 2.50 (dd, J=6.3, 1.7 Hz, 4H), 2.02 (s,
6H).
Example 247:
(3R,3'R)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(pyrro-
lidin-3-ol) (or
(3R,3'R)-1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
pyrrolidin-3-ol))
##STR00489##
[2188] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=813.6. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.00 (s, 2H), 7.49 (d, J=7.6 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.6 Hz, 2H), 5.59 (s, 4H),
4.55-4.50 (m, 2H), 4.33 (d, J=37.0 Hz, 4H), 4.06 (d, J=3.3 Hz, 6H),
3.74-3.40 (m, 7H) 3.25-3.10 (m, 4H), 2.10 (s, 7H).
Example 248:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00490##
[2190] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=922.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.55-8.40 (m, 6H), 7.45 (d, J=7.6 Hz,
2H), 7.38 (d, J=8.4 Hz, 2H), 7.27 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.5
Hz, 2H), 6.88 (d, J=2.3 Hz, 2H), 6.77 (dd, J=8.4, 2.2 Hz, 2H), 5.28
(s, 4H), 5.17 (s, 4H), 4.20-4.05 (m, 6H), 3.05-2.75 (m, 4H),
2.55-2.45 (m, 4H), 1.99 (s, 6H).
Example 249:
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-bromo-2-methoxypyridine-6,3-diyl))dimorpholine (or
3,3'-(6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))dimorpholine)
##STR00491##
[2192] To a 2-dram vial was added
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-bromo-2-methoxynicotinaldehyde) (100 mg, 0.15 mmol),
2-((tributylstannyl)methoxy)ethan-1-amine (55 mg, 0.15 mmol, 1.0
equiv), 4 Angstrom molecular sieves (15 mg), and methylene chloride
(1.0 mL, 0.15M) at room temperature. The mixture was stirred for 2
hours. In a separate vial was added copper(II) triflate (54 mg,
0.15 mmol, 1.0 equiv), 2,6-lutidine (18 OL, 0.15 mmol, 1.0 equiv),
methylene chloride (1.0 mL), and hexafluoro-2-propanol (0.6 mL) at
room temperature. The mixture was stirred for 2 hours. To the
solution of copper was added the suspension of tin reagent (after
filtering off the molecular sieves) dropwise, and the resulting
mixture was stirred overnight at room temperature. The suspension
was diluted with N,N-dimethylformamide and loaded directly onto a
reverse phase preparative HPLC to yield
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))-
bis(5-bromo-2-methoxypyridine-6,3-diyl))dimorpholine. [M+1]=785.5.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.96 (s, 2H), 7.47
(dd, J=7.4, 1.3 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.07 (dd, J=7.7,
1.4 Hz, 2H), 5.58 (s, 4H), 4.57 (dd, J=9.7, 3.9 Hz, 2H), 4.18-3.93
(m, 12H), 3.83 (ddd, J=13.3, 9.3, 4.3 Hz, 2H), 3.36 (d, J=3.5 Hz,
4H), 2.09 (s, 6H).
Example 250:
N,N'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(2-(5-cyanopyridin-3-yl)-4,1-phenylene))bis(methylene))bis(azanediyl-
))bis(ethane-2,1-diyl))diacetamide
##STR00492##
[2194] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=828.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=1.9 Hz, 2H), 8.82 (d, J=2.1
Hz, 2H), 8.25 (t, J=2.1 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.48-7.36
(m, 2H), 7.34-7.19 (m, 4H), 7.14-6.98 (m, 4H), 5.23 (s, 4H), 4.16
(s, 4H), 3.35 (t, J=5.6 Hz, 4H), 3.04 (t, J=5.6 Hz, 4H), 2.03 (s,
6H), 1.94 (s, 6H).
Example 251:
(S)-4-(((6-((3'-(((5-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-1-((5-
-cyanopyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridin-2-yl)oxy)methyl)-2,2'--
dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)pyr-
idin-3-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00493##
[2196] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=924.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.92-8.80 (m, 3H), 8.20 (dd, J=48.0 Hz,
2H), 7.75 (dd, J=8.0, 5.8 Hz, 2H), 7.38 (dd, J=17.4, 7.6 Hz, 2H),
7.28-7.20 (m, 2H), 7.09-7.00 (m, 2H), 6.58 (dd, J=15.5, 8.1 Hz,
2H), 5.63-5.55 (m, 1H), 5.54-5.35 (m, 3H), 4.30-4.20 (m, 4H),
3.49-3.46 (m, 2H), 3.25-2.80 (m, 9H), 2.54 (d, J=6.4 Hz, 2H),
2.49-2.45 (m, 2H), 2.01 (d, J=16.2 Hz, 6H).
Example 252:
(3R,3'R)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-diyl))-
bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3R,3'R)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((5-cyanopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00494##
[2198] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1081.8. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.91 (dd, J=28.7, 2.1 Hz, 5H), 8.33
(s, 2H), 7.40 (d, J=7.6 Hz, 2H), 7.23 (t, J=7.6 Hz, 2H), 7.08 (d,
J=7.5 Hz, 2H), 5.61 (s, 2H), 5.48 (s, 6H), 4.24 (s, 4H), 3.47 (s,
2H), 3.26-3.21 (m, 2H), 3.12 (s, 2H), 3.04 (d, J=10.0 Hz, 2H), 2.54
(d, J=6.3 Hz, 4H), 2.04 (s, 4H).
Example 253:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((6-methoxypyridin-3-yl)methoxy)pyridine-6,3-diyl-
))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((6-methoxypyridin-3-yl)methoxy)pyridine-6,3-
-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00495##
[2200] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1091.8. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.94-8.79 (m, 3H), 8.24 (dd, J=48.8
Hz, 2H), 7.77 (dd, J=8.1, 5.8 Hz, 2H), 7.38 (dd, J=17.0, 7.5 Hz,
2H), 7.28-7.20 (m, 2H), 7.00-7.03 (m, 2H), 6.49 (dd, J=15.4, 8.1
Hz, 2H), 5.63-5.55 (m, 1H), 5.54-5.35 (m, 3H), 4.30-4.19 (m, 4H),
3.49-3.46 (m, 2H), 3.25-2.80 (m, 9H), 2.54 (d, J=6.4 Hz, 2H),
2.49-2.45 (m, 2H), 1.98 (d, J=16.2 Hz, 6H).
Example 254:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-(((2-hydroxyethyl)amino)methyl)-3,1-phenylene))bis(oxy))bi-
s(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-2-(((2-hydroxyethyl)amino)methyl)-5,1-phenylene))bis(oxy))bi-
s(methylene))dinicotinonitrile)
##STR00496##
[2202] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=103.3. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.94 (dd, J=7.2, 2.0 Hz, 4H), 8.29
(t, J=2.1 Hz, 2H), 7.62 (s, 2H), 7.57-7.48 (m, 2H), 7.33 (t, J=7.6
Hz, 2H), 7.18 (dd, J=7.7, 1.4 Hz, 2H), 6.94 (s, 2H), 5.30 (d, J=7.8
Hz, 8H), 4.21 (s, 4H), 3.75-3.67 (m, 4H), 3.08 (d, J=6.6 Hz, 4H),
2.11 (s, 6H).
Example 255:
1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azetidin-3-ol)
(or
1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azeti-
din-3-ol))
##STR00497##
[2204] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=785.5. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.96 (s, 2H), 7.48 (d, J=7.3 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.7, 1.4 Hz, 2H), 5.58 (s, 4H),
4.63-4.53 (m, 2H), 4.35-4.45 (m, 8H), 4.10-4.00 (m, 10H), 2.09 (s,
6H).
Example 256:
1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(N-methylazetid-
ine-3-carboxamide) (or
1,1'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(N-methyla-
zetidine-3-carboxamide))
##STR00498##
[2206] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=867.6. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.96 (s, 2H), 7.48 (d, J=7.2 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.08 (dd, J=7.7, 1.4 Hz, 2H), 5.58 (s, 4H),
4.63-4.53 (m, 2H), 4.35-4.45 (m, 8H), 4.15-4.05 (m, 10H), 3.52 (s,
6H), 2.05 (s, 6H).
Example 257:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-((((R)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bi-
s(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((R)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(4-bromo-2-((((R)-2,3-dihydroxypropyl)amino)methyl)-5,1-phenylene-
))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00499##
[2208] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1023.8. .sup.1H NMR (400
MHz, Acetonitrile-d.sub.3) .delta. 8.98-8.84 (m, 4H), 8.28 (s, 2H),
7.62 (d, J=6.0 Hz, 2H), 7.54 (d, J=7.6 Hz, 2H), 7.33 (t, J=7.6 Hz,
2H), 7.18 (d, J=7.5 Hz, 2H), 6.93 (s, 2H), 5.30 (d, J=6.9 Hz, 8H),
4.21 (d, J=10.3 Hz, 4H), 3.53 (s, 4H), 3.09 (d, J=38.5 Hz, 6H),
2.08 (s, 6H).
Example 258:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-(((R)-2-(hydroxymethyl)azetidin-1-yl)methyl)-3,1-phenylene-
))bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((R)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(4-bromo-2-(((R)-2-(hydroxymethyl)azetidin-1-yl)methyl)-5,1-pheny-
lene))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00500##
[2210] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1015.8. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.03 (dd, J=6.5, 2.0 Hz, 4H), 8.50 (s,
2H), 7.69 (s, 2H), 7.52 (d, J=7.6 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H),
7.18 (s, 2H), 7.16-6.99 (m, 2H), 5.37 (s, 4H), 5.31 (s, 4H),
4.53-4.12 (m, 6H), 3.92 (d, J=8.2 Hz, 2H), 3.77 (t, J=6.9 Hz, 2H),
3.55 (d, J=5.6 Hz, 4H), 2.21 (q, J=8.4 Hz, 4H), 2.03 (s, 6H).
Example 259:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-((((S)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bi-
s(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(4-bromo-2-((((S)-2,3-dihydroxypropyl)amino)methyl)-5,1-phenylene-
))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00501##
[2212] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1023.8. .sup.1H NMR (400
MHz, Acetonitrile-d.sub.3) .delta. 8.98-8.84 (m, 4H), 8.28 (s, 2H),
7.62 (d, J=6.0 Hz, 2H), 7.54 (d, J=7.6 Hz, 2H), 7.33 (t, J=7.6 Hz,
2H), 7.18 (d, J=7.5 Hz, 2H), 6.93 (s, 2H), 5.30 (d, J=6.9 Hz, 8H),
4.21 (d, J=10.3 Hz, 4H), 3.53 (s, 4H), 3.09 (d, J=38.5 Hz, 6H),
2.08 (s, 6H).
Example 260:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-(((S)-2-(hydroxymethyl)azetidin-1-yl)methyl)-3,1-phenylene-
))bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(4-bromo-2-(((S)-2-(hydroxymethyl)azetidin-1-yl)methyl)-5,1-pheny-
lene))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00502##
[2214] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1015.8. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.03 (dd, J=6.5, 2.0 Hz, 4H), 8.50 (s,
2H), 7.69 (s, 2H), 7.52 (d, J=7.6 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H),
7.18 (s, 2H), 7.16-6.99 (m, 2H), 5.37 (s, 4H), 5.31 (s, 4H),
4.53-4.12 (m, 6H), 3.92 (d, J=8.2 Hz, 2H), 3.77 (t, J=6.9 Hz, 2H),
3.55 (d, J=5.6 Hz, 4H), 2.21 (q, J=8.4 Hz, 4H), 2.03 (s, 6H).
Example 261:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(6-((((1H-imidazol-2-yl)methyl)amino)methyl)-4-bromo-3,1-phenylene))b-
is(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-((((1H-imidazol-2-yl)methyl)amino)methyl)-4-bromo-5,1-phenylene))b-
is(oxy))bis(methylene))dinicotinonitrile)
##STR00503##
[2216] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1035.8. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.09-8.89 (m, 4H), 8.43 (s, 2H), 7.68
(s, 2H), 7.51 (d, J=7.6 Hz, 2H), 7.36-7.19 (m, 6H), 7.15 (s, 2H),
7.10 (d, J=7.6 Hz, 2H), 5.32 (d, J=15.7 Hz, 8H), 4.15 (d, J=11.4
Hz, 8H), 2.03 (s, 6H).
Example 262:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-(thiazol-2-ylmethoxy)-4,1-phenylene))bis(methyle-
ne))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00504##
[2218] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=952.9. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 7.83 (d, J=3.3 Hz, 2H), 7.59 (d,
J=2.8 Hz, 2H), 7.50 (d, J=7.6 Hz, 2H), 7.44 (s, 2H), 7.30 (t, J=7.6
Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 7.07 (s, 2H), 5.67 (s, 4H), 5.25
(s, 4H), 4.29 (d, J=43.0 Hz, 6H), 3.14 (d, J=52.2 Hz, 4H), 2.53 (t,
J=7.8 Hz, 4H), 2.05 (s, 6H).
Example 263:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-methoxy-5-(methylsulfonyl)pyridine-6,3-diyl))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxy-5-(methylsulfonyl)pyridine-6,3-diyl))bis(met-
hylene))bis(azanediyl))bis(3-hydroxybutanoic acid))
##STR00505##
[2220] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=875.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.21 (s, 2H), 7.50 (d, J=7.5 Hz, 2H),
7.28 (t, J=7.6 Hz, 2H), 7.11-7.00 (m, 2H), 5.55 (s, 4H), 4.31-4.22
(m, 2H), 4.14 (s, 4H), 4.05 (s, 6H), 3.20 (dd, J=12.7, 3.1 Hz, 2H),
3.01 (s, 6H), 2.99 (dd, J=12.7, 9.9 Hz, 2H), 2.54 (d, J=6.3 Hz,
4H), 2.12 (s, 6H).
Example 264:
2,2'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(ethane-2,1-diyl))bis(isothiazolidine 1,1-dioxide) (or
2,2'-((((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(ethane-2,1-diyl))bis(isothiazolidine 1,1-dioxide))
##STR00506##
[2222] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=967.8. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.95 (s, 2H), 7.52-7.42 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.13-7.02 (m, 2H), 5.58 (s, 4H), 4.18 (s, 4H), 4.06
(s, 6H), 3.54-3.03 (m, 8H), 2.37 (p, J=6.9 Hz, 4H), 2.09 (s,
6H).
Example 265:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((5-cyano-2-fluorobenzyl)oxy)-4,1-phenylene))bis(methylen-
e))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00507##
[2224] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=956.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.92 (dd, J=6.1, 2.3 Hz, 2H), 7.89-7.82
(m, 2H), 7.46-7.32 (m, 6H), 7.25 (t, J=7.6 Hz, 2H), 7.11-7.05 (m,
2H), 6.82 (d, J=2.3 Hz, 2H), 6.76 (dd, J=8.4, 2.3 Hz, 2H), 5.22 (s,
4H), 5.17 (s, 4H), 4.23 (s, 6H), 3.18 (dd, J=12.7, 3.0 Hz, 2H),
2.96 (dd, J=12.7, 9.8 Hz, 2H), 2.51 (dd, J=6.4, 2.5 Hz, 4H), 2.03
(s, 6H).
Example 266:
N,N'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(ox-
y))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))b-
is(ethane-2,1-diyl))dimethanesulfonamide (or
N,N'-((((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(ethane-2,1-diyl))dimethanesulfonamide)
##STR00508##
[2226] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=915.7. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.94 (s, 2H), 7.53-7.39 (m, 2H), 7.24 (t,
J=7.6 Hz, 2H), 7.07 (dd, J=7.8, 1.4 Hz, 2H), 5.58 (s, 4H), 4.17 (s,
4H), 4.06 (s, 6H), 3.41 (t, J=5.8 Hz, 4H), 3.18 (t, J=5.8 Hz, 4H),
3.00 (s, 6H), 2.09 (s, 6H).
Example 267:
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-((5-cyanopyridi-
n-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-
butanoic acid)
##STR00509##
[2228] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=972.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.50-8.39 (m, 6H), 7.44 (d, J=7.6 Hz,
2H), 7.38 (d, J=8.4 Hz, 2H), 7.20 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.5
Hz, 2H), 6.89 (d, J=2.3 Hz, 2H), 6.65 (dd, J=8.4, 2.2 Hz, 2H), 5.26
(s, 4H), 4.25-4.01 (m, 10H), 3.64 (t, J=5.4 Hz, 4H), 3.05-2.75 (m,
4H), 2.55-2.45 (m, 4H).
Example 268:
N,N'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(N-methyl-2-mor-
pholinoethan-1-amine) (or
N,N'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(N-methyl--
2-morpholinoethan-1-amine))
##STR00510##
[2230] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=927.8. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.98 (s, 2H), 7.48 (d, J=7.6 Hz, 2H),
7.25 (t, J=7.6 Hz, 2H), 7.16-6.99 (m, 2H), 5.60 (s, 4H), 4.23 (s,
4H), 4.06 (s, 6H), 3.70 (t, J=4.8 Hz, 6H), 3.47 (dd, J=3.3, 1.6 Hz,
2H), 3.26 (d, J=6.2 Hz, 4H), 3.12 (t, J=1.6 Hz, 2H), 2.88 (t, J=5.9
Hz, 2H), 2.82 (s, 4H), 2.63 (s, 6H), 2.10 (s, 6H).
Example 269:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-((6-morpholinopyridin-3-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-((6-morpholinopyridin-3-yl)methoxy)pyridine--
6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid))
##STR00511##
[2232] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1202.0. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.19 (d, J=2.1 Hz, 2H), 8.11 (dd,
J=9.4, 2.2 Hz, 2H), 8.01 (s, 2H), 7.54-7.43 (m, 2H), 7.35-7.20 (m,
4H), 7.13-7.02 (m, 2H), 5.56 (d, J=2.1 Hz, 2H), 5.48 (s, 4H), 4.19
(s, 2H), 3.92-3.79 (m, 6H), 3.70-3.52 (m, 10H), 3.22-3.10 (m, 4H),
3.03-2.90 (m, 2H), 2.50 (d, J=7.6 Hz, 2H), 2.09 (s, 4H), 1.28 (s,
8H).
Example 270:
4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy)-
)bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(piperazin-2-on-
e) (or
4,4'-((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylen-
e))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(pip-
erazin-2-one))
##STR00512##
[2234] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=839.6. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.95 (s, 2H), 7.48 (d, J=7.6 Hz, 2H),
7.25 (t, J=7.7 Hz, 2H), 7.08 (d, J=7.5 Hz, 2H), 5.58 (s, 4H), 5.48
(s, 2H), 4.11 (s, 4H), 4.04 (s, 4H), 3.63 (s, 4H), 3.57 (s, 2H),
3.47 (t, J=1.6 Hz, 4H), 3.12 (t, J=1.7 Hz, 2H), 2.09 (s, 6H).
Example 271:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-
-ol) (or
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methy-
lene))bis(oxy))bis(2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl-
))bis(ethan-1-ol))
##STR00513##
[2236] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=631.8. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.74 (d, J=8.1 Hz, 2H), 7.40 (dd, J=7.8, 1.4
Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.03 (dd, J=7.7, 1.4 Hz, 2H), 6.51
(d, J=8.1 Hz, 2H), 5.41 (s, 4H), 4.35 (qd, J=7.0, 1.7 Hz, 4H), 4.02
(t, J=5.2 Hz, 4H), 3.63 (t, J=5.3 Hz, 4H), 3.09-2.83 (m, 4H), 1.98
(s, 6H), 1.30 (t, J=7.0 Hz, 6H).
Example 272:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-(5-cyanopyridin-3-yl)-4,1-phenylene))bis(methylene))bis(a-
zanediyl))bis(3-hydroxybutanoic acid)
##STR00514##
[2238] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=862.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.0 Hz, 2H), 8.83 (d, J=2.2
Hz, 2H), 8.26 (t, J=2.1 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.44 (d,
J=7.7 Hz, 2H), 7.34-7.19 (m, 4H), 7.15-7.03 (m, 4H), 5.23 (s, 4H),
4.18 (d, J=5.4 Hz, 2H), 4.15-4.02 (m, 2H), 3.61-3.43 (m, 2H),
3.17-3.02 (m, 2H), 2.86 (dd, J=13.0, 9.6 Hz, 2H), 2.46 (d, J=6.3
Hz, 4H), 2.03 (s, 6H).
Example 273:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(2-((1H-benzo[d]imidazol-2-yl)methoxy)-5-chloro-4,1-phenylen-
e))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00515##
[2240] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1018.9. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.56 (dd, J=5.9, 3.3 Hz, 4H), 7.51 (s,
2H), 7.42 (d, J=7.4 Hz, 2H), 7.32 (s, 2H), 7.23-7.10 (m, 6H), 7.01
(d, J=7.6 Hz, 2H), 5.58 (s, 4H), 5.25 (s, 4H), 4.15 (s, 6H), 3.03
(d, J=12.3 Hz, 2H), 2.92-2.76 (m, 2H), 2.33 (dd, J=15.9, 7.4 Hz,
4H), 1.95 (s, 6H).
Example 274:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azan-
ediyl))bis(3-hydroxy-N,2-dimethylpropanamide) (or
(2S,2'S)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(5-bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis-
(azanediyl))bis(3-hydroxy-N,2-dimethylpropanamide))
##STR00516##
[2242] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=903.7.
Example 275:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-bromo-6-(((pyridin-2-ylmethyl)amino)methyl)-3,1-phenylene))bis(oxy-
))bis(methylene))dinicotinonitrile
##STR00517##
[2244] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=1057.8. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.02 (dd, J=12.5, 2.1 Hz, 4H), 8.53 (d,
J=5.0 Hz, 2H), 8.43 (t, J=2.0 Hz, 2H), 7.82 (td, J=7.8, 1.8 Hz,
2H), 7.69 (s, 2H), 7.52 (d, J=7.7 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H),
7.37 (dd, J=7.5, 5.0 Hz, 2H), 7.29 (t, J=7.6 Hz, 2H), 7.15 (s, 2H),
7.11 (d, J=7.5 Hz, 2H), 5.33 (d, J=11.6 Hz, 8H), 4.24 (d, J=34.5
Hz, 8H), 2.04 (s, 6H).
Example 276:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)methyl)-3,1-
-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((R)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis-
(oxy))bis(4-chloro-2-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)methyl)-
-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00518##
[2246] The title compound was synthesized according to general
reductive amination procedure E. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.02 (m, 4H), 8.89 (m, 4H), 8.48 (d, J=2.1
Hz, 2H), 7.56 (s, 2H), 7.50 (d, J=7.6 Hz, 2H), 7.29 (t, J=7.6 Hz,
2H), 7.20 (s, 2H), 7.11 (d, J=7.6 Hz, 2H), 5.35 (m, 8H), 4.62-4.37
(m, 2H), 4.19 (s, 4H), 3.27 (m 4H), 2.02 (s, 6H), 1.09 (s, 12H).
ES/MS m/z: 993.5 (M+H.sup.+).
Example 277:
5-((4-chloro-5-((3'-((2-chloro-4-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)-
amino)methyl)-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-
methoxy)-2-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)methyl)phenoxy)me-
thyl)nicotinonitrile
##STR00519##
[2248] The title compound was isolated as by-product of Example
276. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd, J=6.6,
2.0 Hz, 2H), 8.85 (s, 4H), 8.48 (t, J=2.1 Hz, 1H), 7.56 (s, 1H),
7.49 (dd, J=7.6, 2.6 Hz, 2H), 7.44 (s, 1H), 7.29 (td, J=7.5, 4.8
Hz, 2H), 7.21 (s, 1H), 7.10 (d, J=7.5 Hz, 2H), 6.83 (s, 1H), 5.35
(d, J=14.4 Hz, 3H), 5.19 (s, 2H), 4.52 (ddd, J=48.7, 15.4, 8.9 Hz,
2H), 4.19 (s, 2H), 4.08 (s, 2H), 3.27 (d, J=45.4 Hz, 4H), 2.09-1.91
(m, 6H), 1.10 (2.times.s, 12H). ES/MS m/z: 877.6 (M+H.sup.+).
Example 278:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(difluorom-
ethylene))bis(4,1-phenylene))bis(methylene))bis(azanediyl))diacetic
acid
##STR00520##
[2250] 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diol and sodium hydride
(60%) were dissolved in DMF. After 5 minutes added
1-bromo-4-(bromodifluoromethyl)benzene neat. Stirring at room
temperature was continued. After 2 hrs, the reaction was heated at
60.degree. C. After 19 hrs, the reaction mixture was cooled to room
temperature. EtOAc was added and the reaction was washed with brine
and dried over sodium sulfate. Filtration and evaporation of
solvents gave
3,3'-bis((4-bromophenyl)difluoromethoxy)-2,2'-dimethyl-1,1'-biphenyl,
which was purified via chromatography on silica gel (el.:
EtOAc/hex). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.77 (d,
J=8.6 Hz, 4H), 7.71 (d, J=8.6 Hz, 4H), 7.48-7.23 (m, 4H), 7.05 (dd,
J=6.8, 2.0 Hz, 2H), 1.87 (s, 6H).
[2251] A reaction vessel was charged with
3,3'-bis((4-bromophenyl)difluoromethoxy)-2,2'-dimethyl-1,1'-biphenyl
(500 mg, 0.8 mmol), potassium vinyl trifluoro borate (227 mg, 2.4
mmol), Pd-dppf (140 mg, 0.2 mmol), cesium carbonate (298 mg, 4.8
mmol), DME and water and was heated at 90.degree. C. for 2 hrs. The
reaction was cooled to room temperature. The volatiles were removed
and the crude was purified via Flash chromatography on silica gel
(el EtOAc hex) to yield
3,3'-bis(difluoro(4-vinylphenyl)methoxy)-2,2'-dimethyl-1,1'-biphenyl.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.72 (d, J=8.1 Hz, 4H),
7.50 (d, J=8.1 Hz, 4H), 7.37 (dd, J=8.3, 1.6 Hz, 2H), 7.26-7.18 (m,
2H), 7.02 (dd, J=7.7, 1.3 Hz, 2H), 6.76 (dd, J=17.6, 10.9 Hz, 2H),
5.83 (dd, J=17.6, 0.8 Hz, 2H), 5.35 (dd, J=10.9, 0.8 Hz, 2H), 1.98
(s, 6H).
[2252]
3,3'-bis(difluoro(4-vinylphenyl)methoxy)-2,2'-dimethyl-1,1'-bipheny-
l (150 mg, 0.29 mmol) was dissolved in THF/water. Osmium tetroxide
(50 uL; 2.5% in tert Butanol) was added followed by lutidine (50
uL) and NaIO.sub.4 (160 mg, 0.75 mmol). The reaction was stirred at
rt for 14 hrs and diluted with EtOAc. The reaction was washed with
aq sodium thiosulfate solution and brine, and was dried over sodium
sulfate. Filtration and evaporation of solvents gave the crude
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(difluorometh-
ylene))dibenzaldehyde which was used in the next step. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 10.11 (s, 2H), 8.08-7.87 (m, 8H),
7.47-7.32 (m, 2H), 7.33-7.24 (m, 6H), 7.05 (dd, J=7.6, 1.3 Hz, 2H),
1.99 (s, 6H).
[2253]
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(dif-
luoromethylene))bis(4,1-phenylene))bis(methylene))bis(azanediyl))diacetic
acid was synthesized according to general reductive amination
procedure E with the appropriate substitutions. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.88 (d, J=8.1 Hz, 4H), 7.67 (d,
J=8.1 Hz, 4H), 7.37 (d, J=8.3 Hz, 2H), 7.29 (t, J=7.9 Hz, 2H), 7.03
(dd, J=7.6, 1.3 Hz, 2H), 4.33 (s, 4H), 3.85 (s, 4H), 1.97 (s, 6H).
ES/MS m/z: 640.9.
Example 279:
(S)-4-((4-(((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)oxy)methyl)benzyl)amino)-3-hydroxybutanoic acid
##STR00521##
[2255] 3-Bromo-2-methylphenol (850 mg, 4.54 mmol) was taken up in
DMF (15 mL) at room temperature under a nitrogen atmosphere. To
this was added sodium hydride 60% dispersion in mineral oil 218.12
mg, 5.45 mmol) and allowed to stir for 15 minutes.
[2256] At this point was added 4-(bromomethyl)benzaldehyde (904.58
mg, 4.54 mmol) and reaction allowed to stir for an additional 15
minutes. Reaction was diluted with EtOAc and quenched slowly with
dilute aq. ammonium chloride. Reaction was extracted 3.times. with
EtOAc and organics were washed with aq. LiCl (2.times.), water,
brine 1.times. then dried over sodium sulfate before filtering and
removing solvents under reduced pressure to afford crude as a
solid.
[2257] Crude was purified by silica gel chromatography using
Hex:EtAc as the eluent to afford
4-((3-bromo-2-methylphenoxy)methyl)benzaldehyde as a solid.
[2258]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (250 mg,
0.48 mmol), 4-((3-bromo-2-methylphenoxy)methyl)benzaldehyde (161.76
mg, 0.53 mmol), Pd(dppf)Cl.sub.2-DCM (49.33 mg, 0.06 mmol),
potassium carbonate (99.31 mg, 1.01 mmol) and 12 mL of 2:1 mixture
of dioxane/water were placed in a microwave vial equipped with stir
bar, sealed and heated in the microwave at 95.degree. C. for 30
minutes. Reaction was diluted in EtAc/H2O and extracted 3.times.
with EtAc. Organics were then washed with ammonium chloride
1.times., water 1.times., brine, then dried over sodium sulfate
before filtering and evaporating organics under reduced pressure to
afford crude residue. Crude material was purified by silica gel
chromatography using Hexanes/EtAc as the eluent (0 to 100% EtAc) to
afford
5-((4-chloro-2-formyl-5-((3'-((4-formylbenzyl)oxy)-2,2'-dimethyl-[-
1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[2259]
(S)-4-((4-(((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)--
2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,-
1'-biphenyl]-3-yl)oxy)methyl)benzyl)amino)-3-hydroxybutanoic acid
was synthesized from
5-((4-chloro-2-formyl-5-((3'-((4-formylbenzyl)oxy)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile using reductive
amination procedure A to afford the desired product as the bis-TFA
salt. MS (m/z) 823.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.02 (dd, J=5.2, 2.0 Hz, 2H), 8.89 (s, 2H),
8.61 (s, 2H), 8.46 (t, J=2.1 Hz, 1H), 7.56 (d, J=3.6 Hz, 1H), 7.53
(s, 3H), 7.47 (dd, J=7.7, 1.4 Hz, 1H), 7.29-7.15 (m, 3H), 7.10-7.02
(m, 2H), 6.70 (d, J=7.5 Hz, 1H), 5.36 (s, 2H), 5.30 (d, J=2.9 Hz,
2H), 5.17 (d, J=3.1 Hz, 2H), 4.15 (m, 6H), 3.00 (s, 2H), 2.84 (s,
3H), 2.46-2.28 (m, 4H), 2.04 (d, J=9.8 Hz, 3H), 1.86 (s, 3H).
Example 280:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((tetrahydrofuran-3-yl)methoxy)-4,1-phenylene))b-
is(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00522##
[2261]
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(-
oxy))bis(2-chloro-5-hydroxybenzaldehyde) (100 mg, 0.18 mmol),
sodium Iodide (81.55 mg, 0.54 mmol), potassium carbonate (150.38
mg, 1.09 mmol) and N,N-Dimethylformamide (5 mL) were placed in a
sealed vessel, stirred and heated to 70.degree. C. for 12 hours.
Reaction was cooled then diluted in EtAc and aqueous lithium
chloride and extracted with EtAc (3.times.). Organics were then
washed with lithium chloride (3.times.), water, brine, then dried
over sodium sulfate before filtering and evaporating organics under
reduced pressure to afford crude residue. Crude material was
purified by silica gel chromatography using Hexanes/EtAc as the
eluent (0 to 100% EtAc) to afford
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(2-chloro-5-((tetrahydrofuran-3-yl)methoxy)benzaldehyde).
[2262]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(5-chloro-2-((tetrahydrofuran-3-yl)methoxy)-4,1-phenyl-
ene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid) was
synthesized from
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-((tetrahydrofuran-3-yl)methoxy)benzaldehyde)
following reductive amination procedure A to afford product as the
bis-TFA salt. MS (m/z) 925.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.50 (dd, J=7.8, 1.4 Hz, 2H), 7.44 (s,
2H), 7.27 (t, J=7.6 Hz, 2H), 7.11 (dd, J=7.7, 1.4 Hz, 2H), 6.94 (d,
J=1.1 Hz, 2H), 5.31 (s, 4H), 4.31-4.05 (m, 10H), 4.01-3.86 (m, 4H),
3.82-3.69 (m, 4H), 3.21 (ddd, J=12.7, 5.2, 3.0 Hz, 2H), 2.99 (ddd,
J=12.3, 9.8, 2.0 Hz, 2H), 2.90-2.75 (m, 2H), 2.54 (dd, J=6.4, 1.1
Hz, 4H), 2.20 (tdd, J=13.1, 9.0, 4.9 Hz, 2H), 2.09 (s, 6H),
1.90-1.76 (m, 2H).
Example 281:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)-3,1-phenylene))-
bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(((1,3-dihydroxypropan-2-yl)amino)methyl)-5,1-phenylene))-
bis(oxy))bis(methylene))dinicotinonitrile)
##STR00523##
[2264]
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)-3,1-pheny-
lene))bis(oxy))bis(methylene))dinicotinonitrile was synthesized
from
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinon-
itrile following reductive amination procedure F using serinol in
place of (3S)-4-amino-3-hydroxybutyric acid to afford the product
as the bis-TFA salt. MS (m/z) 933.3 [M+H].sup.+. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.97 (d, J=2.1 Hz, 2H), 8.92 (d,
J=2.0 Hz, 2H), 8.44-8.40 (m, 2H), 7.53 (s, 2H), 7.50-7.45 (m, 2H),
7.31-7.24 (m, 2H), 7.16-7.09 (m, 2H), 7.08 (s, 2H), 5.37 (s, 4H),
5.32 (s, 4H), 4.33 (s, 4H), 3.81 (dd, J=12.0, 4.5 Hz, 4H), 3.71
(dd, J=12.0, 6.4 Hz, 4H), 3.29-3.22 (m, 2H), 2.08 (s, 6H).
Example 282:
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methy-
l)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (or
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methy-
l)-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile)
##STR00524##
[2266]
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))b-
is(oxy))bis(4-chloro-6-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino-
)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile
was synthesized from
5,5'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinon-
itrile following reductive amination procedure A using Trizma HCl
in place of (3 S)-4-amino-3-hydroxybutyric acid and 10 equivalents
of TEA to afford product as the bis-TFA salt. MS (m/z) 993.3
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.01 (t,
J=2.1 Hz, 4H), 8.50 (t, J=2.1 Hz, 2H), 8.22 (d, J=8.3 Hz, 4H), 7.53
(s, 2H), 7.51-7.46 (m, 2H), 7.28 (t, J=7.6 Hz, 2H), 7.16 (s, 2H),
7.10 (d, J=7.6 Hz, 2H), 5.33 (d, J=8.0 Hz, 8H), 5.23 (s, 4H), 4.23
(s, 4H), 3.58 (s, 12H), 2.02 (s, 6H).
Example 283:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(3-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-
-hydroxybutanoic acid)
##STR00525##
[2268] 3,3'-bis(chloromethyl)-2,2'-dimethyl-1,1'-biphenyl (150 mg,
0.54 mmol), 3-chloro-4-hydroxybenzaldehyde (176.64 mg, 1.13 mmol),
Sodium Iodide (241.59 mg, 1.61 mmol), Sodium carbonate (227.76 mg,
2.15 mmol) and DMF (10 mL) were placed in a round-bottomed flask
equipped with stir bar under nitrogen and heated to 45.degree. C.
with stirring for 12 hours. Reaction was cooled then diluted in
EtAc and aqueous lithium chloride and extracted with EtAc
(3.times.). Organics were then washed with lithium chloride
(3.times.), water, brine, then dried over sodium sulfate before
filtering and evaporating organics under reduced pressure to afford
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))-
bis(oxy))bis(3-chlorobenzaldehyde) as a crude residue.
[2269]
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(met-
hylene))bis(oxy))bis(3-chloro-4,1-phenylene))bis(methylene))bis(azanediyl)-
)bis(3-hydroxybutanoic acid) was synthesized from
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(3-chlorobenzaldehyde) using reductive amination procedure A to
afford the desired product as the bis-TFA salt. MS (m/z) 725.3
[M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.58
(d, J=2.2 Hz, 2H), 7.48 (dd, J=7.7, 1.4 Hz, 2H), 7.42 (dd, J=8.5,
2.2 Hz, 2H), 7.26 (dd, J=16.1, 8.1 Hz, 4H), 7.10 (dd, J=7.7, 1.4
Hz, 2H), 5.25 (s, 4H), 4.29 (m, 2H), 4.18 (s, 4H), 3.19 (dd,
J=12.7, 3.1 Hz, 2H), 2.99 (dd, J=12.7, 9.9 Hz, 2H), 2.53 (d, J=6.3
Hz, 4H), 2.06 (s, 6H).
Example 284:
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-6-(((2-hydroxyethyl)amino)methyl)-3,1-phenylene))bis(oxy))b-
is(methylene))dibenzonitrile (or
3,3'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy-
))bis(4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5,1-phenylene))bis(oxy))b-
is(methylene))dibenzonitrile)
##STR00526##
[2271] The title compound was synthesized using reductive amination
procedure C, using 2-aminoethan-1-ol and acetic acid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.61 (s, 4H), 8.00 (d, J=1.7 Hz,
2H), 7.88-7.78 (m, 3H), 7.62 (t, J=7.8 Hz, 2H), 7.55 (s, 2H), 7.47
(d, J=7.7 Hz, 2H), 7.28 (dq, J=8.1, 5.3, 4.4 Hz, 2H), 7.17 (s, 2H),
7.12-7.08 (m, 2H), 5.30 (d, J=6.7 Hz, 7H), 4.15-4.05 (m, 4H), 3.62
(t, J=5.4 Hz, 5H), 2.94 (t, J=5.8 Hz, 4H), 2.08-1.98 (m, 6H).
LCMS-ESI+ (m/z): [M+H]+ calculated for
C.sub.49H.sub.49Cl.sub.2N.sub.3O.sub.6: 871.3; found: 871.2.
Example 285:
(3S,3'S)-4,4'-((((((2-fluoro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid) (or
(3S,3'S)-4,4'-(((6,6'-(((2-fluoro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis-
(methylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(az-
anediyl))bis(3-hydroxybutanoic acid))
##STR00527##
[2273] Step 1: Methyl 3-bromo-2-fluorobenzoate (500 mg, 2.15 mmol)
dissolved in diethyl ether (15 mL) was cooled to 0.degree. C. and
treated with lithium aluminum hydride (81 mg, 2.13 mmol). The
reaction mixture was slowly warmed to room temperature and stirred
for 6 h. The reaction mixture was again cooled to 0.degree. C. and
methanol was added dropwise slowly followed by water. The reaction
mixture was diluted with ethyl acetate and washed with water. The
organic layer was concentrated to give
(3-bromo-2-fluorophenyl)methanol.
[2274] Step 2: Preparation of
6-((3-bromo-2-fluorobenzyl)oxy)-2-methoxynicotinaldehyde.
(3-bromo-2-fluorophenyl)methanol (342 mg, 1.67 mmol) dissolved in
dimethylformamide (10 mL) was treated with sodium hydride (72 mg,
1.80 mmol, 60% dispersion in mineral oil). The suspension was
stirred at room temperature for 10 min before
6-chloro-2-methoxynicotinaldehyde (287 mg, 1.67 mmol) was added.
The reaction mixture was heated at 90.degree. C. for 2 h. After
cooling to room temperature, the reaction mixture was diluted with
ethyl acetate and washed with water. The organic layer was
concentrated and purified by column chromatography to give
6-((3-bromo-2-fluorobenzyl)oxy)-2-methoxynicotinaldehyde.
[2275] Step 3: Preparation of
6-((2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-
-methoxynicotinaldehyde.
6-((3-bromo-2-fluorobenzyl)oxy)-2-methoxynicotinaldehyde (100 mg,
0.29 mmol) dissolved in 1,4-dioxane (3 mL) was treated with bis
(pinacolato) diboron (112 mg, 0.44 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (25
mg, 0.031 mmol), and potassium acetate (87 mg, 0.89 mmol). The
reaction mixture was heated at 85.degree. C. for 4 h. After cooling
to room temperature, the reaction mixture was diluted with ethyl
acetate and washed with water. The organic layer was concentrated
and purified by column chromatography to give
6-((2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-
-methoxynicotinaldehyde.
[2276] Step 4: Preparation of
6,6'-(((2-fluoro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(o-
xy))bis(2-methoxynicotinaldehyde).
6-((2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-
-methoxynicotinaldehyde (88 mg, 0.23 mmol) and
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxynicotinaldehyde (83 mg,
0.24 mmol) dissolved in 2-methyltetrahydrofuran (2 mL) was treated
with tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.02 mmol)
and sodium carbonate (190 .mu.l, 0.38 mmol, 2M solution in water).
The reaction mixture was heated in the microwave at 105.degree. C.
for 90 min. After cooling to room temperature, the reaction mixture
was diluted with ethyl acetate and washed with water. The organic
layer was concentrated and purified by column chromatography to
give
6,6'-(((2-fluoro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(o-
xy))bis(2-methoxynicotinaldehyde).
[2277] Step 5: Preparation of
(3S,3'S)-4,4'-((((((2-fluoro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(meth-
ylene))bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanedi-
yl))bis(3-hydroxybutanoic acid). The title compound was synthesized
using general reductive amination procedure B. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.62 (s, 2H), 7.74 (d, J=8.1 Hz, 1H),
7.60-7.48 (m, 1H), 7.28 (qd, J=7.4, 3.1 Hz, 1H), 7.18 (d, J=7.3 Hz,
1H), 6.51 (d, J=8.0 Hz, 1H), 5.45 (t, J=8.4 Hz, 2H), 4.21-4.11 (m,
1H), 4.11-3.98 (m, 2H), 3.90 (d, J=12.8 Hz, 3H), 3.00 (d, J=12.2
Hz, 1H), 2.84 (s, 1H), 2.44-2.35 (m, 1H). LCMS-ESI+ (m/z): [M+H]+
calculated for C.sub.37H.sub.43FN.sub.4O.sub.10: 723.3; found:
723.2.
Example 286:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzo[d]thiazol-6-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00528##
[2279] Step 1: Methyl 2-bromobenzo[d]thiazole-6-carboxylate (500
mg, 1.84 mmol) dissolved in diethyl ether (13 mL) was cooled to
0.degree. C. and treated with lithium aluminum hydride (70 mg, 1.84
mmol). The reaction mixture was slowly warmed to room temperature
and stirred for 4 h. The reaction mixture was again cooled to
0.degree. C. and methanol was added dropwise slowly followed by
water. The reaction mixture was diluted with ethyl acetate and
washed with water. The organic layer was concentrated to give
(2-bromobenzo[d]thiazol-6-yl)methanol.
[2280] Step 2: (2-bromobenzo[d]thiazol-6-yl)methanol (374 mg, 1.53
mmol) dissolved in dichloromethane (12 mL) was treated with
Dess-Martin periodinane (682 mg, 1.61 mmol). The reaction mixture
was stirred at room temperature overnight and quenched by slow
dropwise addition of saturated sodium thiosulfate solution. The
reaction mixture was diluted with ethyl acetate and washed with
water. The organic layer was concentrated to give
2-bromobenzo[d]thiazole-6-carbaldehyde.
[2281] Step 3: 2-bromobenzo[d]thiazole-6-carbaldehyde (50 mg, 0.21
mmol) and (3-bromo-2-methylphenyl)boronic acid (25 mg, 0.12 mmol)
dissolved in 2-methyltetrahydrofuran (3 mL) was treated with
tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol) and
sodium carbonate (130 .mu.l, 0.26 mmol, 2M solution in water). The
reaction mixture was heated in the microwave at 105.degree. C. for
25 min. After cooling to room temperature, the reaction mixture was
diluted with ethyl acetate and washed with water. The organic layer
was concentrated and purified by column chromatography to give
2-(3-bromo-2-methylphenyl)benzo[d]thiazole-6-carbaldehyde.
[2282] Step 4:
2-(3-bromo-2-methylphenyl)benzo[d]thiazole-6-carbaldehyde (28 mg,
0.08 mmol) and
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (28 mg, 0.05
mmol) dissolved in 2-methyltetrahydrofuran (3 mL) was treated with
tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.01 mmol) and
sodium carbonate (60 .mu.l, 0.12 mmol, 2M solution in water). The
reaction mixture was heated in the microwave at 105.degree. C. for
90 min. After cooling to room temperature, the reaction mixture was
diluted with ethyl acetate and washed with water. The organic layer
was concentrated and purified by column chromatography to give
5-((4-chloro-2-formyl-5-((3'-(6-formylbenzo[d]thiazol-2-yl)-2,2'-dimethyl-
-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[2283] Step 5:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzo[d]thiazol-6-yl)methyl)amino)-3-hydroxybutanoic
acid was synthesized using general reductive amination procedure B.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd, J=5.8, 2.1
Hz, 2H), 8.93 (s, 2H), 8.56 (s, 2H), 8.46 (t, J=2.1 Hz, 1H), 8.28
(d, J=1.6 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.78 (dd, J=7.9, 1.3 Hz,
1H), 7.69 (dd, J=8.5, 1.7 Hz, 1H), 7.57 (s, 1H), 7.55-7.44 (m, 2H),
7.32 (t, J=7.6 Hz, 2H), 7.21-7.12 (m, 2H), 5.55 (s, 2H), 5.40-5.29
(m, 4H), 4.33 (s, 2H), 4.13 (d, J=11.1 Hz, 4H), 3.02 (s, 3H), 2.86
(d, J=3.9 Hz, 3H), 2.23 (s, 3H), 2.08 (s, 3H). LCMS-ESI+ (m/z):
[M+H]+ calculated for C.sub.45H.sub.44ClN.sub.5O.sub.8S: 850.3;
found: 850.2.
Example 287: Diethyl
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))diacetate (or diethyl
2,2'-(((6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'--
diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(-
azanediyl))diacetate)
##STR00529##
[2285] A solution of
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-chloro-2-methoxynicotinaldehyde) (130 mg, 0.215 mmol)
was treated using general reductive amination procedure E,
substituting ethyl glycinate for (S)-4-amino-3-hydroxybutanoic
acid. Purification by prep RP-HPLC (10-75% acetonitrile in water,
0.1% trifluoroacetic acid) furnished diethyl
2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azane-
diyl))diacetate as a solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.26 (s, 4H), 7.93 (s, 2H), 7.43 (dd, J=6.9, 1.9 Hz, 2H),
7.39-7.28 (m, 4H), 6.60 (dd, J=6.9, 5.1 Hz, 2H), 4.20 (q, J=7.1 Hz,
4H), 4.10 (s, 4H), 3.97 (d, J=6.5 Hz, 10H), 2.91 (ddd, J=13.4, 8.4,
4.8 Hz, 2H), 2.85-2.60 (m, 4H), 2.16-2.02 (m, 2H), 1.23 (t, J=7.1
Hz, 6H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.40H.sub.44Cl.sub.2N.sub.4O.sub.8: 778.3; found: 777.8.
Example 288: (S)-4-((4-((4`
`-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-3'-chloro-2,2'-dimethy-
l-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00530##
[2287]
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-3'-
'-chloro-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((-
5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
was synthesized in analogy to Example 16. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=12.2, 2.1 Hz, 2H), 8.37 (d,
J=2.1 Hz, 1H), 7.51 (s, 1H), 7.46 (dd, J=7.7, 1.4 Hz, 1H), 7.39 (d,
J=2.1 Hz, 1H), 7.35-6.99 (m, 8H), 5.37 (s, 2H), 5.31 (s, 2H), 4.44
(dd, J=5.6, 4.4 Hz, 2H), 4.35 (dt, J=9.8, 3.2 Hz, 1H), 4.23 (s,
3H), 3.60 (dd, J=5.6, 4.4 Hz, 2H), 3.47 (dd, J=12.7, 3.1 Hz, 1H),
3.26-3.13 (m, 2H), 2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.58 (d, J=6.3
Hz, 2H), 2.51 (dd, J=6.3, 1.2 Hz, 2H), 2.13 (s, 3H), 1.88 (s, 3H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calculated for
C.sub.45H.sub.47Cl.sub.2N.sub.4O.sub.9: 857.27; found: 857.07.
Example 289:
(S)-2-(((5-chloro-6-((4-(2-chloro-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)-2,3--
dihydro-1H-inden-1-yl)oxy)-2-((5-cyanopyridin-3-yl)methoxy)pyridin-3-yl)me-
thyl)amino)-2-methylpropanoic acid
##STR00531##
[2289] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=757.99, 759.82. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.12-9.02 (m, 3H), 8.97 (d, J=2.0
Hz, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.66
(d, J=8.4 Hz, 2H), 7.57-7.42 (m, 2H), 7.42 (s, 2H), 7.34-7.22 (m,
3H), 6.55 (s, 1H), 5.57 (s, 2H), 4.16 (s, 2H), 2.84 (s, 2H), 2.73
(d, J=12.4 Hz, 1H), 2.52 (s, 1H), 1.95 (dq, J=13.8, 7.3 Hz, 1H),
1.53 (s, 6H).
Example 290:
(2S)-2-(((5-chloro-6-(((1S)-4-(2-chloro-4'-(1-methylpyrrolidin-2-yl)-[1,1-
'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-cyanopyridin-3-yl)m-
ethoxy)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic
acid
##STR00532##
[2291] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=778.05. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.84 (s, 1H), 9.06-9.00 (m, 2H), 8.96
(s, 1H), 8.47 (s, 1H), 8.01 (d, J=9.3 Hz, 1H), 7.67-7.56 (m, 4H),
7.51 (t, J=7.6 Hz, 1H), 7.43 (dd, J=7.7, 1.8 Hz, 1H), 7.34-7.24 (m,
2H), 6.53 (s, 1H), 5.56 (s, 2H), 4.46-4.37 (m, 1H), 4.17 (d, J=7.4
Hz, 2H), 3.75 (d, J=11.6 Hz, 2H), 3.28-3.18 (m, 2H), 2.82 (s, 2H),
2.71 (d, J=4.4 Hz, 3H), 2.26-2.09 (m, 1H), 2.15 (s, 2H), 1.94 (s,
2H), 1.43 (s, 3H), 1.20 (d, J=6.7 Hz, 1H).
Example 291:
(S)-4-(((5-chloro-6-(((S)-4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy-
)-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-cyanopyridin--
3-yl)methoxy)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00533##
[2293] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=798.03. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.02 (d, J=2.0 Hz, 1H), 8.96 (s, 1H),
8.73 (s, 4H), 8.46 (s, 1H), 8.02 (s, 1H), 7.46 (t, J=7.5 Hz, 1H),
7.44-7.37 (m, 3H), 7.37-7.18 (m, 4H), 7.07 (d, J=8.8 Hz, 2H), 6.50
(d, J=5.9 Hz, 1H), 5.63 (s, 1H), 5.57 (s, 2H), 5.27 (s, 1H), 4.30
(t, J=5.1 Hz, 2H), 4.17 (s, 4H), 3.68 (t, J=5.3 Hz, 2H), 3.11 (d,
J=7.8 Hz, 3H), 3.00-2.59 (m, 3H), 2.48-2.32 (m, 2H), 1.93 (d, J=6.1
Hz, 1H).
Example 292:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''--
(pyrrolidin-2-ylmethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-
-3-hydroxy-2-methylpropanoic acid
##STR00534##
[2295] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=745.07. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.37 (s, 1H), 9.86 (d, J=47.2 Hz, 1H),
9.02 (d, J=2.1 Hz, 1H), 8.96 (s, 1H), 8.67 (s, 3H), 8.46 (s, 1H),
7.80 (d, J=8.2 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.25 (s, 3H), 7.16
(dd, J=15.4, 3.0 Hz, 1H), 7.16 (s, 1H), 6.92 (d, J=7.4 Hz, 1H),
6.49 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 5.62 (s, 1H), 5.55 (s, 2H),
5.49 (s, 1H), 4.44 (s, 1H), 4.38 (s, 1H), 4.16 (d, J=5.8 Hz, mH),
3.67 (s, 1H), 3.37 (s, 1H), 3.30 (d, J=6.0 Hz, 1H), 3.17-3.02 (m,
1H), 2.94 (d, J=32.1 Hz, 1H), 2.73 (q, J=7.9, 7.4 Hz, 1H), 2.60
(dt, J=15.8, 7.3 Hz, 1H), 2.52 (s, 2H), 2.48-2.32 (m, 2H),
2.29-2.22 (m, 1H), 2.16 (s, 2H), 1.97-1.78 (m, 2H).
Example 293:
(S)-4-(((6-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)naphthalen-1-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00535##
[2297] The title compound was synthesized according to general
reductive amination procedure A. 843.427 (M+1). .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.96 (d, J=2.1 Hz, 1H), 8.93 (d,
J=2.0 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.07
(d, J=8.2 Hz, 1H), 7.75-7.71 (m, 1H), 7.69 (dd, J=8.7, 1.8 Hz, 1H),
7.61 (dd, J=8.3, 7.1 Hz, 1H), 7.52 (s, 1H), 7.50-7.46 (m, 1H),
7.40-7.32 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.18 (ddd, J=11.9, 7.4,
1.7 Hz, 2H), 7.09 (s, 1H), 5.39 (s, 2H), 5.33 (s, 2H), 4.82 (s,
2H), 4.42 (dtd, J=9.4, 6.2, 3.0 Hz, 1H), 4.24 (s, 3H), 3.38 (dd,
J=12.8, 3.1 Hz, 1H), 3.24-3.14 (m, 2H), 3.02-2.94 (m, 1H), 2.59 (d,
J=6.2 Hz, 2H), 2.55-2.50 (m, 2H), 2.19 (s, 3H), 1.95 (s, 3H).
Example 294:
(3-((5-chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((3-p-
hosphonopropyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-hydroxybenzyl)amino)propyl)phosphonic acid
##STR00536##
[2299] Tetraethyl
(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bi-
s(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))-
bis(azanediyl))bis(propane-3,1-diyl))bis(phosphonate) was
synthesized according to general reductive amination procedure D.
MS (Chemical Ionization, TFA): m/z 1041.3
[M(.sup.35Cl).sub.2+H.sup.+], 1043.3
[M(.sup.35Cl)(.sup.37Cl)+H.sup.+], 1045.3
[M(.sup.37Cl).sub.2+H.sup.+]. Phosphodiester (10.2 mg, 0.010 mmol)
was dissolved in ACN and 2,6-lutidine (20 .mu.L, 0.17 mmol) added,
then TMSBr (63.5 .mu.L, 0.48 mmol) added sequentially in small
portions at room temperature.
(3-((5-chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((3-p-
hosphonopropyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)-2-hydroxybenzyl)amino)propyl)phosphonic acid isolated
by prep. HPLC. MS (Chemical Ionization, TFA): m/z 913.2
[M(.sup.35Cl).sub.2+H.sup.+], 915.2
[M(.sup.35Cl)(.sup.37Cl)+H.sup.+], 917.2
[M(.sup.37Cl).sub.2+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.01 (broad s, 2H); 8.48 (broad s, 1H); 7.51 (s, 1H); 7.46
(m, 2H); 7.38 (s, 1H); 7.25 (m, 2H); 7.10 (m, 4H); 6.77 (s, 1H);
5.35 (m, 4H); 5.19 (m, 2H); 4.00 (s, 2H); 3.92 (s, 2H); 2.91 (m,
4H); 1.93 (s, 3H), 1.83 (s, 3H); 1.78 (m, 4H); 1.53 (m, 4H).
Example 295:
(S)-2-(((5-chloro-6-(((1S,1'S)-1'-((3-chloro-6-((5-cyanopyridin-3-yl)meth-
oxy)-5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)oxy)-2,2',3,3'-tetrahyd-
ro-1H,1'H-[4,4'-biinden]-1-yl)oxy)-2-((5-cyanopyridin-3-yl)methoxy)pyridin-
-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00537##
[2301] To a mixture of (S)-2-amino-3-hydroxy-2-methylpropanoic acid
(88.27 mg, 0.74 mmol), KOH (41.58 mg, 0.74 mmol) in a 40 mL vial
was added EtOH (3 mL) and sonicated for 5 min. To this mixture was
added solution of
5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)-
bis(oxy))bis(5-chloro-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))d-
inicotinonitrile (60 mg, 0.074 mmol) in CH.sub.2Cl.sub.2 (0.5 ml),
at once and stirred for 50 min. To this mix was added
2-aminoethan-1-ol (45.27 mg, 0.741 mmol) and allowed to stir for
another 50 min. To well stirring mix was added NaBH(OAc).sub.3 (157
mg, 0.741 mmol) followed by AcOH (60 .mu.L). The mixture was left
stirring at RT for additional 2 h. At this point the reaction was
quenched with 2 N HCl (2 mL, pH .about.2) and stirred for 5 min.
The solvent was concentrated to dryness under Vacuum. Purification
by prep RP-HPLC (10-90% acetonitrile in water, 0.1% trifluoroacetic
acid) furnished product
(S)-2-(((5-chloro-6-(((1S,1'S)-1'-((3-chloro-6-((5-cyanopyridin-3-yl)meth-
oxy)-5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)oxy)-2,2',3,3'-tetrahyd-
ro-1H,1'H-[4,4'-biinden]-1-yl)oxy)-2-((5-cyanopyridin-3-yl)methoxy)pyridin-
-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. [M+1]=958.3.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.96 (d, J=2.1 Hz,
2H), 8.84 (d, J=2.0 Hz, 2H), 8.37 (t, J=2.1 Hz, 2H), 7.90 (d, J=3.2
Hz, 2H), 7.33-7.13 (m, 6H), 6.50 (t, J=6.1 Hz, 2H), 5.64 (s, 4H),
4.28 (m, 4H), 3.89-3.78 (m, 4H), 3.20 (t, J=5.2 Hz, 3H), 3.02-2.70
(m, 4H), 2.69-2.45 (m, 4H), 2.20-1.73 (m, 3H).
Example 296:
(S)-2-(((3-(3'-((4-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-2--
chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)-8-chloroquinolin-6-yl)methyl)amino)-3-hydroxy-2-methylpro-
panoic acid
##STR00538##
[2303] The title compound was synthesized following standard Suzuki
coupling procedure described in Example 31 followed by the
reductive amination shown in Example 40. [M+1]=879.0. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 9.03 (d, J=2.1 Hz, 1H), 8.98
(d, J=2.1 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.1 Hz, 1H),
8.42 (t, J=2.0 Hz, 1H), 8.14 (s, 2H), 7.55 (s, 1H), 7.50 (d, J=7.5
Hz, 1H), 7.46-7.36 (m, 2H), 7.30 (t, J=7.6 Hz, 1H), 7.25 (dd,
J=7.3, 1.7 Hz, 1H), 7.22-7.16 (m, 1H), 7.10 (s, 1H), 5.36 (d,
J=14.5 Hz, 4H), 4.49 (d, J=3.5 Hz, 2H), 4.29 (s, 2H), 4.14 (d,
J=12.2 Hz, 1H), 4.01 (d, J=12.1 Hz, 1H), 3.92 (d, J=12.2 Hz, 1H),
3.81 (d, J=12.2 Hz, 1H), 2.19 (s, 3H), 1.97 (s, 3H), 1.67 (s, 4H),
1.53 (s, 3H).
Example 297:
(S)-4-(((3-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethy-[1,1'-biphe-
nyl]-3-yl)-8-chloroquinolin-6-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00539##
[2305] The title compound was synthesized following standard Suzuki
coupling procedure described in Example 31 followed by the
reductive amination shown in Example 42. [M+1]=879.0. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 9.03 (d, J=2.1 Hz, 1H), 8.96
(d, J=2.1 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H),
8.38 (t, J=2.1 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 8.10 (d, J=1.8 Hz,
1H), 7.50 (d, J=11.1 Hz, 2H), 7.47-7.37 (m, 2H), 7.30 (t, J=7.6 Hz,
1H), 7.25 (dd, J=7.3, 1.7 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.09 (s,
1H), 5.38 (s, 2H), 5.33 (s, 2H), 4.47 (s, 2H), 4.33 (ddd, J=9.5,
6.3, 3.0 Hz, 1H), 4.24 (s, 3H), 3.28 (s, 1H), 3.20 (dd, J=12.7, 3.0
Hz, 1H), 3.10 (dd, J=12.6, 9.8 Hz, 1H), 2.97 (dd, J=12.7, 9.8 Hz,
1H), 2.56 (d, J=6.3 Hz, 2H), 2.52 (dd, J=6.3, 1.2 Hz, 2H), 2.18 (s,
3H), 1.97 (s, 3H).
Example 298:
(2S,2'S)-2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-chloro-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)pyridin-
e-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic
acid)
##STR00540##
[2307] The title compound was synthesized following standard
synthesis procedure described in Example 4 using intermediate
6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis-
(oxy))bis(5-chloro-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldeh-
yde) and (S)-2-amino-3-hydroxy-2-methylpropanoic acid.
[M+1]=1122.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.05
(dd, J=11.3, 2.1 Hz, 4H), 8.53 (t, J=2.1 Hz, 2H), 7.93 (s, 2H),
7.31-7.14 (m, 6H), 6.53 (dd, J=6.8, 4.9 Hz, 2H), 5.70 (s, 4H), 4.33
(s, 4H), 4.08 (d, J=12.2 Hz, 2H), 3.87 (d, J=12.2 Hz, 2H), 3.31 (s,
4H), 3.17 (s, 6H), 3.02-2.69 (m, 4H), 2.57 (dq, J=13.4, 7.1 Hz,
2H), 2.20-1.99 (m, 2H), 1.61 (s, 6H).
Example 299:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(2-
-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-[1,1'-biphenyl]-3-yl)meth-
oxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00541##
[2309] The title compound was synthesized following previously
described Suzuki cross coupling, reductive amination, and TFA
deprotection procedures. [M+1]=771.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.90 (d, J=2.0
Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.59 (d,
J=1.5 Hz, 1H), 7.55 (s, 1H), 7.47 (dd, J=7.7, 1.4 Hz, 1H),
7.37-7.21 (m, 4H), 7.16 (dd, J=7.7, 1.4 Hz, 1H), 7.13-7.04 (m, 2H),
5.36 (s, 2H), 5.33 (s, 2H), 5.11 (t, J=7.8 Hz, 1H), 4.28 (s, 2H),
4.01 (d, J=12.1 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.70-3.45 (m,
2H), 2.70-2.59 (m, 1H), 2.44 (dd, J=13.2, 7.9 Hz, 1H), 2.40-2.20
(m, 2H), 2.17 (s, 3H), 1.88 (s, 3H), 1.53 (s, 3H).
Example 300:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''-(-
2-(pyrrolidin-1-yl)ethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amin-
o)-3-hydroxybutanoic acid
##STR00542##
[2311] Step 1: The reaction mixture of
1-bromo-4-(2-bromoethyl)benzene (300 mg, 1.13 mmol), potassium
carbonate (471.24 mg, 3.41 mmol) and pyrrolidine (0.09 ml, 1.14
mmol) in acetonitrile (6 mL) was stirred at rt overnight. The
reaction mixture was then filtered. The filtrate was concentrated
down and the residue was purified by silica gel column
chromatography to afford 1-(4-bromophenethyl)pyrrolidine.
[2312] Step 2: The reaction mixture of
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (100 mg, 0.16 mmol), 1-(4-bromophenethyl)pyrrolidine (101.28 mg,
0.4 mmol), Tetrakis(triphenylphosphine)palladium(0) (18.98 mg, 0.02
mmol) and Potassium Carbonate (68.09 mg, 0.49 mmol) in 1,4-dioxane
(3 mL) and water (0.4 mL) was stirred at 90.degree. C. for 2 h.
After cooling down, the reaction mixture was partitioned between
ethyl acetate and water. The ethyl acetate layer was taken and
concentrated. The residue was purified by silica gel column,
affording
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-(pyrrolidin-1-yl)ethyl)-[1,1':3',1'-
'-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[M+H].sup.+ 656.9
[2313] Step-3: Following general reductive amination procedure G,
5-((4-chloro-5-((2,2'-dimethyl-4''-(2-(pyrrolidin-1-yl)ethyl)-[1,1':3',1'-
'-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
was converted to
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''-(-
2-(pyrrolidin-1-yl)ethyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amin-
o)-3-hydroxybutanoic acid as the bis-TFA salt. [M+1]=759.9. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=14.7, 2.0 Hz,
2H), 8.37 (t, J=2.1 Hz, 1H), 7.50 (s, 1H), 7.46 (dd, J=7.6, 1.4 Hz,
1H), 7.42-7.23 (m, 6H), 7.16 (ddd, J=16.5, 7.7, 1.5 Hz, 2H),
7.13-7.01 (m, 2H), 5.37 (s, 2H), 5.31 (s, 2H), 4.23 (s, 3H),
3.54-3.45 (m, 2H), 3.24-3.06 (m, 5H), 2.97 (dd, J=12.8, 9.8 Hz,
1H), 2.51 (d, J=6.3 Hz, 2H), 2.18 (s, 2H), 2.14 (s, 3H), 2.04 (s,
2H), 1.87 (s, 3H).
Example 301:
(2S)-2-((5-chloro-4-((2'-chloro-4''-((dimethylamino)methyl)-6'-fluoro-2-m-
ethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methox-
y)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00543##
[2315]
(2S)-2-((5-chloro-4-((2'-chloro-4''-((dimethylamino)methyl)-6'-fluo-
ro-2-methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)-
methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid was
synthesized according to general reductive amination procedure D
using
5-((4-chloro-5-((2'-chloro-4''-((dimethylamino)methyl)-6'-fluoro-2-methyl-
-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitr-
ile in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(S)-2-amino-3-hydroxy-2-methylpropanoic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.97 (d, J=2.1 Hz, 1H), 8.91 (d,
J=2.0 Hz, 1H), 8.40 (s, 1H), 7.59 (s, 4H), 7.59-7.48 (m, 2H), 7.46
(dd, J=8.6, 6.0 Hz, 1H), 7.36-7.26 (m, 2H), 7.19 (d, J=7.6 Hz, 1H),
7.04 (s, 1H), 5.35 (s, 2H), 5.33 (s, 2H), 4.37 (s, 2H), 4.27 (s,
2H), 4.00 (d, J=12.1 Hz, 1H), 3.79 (d, J=12.1 Hz, 1H), 2.90 (s,
6H), 2.19 (s, 3H), 1.51 (s, 3H); LRMS: 757.2.
Example 302:
(2R)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''--
(quinuclidin-3-yloxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-
-hydroxy-2-methylpropanoic acid
##STR00544##
[2317]
(2R)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethy-
l-4''-(quinuclidin-3-yloxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)am-
ino)-3-hydroxy-2-methylpropanoic acid was synthesized according to
general reductive amination procedure D using
5-((4-chloro-5-((2,2'-dimethyl-4''-(quinuclidin-3-yloxy)-[1,1':3',1''-ter-
phenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile in
place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(R)-2-amino-3-hydroxy-2-methylpropanoic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d,
J=1.9 Hz, 1H), 8.42 (s, 1H), 7.64 (dd, J=12.7, 7.5 Hz, 1H), 7.55
(s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.28 (dd, J=13.2, 7.9 Hz, 4H),
7.18 (d, J=6.8 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.09-6.98 (m, 3H),
5.36 (s, 2H), 5.32 (s, 2H), 4.93 (s, 1H), 4.28 (s, 2H), 4.01 (d,
J=12.1 Hz, 1H), 3.89-3.72 (m, 2H), 3.58-3.30 (m, 5H), 2.55 (s, 1H),
2.43-2.30 (m, 1H), 2.22-2.06 (m, 1H), 2.14 (s, 3H), 2.01 (d, J=8.7
Hz, 1H), 1.96-1.81 (m, 1H), 1.88 (s, 3H), 1.52 (s, 3H); LRMS:
787.3.
Example 303:
(2S,4S)-1-((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)etho-
xy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3--
yl)methoxy)pyridin-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic
acid
##STR00545##
[2319]
(2S,4S)-1-((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amin-
)ethoxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyrid-
in-3-yl)methoxy)pyridin-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic
acid was synthesized according to general reductive amination
procedure D using
5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)met-
hoxy)nicotinaldehyde 2,2,2-trifluoroacetate (1 equiv) and
N,N-diisopropylethylamine (3 equiv) in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 9.04 (d, J=2.3 Hz, 1H), 8.96 (d,
J=2.0 Hz, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.58 (d, J=7.6 Hz, 1H),
7.46-7.34 (m, 5H), 7.30 (d, J=7.6 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H),
7.09 (d, J=8.3 Hz, 2H), 5.75-5.49 (m, 4H), 4.61-4.26 (m, 6H),
3.90-3.84 (m, 2H), 3.58-3.51 (m, 3H), 3.40-3.27 (m, 1H), 3.29-3.21
(m, 2H), 3.17 (d, J=0.9 Hz, 3H), 2.74-2.67 (m, 1H), 2.23 (d, J=13.9
Hz, 1H); LRMS: 871.2.
Example 304:
2-(((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,-
1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)meth-
oxy)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid
##STR00546##
[2321] N,N-diisopropylethylamine (155 .mu.L, 0.888 mmol) was added
via syringe to a stirred mixture of 2-(trimethylsilyl)ethyl
(2-((2',2''-dichloro-3''-(((3-chloro-5-formyl-6-((5-(methylsulfonyl)pyrid-
in-3-yl)methoxy)pyridin-2-yl)oxy)methyl)-[1,1':3',1''-terphenyl]-4-yl)oxy)-
ethyl)(2-hydroxyethyl)carbamate (100 mg, 0.111 mmol) and methyl
2-amino-2-methylpropanoate hydrochloride (102 mg, 0.666 mmol) in
dimethylsulfoxide (2.5 mL) at room temperature, and the resulting
mixture was heated to 60.degree. C. in a heating block. After 10
min, sodium triacetoxyborohydride (141 mg, 0.666 mmol) was added as
a solid. After 1 h, the resulting mixture was allowed to cool to
room temperature. Saturated aqueous sodium carbonate solution (10
mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added
sequentially, and the organic layer was washed with water
(3.times.60 mL), was dried over anhydrous magnesium sulfate, was
filtered, and was concentrated under reduced pressure. The residue
was dissolved with dichloromethane (5.0 mL), and the resulting
mixture was stirred at room temperature. Trifluoroacetic acid (2.0
mL) was added via syringe. After 60 min, the resulting mixture was
concentrated under reduced pressure, and the residue was dried
azeotropically by concentration of a toluene solution under reduced
pressure (2.times.3 mL). The residue was dissolved with
dimethylsulfoxide, and the resulting mixture was stirred at room
temperature. Aqueous sodium hydroxide solution (2.0 M, 370 .mu.L,
0.64 mmol) was added via syringe. After 15 min, trifluoroacetic
acid (200 .mu.L) was added via syringe, and the resulting mixture
was filtered and was purified by reverse phase preparative HPLC
(0.1% trifluoroacetic acid in acetonitrile/water) to give
2-(((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,-
1':3',1''-terphenyl]-3-yl)methoxy)-2-((5-(methylsulfonyl)pyridin-3-yl)meth-
oxy)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 9.04 (d, J=2.2 Hz, 1H), 8.96
(d, J=2.0 Hz, 1H), 8.46 (s, 1H), 7.95 (s, 1H), 7.54 (d, J=7.2 Hz,
1H), 7.47-7.35 (m, 5H), 7.28 (d, J=6.8 Hz, 1H), 7.25 (dd, J=7.3,
2.0 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 5.71 (d, J=13.6 Hz, 1H),
5.65-5.47 (m, 3H), 4.40-4.31 (m, 2H), 4.21 (s, 2H), 3.90-3.82 (m,
2H), 3.54 (t, J=5.0 Hz, 2H), 3.28-3.23 (m, 2H), 3.16 (s, 3H), 1.61
(s, 6H); LRMS: 843.3.
Example 305:
(S)-2-(((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-6-((3'-((R)-1-(dimethy-
lamino)-1-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-b-
iphenyl]-3-yl)methoxy)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropano-
ic acid
##STR00547##
[2323]
(S)-2-(((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-6-((3'-((R)-1-(d-
imethylamino)-1-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[-
1,1'-biphenyl]-3-yl)methoxy)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylp-
ropanoic acid was synthesized in a manner similar to Procedure D
using 5
(R)-5-(((5-chloro-6-((3'-(1-(dimethylamino)-1-(hydroxymethyl)-2,3-dihydro-
-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-3-formylpyridi-
n-2-yl)oxy)methyl)nicotinonitrile in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using
(S)-2-amino-3-hydroxy-2-methylpropanoic acid in place
(1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d,
J=1.9 Hz, 1H), 8.42 (s, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.55 (s, 1H),
7.47 (d, J=7.6 Hz, 1H), 7.40-7.23 (m, 4H), 7.21 (d, J=7.4 Hz, 1H),
7.15 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.08 (s, 1H), 5.37
(s, 2H), 5.32 (s, 2H), 4.28 (s, 2H), 4.05 (d, J=12.2 Hz, 1H), 4.01
(d, J=12.2 Hz, 1H), 3.93 (d, J=12.1 Hz, 1H), 3.80 (d, J=12.2 Hz,
1H), 3.23-3.13 (m, 2H), 2.92 (s, 3H), 2.70-2.51 (m, 1H), 2.65 (s,
3H), 2.26-2.16 (m, 1H), 2.15 (s, 3H), 1.89 (s, 3H), 1.52 (s, 3H);
LRMS: 775.3.
Example 306:
5-(((5-chloro-6-((4''-(2-(dimethylamino)-1-hydroxyethyl)-2,2'-dimethyl-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-3-(((2-hydroxyethyl)amino)methyl)pyrid-
in-2-yl)oxy)methyl)nicotinonitrile
##STR00548##
[2325] Step 1. 2-Bromo-1-(4-bromophenyl)ethan-1-one (1.50 g, 5.40
mmol) was added as a solid to a stirred mixture of dimethylamine
solution (2.0 M in tetrahydrofuran, 8.10 mL, 16 mmol), sodium
carbonate (572 mg, 5.40 mmol), and water (2.0 mL) at room
temperature, and the resulting mixture was heated to 65.degree. C.
in a heating block. After 25 min, methanol (10.0 mL) was added, and
the resulting mixture was cooled to 0.degree. C. After 5 min,
sodium borohydride (613 mg, 16.2 mmol) was added as a solid under a
nitrogen atmosphere, and the resulting mixture was allowed to warm
to room temperature. After 15 min, ethyl acetate (70 mL) was added.
The organic layer was washed with brine (40 mL), was dried over
sodium sulfate, was filtered, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (0 to 20% methanol in dichloromethane) to give
1-(4-bromophenyl)-2-(dimethylamino)ethan-1-ol.
[2326] Step 2. A stirred mixture of
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (25 mg, 0.041 mmol),
1-(4-bromophenyl)-2-(dimethylamino)ethan-1-ol (20 mg, 0.082 mmol),
saturated aqueous sodium carbonate solution (2.0 M, 164 .mu.L, 0.33
mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (2 mg, 0.002 mmol) in
1,4-dioxane (1.5 mL) was heated to 105.degree. C. in a heating
block. After 60 min, the resulting mixture was purified by flash
column chromatography on silica gel (0 to 20% methanol in
dichloromethane) to give
5-(((5-chloro-6-((4''-(2-(dimethylamino)-1-hydroxyethyl)-2,2'-dimeth-
yl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-3-formylpyridin-2-yl)oxy)methyl)n-
icotinonitrile.
[2327] Step 3.
5-(((5-chloro-6-((4''-(2-(dimethylamino)-1-hydroxyethyl)-2,2'-dimethyl-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-3-(((2-hydroxyethyl)amino)methyl)pyrid-
in-2-yl)oxy)methyl)nicotinonitrile was synthesized in a manner
similar to Procedure D using
5-(((5-chloro-6-((4''-(2-(dimethylamino)-1-hydroxyethyl)-2,2'-dimethyl-[1-
,1':3',1''-terphenyl]-3-yl)methoxy)-3-formylpyridin-2-yl)oxy)methyl)nicoti-
nonitrile in place of
6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))b-
is(5-chloro-2-methoxynicotinaldehyde) and using ethanolamine in
place (1R,2R)-2-aminocyclopentane-1-carboxylic acid. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.93
(d, J=2.0 Hz, 1H), 8.38 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.51 (s,
1H), 7.46 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.33-7.23 (m,
2H), 7.19 (d, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.13-7.04 (m,
2H), 5.37 (s, 2H), 5.31 (s, 2H), 5.12 (dd, J=10.4, 3.7 Hz, 1H),
4.23 (s, 2H), 3.81-3.75 (m, 2H), 3.17-3.08 (m, 2H), 3.03 (s, 3H),
2.96 (s, 3H), 2.14 (s, 3H), 1.87 (s, 3H); LRMS: 691.3.
Example 307:
(S)-4-(((6-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydr-
oxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3--
yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00549##
[2329] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=792.084. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 9.04-8.81 (m, 2H), 8.37 (d, J=8.4
Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.56 (s, 1H), 7.51-7.02 (m, 8H),
5.39 (s, 2H), 5.32 (s, 2H), 4.50 (d, J=21.8 Hz, 2H), 4.33 (d,
J=19.1 Hz, 4H), 3.69-3.40 (m, 2H), 3.42-3.15 (m, 3H), 3.15-2.98 (m,
1H), 2.91 (s, 3H), 2.57 (d, J=6.3 Hz, 2H), 2.42-2.00 (m, 2H), 2.14
(s, 3H), 2.04 (s, 3H).
Example 308:
(S)-4-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydrox-
ypyrrolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-terph-
enyl]-4-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00550##
[2331] 5-((5-((3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)
methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (500 mg,
0.89 mmol) was dissolved in DMF (8 ml) and ethanol (1.6 ml),
(R)-pyrrolidin-3-ol (388 mg, 4.45 mmol) was added. The mixture was
left stirring at RT for 15 min; sodium triacetoxyborohydride (1.13
g, 5.34 mmol) was added. The mixture was left stirring at RT for 10
min. Complete clean conversion occurred. Ethyl acetate and water
were added to quench the reaction. The organic layer was washed
with saturated aqueous sodium bicarbonate and then concentrated
under vacuum to give
(R)-5-((5-((3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)
methoxy)-4-chloro-2-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nico-
tinonitrile as the crude. The crude (180 mg, 0.28 mmol) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (106
mg, 0.46 mmol) were dissolved in 1,4-dioxane (4 ml) and water (0.8
ml), added K.sub.2CO.sub.3 (78.6 mg, 0.57 mmol) and
tetrakis(triphenylphosphine)palladium(0) (65.7 mg, 0.057 mmol). The
mixture was purged with argon and then heated to 82.degree. C.
After stirring for 1 h, the mixture was cooled to RT, diluted with
ethyl acetate and water. The organic layer was washed with brine,
concentrated under vacuum. The residue was purified by silica gel
chromatography using EtOAc/MeOH as the eluent to afford
(R)-5-((4-chloro-5-((4''-formyl-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-y-
l)methoxy)-2-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nicotinonitr-
ile.
[2332]
(S)-4-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3--
hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-
-terphenyl]-4-yl)methyl)amino)-3-hydroxybutanoic acid was
synthesized according to general reductive amination procedure G.
[M+1]=761.111. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
9.01-8.88 (m, 2H), 8.37 (s, 1H), 7.57 (d, J=8.6 Hz, 3H), 7.53-7.40
(m, 3H), 7.38-7.00 (m, 6H), 5.39 (s, 2H), 5.32 (s, 2H), 4.50 (d,
J=21.8 Hz, 2H), 4.42-4.18 (m, 4H), 3.72-3.41 (m, 2H), 3.38-3.22 (m,
2H), 3.25 (dd, J=12.7, 3.1 Hz, 1H), 3.05 (dd, J=12.7, 9.9 Hz, 1H),
2.38-2.05 (m, 2H), 2.55 (d, J=6.3 Hz, 2H), 2.14 (s, 3H), 1.88 (s,
3H).
Example 309:
(S)-4-((2-((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hyd-
roxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-te-
rphenyl]-4-yl)oxy)ethyl)amino)-3-hydroxybutanoic acid
##STR00551##
[2334]
5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1'-
'-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(200 mg, 0.29 mmol) was dissolved in DMF (2 ml) and ethanol (0.4
ml), (R)-pyrrolidin-3-ol (126 mg, 1.45 mmol) was added. The mixture
was left stirring at RT for 30 min; sodium triacetoxyborohydride
(429 mg, 2.03 mmol) was added. The mixture was left stirring at RT
for 15 min. Complete clean conversion occurred. Ethyl acetate and
water were added to quench the reaction. The organic layer was
washed with saturated aqueous sodium bicarbonate and then
concentrated under vacuum to give
(R)-5-((4-chloro-5-((4''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''--
terphenyl]-3-yl)methoxy)-2-((3-hydroxypyrro
idin-1-yl)methyl)phenoxy)methyl)nicotinonitrile as the crude. The
crude was dissolved in 1,4-dioxane (4 ml), hydrochloric acid
(conc., 0.4 ml) was added dropwise, and the mixture was left
stirring at RT for 2 h. Ethyl acetate and water were added to the
mixture. The organic layer was washed with saturated aqueous sodium
bicarbonate and then concentrated under vacuum to give
(R)-5-((4-chloro-5-((2,2'-dimethyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphen-
yl]-3-yl)methoxy)-2-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nicot-
inonitrile as crude.
[2335]
(S)-4-((2-((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methopxy)-4-(((R-
)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3'-
,1''-terphenyl]-4-yl)oxy)ethyl)amino)-3-hydroxybutanoic acid was
synthesized according to general reductive amination procedure G.
[M+1]=791.105. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
9.01-8.89 (m, 2H), 8.37 (s, 1H), 7.56 (s, 1H), 7.46 (d, J=7.6 Hz,
1H), 7.36-7.22 (m, 5H), 7.23-7.00 (m, 5H), 5.39 (s, 2H), 5.32 (s,
2H), 4.50 (d, J=22.2 Hz, 2H), 4.35 (t, J=5.0 Hz, 4H), 3.54 (t,
J=5.1 Hz, 3H), 3.35-3.20 (m, 3H), 3.18-3.05 (m, 2H), 2.58 (d, J=6.3
Hz, 2H), 2.35-1.82 (m, 2H), 2.14 (s, 3H), 1.88 (s, 3H).
Example 310:
(R)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(2-((2-hydroxye-
thyl)amino)ethoxy)-2,2'-dimethyl-3''-(methylsulfonyl)-[1,1':3',1''-terphen-
yl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00552##
[2337] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=843.111. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.98 (s, 1H), 8.91 (s, 1H), 8.42 (s,
1H), 7.87 (d, J=2.2 Hz, 1H), 7.74 (dd, J=8.5, 2.3 Hz, 1H), 7.55 (s,
1H), 7.53-7.11 (m, 7H), 7.08 (s, 1H), 5.36 (s, 2H), 5.33 (s, 2H),
4.66-4.52 (m, 2H), 4.28 (s, 2H), 4.01 (d, J=12.2 Hz, 1H), 3.93-3.72
(m, 3H), 3.71-3.59 (m, 2H), 3.33 (s, 3H), 3.35-3.30 (m, 2H), 2.15
(s, 3H), 1.90 (s, 3H), 1.52 (s, 3H).
Example 311: (S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)
methoxy)-4-((4''-(2-((2-hydroxyethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3'-
,1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic
acid
##STR00553##
[2339] 3-bromo-4'-(2,2-diethoxyethoxy)-2-methyl-1,1'-biphenyl (1.6
g, 4.22 mmol) was dissolved in 1,4-dioxane (4 ml). Hydrochloric
acid (conc., 0.8 ml) was added dropwise, the mixture was left
stirring at RT for 2 h. Ethyl acetate and water were added to the
mixture. The organic layer was washed with saturated aqueous sodium
bicarbonate and then concentrated under vacuum to give
2-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy) acetaldehyde as
the crude.
[2340] 2-aminoethan-1-ol (1.29 g, 21.1.3 mmol) was dissolved in
ethanol (20 ml), 2-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)
acetaldehyde (the above crude, 4.22 mmol) in CH.sub.2Cl.sub.2 (8
ml) was added. The mixture was left stirring at RT for 30 min.
Sodium triacetoxyborohydride (5 g, 23.6 mmol) was added. The
mixture was left stirring at RT for 30 min, complete conversion
occurred. Ethyl acetate and water were added to quench the
reaction. The organic layer was washed with saturated aqueous
sodium bicarbonate and concentrated under vacuum. The residue crude
was then dissolved in THF (15 ml), di-tert-butyl dicarbonate (2 g,
9.19 mmol) was added followed by addition of trimethylamine (1.49
g, 14.7 mmol). The mixture was left stirring at RT. LCMS showed
complete conversion after 15 min. Ethyl acetate and water were
added to the mixture. The organic layer was concentrated under
vacuum. The residue was purified by silica gel chromatography using
Hexanes/EtOAc as the eluent to afford tert-butyl
(2-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)ethyl)
(2-hydroxyethyl) carbamate.
[2341] Tert-butyl
(2-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)ethyl)
(2-hydroxyethyl) carbamate (1.45 g, 3.22 mmol) and
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (2.04 g, 3.93
mmol) were suspended in DMF (25.5 ml) and H.sub.2O (3.7 ml), added
K.sub.2CO.sub.3 (0.54 g, 3.91 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.26 g, 0.32 mmol). The mixture was
purged with argon and then heated to 83.degree. C. After stirring
for 1 h, the mixture was cooled to RT, diluted with ethyl acetate
and water. The organic layer was washed with brine, concentrated
under vacuum. The residue was purified by silica gel chromatography
using Hexanes/EtOAc as the eluent to afford tert-butyl
(2-((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)meth-
yl)-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-yl)oxy)ethyl)(2-hydroxyethyl-
)carbamate.
[2342] The title compound
((S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(2-((2-hydroxy-
ethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)ben-
zyl)amino)-3-hydroxy-2-methylpropanoic acid) was synthesized
according to general reductive amination procedure G, followed by
Boc-deprotection using 20% TFA in CH.sub.2Cl.sub.2. [M+1]=765.37.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz,
1H), 8.91 (d, J=2.0 Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.55 (s, 1H),
7.46 (d, J=7.5 Hz, 1H), 7.39-6.91 (m, 10H), 5.36 (s, 2H), 5.32 (s,
2H), 4.39-4.28 (m, 2H), 4.28 (s, 2H), 4.00 (d, J=12.1 Hz, 1H),
3.92-3.81 (m, 2H), 3.79 (d, J=12.2 Hz, 1H), 3.57-3.48 (m, 2H), 3.29
(s, 2H), 2.14 (s, 3H), 1.87 (s, 3H), 1.52 (s, 3H).
Example 312:
(S)-4-((2-((3-carbamoyl-3''-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)me-
thyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2',2'-dimet-
hyl-[1,1':3',1''-terphenyl]-4-yl)oxy)ethyl)amino)-3-hydroxybutanoic
acid
##STR00554##
[2344] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=866.134. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=10.8, 2.1 Hz, 2H), 8.37
(s, 1H), 7.62 (d, J=2.3 Hz, 1H), 7.55-7.41 (m, 3H), 7.37-6.94 (m,
7H), 5.37 (s, 2H), 5.31 (s, 2H), 4.53-4.44 (m, 2H), 4.23 (s, 3H),
3.54 (d, J=5.0 Hz, 2H), 3.24-3.07 (m, 2H), 2.97 (dd, J=12.8, 9.8
Hz, 1H), 2.65 (s, 2H), 2.58 (dd, J=6.3, 3.7 Hz, 2H), 2.52 (dd,
J=6.2, 1.3 Hz, 2H), 2.14 (s, 3H), 1.90 (s, 3H).
Example 313:
(S)-2-((4-((4''-(2-(((S)-2-carboxy-1-hydroxypropan-2-yl)amino)ethoxy)-2,2-
'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyrid-
in-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00555##
[2346] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=823.064. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d,
J=2.0 Hz, 1H), 8.42 (s, 1H), 7.55 (s, 1H), 7.46 (d, J=7.6 Hz, 1H),
7.36-6.97 (m, 9H), 5.36 (s, 2H), 5.32 (s, 2H), 4.37 (t, J=5.1 Hz,
2H), 4.28 (s, 2H), 4.03 (dd, J=14.7, 12.1 Hz, 2H), 3.82 (dd,
J=16.0, 12.1 Hz, 2H), 3.56 (t, J=5.2 Hz, 2H), 2.15 (s, 3H), 1.88
(s, 3H), 1.60 (s, 3H), 1.52 (s, 3H).
Example 314: (S)-4-((4-((4`
`-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-3'-fluoro-2,2'-dimethy-
l-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00556##
[2348] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=841.176. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=11.9, 2.0 Hz, 2H), 8.37
(t, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.50-7.40 (m, 1H), 7.35-7.00 (m,
9H), 5.37 (s, 2H), 5.31 (s, 2H), 4.50-4.36 (m, 2H), 4.35 (dt,
J=9.8, 3.3 Hz, 1H), 4.23 (s, 2H), 3.60-3.52 (m, 2H), 3.38 (dd,
J=12.7, 3.0 Hz, 1H), 3.24-3.09 (m, 2H), 2.97 (dd, J=12.7, 9.8 Hz,
1H), 2.65 (s, 1H), 2.58 (d, J=6.3 Hz, 2H), 2.51 (dd, J=6.3, 1.0 Hz,
2H), 2.13 (s, 3H), 1.89 (s, 3H).
Example 315: (S)-4-((4-((4`
`-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2'-chloro-2,2'-dimethy-
l-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00557##
[2350] The title compound was synthesized according to general
reductive amination procedure G. [M+1]=857.047. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=11.0, 2.0 Hz, 2H), 8.37
(s, 1H), 7.50 (d, J=1.3 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.35-6.98
(m, 9H), 5.37 (s, 2H), 5.31 (s, 2H), 4.35 (q, J=6.1, 5.5 Hz, 3H),
4.23 (s, 3H), 3.54 (t, J=5.1 Hz, 2H), 3.41-3.32 (m, 1H), 3.23-3.05
(m, 2H), 2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.58 (d, J=6.3 Hz, 2H),
2.51 (dd, J=6.2, 1.1 Hz, 2H), 2.13 (d, J=4.2 Hz, 3H), 1.74 (d,
J=2.5 Hz, 3H).
Example 317:
(3S,3'S)-4,4'-(((3,3'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-q-
uaterphenyl]-4,4'''-diyl)bis(methylene))bis(azanediyl))bis(3-hydroxybutano-
ic acid)
##STR00558##
[2352] The title compound was prepared analogously to Example 322
according to general reductive amination procedure G. [M+1]=657.32.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.44 (d, J=7.7 Hz,
2H), 7.32 (t, J=7.6 Hz, 2H), 7.22 (dd, J=7.7, 1.4 Hz, 2H), 7.15
(dd, J=7.5, 1.5 Hz, 2H), 7.06 (d, J=1.4 Hz, 2H), 7.00 (dd, J=7.6,
1.5 Hz, 2H), 4.36-4.24 (m, 6H), 3.95 (s, 6H), 3.24 (dd, J=12.7, 3.1
Hz, 2H), 3.03 (dd, J=12.8, 9.8 Hz, 2H), 2.56 (d, J=6.3 Hz, 4H),
1.96 (s, 6H).
Example 323:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''--
((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl-
)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00559##
[2354] The title compound was synthesized according to general
reductive amination procedure H with
5-(aminomethyl)pyrrolidin-2-one hydrochloride in place of
(2S,4R)-4-hydroxypiperidine-2-carboxylic acid. [M+1]=788.98.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz,
1H), 8.91 (d, J=1.9 Hz, 1H), 8.45-8.35 (m, 1H), 7.58 (d, J=8.1 Hz,
2H), 7.55 (s, 1H), 7.47 (d, J=8.2 Hz, 3H), 7.32 (t, J=7.6 Hz, 1H),
7.27 (t, J=7.6 Hz, 1H), 7.23-7.17 (m, 1H), 7.17-7.10 (m, 2H), 7.08
(s, 1H), 5.36 (s, 2H), 5.32 (s, 2H), 4.37-4.25 (m, 4H), 4.06-3.97
(m, 2H), 3.80 (d, J=12.1 Hz, 1H), 3.27-3.20 (m, 2H), 2.50-2.30 (m,
3H), 2.14 (s, 3H), 2.00-1.81 (m, 4H), 1.52 (s, 3H).
Example 324:
(S)-4-(((3-(3-cyanopropoxy)-4'''-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-
',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4-yl)methyl)amino)-3-hy-
droxybutanoic acid
##STR00560##
[2356] 4-bromo-2-hydroxybenzaldehyde (220 mg, 1.1 mmol),
4-bromobutanenitrile (148 mg, 1 mmol) and K.sub.2CO.sub.3 (276 mg,
2 mmol) were suspended in DMF (4 mL). The mixture was sealed, and
heated at 70.degree. C. for 12 h. The mixture was diluted with
ether (50 mL), and washed with aq. 1 M NaOH and brine. The organic
layer was dried over Mg.sub.2SO.sub.4, and concentrated to provide
260 mg (97%) of 4-(5-bromo-2-formylphenoxy)butanenitrile.
[2357]
2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolane) (20 mg, 0.04 mmol),
4-(5-bromo-2-formylphenoxy)butanenitrile (14 mg, 0.05 mmol),
Pd(PPh3)4 (5 mg, 0.004 mmol), and K2CO3 (20 mg, 0.14 mmol) were
charged in a vial and suspended in Dioxane (1 mL) and water (0.1
mL). The mixture was sparged with argon for 2 min, and sealed with
a teflon coated cap. The mixture was stirred at 90.degree. C. for 4
h. After cooling to room temperature, the reaction was diluted with
ethyl acetate and brine. The organic layer was separated, dried
with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to
provide
(R)-4-((4-formyl-4'''-((3-hydroxypyrrolidin-1-yl)methyl)-2',2''-dimethyl--
[1,1':3',1'':3'',1'''-quaterphenyl]-3-yl)oxy)butanenitrile as the
crude product.
[2358] The title compound was synthesized following general
reductive amination procedure G using
(R)-4-((4-formyl-4'''-((3-hydroxypyrrolidin-1-yl)methyl)-2',2''-dimethyl--
[1,1':3',1'':3',1'''-quaterphenyl]-3-yl)oxy)butanenitrile as the
crude starting material. [M+1]=648.38. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.64-7.55 (m, 2H), 7.47 (d, J=7.8 Hz,
3H), 7.32 (t, J=7.9 Hz, 2H), 7.27-7.19 (m, 2H), 7.15 (dt, J=7.5,
1.8 Hz, 2H), 7.08 (d, J=1.5 Hz, 1H), 7.03 (dd, J=7.7, 1.5 Hz, 1H),
4.67-4.28 (m, 6H), 4.25 (t, J=5.7 Hz, 2H), 3.82-3.41 (m, 2H),
3.40-3.21 (m, 3H), 3.08 (dd, J=12.7, 9.8 Hz, 1H), 2.71 (t, J=6.8
Hz, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.50-1.98 (m, 4H), 1.95 (d, J=5.7
Hz, 6H).
Example 325:
(S)-3-hydroxy-4-(((4'''-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2',2'-dime-
thyl-3-(trifluoromethoxy)-[1,1':3',1'':3'',1'''-quaterphenyl]-4-yl)methyl)-
amino)butanoic acid
##STR00561##
[2360] The title compound was prepared analogously to Example 324
according to general reductive amination procedure G using
4-bromo-2-(trifluoromethoxy)benzaldehyde in place of
4-(5-bromo-2-formylphenoxy)butanenitrile in the previous Suzuki
cross-coupling step. [M+1]=649.40. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.73 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.0
Hz, 2H), 7.53-7.45 (m, 3H), 7.45-7.39 (m, 1H), 7.39-7.29 (m, 2H),
7.29-7.10 (m, 4H), 4.70-4.17 (m, 6H), 3.83-3.42 (m, 2H), 3.33 (m,
3H), 3.11 (dd, J=12.7, 9.9 Hz, 1H), 2.57 (d, J=6.3 Hz, 2H),
2.51-1.99 (m, 2H), 1.99-1.88 (m, 6H).
Example 326:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-((((5-cyanopyri-
din-3-yl)methyl)amino)methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00562##
[2362] (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid
(1 g, 4 mmol), 1,3-dibromo-2-methylbenzene (2 g, 8 mmol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.32 g, 0.4 mmol) and potassium
carbonate (1.6 g, 12 mmol) were suspended in 10 mL dioxane and 1 mL
water. The mixture was sparged for 5 min with argon and heated to
90.degree. C. in a heating block for 4 h. After cooling to room
temperature, the reaction was diluted with EtOAc and brine. The
organic layer was separated, dried with Na.sub.2SO.sub.4 and
concentrated. Purified by silica gel chromatography (eluting with
EtOAc-Hex) to provide tert-butyl
((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate.
[2363] Tert-butyl
((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate (135 mg,
0.36 mmol) was dissolved in 5 mL DCM. 1 mL of TFA was added
dropwise and stirred for 2 h. The reaction was diluted with DCM,
and quenched carefully with sat NaHCO.sub.3. The organic layer was
separated, and the aqueous layer was extracted with DCM. The
combined organics were dried over Na2SO4, filtered, and
concentrated to provide the crude amine. To this amine was added
5-formylnicotinonitrile (53 mg, 0.4 mmol), and DCM (5 mL). The
resulting solution was allowed to stir for 1 h at room temperature.
Sodium triacetoxyborohydride (230.22 mg, 1.09 mmol) was added in
one portion, and stirred for an additional 3 h. The reaction was
diluted with DCM, and washed with NaHCO.sub.3, and Brine. The
organic layer was dried over Na.sub.2SO.sub.4, and concentrated and
purified silica gel chromatography (20% MeOH in DCM) to provide
5-((((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)amino)methyl)nicotin-
onitrile.
[2364]
5-((((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)amino)methyl)n-
icotinonitrile (40 mg, 0.1 mmol), Intermediate 13 (40 mg, 0.08
mmol), Pd(PPh3)4 (9 mg, 0.008 mmol), and K.sub.2CO.sub.3 (32 mg,
0.23 mmol) were charged in a vial and suspended in Dioxane (2 mL)
and water (0.2 mL). The mixture was sparged with argon for 2 min,
and sealed with a teflon coated cap. The mixture was stirred at
90.degree. C. for 4 h. After cooling to room temperature, the
reaction was diluted with ethyl acetate and brine. The organic
layer was separated, dried with anhydrous sodium sulfate, filtered,
and concentrated to provide
5-((4-chloro-5-((4''-((((5-cyanopyridin-3-yl)methyl)amino)methyl)-2,2'-di-
methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicoti-
nonitrile.
[2365] The title compound was synthesized following general
reductive amination procedure G using
5-((4-chloro-5-((4''-((((5-cyanopyridin-3-yl)methyl)amino)methyl)-2,2'-di-
methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicoti-
nonitrile as the crude starting material. [M+1]=807.73. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 9.00 (d, J=1.9 Hz, 1H), 8.95
(d, J=2.1 Hz, 1H), 8.93 (t, J=2.4 Hz, 2H), 8.34 (d, J=20.0 Hz, 2H),
7.58 (d, J=8.0 Hz, 2H), 7.52-7.38 (m, 4H), 7.37-7.09 (m, 5H), 7.08
(s, 1H), 5.38 (s, 2H), 5.31 (s, 2H), 4.45 (s, 2H), 4.39 (s, 2H),
4.30-4.17 (m, 3H), 3.20 (dd, J=12.8, 3.0 Hz, 1H), 3.01-2.92 (m,
1H), 2.57-2.46 (m, 2H), 2.14 (s, 3H), 1.88 (s, 3H).
Example 327:
(S)-4-((2-((3'-((S)-1-((3-bromo-5-((((S)-3-carboxy-2-hydroxypropyl)amino)-
methyl)-6-(3-cyanopropoxy)pyridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-2'--
methyl-[1,1'-biphenyl]-4-yl)oxy)ethyl)amino)-3-hydroxybutanoic
acid
##STR00563##
[2367]
(R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H--
inden-1-ol (2 g, 7.7 mmol), 1,3-dibromo-2-methylbenzene (3.8 g,
15.4 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.44 g, 0.77 mmol)
and potassium carbonate (2.1 g, 15.4 mmol) were suspended in 20 mL
dioxane and 2 mL water. The mixture was sparged for 10 min with
argon and heated to 90.degree. C. in a heating block for 4 h. After
cooling to room temperature, the reaction was diluted with EtOAc
and brine. The organic layer was separated, dried with
Na.sub.2SO.sub.4 and concentrated. Purified by silica gel
chromatography (eluting with EtOAc-Hex) to provide
(R)-4-(3-bromo-2-methylphenyl)-2,3-dihydro-1H-inden-1-ol.
[2368] 4-bromophenol (2 g, 11.6 mmol), K.sub.2CO.sub.3 (3.2 g,
23.12 mmol), and 2-bromoethan-1-ol (4.3 g, 34.7 mmol) were
suspended in DMF (15 mL). The reaction was heated at 110.degree. C.
for 16 h. The reaction was cooled, and diluted with ether (200 mL).
The ether layer was washed with water, aq. 1 M NaOH, brine, dried
over anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to provide the crude alcohol. This crude alcohol was added
TBSC1 (5.2 g, 34 mmol) and suspended in DMF (15 mL). Imidazole (2.4
g, 34.7 mmol) was added in portions, and the mixture was stirred at
room temperature for 6 h. The reaction was diluted with ether (200
mL) and was washed with water (2.times.), brine, dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure.
Purification by silica gel chromatography (eluting with EtOAc-Hex)
provided (2-(4-bromophenoxy)ethoxy)(tert-butyl)dimethylsilane.
[2369] (2-(4-bromophenoxy)ethoxy)(tert-butyl)dimethylsilane (2.15
g, 6.5 mmol), bis(pinacolato)diboron (2.0 g, 7.8 mmol), KOAc (1.5
g, 15 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride (0.41 g, 0.50 mmol) were suspended in 10 mL dioxane and
argon was bubbled through the mixture for 5 min. The reaction was
heated to 90 C for 3 h, after which the reaction was cooled to room
temperature and diluted with 100 mL EtOAc. The reaction mixture was
filtered through a celite pad, concentrated under reduced pressure,
and purified by silica gel chromatography to provide
tert-butyldimethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy)ethoxy)silane.
[2370] (R)-4-(3-bromo-2-methylphenyl)-2,3-dihydro-1H-inden-1-ol
(1.5 g, 4.9 mmol),
tert-butyldimethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy)ethoxy)silane. (2.06 g, 5.4 mmol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.20 g, 0.25 mmol) and potassium
carbonate (2.1 g, 15 mmol) were suspended in 15 mL dioxane and 1.5
mL water. The mixture was sparged for 10 min with argon and heated
to 90.degree. C. in a heating block for 4 h. After cooling to room
temperature, the reaction was diluted with EtOAc and brine. The
organic layer was separated, dried with Na.sub.2SO.sub.4 and
concentrated. Purified by silica gel chromatography (eluting with
EtOAc-Hex) to provide
(S)-4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methyl-[1,1'-bipheny-
l]-3-yl)-2,3-dihydro-1H-inden-1-ol.
[2371]
(S)-4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methyl-[1,1'-b-
iphenyl]-3-yl)-2,3-dihydro-1H-inden-1-ol. (1.75 g, 3.7 mmol),
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (1.9 g, 7.37
mmol), cesium carbonate (2.4 g, 7.37 mmol), palladium (II) acetate
(83 mg, 0.37 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl(t-butyl
Xphos) (235 mg, 0.55 mmol) in toluene (20 mL) was heated to
85.degree. C. After 3 h, the resulting mixture was allowed to cool
to room temperature, was filtered through celite, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography (ethyl acetate in hexanes) to provide
(S)-6-((4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methyl-[1,1'-bip-
henyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)ethoxy)ni-
cotinaldehyde.
[2372]
(S)-6-((4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methyl-[1,-
1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde 487 mg, 0.7 mmol), and sodium acetate (126 mg,
2.1 mmol) was suspended in 12 mL acetic acid, and the resulting
suspension was sonicated for 5 min. Bromine (0.043 ml, 0.84 mmol)
was diluted in acetic acid (1 mL) and the resulting solution was
added dropwise to the aldehyde. After 40 min, the reaction was
diluted with methylene chloride (50 mL) and aqueous 2 M NaOH (100
mL). After stirring for 10 min, the organic layer was separated,
and the aqueous extracted with methylene chloride (75 mL). The
combined organic layers were dried, concentrated, and purified via
column chromatography to provide
(S)-5-bromo-6-((4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methyl-[-
1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)e-
thoxy)nicotinaldehyde.
[2373]
(S)-5-bromo-6-((4-(4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-me-
thyl-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethyls-
ilyl)ethoxy)nicotinaldehyde. (70 mg, 0.09 mmol) and cesium fluoride
(109 mg, 0.72 mmol) were suspended in N,N-dimethylformamide (1 mL).
The suspension was heated to 60.degree. C. for 1.5 h. After
complete desilylation as observed by LCMS, 4-Bromobutyronitrile
(80.21 mg, 0.54 mmol) was added and the resulting solution was
stirred for an additional 3 h, at 75.degree. C. The reaction was
cooled, and diluted with ethyl acetate (25 mL). The organic layer
was washed with water, brine, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure to provide the crude
alcohol. The crude alcohol was dissolved in DCM (1 mL) and
Dess-Martin periodinane (115 mg, 0.27 mmol) was added. After
stirring for 12 h at room temperature, the reaction was poured into
15 mL of 1N aqueous sodium hydroxide and extracted with methylene
chloride (3.times.). The combined organics were dried over
anhydrous sodium sulfate, filtered, and concentrated to provide
(S)-4-((5-bromo-3-formyl-6-((4-(2-methyl-4'-(2-oxoethoxy)-[1,1'-biphenyl]-
-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)pyridin-2-yl)oxy)butanenitrile
as the crude product.
[2374] The title compound was synthesized following general
reductive amination procedure G using
(S)-4-((5-bromo-3-formyl-6-((4-(2-methyl-4'-(2-oxoethoxy)-[1,1'-biphenyl]-
-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)pyridin-2-yl)oxy)butanenitrile
as the crude starting material. [M+1]=831.295. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.99 (s, 1H), 7.42 (t, J=7.3 Hz,
1H), 7.36-7.23 (m, 4H), 7.21-7.16 (m, 2H), 7.15-7.05 (m, 3H), 6.60
(t, J=5.7 Hz, 1H), 4.61 (t, J=5.9 Hz, 2H), 4.42-4.26 (m, 4H),
4.26-4.21 (m, 2H), 3.54 (t, J=5.2 Hz, 2H), 3.35 (dd, J=12.7, 3.1
Hz, 1H), 3.29-3.25 (m, 1H), 3.18-3.01 (m, 2H), 3.00-2.62 (m, 5H),
2.61-2.48 (m, 4H), 2.33-2.05 (m, 3H), 2.02-1.92 (m, 3H).
Example 328:
(3S,3'S)-4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene-
))bis(oxy))bis(5-bromo-2-(((S)-5-oxopyrrolidin-2-yl)methoxy)pyridine-6,3-d-
iyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00564##
[2376] The title compound was synthesized analogously to Example
121 using (S)-5-(hydroxymethyl)pyrrolidin-2-one in place of
5-(hydroxymethyl)isophthalonitrile, and following reductive
amination procedure G. MS (m/z) 522.23 (M+2H).sup.2+. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.96 (s, 2H), 7.50-7.41 (m,
2H), 7.24 (t, J=7.6 Hz, 2H), 7.12-7.02 (m, 2H), 5.66-5.48 (m, 4H),
4.71-4.58 (m, 2H), 4.58-4.44 (m, 2H), 4.38-4.26 (m, 2H), 4.22-4.07
(m, 4H), 3.53-3.34 (m, 4H), 3.26-3.13 (m, 2H), 3.07-2.86 (m, 4H),
2.64-2.46 (m, 4H), 2.45-2.27 (m, 2H), 2.15-1.93 (m, 8H).
Example 329:
(S)-2-((4-((3'-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxy-2-methylpropanoic acid
##STR00565##
[2378] N,N-Diisopropylethylamine (380 .mu.L, 2.18 mmol) was added
to a solution of
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate (830 mg, 2.18 mmol),
3-((tert-butoxycarbonyl)amino)propanoic acid (413 mg, 2.18 mmol)
and 3-bromo-2-methylbenzohydrazide (500 mg, 2.18 mmol) in
dimethylformamide (3 mL). After 18 h the reaction was complete. The
reaction was diluted with ethyl acetate (20 mL) and washed with
water (3.times.10 mL) and brine (10 mL). The organic phase was
dried over sodium sulfate and the solvent was removed under reduced
pressure. The residue was subjected to flash chromatography (0-100%
ethyl acetate/hexanes). The fractions containing product were
combined and the solvent was removed under reduced pressure,
providing tert-butyl
(3-(2-(3-bromo-2-methylbenzoyl)hydrazinyl)-3-oxopropyl)carbamate.
[2379] 4-Toluenesulfonyl chloride (539 mg, 2.83 mmol) was added to
a mixture of tert-butyl
(3-(2-(3-bromo-2-methylbenzoyl)hydrazinyl)-3-oxopropyl)carbamate
(755 mg, 1.89 mmol), and triethylamine (789 .mu.L, 5.66 mmol) in
dichloromethane (10 mL). After 45 min the solvent was removed under
reduced pressure. The residue was taken up in ethyl acetate (70 mL)
and washed with saturated ammonium chloride (20 mL), saturated
sodium bicarbonate (2.times.20 mL) and brine (20 mL). The organic
phase was dried over sodium sulfate and the solvent was removed
under reduced pressure. The residue was subjected to flash
chromatography (0-100% ethyl acetate/hexanes). The fractions
containing product were combined and the solvent was removed under
reduced pressure, providing tert-butyl
(2-(5-(3-bromo-2-methylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate.
[2380]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (200 mg,
0.386 mmol), tert-butyl
(2-(5-(3-bromo-2-methylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate
(221 mg, 0.578 mmol), tetrakis(triphenylphosphine)palladium (0)
(44.5 mg, 0.0386 mmol), potassium carbonate (107 mg, 0.771 mmol) in
water (1 mL), and dimethylformamide (10 mL) was degassed with argon
for 2 minutes. The above were combined and heated at 90.degree. C.
for 1 hour. The reaction was diluted with ethyl acetate (20 mL) and
washed with water (3.times.10 mL) and brine (10 mL). The organic
phase was dried over sodium sulfate and the solvent was removed
under reduced pressure. The residue was subjected to flash
chromatography (0-100% EtOAc/hexanes). The fractions containing
product and the solvent was removed under reduced pressure
providing tert-butyl
(2-(5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)met-
hyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbam-
ate.
[2381] A mixture of (S)-2-amino-3-hydroxy-2-methylpropanoic acid
(86 mg, 0.76 mmol), potassium hydroxide (40.4 mg, 0.76 mmol), in
ethanol (3 mL) was sonicated until most material dissolved. A
solution of tert-butyl
(2-(5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)met-
hyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbam-
ate (100 mg, 0.144 mmol). After 5 minutes acetic acid (1 drop) and
sodium triacetoxyborohydride (153 mg, 0.76 mmol). After 45 min the
solvent was removed under reduced pressure. The residue was taken
up in dimethylformamide (0.7 mL), water (0.5 ml), methanol (0.5 mL)
with 0.1 mL oftrifluoroacetic acid and filtered. The solution was
subjected to preparative HPLC (eluant: 0.1% trifluoroacetic acid in
acetonitrile/water). The fractions containing product were combined
and subjected to lyophilization. The residue was taken up in
dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL). After 40
minutes the reaction was diluted with acetonitrile (5 mL) and
co-evaporated until .about.1 mL remained. The material was
co-evaporated with acetonitrile two more times. The residue was
taken up in methanol (0.5 mL) and water (0.5 mL). The solution was
subjected to preparative HPLC (eluant: 0.1% trifluoroacetic acid in
acetonitrile/water). The fractions containing product were combined
and subjected to lyophilization, providing
(S)-2-((4-((3'-(5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,34-oxadiazol-2--
yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridi-
n-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid.
[M+1]=697.14. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.98
(d, J=2.1 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H),
7.93 (dd, J=7.9, 1.4 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=7.6 Hz, 1H),
7.47 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz,
1H), 7.14 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 5.38 (s, 2H), 5.34 (s,
2H), 4.28 (s, 2H), 4.00 (d, J=12.1 Hz, 1H), 3.79 (d, J=12.1 Hz,
1H), 3.52 (t, J=6.8 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.33 (s, 3H),
2.11 (s, 3H), 1.52 (s, 3H).
Example 330:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(1-
-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-3-yl)methoxy)benz-
yl)amino)-3-hydroxybutanoic acid
##STR00566##
[2383] Potassium carbonate (4.44 g, 32.2 mmol) was added to a
solution of the 3-bromo-2-methylbenzaldehyde (3.2 g, 16.1 mmol) and
dimethyl (1-diazo-2-oxopropyl)phosphonate (3.7 g, 19.3 mol) in
methanol (30 mL). After 1 h solid was removed by filtration. The
solvent was removed under reduced pressure. The residue was
subjected to flash chromatography (0-50% ethyl acetate/hexanes).
The fractions containing product were combined and the solvent was
removed under reduced pressure, providing
1-bromo-3-ethynyl-2-methylbenzene.
[2384] A solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (1 M, 19.9 mL, 19.9 mmol) was added to a solution
of 1-bromo-3-ethynyl-2-methylbenzene (2.59 g, 13.3 mmol) in
tetrahydrofuran (30 mL) at -78.degree. C. over a period of 2
minutes. After 15 min triisopropylsilyl chloride (3.1 mL, 14.6
mmol) was added dropwise. After 10 min the reaction was warmed to
0.degree. C. After another 20 min the reaction was complete. The
reaction was quenched with saturated ammonium chloride (75 mL). The
aqueous phase was extracted with DCM (3.times.50 mL). The combined
organic phases were washed with brine (50 mL) and dried over sodium
sulfate. The solvent was removed under reduced pressure. The
residue was subjected to flash chromatography (0-10% ethyl
acetate/hexanes). The fractions containing product were combined
and the solvent was removed under reduced pressure, providing
((3-bromo-2-methylphenyl)ethynyl)triisopropylsilane.
[2385]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (3.0 g,
5.78 mmol), ((3-bromo-2-methylphenyl)ethynyl)triisopropylsilane
(2.64 g, 7.52 mmol), tetrakis(triphenylphosphine)palladium(0) (668
mg, 0.578 mmol), potassium carbonate (1.60 g, 11.6 mmol) in water
(5 mL), and dimethylformamide (30 mL) was degassed with argon for 2
minutes. The above were combined and heated at 90.degree. C. for 1
hour. The reaction was diluted with ethyl acetate (100 mL) and
washed with water (3.times.50 mL) and brine (50 mL). The organic
phase was dried over sodium sulfate and the solvent was removed
under reduced pressure. The residue was subjected to flash
chromatography (0-100% EtOAc/hexanes). The fractions containing
product and the solvent was removed under reduced pressure
providing
5-((4-chloro-5-((2,2'-dimethyl-3'-((triisopropylsilyl)ethynyl)--
[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[2386] A solution of tetrabutylammonium fluoride (1 M, 4.7 mL, 4.69
mmol) in tetrahydrofuran was added to a solution of
5-((4-chloro-5-((2,2'-dimethyl-3'-((triisopropylsilyl)ethynyl)-[1,1'-biph-
enyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (2.83 g,
4.27 mmol) in tetrahydrofuran (20 mL) at 0.degree. C. After 10
minutes the reaction was diluted with ethyl acetate (150 ml) and
washed with water (2.times.50 mL) lithium chloride (1 M, 2.times.50
mL) and brine (50 mL). The organic phase was dried over sodium
sulfate and the solvent was removed under reduced pressure. The
residue was subjected to flash chromatography (0-100% ethyl
acetate/hexanes). The fractions containing product were combined
and the solvent was removed under reduced pressure, providing
5-((4-chloro-5-((3'-ethynyl-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-
methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[2387]
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-ethynyl-2,-
2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid was synthesized according to general reductive amination
procedure G.
[2388] tert-butyl 4-azidopiperidine-1-carboxylate (14 mg 0.0621
mmol) was added to a mixture of
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-ethynyl-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid (30 mg, 0.0414 mmol) copper powder (26.3 mg, 0.00415 mmol)
saturated copper (II) sulfate (1.26 M, 32 .mu.L, 0.00416 mmol) in
tetrahydrofuran (3 mL). After 24 h the solvent was removed under
reduced pressure. The residue was taken up in dimethylformamide
(0.7 mL), water (0.5 ml), methanol (0.5 mL) with 0.1 mL of
trifluoroacetic acid and filtered. The solution was subjected to
preparative HPLC (eluant: 0.1% trifluoroacetic acid in
acetonitrile/water). The fractions containing product were combined
and subjected to lyophilization.
[2389] The residue was taken up in dichloromethane (5 mL) and
trifluoroacetic acid (0.5 mL). After 40 minutes the reaction was
diluted with acetonitrile (5 mL) and co-evaporated until .about.1
mL remained. The material was co-evaporated with acetonitrile two
more times. The residue was taken up in methanol (0.5 mL) and water
(0.5 mL). The solution was subjected to preparative HPLC HPLC
(eluant: 0.1% trifluoroacetic acid in acetonitrile/water). The
fractions containing product were combined and subjected to
lyophilization, providing
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(1-
-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-3-yl)methoxy)benz-
yl)amino)-3-hydroxybutanoic acid bis trifluoroacetate.
[M+1]=736.11. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.96
(d, J=2.1 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H),
8.23 (s, 1H), 7.60-7.54 (m, 1H), 7.51 (s, 1H), 7.50-7.46 (m, 1H),
7.39-7.32 (m, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.21-7.11 (m, 2H), 7.09
(s, 1H), 5.38 (s, 2H), 5.32 (s, 2H), 5.00-4.89 (m, 1H), 4.30-4.18
(m, 3H), 3.64 (t, J=4.1 Hz, 1H), 3.60 (t, J=4.1 Hz, 1H), 3.28-3.16
(m, 1H), 2.98 (dd, J=12.8, 9.8 Hz, 1H), 2.57-2.48 (m, 3H),
2.48-2.35 (m, 2H), 2.13 (s, 3H), 2.08 (s, 3H).
Example 331:
5-[[5-[[3-(3-bromo-2-methyl-phenyl)-2-methyl-phenyl]methoxy]-4-chloro-2-f-
ormylphenoxy]methyl]pyridine-3-carbonitrile
##STR00567##
[2391] The title compound was synthesized in analogy to Example
330, replacing tert-butyl 4-azidopiperidine-1-carboxylate with
3-(azidomethyl)pyrrolidine. [M+1]=736.1. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.10 (s, 1H), 9.03 (d, J=2.0 Hz, 1H), 9.02
(d, J=2.2 Hz, 1H), 8.86 (s, 1H), 8.56 (s, 2H), 8.47 (t, J=2.1 Hz,
1H), 8.45 (d, J=0.9 Hz, 1H), 7.74-7.67 (m, 1H), 7.57 (s, 1H), 7.50
(d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H),
7.19 (s, 1H), 7.18-7.07 (m, 2H), 5.54 (s, 1H), 5.37 (s, 2H), 5.32
(s, 2H), 4.85-4.66 (m, 2H), 4.21-4.08 (m, 4H), 4.03 (s, 1H), 3.26
(s, 1H), 3.19 (m, 1H), 2.99 (s, 1H), 2.85 (d, J=15.5 Hz, 1H),
2.44-2.36 (m, 1H), 2.14 (m, 1H), 2.08 (s, 3H), 2.06 (s, 3H),
2.02-1.84 (m, 1H), 1.74 (dt, J=12.9, 8.6 Hz, 1H).
Example 332:
(S)-2-(((5-chloro-6-(((S)-4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy-
)-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((3,5-dicyanobenz-
yl)oxy)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic
acid
##STR00568## ##STR00569##
[2393] In a glass vial,
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (172.00 mg, 0.30
mmol) was dissolved in 5.00 ml of DMF. To this solution, CsF
(180.00 mg, 1.0 mmol) was added at room temperature and mixture was
stirred at 60.degree. C. LCMS showed formation of desired product
after 2 hours. In the same reaction flask,
5-(bromomethyl)isophthalonitrile (140.00 mg, 0.63 mmol) and
K.sub.2CO.sub.3 (160.00 mg, 1.0 mmol) were added at room
temperature. Mixture was then stirred at 60.degree. C. under Argon
for 1 hour. Crude was diluted with DCM and washed with water.
Organic layer was dried over magnesium sulfate and volatiles were
removed under reduced pressure. Crude was dry-loaded to a silica
gel column and eluted with 0-20% DCM/EtOAc to afford
(S)-5-(((6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5--
chloro-3-formylpyridin-2-yl)oxy)methyl)isophthalonitrile.
[2394] In a round flask, 2-(trimethylsilyl)ethyl
(2-hydroxyethyl)(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenox-
y)ethyl)carbamate (146.00 mg, 0.32 mmol),
(S)-5-(((6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5--
chloro-3-formylpyridin-2-yl)oxy)methyl)isophthalonitrile (200.00
mg, 0.32 mmol), PdCl.sub.2(dppf) (24.00 mg, 0.032 mmol), and
K.sub.2CO.sub.3 (89.00 mg, 0.65 mmol) were dissolved in 10.00 ml of
dioxane and 1.00 ml of water. Flask was evacuated and filled with
Argon. Mixture was stirred at 85.degree. C. overnight. Crude was
diluted with EtOAc and filtrated through celite. Volatiles were
removed under reduced pressure and crude was dry-loaded to a silica
gel column and eluted with 0-30% EtOAc/Hex to afford
2-(trimethylsilyl)ethyl
(S)-(2-((2'-chloro-3'-(1-((3-chloro-6-((3,5-dicyanobenzyl)oxy)-5-formylpy-
ridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-[1,1'-biphenyl]-4-yl)oxy)ethyl)-
(2-hydroxyethyl)carbamate.
[2395] In a round flask, 2-(trimethylsilyl)ethyl
(S)-(2-((2'-chloro-3'-(1-((3-chloro-6-((3,5-dicyanobenzyl)oxy)-5-formylpy-
ridin-2-yl)oxy)-2,3-dihydro-H-inden-4-yl)-[1,1'-biphenyl]-4-yl)oxy)ethyl)(-
2-hydroxyethyl)carbamate (268.00 mg, 0.31 mmol) was dissolved in
5.00 ml of DMF and CsF (188.00 mg, 1.0 mmol) was added at room
temperature. Mixture was stirred at 60.degree. C. for 3 hours. LCMS
showed formation of desired product. Crude was diluted with EtOAc
and washed with water. Organic layer was dried over magnesium
sulfate and volatiles were removed under reduced pressure.
Volatiles were removed under reduced pressure and crude was
dry-loaded to a silica gel column and eluted with 30-100% EtOAc/Hex
to afford
(S)-5-(((5-chloro-6-((4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy)-[1-
,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-formylpyridin-2-yl)ox-
y)methyl)isophthalonitrile.
[2396]
(S)-2-(((5-chloro-6-(((S)-4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)-
ethoxy)-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((3,5-dicya-
nobenzyl)oxy)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic
acid was synthesized according to general reductive amination
procedure D. [M+1]=822.25. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 8.22 (d, J=8.7 Hz, 2H), 8.05 (d, J=18.6 Hz, 1H), 7.95 (s,
1H), 7.48-7.33 (m, 4H), 7.20 (d, J=6.0 Hz, 2H), 7.10 (d, J=8.5 Hz,
2H), 6.48 (s, 2H), 5.60 (d, J=10.3 Hz, 3H), 4.36 (t, J=5.0 Hz, 2H),
4.29 (s, 2H), 4.02 (d, J=12.1 Hz, 2H), 3.88-3.77 (m, 3H), 3.53 (t,
J=4.9 Hz, 2H), 3.47 (s, 1H), 3.28-3.20 (m, 2H), 3.11 (s, 2H), 1.54
(s, 3H).
Example 333:
(R)-5-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((3-hydroxypyr-
rolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-terphenyl-
]-4-yl)methyl)amino)pentanoic acid
##STR00570##
[2398]
(R)-5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-((3-hydroxypyrrolidin-1-y-
l)methyl)phenoxy)methyl)nicotinonitrile was synthesized according
to general reductive amination procedure D.
[2399] In a round flask,
(R)-5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-((3-hydroxypyrrolidin-1-yl)meth-
yl)phenoxy)methyl)nicotinonitrile (560.00 mg, 0.87 mmol),
4-bromobenzaldehyde (166.00 mg, 0.87 mmol), PdCl.sub.2dppf (80.00
mg, 0.13 mmol), and Cs.sub.2CO.sub.3 (565.00 mg, 2.0 mmol) were
dissolved in 15.00 ml of dioxane and 1.50 ml of water. Flask was
evacuated and filled with Argon. Mixture was stirred at 85.degree.
C. overnight. Crude was diluted with EtOAc and filtrated through
celite. Volatiles were removed under reduced pressure and crude was
dry-loaded to a silica gel column and eluted with 0-100% EtOAc/Hex
to provide
(R)-5-((4-chloro-5-((4''-formyl-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-y-
l)methoxy)-2-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nicotinonitr-
ile.
[2400]
(R)-5-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((3-hydr-
oxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-ter-
phenyl]-4-yl)methyl)amino)pentanoic acid was synthesized according
to general reductive amination procedure D. [M+1]=759.33. .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 9.08-8.79 (m, 2H), 8.37 (d,
J=7.6 Hz, 1H), 7.60-7.52 (m, 3H), 7.51-7.42 (m, 3H), 7.29 (dt,
J=15.8, 7.6 Hz, 2H), 7.20 (dd, J=7.7, 1.5 Hz, 1H), 7.19-7.07 (m,
4H), 5.39 (s, 2H), 5.32 (s, 2H), 4.50 (d, J=22.4 Hz, 2H), 4.35 (s,
1H), 4.25 (s, 2H), 3.55 (td, J=34.3, 30.5, 9.9 Hz, 2H), 3.29 (s,
2H), 3.15-3.04 (m, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.14 (s, 3H), 2.05
(d, J=35.0 Hz, 2H), 1.88 (s, 3H), 1.83-1.62 (m, 4H).
Example 334:
4-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyethyl)-
amino)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-yl)-
methyl)amino)butanoic acid
##STR00571## ##STR00572##
[2402]
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-(((2-hydroxyethyl)amino)methy-
l)phenoxy)methyDnicotinonitrile was synthesized according to
general reductive amination procedure E.
[2403] In a round bottom flask, Boc anhydride (1.0 g, 2.0 mmol) and
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-(((2-hydroxyethyl)amino)methyl)phen-
oxy)methyl)nicotinonitrile (337.05 mg, 2.0 mmol) were dissolved in
10.00 ml of DCM. To this solution was added one pellet of 4-DMAP at
room temperature. Mixture was stirred at room temperature for 30
min. LCMS showed partial conversion to the desired product. An
additional 337.00 mg of Boc anhydride were added at room
temperature and the mixture was stirred for another 30 min.
Methanol was added to the reaction mixture and volatiles were
removed under reduced pressure. Crude was dry-loaded to a silica
gel column and eluted with 50-100% EtOAc/Hex to afford tert-butyl
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(4,4,5,5--
tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)benzyl)(-
2-hydroxyethyl)carbamate.
[2404] In a round bottom flask tert-butyl
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(4,4,5,5--
tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yOmethoxy)benzyl)(2-
-hydroxyethyl)carbamate (230.00 mg, 0.31 mmol), 4-bromobenzaldehyde
(56.50 mg, 0.31 mmol), PdCl.sub.2dppf (9.00 mg, 0.013 mmol), and
Cs.sub.2CO.sub.3 (198.00 mg, 0.6 mmol) were dissolved in 10.00 ml
of dioxane and 1.00 ml of water. Flask was evacuated and filled
with Argon. Mixture was stirred at 100.degree. C. overnight. Crude
was diluted with EtOAc and filtrated through celite. Volatiles were
removed under reduced pressure and crude was dry-loaded to a silica
gel column and eluted with 0-100% EtOAc/Hex to afford tert-butyl
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-formyl-2,2'-dimethyl-[-
1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)(2-hydroxyethyl)carbamate.
[2405]
4-(((3''-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)-2-
-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2',2''-dimethyl-[1-
,1':3',1''-terphenyl]-4-yl)methyl)amino)butanoic acid was
synthesized according to general reductive amination procedure
D.
[2406] In a round bottom flask,
4-(((3''-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2',2''-dimethyl-[1,1':3'-
,1''-terphenyl]-4-yl)methyl)amino)butanoic acid was dissolved in
5.00 mL of DCM and 0.8 mL of TFA was added to the solution at room
temperature. Mixture was stirred at ambient temperature for 30 min.
Volatiles were removed under reduced pressure and crude was
dissolved in acetonitrile/water mixture and loaded into Gilson and
purified by reverse phase chromatography (0.1% trifluoroacetic acid
in acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt. [M+1]=719.30. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.94 (d, J=13.9 Hz, 2H), 8.38 (d, J=1.7
Hz, 1H), 7.66-7.39 (m, 6H), 7.40-7.10 (m, 5H), 7.08 (s, 1H), 5.37
(s, 2H), 5.31 (s, 2H), 4.25 (d, J=13.0 Hz, 4H), 3.83-3.70 (m, 2H),
3.20-3.07 (m, 4H), 2.48 (t, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.04-1.98
(m, 2H), 1.87 (s, 3H).
Example 335:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4'-(((S)-3-hydroxyp-
yrrolidin-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-
benzyl)amino)-3-hydroxybutanoic acid
##STR00573##
[2408] In a round bottom flask, 4-bromobenzaldehyde (2.0 g, 11.00
mmol), B.sub.2Pin.sub.2 (3.00 g, 12.00 mmol), PdCl.sub.2(dppf)
(328.00 mg, 0.5 mmol) and KOAc (3.2 g, 32.00 mmol) were dissolved
in 100.00 ml of dioxane. Flask was capped, then evacuated and
filled with argon. Mixture was stirred under argon over the weekend
at 100.degree. C. Crude was filtered through celite and volatiles
were removed under reduced pressure. Crude was dry-loaded to a
silica gel column and eluted with 0-30% EtOAc/Hex to afford
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.
[2409] In a round bottom flask,
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.5 g,
11.00 mmol), 2,6-dibromotoluene (2.85 g, 11.00 mmol),
PdCl.sub.2(dppf) (457.00 mg, 0.7 mmol) and Cs.sub.2CO.sub.3 (8.8 g,
27.00 mmol) were dissolved in 100.00 ml of dioxane and 10.00 ml of
water. Flask was capped, then evacuated and filled with argon.
Mixture was stirred under argon overnight at 100.degree. C. Crude
was filtered through celite and volatiles were removed under
reduced pressure. Crude was dry-loaded to a silica gel column and
eluted with 0-30% EtOAc/Hex to afford
3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde.
[2410]
(S)-1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)pyrrolidin-3-
-ol was synthesized according to general reductive amination
procedure E.
[2411] In a round bottom flask,
(S)-1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)pyrrolidin-3-ol
(445.00 mg, 1.10 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (600.00 mg, 1.10
mmol), PdCl.sub.2(dppf) (24.00 mg, 0.05 mmol) and Cs.sub.2CO.sub.3
(942.00 mg, 3.00 mmol) were dissolved in 10.00 ml of dioxane and
1.00 ml of water. Flask was capped, then evacuated and filled with
argon. Mixture was stirred under argon for six hours at 100.degree.
C. Crude was filtered through celite and volatiles were removed
under reduced pressure. Crude was dry-loaded to a silica gel column
and eluted with 80-100% EtOAc/Hex to afford
(S)-5-((4-chloro-2-formyl-5-((4''-((3-hydroxypyrrolidin-1-yl)me-
thyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)phenoxy)methyl)ni-
cotinonitrile.
[2412]
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(((S)-3-h-
ydroxypyrrolidin-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxybutanoic acid was synthesized
according to general reductive amination procedure D. [M+1]=761.31.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.94 (dd, J=11.1,
2.1 Hz, 2H), 8.37 (t, J=2.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.48
(dd, J=14.2, 7.0 Hz, 4H), 7.37-7.09 (m, 5H), 7.08 (s, 1H), 5.38 (s,
2H), 5.31 (s, 2H), 4.76-4.30 (m, 4H), 4.23 (s, 3H), 3.76-3.30 (m,
2H), 3.20 (dd, J=12.7, 3.0 Hz, 1H), 2.97 (dd, J=12.7, 9.8 Hz, 1H),
2.65 (s, OH), 2.51 (dd, J=6.2, 1.2 Hz, 2H), 2.14 (s, 3H), 1.89 (s,
3H).
Example 336:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4'-(((S)-3-hydroxyp-
yrrolidin-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-
benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00574##
[2414] The title compound was synthesized according to Example 335.
[M+1]=761.31. .sup.1H NMR (400 MHz, Methanol-d4) .delta. 9.07-8.93
(m, 1H), 8.96-8.85 (m, 1H), 8.42 (t, J=2.0 Hz, 1H), 7.63-7.56 (m,
2H), 7.55 (s, 1H), 7.49-7.45 (m, 3H), 7.35-7.19 (m, 3H), 7.13 (ddd,
J=11.3, 7.6, 1.4 Hz, 2H), 7.08 (s, 1H), 5.37 (s, 2H), 5.32 (s, 2H),
4.49 (dd, J=45.7, 26.2 Hz, 3H), 4.28 (s, 2H), 4.01 (d, J=12.1 Hz,
1H), 3.81 (d, J=12.1 Hz, 1H), 3.77-3.42 (m, 2H), 3.40-3.32 (m, 2H),
2.65 (s, 2H), 2.14 (s, 3H), 1.88 (s, 3H), 1.53 (s, 3H).
Example 337:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(4-((2-hydroxyet-
hyl)amino)quinazolin-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benz-
yl)amino)-3-hydroxybutanoic acid
##STR00575## ##STR00576##
[2416] In a glass vial, dissolve 6-bromo-4-chloroquinazoline (100
mg, 0.41 mmol) in 3.00 ml of ethanolamine at room temperature. Vial
was capped and solution was stirred at 110.degree. C. overnight.
LCMS showed formation of the desired product. Crude was diluted
with EtOAc and washed with water. Organic layer was dried over
magnesium sulfate and volatiles were removed under reduced pressure
to afford 2-((6-bromoquinazolin-4-yl)amino)ethan-1-ol, which was
taken to the next step without further purification.
[2417] In a round bottom flask,
2-((6-bromoquinazolin-4-yl)amino)ethan-1-ol (110.00 mg, 0.41 mmol)
was dissolved in 5.00 ml of DCM. To this solution was added Boc
anhydride (223.8 mg, 1.0 mmol) and triethylamine (166.00 mg, 2.0
mmol) at room temperature. Flask was capped and the reaction
mixture was stirred at room temperature for 1 hour. LCMS showed
conversion of the desired product. Volatiles were removed under
reduced pressure to afford tert-butyl
(6-bromoquinazolin-4-yl)(2-hydroxyethyl)carbamate.
[2418] In a round bottom flask, tert-butyl
(6-bromoquinazolin-4-yl)(2-hydroxyethyl)carbamate (80.00 mg, 0.22
mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (80.00 mg, 0.13
mmol), PdCl.sub.2(dppf) (5.00 mg, 0.008 mmol) and Cs.sub.2CO.sub.3
(96.00 mg, 0.29 mmol) were dissolved in 10.00 ml of dioxane and
1.00 ml of water. Flask was capped, then evacuated and filled with
argon. Mixture was stirred under argon overnight at 100.degree. C.
Crude was filtered through celite and volatiles were removed under
reduced pressure. Crude was dry-loaded to a silica gel column and
eluted with 80-100% EtOAc/Hex to afford (tert-butyl
(6-(3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methy-
l)-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-yl)quinazolin-4-yl)(2-hydroxy-
ethyl)carbamate.
[2419]
(S)-4-((4-((3'-(4-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)quina-
zolin-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cya-
nopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
synthesized according to general reductive amination procedure
D.
[2420] In a round bottom flask,
(S)-4-((4-((3'-(4-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)quinazolin--
6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyri-
din-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was dissolved
in 5.00 mL of DCM and 0.8 ml of TFA were added to the solution at
room temperature. Mixture was stirred at ambient temperature for 30
min. Volatiles were removed under reduced pressure and crude was
dissolved in acetonitrile/water mixture and loaded into Gilson and
purified by reverse phase chromatography (0.1% trifluoroacetic acid
in acetonitrile/water) providing the final compound upon
lyophilization as the bis-TFA salt. [M+1]=773.29. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 9.00-8.88 (m, 2H), 8.77 (s, 1H),
8.39 (d, J=14.6 Hz, 2H), 8.07 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz,
1H), 7.49 (d, J=14.0 Hz, 2H), 7.41-7.14 (m, 5H), 7.08 (s, 1H), 5.38
(s, 2H), 5.32 (s, 2H), 4.29-4.15 (m, 3H), 3.97 (t, J=5.5 Hz, 2H),
3.86 (t, J=5.4 Hz, 2H), 3.23-3.09 (m, 1H), 3.03-2.91 (m, 1H),
2.56-2.46 (m, 2H), 2.16 (s, 3H), 1.94 (s, 3H).
Example 338:
(1R,3S)-3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(2-((2-hydr-
oxyethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-
benzyl)amino)cyclopentane-1-carboxylic acid
##STR00577##
[2422]
(1R,3S)-3-((4-((4''-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-
ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-
-cyanopyridin-3-yl)methoxy)benzyl)amino)cyclopentane-1-carboxylic
acid was synthesized according to general reductive amination
procedure E.
[2423] In a round bottom flask,
(1R,3S)-3-((4-((4''-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethoxy-
)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyano-
pyridin-3-yl)methoxy)benzyl)amino)cyclopentane-1-carboxylic acid
was dissolved in 5.00 mL of DCM and 0.8 ml of TFA were added to the
solution at room temperature. Mixture was stirred at ambient
temperature for 30 min. Volatiles were removed under reduced
pressure and crude was dissolved in acetonitrile/water mixture and
loaded into Gilson and purified by reverse phase chromatography
(0.1% trifluoroacetic acid in acetonitrile/water) providing the
title compound upon lyophilization as the bis-TFA salt.
[M+1]=775.33. .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.95 (dd,
J=12.8, 2.0 Hz, 2H), 8.37 (t, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.45 (d,
J=7.6 Hz, 1H), 7.33-7.21 (m, 4H), 7.16 (ddd, J=17.9, 7.7, 1.4 Hz,
2H), 7.12-7.03 (m, 4H), 5.37 (s, 2H), 5.31 (s, 2H), 4.40-4.32 (m,
2H), 4.19 (s, 2H), 3.91-3.81 (m, 2H), 3.68 (p, J=7.2 Hz, 1H), 3.53
(t, J=5.0 Hz, 2H), 3.28-3.19 (m, 2H), 2.91 (p, J=7.3 Hz, 1H), 2.29
(dt, J=14.8, 7.7 Hz, 1H), 2.14 (s, 4H), 2.02-1.84 (m, 6H), 1.72
(dq, J=14.6, 7.7 Hz, 1H).
Example 339:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4-(pi-
perazin-1-yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-
butanoic acid
##STR00578##
[2425] In a round bottom flask, tert-butyl
4-(4-bromophenyl)piperazine-1-carboxylate (69.00 mg, 0.20 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (117.00 mg, 0.19
mmol), PdCl.sub.2(dppf) (5.00 mg, 0.008 mmol) and Cs.sub.2CO.sub.3
(125.00 mg, 0.38 mmol) were dissolved in 10.00 ml of dioxane and
1.00 ml of water. Flask was capped, then evacuated and filled with
argon. Mixture was stirred under argon overnight at 100.degree. C.
Crude was filtered through celite and volatiles were removed under
reduced pressure. Crude was dry-loaded to a silica gel column and
eluted with 50-100% EtOAc/Hex to tert-butyl
4-(3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl-
)-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-yl)piperazine-1-carboxylate.
[2426]
(S)-4-((4-((4''-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2'-dimeth-
yl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)-
methoxy)benzyl)amino)-3-hydroxybutanoic acid was synthesized
according to general reductive amination procedure E.
[2427] In a round bottom flask,
(S)-4-((4-((4''-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2'-dimethyl-[1,-
1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methox-
y)benzyl)amino)-3-hydroxybutanoic acid was dissolved in 5.00 ml of
DCM and 0.8 ml of TFA were added to the solution at room
temperature. Mixture was stirred at ambient temperature for 30 min.
Volatiles were removed under reduced pressure and crude was
dissolved in acetonitrile/water mixture and loaded into Gilson and
purified by reverse phase chromatography (0.1% trifluoroacetic acid
in acetonitrile/water) providing the title compound upon
lyophilization as the bis-TFA salt. [M+1]=746.31. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.94 (dd, J=12.2, 2.0 Hz, 2H), 8.38 (t,
J=2.1 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.36-7.00 (m,
10H), 5.37 (s, 2H), 5.31 (s, 2H), 4.23 (s, 3H), 3.50-3.37 (m, 8H),
3.19 (dd, J=12.7, 3.0 Hz, 1H), 2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.51
(dd, J=6.3, 1.0 Hz, 2H), 2.14 (s, 3H), 1.88 (s, 3H).
Example 340:
(S)-2-(((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-6-((2,2'-dichloro-4'-(-
2-((2-hydroxyethyl)amino)ethoxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)pyri-
din-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00579## ##STR00580##
[2429] Step 1: To a mixture of
(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol
(2.5 g, 9.3 mmol), 1,3-dibromo-2-chlorobenzene (3.775 g, 14.0
mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (760 mg, 0.93 mmol) and
potassium carbonate (2.57 g, 18.62 mmol) under N.sub.2 was added a
mixture of solvents (30 mL dioxane and 7.5 mL water) and heated to
85.degree. C. for 2 h. After cooling to room temperature, the
reaction was concentrated and diluted with CH.sub.2Cl.sub.2 and
water. The organic layer was separated, dried with Na.sub.2SO.sub.4
and concentrated. The residue was purified by silica gel
chromatography (eluting with 5% to 40% EtOAc-Hex) to give
(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol.
[2430] Step 2: To
(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol (2.90 g, 8.73
mmol) in DMF (25 mL) at 0.degree. C. was added NaH (60%, 420 mg).
The reaction mixture was stirred at 0.degree. C. for 1 h.
6-Chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (2.25 g, 8.73
mmol) was added into the mixture in one portion, and the mixture
was stirred at rt for 12 h. Then the mixture was treated with aq.
NH.sub.4Cl (45 mL), extracted with CH.sub.2Cl.sub.2 (3.times.50
mL). The organic phase was washed with water (3.times.50 mL), dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
by silica gel column chromatography (0-30% EtOAc/hex) to yield
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-2-(2-(trimethyls-
ilyl)ethoxy)nicotinaldehyde.
[2431] Step 3: To
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-2-(2-(trimethyls-
ilyl)ethoxy)nicotinaldehyde (2.35 g, 4.25 mmol) in a mixture of
acetonitrile (10 mL) and chloroform (10 mL) was added CMBG (980 mg,
5 mmol) at 0.degree. C. Then, 4N HCl in dioxane (1.17 mL) was added
dropwise in 15 min. The reaction mixture was warmed to rt and
stirred for 30 min. Then the mixture was treated with aq.
NaHCO.sub.3 (30 mL), extracted with DCM (3.times.30 mL), washed
with water (10 mL), dried (Na.sub.2SO.sub.4), and concentrated. The
residue was purified by silica gel column chromatography (0-15%
EtOAc/hex) to yield
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde.
[2432] Step 4: To
6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde (954 mg, 1.62 mmol) in DMF (8
mL) was added CsF (986 mg, 6 mmol). The mixture was heated to
60.degree. C. for 30 min. 5-(Chloromethyl)nicotinonitrile (371 mg,
2 mmol) was added and the mixture was stirred at 60.degree. C. for
additional 90 min. The reaction mixture was cooled to rt, filtered
over celite, and concentrated in vacuum, extracted with DCM, washed
with water, dried (Na.sub.2SO.sub.4), and concentrated. The residue
was purified by silica gel column chromatography (0-70% EtOAc/hex)
to yield
5-(((6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-3--
formylpyridin-2-yl)oxy)methyl)nicotinonitrile.
[2433] Step 5: To a mixture of
5-(((6-((3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-3--
formylpyridin-2-yl)oxy)methyl)nicotinonitrile (217 mg, 0.36 mmol),
2-(trimethylsilyl)ethyl
(2-hydroxyethyl)(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenox-
y)ethyl)carbamate (243 mg, 0.54 mmol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (14 mg, 0.018 mmol) and sodium
carbonate (152 mg, 1 mmol) under N2 was added a mixture of solvents
(2 mL dioxane and 0.2 mL water) and heated to 90.degree. C. for 12
h. The reaction mixture was cooled to rt, filtered over celite,
concentrated in vacuum. CH.sub.2Cl.sub.2 and water were added. The
aqueous layer was extracted with CH.sub.2Cl.sub.2. The organic
layer was dried and concentrated. The residue was purified by
silica gel column chromatography with 0-70% EtOAc in hexanes to
give 2-(trimethylsilyl)ethyl
(2-((2',2''-dichloro-3''-(((3-chloro-6-((5-cyanopyridin-3-yl)methoxy)-5-f-
ormylpyridin-2-yl)oxy)methyl)-[1,1':3',1''-terphenyl]-4-yl)oxy)ethyl)(2-hy-
droxyethyl)carbamate.
[2434] Step 6: To 2-(trimethylsilyl)ethyl
(2-((2',2''-dichloro-3''-(((3-chloro-6-((5-cyanopyridin-3-yl)methoxy)-5-f-
ormylpyridin-2-yl)oxy)methyl)-[1,1':3',1''-terphenyl]-4-yl)oxy)ethyl)(2-hy-
droxyethyl)carbamate (300 mg, 0.35 mmol) in DMF (8 mL) was added
CsF (215 mg, 1 mmol). The mixture was heated to 60.degree. C. for
90 min. The reaction mixture was cooled to rt, treated with water,
extracted with DCM. The organic phase was washed with water, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was used for next
reaction directly.
[2435] Step 7: To a mixture of
(S)-2-amino-3-hydroxy-2-methylpropanoic acid (115 mg, 0.96 mmol)
and
5-(((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-[1,-
1':3',1''-terphenyl]-3-yl)methoxy)-3-formylpyridin-2-yl)oxy)methyl)nicotin-
onitrile (85 mg, 0.12 mmol) in DMSO (2.5 mL) was added DIPEA (125
mg, 168 .mu.L, 0.97 mmol). The mixture was heated to 60.degree. C.
for 15 min. Then sodium triacetoxyborohydride was added, and the
mixture was stirred at 60.degree. C. for 60 min. The mixture was
diluted with Acetonitrile and water, filtered and purified by
Gilson prepared HPLC (30-85% B in 20 min) to afford
(S)-2-(((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-6-((2,2'-dichloro-4''--
(2-((2-hydroxyethyl)amino)ethoxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)pyr-
idin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.91 (s, 1H), 8.84 (s, 1H),
8.29 (s, 1H), 7.96 (s, 1H), 7.57 (m, 1H), 7.47-7.33 (m, 5H),
7.32-7.16 (m, 2H), 7.09 (m, 2H), 5.73-5.38 (m, 4H), 4.43 (m, 1H),
4.36 (m, 2H), 4.27 (s, 2H), 4.04 (m, 1H), 3.96-3.79 (m, 5H),
3.61-3.34 (m, 4H), 3.26 (m, 2H), 1.56 (s, 3H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.40H.sub.38Cl.sub.3NSO.sub.7:
806.2; found: 808.0.
Example 341:
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2'-chlor-
o-2-methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyrid-
in-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00581##
[2437] Step 1: To a mixture of 1,3-dibromo-2-chlorobenzene (1.47 g,
5.45 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(800 mg, 3.64 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (297 mg, 0.36
mmol) and potassium carbonate (1.005 g, 7.27 mmol) under N2 was
added a mixture of solvents (12 mL and 3 mL water) and heated to
85.degree. C. for 2 h. After cooling to room temperature, the
reaction was diluted with CH.sub.2Cl.sub.2 and water. The organic
layer was separated, dried with Na.sub.2SO.sub.4 and concentrated.
The residue was purified by silica gel chromatography (eluting with
5% to 40% EtOAc-Hex) to give
3'-bromo-2'-chloro-[1,1'-biphenyl]-4-ol.
[2438] Step 2: Powdered potassium carbonate (1250 mg, 9.05 mmol)
was added to a stirred solution of
3'-bromo-2'-chloro-[1,1'-biphenyl]-4-ol (1026 mg, 3.6 mmol) and
bromoacetaldehyde diethyl acetal (1.13 mL, 7.24 mmol) in anhydrous
DMF (10 mL). The resultant mixture is stirred at 95.degree. C.
under nitrogen overnight. The mixture was cooled to ambient
temperature; then water and CH.sub.2Cl.sub.2 are added to the
mixture. The organic layer is separated, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The oil is
chromatographed on silica (gradient 5-20 percent EtOAc in hexanes)
to give 3-bromo-2-chloro-4'-(2,2-diethoxyethoxy)-1,1'-biphenyl.
[2439] Step 3: A mixture of
3-bromo-2-chloro-4'-(2,2-diethoxyethoxy)-1,1'-biphenyl (285 mg,
0.71 mmol),
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (370 mg,
0.71 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089
mmol) and sodium bicarbonate (197 mg, 1.42 mmol) under N.sub.2 was
added a mixture of solvents (8 mL DMF and 2 mL water) and heated to
85.degree. C. for 1 h. The reaction mixture was concentrated in
vacuum, CH.sub.2Cl.sub.2 and water were added. The aqueous layer
was extracted with CH.sub.2Cl.sub.2. The organic layer was dried
and concentrated. The residue was purified by silica gel column
chromatography with 0-70% EtOAc in hexanes to give
5-((4-chloro-5-((2'-chloro-4''-(2,2-diethoxyethoxy)-2-methyl-[1,1':3',1''-
-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[2440] Step 4:
5-((4-chloro-5-((2'-chloro-4''-(2,2-diethoxyethoxy)-2-methyl-[1,1':3',1''-
-terphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
(55 mg, 0.077 mmol) was dissolved in 1,4-dioxane (2 mL), 0.2 ml
(conc, aq) HCl was added to the clear solution. The mixture was
left stirring at RT overnight. Sat. NaHCO.sub.3 and EtOAc were
added to the mixture. The organic layer was concentrated in vacuum.
The crude residue was used in the next step.
[2441] Step 5: Fine powder of KOH (34 mg, 0.61 mmol),
(S)-4-amino-3-hydroxybutanoic acid (73 mg, 0.61 mmol) were taken
into a small round bottle flask, added ethanol (3 mL), flushed with
N.sub.2, sonicated to give a clear solution. To the solution was
added solution of
5-((4-chloro-5-((2'-chloro-2-methyl-4''-(2-oxoethoxy)-[1,1':3',1''-terphe-
nyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (49 mg,
0.061 mmol) in DCM (3 mL) at once. The mixture is stirred at RT for
30 min. To this was added NaBH(OAc).sub.3 (130 mg, 0.61 mmol) at
once followed by 3 drops of AcOH. The reaction mixture was stirred
at rt for 3 h. The reaction mixture was diluted with water (2-3
mL), added 2N HCl solution to pH 4, concentrated to small volume,
filtered, purified by Gilson prepared HPLC (30-90% B in 20 min) to
afford
(S)-4-((4-((4''-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)-2'-chlor-
o-2-methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyrid-
in-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.93 (m, 2H), 8.36 (m, 1H),
7.53-7.45 (m, 2H), 7.45-7.38 (m, 3H), 7.36 (m, 1H), 7.31-7.19 (m,
2H), 7.16 (m, 1H), 7.13-7.05 (m, 2H), 7.04 (s, 1H), 5.33 (m, 4H),
4.35 (m, 3H), 4.29-4.15 (m, 3H), 3.61-3.49 (m, 2H), 3.41-3.31 (m,
1H), 3.24-3.07 (m, 2H), 2.97 (m, 1H), 2.58 (d, 2H), 2.51 (m, 2H),
2.18 (s, 3H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.44H.sub.44Cl.sub.2N.sub.4O.sub.9: 843.3; found: 843.2.
Example 342:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''-(-
(R)-pyrrolidin-3-yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3--
hydroxy-2-methylpropanoic acid and
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4-((S-
)-pyrrolidin-3-yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-hy-
droxy-2-methylpropanoic
##STR00582##
[2443]
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotino-
nitrile (60 mg, 0.099 mmol), 3-(4-bromophenyl)pyrrolidine
hydrochloride (32 mg, 0.12 mmol), potassium carbonate (41 mg, 0.30
mmol) and tetrakis(triphenylphosphine)palladium (11 mg, 0.010 mmol)
were combined in a reaction vessel. Dioxane (2.0 mL) and water
(0.40 mL) were injected and the resulting suspension was sparged
with argon (via a balloon filled with argon) for 10 minutes. The
reaction mixture was stirred at 90.degree. C. for 5 h. Analysis by
tlc/LCMS indicated consumption of the boronate starting material
and formation of the desired product. The reaction mixture was
cooled to rt, and quenched by the addition of sat aq NH.sub.4Cl and
EtOAc. The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The desired product,
5-((4-chloro-5-((2,2'-dimethyl-4''-(pyrrolidin-3-yl)-[1,1':3',1''-terphen-
yl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (62 mg,
[M+1]=628.97) was carried forward with no further purification.
[2444] A solution of
5-((4-chloro-5-((2,2'-dimethyl-4''-(pyrrolidin-3-yl)-[1,1':3',1''-terphen-
yl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (25 mg,
0.040 mmol) was treated using general reductive amination procedure
G. Purification by prep RP-HPLC (10-90% acetonitrile in water, 0.1%
trifluoroacetic acid) furnished
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''-(-
(R)-pyrrolidin-3-yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3--
hydroxy-2-methylpropanoic acid and
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''-(-
(S)-pyrrolidin-3-yl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3--
hydroxy-2-methylpropanoic as a mixture of epimers as the bis-TFA
salts. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.43H.sub.43ClN.sub.4O.sub.5: 731.30; found: 731.71. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H),
8.91 (d, J=2.0 Hz, 1H), 8.45-8.38 (m, 1H), 7.55 (s, 1H), 7.46 (d,
J=7.5 Hz, 1H), 7.44-7.38 (m, 2H), 7.38-7.33 (m, 2H), 7.33-7.24 (m,
3H), 7.22-7.18 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.12-7.07 (m, 2H),
5.36 (s, 2H), 5.32 (s, 2H), 4.27 (s, 2H), 3.99 (d, J=12.1 Hz, 1H),
3.82-3.70 (m, 2H), 3.67-3.51 (m, 2H), 3.46-3.33 (m, 1H), 3.25 (t,
J=11.0 Hz, 1H), 3.04 (s, 1H), 2.57-2.41 (m, 1H), 2.23-2.15 (m, 1H),
2.14 (s, 3H), 1.87 (s, 3H), 1.51 (s, 3H).
Example 343:
(S)-2-((4-((3'-((R)-2-amino-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxy-2-methylpropanoic acid and
(S)-2-((4-((3'-((S)-2-amino-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxy-2-methylpropanoic acid
##STR00583##
[2446]
(S)-2-((4-((3'-((R)-2-amino-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)b-
enzyl)amino)-3-hydroxy-2-methylpropanoic acid and
(S)-2-((4-((3'-((S)-2-amino-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxy-2-methylpropanoic acid were prepared as an
epmieric mixture of bis-TFA salts by a sequence identical to the
route used to prepare Example 342 except
5-bromo-2,3-dihydro-1H-inden-2-amine hydrochloride was used instead
of 3-(4-bromophenyl)pyrrolidine hydrochloride, and the intermediate
was purified by SiO.sub.2 chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) prior to reductive amination (via Procedure
G). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.42H.sub.41ClN.sub.4O.sub.5: 717.28; found: 717.78. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.06-8.96 (m, 2H), 8.87 (s, 2H),
8.48 (t, J=2.1 Hz, 1H), 8.03 (m, 2H), 7.57 (s, 1H), 7.50-7.44 (m,
1H), 7.37-7.24 (m, 4H), 7.16 (dt, J=9.9, 7.3 Hz, 4H), 7.07 (dd,
J=7.4, 1.4 Hz, 1H), 5.76 (s, 1H), 5.38-5.26 (m, 4H), 4.23-3.98 (m,
3H), 3.79 (d, J=11.8 Hz, 1H), 3.70 (d, J=11.8 Hz, 1H), 2.96 (d,
J=16.4 Hz, 2H), 2.08 (s, 3H), 1.84 (s, 3H), 1.33 (s, 3H).
Example 344:
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(2-((2-hydroxyet-
hyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzy-
l)piperidine-2-carboxylic acid
##STR00584##
[2448] The title compound was prepared according to general
reductive amination procedure H with one modification--DMF was used
as the only solvent. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.45H.sub.47ClN.sub.4O.sub.6: 775.33; found: 775.90. .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 8.94 (d, J=2.1 Hz, 1H), 8.92 (d,
J=2.0 Hz, 1H), 8.38 (q, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.46 (dd,
J=7.8, 1.9 Hz, 1H), 7.32-7.24 (m, 4H), 7.21-7.12 (m, 2H), 7.11-7.05
(m, 4H), 5.35 (s, 2H), 5.32 (s, 2H), 4.51-4.40 (m, 1H), 4.35 (dd,
J=6.8, 3.3 Hz, 3H), 3.98-3.76 (m, 3H), 3.53 (t, J=5.0 Hz, 2H), 3.39
(s, 1H), 3.28-3.21 (m, 2H), 3.08-2.88 (m, 1H), 2.35-2.17 (m, 1H),
2.13 (s, 3H), 1.90-1.49 (m, 9H).
Example 345:
(R)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(2-((2-hydroxyet-
hyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzy-
l)pyrrolidine-3-carboxylic acid
##STR00585##
[2450] The title compound was prepared according to general
reductive amination procedure G. LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.44H.sub.45ClN.sub.4O.sub.6: 761.31; found: 761.68.
.sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.96 (d, J=2.1 Hz, 1H),
8.93 (d, J=2.0 Hz, 1H), 8.37 (t, J=2.1 Hz, 1H), 7.56 (s, 1H), 7.46
(dd, J=7.5, 1.3 Hz, 1H), 7.34-7.23 (m, 4H), 7.17 (ddd, J=15.3, 7.7,
1.4 Hz, 2H), 7.12-7.00 (m, 4H), 5.39 (s, 2H), 5.32 (s, 2H), 4.40
(s, 2H), 4.38-4.30 (m, 2H), 3.94-3.81 (m, 2H), 3.80-3.20 (m, 9H),
2.55-2.25 (m, 2H), 2.14 (s, 3H), 1.87 (s, 3H).
Example 346:
(S)-4-(((6-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00586##
[2452] Step 1: To a solution of
5-(methoxycarbonyl)pyridine-2-carboxylic acid (500 mg, 2.76 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU reagent, 1.36 g, 3.59 mmol) in DMF (6.0
mL) was added N,N-diisopropyethylamine (1.44 mL, 8.28 mmol). After
10 min, 2-amino-6-bromotoluene (0.410 mL, 3.31 mmol) was added to
the reaction mixture. The reaction mixture was maintained at rt
overnight, and then quenched by the addition of sat aq NH.sub.4Cl
and EtOAc. The layers were separated and the aqueous layer was
further extracted with EtOAc. The organic layers were combined,
washed with 10% aq LiCl, dried (over Na.sub.2SO.sub.4), filtered
then concentrated in vacuo. The crude mixture was purified by
SiO.sub.2 chromatography (eluting with 0-100% EtOAc/hex) to afford
methyl 6-((3-bromo-2-methylphenyl)carbamoyl)nicotinate
([M+1]=319.19, 351.20).
[2453] Step 2: To a solution of methyl
6-((3-bromo-2-methylphenyl)carbamoyl)nicotinate (450 mg, 1.29 mmol)
in thf (13 mL) was added 2 M Lithium borohydride (1.61 mL) then
methanol (0.130 mL, 3.22 mmol, note: evolution of gas during
addition, so adequate ventilation of the reaction vessel is
required). Analysis by tlc indicated consumption of the starting
material. The reaction mixture was quenched by the addition of sat
aq NaHCO.sub.3 and EtOAc, and the mixture was stirred for 10 min.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The resultant alcohol intermediate was dissolved in
dichloromethane (26 mL), cooled in an ice-water bath then
Dess-Martin periodinane (820 mg, 1.93 mmol) was added to the
reaction mixture. The reaction mixture was stirred in the bath for
3 h (allowing the mixture to slowly to warm to rt). Analysis by
tlc/LCMS indicated consumption of the alcohol intermediate and
formation of the desired product. The reaction mixture was quenched
by the addition of 10% aq sodium thiosulfate and EtOAc and the
mixture was stirred for 10 min. The layers were separated and the
aqueous layer was further extracted with EtOAc. The organic layers
were combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo. The crude mixture was purified
by SiO.sub.2 chromatography (0-100% EtOAc/hex) to afford
N-(3-bromo-2-methylphenyl)-5-formylpicolinamide ([M+1]=319.28,
321.24).
[2454] Step 3: N-(3-Bromo-2-methylphenyl)-5-formylpicolinamide (48
mg, 0.15 mmol),
5-[[4-chloro-2-formyl-5-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]methoxy]phenoxy]methyl]pyridine-3-carbonitrile (60
mg, 0.12 mmol), potassium carbonate (56 mg, 0.41 mmol) and XPhos
Palladacycle precatalyst (18 mg, 24 umol) were combined in a
reaction vessel. Dioxane (1.0 mL) and water (0.20 mL) were injected
and the resulting suspension was sparged with argon (via a balloon
filled with argon) for 10 minutes. The reaction mixture was stirred
at 95.degree. C. for 10 h. Analysis by tlc/LCMS indicated
consumption of the boronate starting material and formation of the
desired product. The reaction mixture was cooled to rt, and
quenched by the addition of sat aq NH.sub.4Cl and EtOAc. The layers
were separated and the aqueous layer was further extracted with
EtOAc. The organic layers were combined, washed with brine, dried
(over Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The
crude mixture was purified by SiO.sub.2 chromatography (eluting
with 0-100% EtOAc/hex) to afford
N-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylpheno-
xy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
([M+1]=631.41).
[2455] Step 4:
(S)-4-(((6-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid (30 mg, 46%) was prepared as the bis-TFA salt by reductive
amination (general procedure G) of
N-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide (39 mg,
0.062 mmol) and (S)-4-amino-3-hydroxybutanoic acid. LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.44H.sub.45ClN.sub.6O.sub.9:
837.30; found: 837.49. .sup.1H NMR (400 MHz, Methanol-d4) .delta.
1H NMR (400 MHz, Methanol-d4) .delta. 8.96 (d, J=2.1 Hz, 1H), 8.93
(d, J=2.0 Hz, 1H), 8.82 (dd, J=2.2, 0.9 Hz, 1H), 8.38 (t, J=2.1 Hz,
1H), 8.31 (dd, J=8.1, 0.8 Hz, 1H), 8.18 (dd, J=8.1, 2.2 Hz, 1H),
7.85 (dd, J=8.0, 1.3 Hz, 1H), 7.51 (s, 1H), 7.48 (dd, J=7.7, 1.4
Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.15 (dd,
J=7.6, 1.4 Hz, 1H), 7.09 (s, 1H), 7.04 (dd, J=7.6, 1.3 Hz, 1H),
5.38 (s, 2H), 5.32 (s, 2H), 4.43 (s, 2H), 4.33 (dtd, J=9.4, 6.3,
3.0 Hz, 1H), 4.23 (d, J=6.5 Hz, 3H), 3.20 (dd, J=12.8, 3.1 Hz, 1H),
3.11 (dd, J=12.6, 9.9 Hz, 1H), 3.05-2.92 (m, 1H), 2.57 (d, J=6.3
Hz, 2H), 2.51 (dd, J=6.3, 0.9 Hz, 2H), 2.13 (s, 3H), 2.04 (s,
3H).
Example 347:
(S)-4-((4-((3'-(1-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)-3-methy-
l-1H-indazol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2--
((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid
##STR00587##
[2457]
(S)-4-((4-((3'-(1-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)-3-
-methyl-1H-indazol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chl-
oro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid was prepared as the bis-TFA salt by a sequence identical to
the route used to prepare Example 209 starting with
5-bromo-3-methyl-1H-indazole instead of 5-bromo-1H-indazole.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.47H.sub.50ClN.sub.6O.sub.8: 861.34; found: 861.37. .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 8.95 (d, J=2.1 Hz, 1H), 8.92 (d,
J=2.0 Hz, 1H), 8.37 (t, J=2.1 Hz, 1H), 7.75-7.63 (m, 1H), 7.64-7.55
(m, 1H), 7.51 (s, 1H), 7.49-7.37 (m, 2H), 7.37-7.21 (m, 3H),
7.21-7.15 (m, 1H), 7.11 (dd, J=7.4, 1.6 Hz, 1H), 7.08 (s, 1H), 5.37
(s, 2H), 5.32 (s, 2H), 4.78-4.59 (m, 2H), 4.31 (dtd, J=9.6, 6.5,
3.2 Hz, 1H), 4.26-4.16 (m, 3H), 3.64 (tq, J=12.9, 6.6, 5.8 Hz, 2H),
3.38-3.31 (m, 1H), 3.25-3.07 (m, 2H), 2.97 (dd, J=12.8, 9.8 Hz,
1H), 2.58 (s, 3H), 2.56 (d, J=6.3 Hz, 2H), 2.51 (dd, J=6.3, 1.1 Hz,
2H), 2.16 (s, 3H), 1.88 (s, 3H).
Example 348:
(S)-4-((4-((3'-(3-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)benzofur-
an-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanop-
yridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00588##
[2459] Step 1: To a solution of 2-(6-hydroxy-1-benzofuran-3-yl)
acetic acid (2.00 g, 10.4 mmol) in methanol (11.0 mL) was added
cone sulfuric acid (1.2 m). The reaction mixture was stirred at 60
Cream overnight. Analysis by tlc/LCMS indicated consumption of the
starting material and formation of the amine product
([M+1]=207.09). The reaction mixture was cooled to rt, then
carefully quenched by the addition of 1N NaOH (to pH.about.6-7) and
extracted with EtOAc (3.times.). The organic layers were combined,
washed with brine, dried (over Na.sub.2SO.sub.4), filtered then
concentrated in vacuo to afford methyl
2-(6-hydroxybenzofuran-3-yl)acetate (2.15 g, quant), which was
immediately processed in the subsequent step.
[2460] Step 2: To a solution of methyl
2-(6-hydroxybenzofuran-3-yl)acetate (2.15 g, 10.4 mmol) and
N,N-diisopropylethylamine (4.53 mL, 26.0 mmol) in dichloromethane
(25 mL) cooled in an ice-water bath was slowly added
trifluoromethanesulfonic anhydride (2.01 mL, 12.0 mmol) as a steady
stream down the side of the reaction vessel. The reaction mixture
was maintained in the bath for 1 h, and then quenched by the
addition of sat aq NaHCO.sub.3 and EtOAc. The layers were separated
and the aqueous layer was further extracted with EtOAc. The organic
layers were combined, washed with brine, dried (over
Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The crude
mixture was purified by SiO.sub.2 chromatography (eluting with
0-50% EtOAc/hex) to afford the desired product methyl
2-(6-(((trifluoromethyl)sulfonyl)oxy)benzofuran-3-yl)acetate
([M+1]=339.50).
[2461] Step 3: Methyl
2-(6-(((trifluoromethyl)sulfonyl)oxy)benzofuran-3-yl)acetate (500
mg, 1.48 mmol), 2 (3-Bromo-2-methylphenyl)boronic acid (3.18 g,
1.48 mmol), potassium carbonate (613 mg, 4.44 mmol) and
tetrakis(triphenylphosphine)palladium (128 mg, 0.111 mmol) were
combined in a reaction vessel. Dioxane (10.0 mL) and water (2.00
mL) were added and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 90.degree. C. for 5 h. Analysis by tlc/LCMS
indicated consumption of the starting materials. The reaction
mixture was cooled to rt, and quenched by the addition of sat aq
NH.sub.4Cl and EtOAc. The layers were separated and the aqueous
layer was further extracted with EtOAc. The organic layers were
combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo. The crude mixture was purified
by SiO.sub.2 chromatography (0-100% EtOAc/hex) to afford methyl
2-(6-(3-bromo-2-methylphenyl)benzofuran-3-yl)acetate.
[2462] Step 4: To a solution of methyl
2-(6-(3-bromo-2-methylphenyl)benzofuran-3-yl)acetate (350 mg, 0.974
mmol) in thf (10.0 mL) and dichloromethane (10.0 mL) was added 2 M
Lithium borohydride (1.46 mL) then methanol (0.118 mL, 2.92 mmol,
note: evolution of gas during addition, so adequate ventilation of
the reaction vessel is required). Analysis by tlc indicated
consumption of the starting material. The reaction mixture was
quenched by the addition of sat aq NaHCO.sub.3 and EtOAc, and the
mixture was stirred for 10 min. The layers were separated and the
aqueous layer was further extracted with EtOAc. The organic layers
were combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo to afford the desired product
2-(6-(3-bromo-2-methylphenyl)benzofuran-3-yl)ethanol, which was
processed in the subsequent step immediately.
[2463] Step 5: 2-(6-(3-bromo-2-methylphenyl)benzofuran-3-yl)ethanol
(58 mg, 0.17 mmol),
5-[[4-chloro-2-formyl-5-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]methoxy]phenoxy]methyl]pyridine-3-carbonitrile (60
mg, 0.12 mmol), potassium carbonate (56 mg, 0.41 mmol) and
tetrakis(triphenylphosphine)palladium (21 mg, 0.017 mmol) were
combined in a reaction vessel. Dioxane (0.80 mL) and water (0.20
mL) were added and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 90.degree. C. for 5 h. Analysis by tlc/LCMS
indicated consumption of the starting materials. The reaction
mixture was cooled to rt, and quenched by the addition of sat aq
NH.sub.4Cl and EtOAc. The layers were separated and the aqueous
layer was further extracted with EtOAc. The organic layers were
combined, washed with brine, dried (over Na.sub.2SO.sub.4),
filtered then concentrated in vacuo. The crude mixture (110 mg
crude, [M+1]=643.35) was dissolved in dihclromethane (2.0 mL) and
cooled in an ice-water bath. Dess-Martin periodinane (59 mg, 0.14
mmol) was added to the reaction mixture, and the mixture was
stirred overnight with warming to rt. Analysis by tlc/LCMS
indicated consumption of the starting material. The reaction
mixture was quenched by the addition of 10% aq sodium thiosulfate
and EtOAc and the mixture was stirred for 10 min. The layers were
separated and the aqueous layer was further extracted with EtOAc.
The organic layers were combined, washed with brine, dried (over
Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The crude
mixture was purified by SiO.sub.2 chromatography (0-100% EtOAc/hex)
to afford
5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxoethyl)benzofuran-6-yl)-[1,1'-b-
iphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
([M+1]=641.39).
[2464] Step 6:
(S)-4-((4-((3'-(3-(2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)benzofur-
an-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanop-
yridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
prepared as the bis-TFA salt by reductive amination (general
procedure G) of
5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxoethyl)benzofuran-6-yl)-[1,1'-b-
iphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile and
(S)-4-amino-3-hydroxybutanoic acid. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.47H.sub.47ClN.sub.4O.sub.9: 847.31;
found: 847.37. .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.95 (d,
J=2.1 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.42-8.31 (m, 1H), 7.76 (s,
1H), 7.71 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.49-7.42 (m, 2H),
7.36-7.23 (m, 4H), 7.21-7.14 (m, 1H), 7.11 (d, J=7.4 Hz, 1H), 7.08
(s, 1H), 5.37 (s, 2H), 5.32 (s, 2H), 4.41-4.22 (m, 1H), 4.22 (d,
J=12.9 Hz, 3H), 3.51-3.38 (m, 3H), 3.24-3.05 (m, 6H), 3.03-2.93 (m,
1H), 2.57 (d, J=6.3 Hz, 2H), 2.51 (dd, J=6.3, 1.2 Hz, 2H), 2.16 (s,
3H), 1.90 (s, 3H).
Example 349:
(S)-4-((4-((4''-((2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)carbamoyl-
)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyano-
pyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00589##
[2466] Step 1: To a solution of 5-Bromo-pyridine-2-carboxylic acid
(1.00 g, 4.95 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU reagent, 2.35 g, 6.19 mmol) and
N,N-diisopropyethylamine (1.73 mL, 9.90 mmol) in DMF (10.0 mL) was
added 2,2-dimethoxyethylamine (0.810 mL, 7.43 mmol). The reaction
mixture was maintained at rt overnight, and then quenched by the
addition of sat aq NH.sub.4Cl and EtOAc. The layers were separated
and the aqueous layer was further extracted with EtOAc. The organic
layers were combined, washed with 10% aq LiCl, dried (over
Na.sub.2SO.sub.4), filtered then concentrated in vacuo. The crude
mixture was purified by SiO.sub.2 chromatography (eluting with
0-100% EtOAc/hex) to afford
5-bromo-N-(2,2-dimethoxyethyl)picolinamide.
[2467] Step 2:
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (100 mg, 0.16 mmol), 4-bromo-N-(2,2-dimethoxyethyl)benzamide (57
mg, 0.20 mmol), potassium carbonate (68 mg, 0.49 mmol) and
tetrakis(triphenylphosphine)palladium (9.5 mg, 8.0 umol) were
combined in a reaction vessel. Dioxane (2.0 mL) and water (0.40 mL)
were injected and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 90.degree. C. for 3 h. Analysis by tlc/LCMS
indicated consumption of the boronate starting material and
formation of the desired product. The reaction mixture was cooled
to rt, and quenched by the addition of sat aq NH.sub.4Cl and EtOAc.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO.sub.2 chromatography
(eluting with 0-100% EtOAc/hex) to afford,
5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-N-(2,2-dimethoxyethyl)picolinamide
([M+1]=691.22).
[2468] Step 3: To a solution of
5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-N-(2,2-dimethoxyethyl)picolinamide
(60 mg, 0.087 mmol) in THF (1.0 mL) was added (0.50 mL) of 4N HCl
then 20 drops of conc. HCl. The mixture was stirred at rt
overnight. Analysis by LCMS indicated formation of the desired
product. The reaction mixture was poured into a mixture of brine
and EtOAc. The layers were separated and the aqueous layer was
further extracted with EtOAc. The organic layers were combined,
washed with brine, dried (over Na.sub.2SO.sub.4), filtered then
concentrated in vacuo.
5-(3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-N-(2-oxoethyl)picolinamide
([M+1]=645.42) was processed in the next step immediately.
[2469] Step 4:
((S)-4-((4-((4''-((2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethyl)carbamoy-
l)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyan-
opyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid (13 mg,
16%) was prepared as the bis-TFA salt by reductive amination
(general procedure G) of
5-(3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-N-(2-oxoethyl)picolinamide and
(S)-4-amino-3-hydroxybutanoic acid. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.45H.sub.48ClN.sub.6O.sub.9: 851.32;
found: 851.41. .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.96 (d,
J=2.1 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.66 (dd, J=2.3, 0.9 Hz,
1H), 8.38 (d, J=2.2 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.99 (dd,
J=8.0, 2.2 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39 (t,
J=7.5 Hz, 1H), 7.28 (dd, J=7.6, 4.2 Hz, 2H), 7.24-7.17 (m, 1H),
7.20-7.13 (m, 1H), 7.08 (s, 1H), 5.38 (s, 2H), 5.31 (s, 2H),
4.39-4.13 (m, 4H), 3.79 (t, J=5.9 Hz, 2H), 3.20 (dd, J=12.7, 3.1
Hz, 1H), 3.10 (dd, J=12.5, 9.7 Hz, 1H), 3.03-2.91 (m, 1H), 2.56 (d,
J=6.3 Hz, 2H), 2.53-2.48 (m, 2H), 2.15 (s, 3H), 1.91 (s, 3H).
Example 350:
(S)-4-((4-((3'-(5-((2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)methyl-
)thiazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5--
cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00590##
[2471] Step 1: (3-bromo-2-methylphenyl)boronic acid (350 mg, 1.63
mmol), methyl 2-bromothiazole-5-carboxylate (470 mg, 2.12 mmol),
potassium carbonate (788 mg, 5.70 mmol) and
tetrakis(triphenylphosphine)palladium (113 mg, 98.0 umol) were
combined in a reaction vessel. Dioxane (12.0 mL) and water (3.00
mL) were added and the resulting suspension was sparged with argon
(via a balloon filled with argon) for 10 minutes. The reaction
mixture was stirred at 95.degree. C. for 7 h. The reaction mixture
was cooled to rt, and quenched by the addition of sat aq NH.sub.4Cl
and EtOAc. The layers were separated and the aqueous layer was
further extracted with EtOAc. The organic layers were combined,
washed with brine, dried (over Na.sub.2SO.sub.4), filtered then
concentrated in vacuo. The crude mixture was purified by SiO.sub.2
chromatography (eluting with 0-100% EtOAc/hex) to afford methyl
2-(3-bromo-2-methylphenyl)thiazole-5-carboxylate.
[2472] Step 2: To a solution of to methyl
2-(3-bromo-2-methylphenyl)thiazole-5-carboxylate (250 mg, 0.801
mmol) in thf (7.00 mL) was added 2 M Lithium borohydride (1.20 mL)
then methanol (0.097 mL, 2.40 mmol, note: evolution of gas during
addition, so adequate ventilation of the reaction vessel is
required). Analysis by tlc indicated consumption of the starting
material. The reaction mixture was quenched by the addition of sat
aq NaHCO.sub.3 and EtOAc, and the mixture was stirred for 10 min.
The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo to afford (2-(3-bromo-2-methylphenyl)thiazol-5-yl)methanol
([M+1]=284.35, 286.22).
[2473] Step 3: To a solution of
(2-(3-bromo-2-methylphenyl)thiazol-5-yl)methanol (100 mg, 0.35
mmol) in DMF (2.0 mL) cooled in an ice-water bath was sodium
hydride (60 wt %, 16 mg, 0.42 mmol) then bromoacetaldehyde dimethyl
acetal (0.21 mL, 1.8 mmol). The reaction mixture was allowed to
stir in the bath overnight (with slow warming to rt). The reaction
mixture was quenched by the addition of sat aq NH.sub.4Cl and
EtOAc. The layers were separated and the aqueous layer was further
extracted with EtOAc. The organic layers were combined, washed with
brine, dried (over Na.sub.2SO.sub.4), filtered then concentrated in
vacuo. The crude mixture was purified by SiO.sub.2 chromatography
(eluting with 0-100% EtOAc/hex) to afford
2-(3-bromo-2-methylphenyl)-5-((2,2-dimethoxyethoxy)methyl)thiazole
([M+1]=372.48, 374.23).
[2474] Step 4:
(S)-4-((4-((3'-(5-((2-(((S)-3-carboxy-2-hydroxypropyl)amino)ethoxy)methyl-
)thiazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5--
cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
prepared as the bis-TFA salt by a sequence identical to the route
used to prepare Example 209 starting with
2-(3-bromo-2-methylphenyl)-5-((2,2-dimethoxyethoxy)methyl)thiazole
instead of
5-(3-bromo-2-methylphenyl)-1-(2,2-dimethoxyethyl)-1H-indazole.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.43H.sub.46ClN.sub.5O.sub.9S: 844.28; found: 844.14. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.96 (s, 1H), 8.93 (s, 1H),
8.38 (d, J=2.3 Hz, 1H), 7.87 (s, 1H), 7.58 (d, J=7.7 Hz, 1H),
7.56-7.45 (m, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.33-7.22 (m, 2H), 7.14
(d, J=7.6 Hz, 1H), 7.08 (s, 1H), 5.38 (s, 2H), 5.32 (s, 2H), 4.89
(s, 2H), 4.33-4.09 (m, 3H), 3.83 (t, J=5.3 Hz, 2H), 3.28-3.15 (m,
3H), 3.09-2.92 (m, 2H), 2.54 (d, J=6.3 Hz, 2H), 2.52 (d, J=6.4 Hz,
2H), 2.16-2.07 (m, 6H).
Example 351:
(S)-4-(((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-
-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((3,5-dicyanobenzyl)oxy)pyridin-3-
-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00591##
[2476] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=833.01. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.15-8.07 (m, 3H), 7.95 (s, 1H),
7.56-7.49 (m, 1H), 7.48-7.36 (m, 5H), 7.27 (ddd, J=23.0, 7.4, 1.9
Hz, 2H), 7.14-7.06 (m, 2H), 5.63-5.49 (m, 2H), 5.49 (s, 2H), 4.88
(s, 5H), 4.40-4.33 (m, 2H), 4.26 (s, 3H), 3.90-3.82 (m, 2H),
3.58-3.50 (m, 2H), 3.30-3.21 (m, 3H), 3.04 (dd, J=12.8, 9.8 Hz,
1H), 2.55 (d, J=6.4 Hz, 2H).
Example 352:
(S)-2-(((5-chloro-6-((2,2'-dichloro-4''-(2-((2-hydroxyethyl)amino)ethoxy)-
-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-((3,5-dicyanobenzyl)oxy)pyridin-3-
-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00592##
[2478] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=833.01. .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.10 (dd, J=7.7, 1.5 Hz, 3H), 7.84 (d,
J=8.1 Hz, 1H), 7.51-7.31 (m, 6H), 7.24 (ddd, J=17.7, 7.3, 1.8 Hz,
2H), 7.13-7.06 (m, 2H), 6.64 (d, J=8.1 Hz, 1H), 5.54 (d, J=13.8 Hz,
1H), 5.47 (s, 3H), 4.40-4.32 (m, 2H), 4.29 (s, 2H), 4.05 (d, J=12.1
Hz, 1H), 3.89-3.79 (m, 3H), 3.54 (t, J=5.0 Hz, 2H), 3.30-3.22 (m,
2H), 1.57 (s, 3H), 1.30 (d, J=16.3 Hz, 2H).
Example 353:
(S)-4-((4-((4''-((S)-2-amino-3-hydroxypropoxy)-2,2'-dimethyl-[1,1':3',1''-
-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxybutanoic acid
##STR00593##
[2480] To a solution of
(R)-4-Hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid
tert-butyl ester (0.66 g, 2.86 mmol) and DMF was added NaH (14 mg,
2 equiv.). After 5 min., 1-Bromo-4-fluorobenzene 99% (0.31 ml, 2.86
mmol) was added. The mixture was then warmed to 80 C. After 16 h,
the flask was cooled and to it added water and extracted with
EtAOc. The organic layers are washed with brine, dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. Flash
column chromatography was carried out using Hexanes EtOAc to
isolate tert-butyl
(R)-4-((4-bromophenoxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate.
[M+1]=387.3.
[2481] Tert-butyl
(R)-4-(((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)-
methyl)-2',2''-dimethyl-[1,1':3',1''-terphenyl]-4-ypoxy)methyl)-2,2-dimeth-
yloxazolidine-3-carboxylate was prepared analogous to Intermediate
23. [M+1]=789.40.
[2482]
(S)-4-((4-((4''-((S)-2-amino-3-hydroxypropoxy)-2,2'-dimethyl-[1,1':-
3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)b-
enzypamino)-3-hydroxybutanoic acid was synthesized according to
general reductive amination procedure D after which the mixture was
worked up (EtOAc and water, extracted, dried over MgSO4, filtered
and concentrated under reduced pressure) before being treated with
TFA and DCM. [M+1]=751.01. .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 8.94 (dd, J=11.3, 2.0 Hz, 2H), 8.37 (t, J=2.1 Hz, 1H), 7.48
(d, J=24.9 Hz, 2H), 7.33-7.22 (m, 4H), 7.22-7.11 (m, 2H), 7.12-7.04
(m, 3H), 5.34 (d, J=25.9 Hz, 4H), 4.88-4.79 (m, 1H), 4.30 (dd,
J=10.4, 4.0 Hz, 1H), 4.24 (s, 3H), 4.25-4.17 (m, 1H), 3.95-3.78 (m,
2H), 3.67 (s, 1H), 3.20 (dd, J=12.7, 3.0 Hz, 1H), 2.98 (dd, J=12.7,
9.8 Hz, 1H), 2.52 (dd, J=6.2, 1.3 Hz, 2H), 2.14 (s, 3H), 1.88 (s,
3H).
Example 354:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(((S)-1-(2-hydr-
oxyethyl)piperidin-3-yl)oxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)me-
thoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00594##
[2484]
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(((S)-1-(-
2-hydroxyethyl)piperidin-3-yl)oxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-
-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was prepared in
analogy to Example 353. [M+1]=805.37. .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 8.94 (dd, J=11.5, 2.1 Hz, 3H), 8.37 (s, 1H),
7.55-7.39 (m, 4H), 7.38-6.91 (m, 17H), 5.34 (d, J=24.9 Hz, 7H),
4.93 (s, 1H), 4.24 (s, 4H), 4.04-3.76 (m, 5H), 3.66-3.34 (m, 1H),
3.20 (dd, J=12.7, 3.0 Hz, 2H), 3.06-2.90 (m, 4H), 2.86 (d, J=0.7
Hz, 2H), 2.52 (dd, J=6.3, 1.2 Hz, 4H), 2.14 (s, 5H), 1.89 (s,
6H).
Example 355:
(S)-4-((5-chloro-4-((3'-((2-chloro-5-methoxy-4-(((2-(methylsulfonamido)-2-
-oxoethyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl[1,1'-biphenyl]-3-yl)m-
ethoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic
acid
##STR00595##
[2486] The title compound was prepared according to reductive
amination procedure D. [M+1]=920.32. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=14.9, 2.0 Hz, 2H), 8.38 (t,
J=2.1 Hz, 1H), 7.97 (s, 1H), 7.60-7.38 (m, 4H), 7.27 (q, J=7.5 Hz,
1H), 7.12 (ddd, J=7.7, 2.9, 1.4 Hz, 1H), 6.96 (s, 1H), 5.38 (s,
2H), 5.31 (d, J=3.0 Hz, 2H), 4.32-4.15 (m, 2H), 3.97 (s, 3H), 3.87
(s, H), 3.26 (s, 2H), 2.99 (s, 2H), 2.86 (d, J=0.7 Hz, 1H), 2.08
(d, J=1.6 Hz, 6H).
Example 356:
(4-((3'-((4-(((carboxymethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3--
yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-m-
ethoxy-5-(trifluoromethyl)benzyl)glycine
##STR00596##
[2488] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=833.27. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.95 (dd, J=16.9, 2.0 Hz, 2H), 8.40
(t, J=2.1 Hz, 1H), 7.55-7.44 (m, 3H), 7.28 (q, J=7.7 Hz, 2H), 7.13
(ddd, J=7.7, 4.7, 1.3 Hz, 2H), 7.09 (s, 1H), 7.02 (s, 1H),
5.41-5.30 (m, 5H), 4.27 (d, J=5.7 Hz, 3H), 4.04 (s, 3H), 3.87 (d,
J=0.7 Hz, 3H), 2.07 (d, J=9.6 Hz, 5H).
Example 357:
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-m-
ethoxy-5-(trifluoromethyl)benzyl)amino)-3-hydroxybutanoic acid
##STR00597##
[2490] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=819.18. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.51 (dt, J=7.7, 1.7 Hz, 1H), 7.43
(s, 1H), 7.29 (td, J=7.7, 2.2 Hz, 1H), 7.12 (ddd, J=7.7, 2.7, 1.4
Hz, 1H), 7.02 (s, 2H), 5.40-5.27 (m, 3H), 4.29 (tdd, J=9.5, 6.4,
4.2 Hz, 1H), 4.23 (s, 1H), 4.17 (s, 1H), 4.04 (s, 2H), 3.96 (s,
2H), 3.19 (ddd, J=12.7, 8.3, 3.1 Hz, 2H), 2.98 (ddd, J=12.8, 9.8,
8.7 Hz, 2H), 2.54 (dd, J=6.3, 3.3 Hz, 3H), 2.20-2.03 (m, 3H).
Example 358:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3''-(-
(methylamino)methyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3--
hydroxy-2-methylpropanoic acid
##STR00598##
[2492] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=705.4. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d, J=1.9
Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.59-7.51 (m, 2H), 7.51-7.38 (m,
4H), 7.34-7.22 (m, 3H), 7.17-7.06 (m, 3H), 5.37 (s, 2H), 5.32 (s,
2H), 4.29 (s, 2H), 4.25 (s, 2H), 4.01 (d, J=12.1 Hz, 1H), 3.81 (d,
J=12.1 Hz, 1H), 2.74 (s, 3H), 2.14 (s, 3H), 1.89 (s, 3H), 1.53 (s,
3H).
Example 359:
(S)-4-(((6-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)-4-chloronaphthalen-1-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00599##
[2494] A flask was charged with TiCl.sub.4 (1 M in DCM, 15.8 mL,
15.8 mmol) and DCM (12 mL). dichloromethyl methyl ether (1.27 mL,
14.4 mmol) was added, and the mixture was cooled to 0.degree. C. A
solution of 7-bromonaphthalen-1-ol (1.6 g, 7.2 mmol) in DCM (10 mL)
was then added dropwise. The mixture was warmed to rt and stirred 3
h, at which time TLC showed complete consumption of starting
material. The mixture was diluted with DCM (100 mL), and 2N HCl
(100 mL) was carefully added. The biphasic mixture was filtered to
remove titanium salts, and the biphasic mixture separated. The
aqueous layer was extracted with DCM (3.times.100 mL), and the
combined organics were dried (MgSO.sub.4) and concentrated. The
residue was purified by column chromatography (SiO.sub.2, 0-100%
EtOAc/hex) to yield 6-bromo-4-hydroxy-1-naphthaldehyde.
[2495] A flask was charged with
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (70 mg, 0.115 mmol), 6-bromo-4-hydroxy-1-naphthaldehyde (35 mg,
0.138 mmol), Na.sub.2CO.sub.3 (61 mg, 0.58 mmol), Pd XPhos G2 (4
mg, 0.06 mmol), dioxane (2 mL), and water (0.2 mL). The flask was
subjected to 3 vaccuum/argon cycles, then heated to 90.degree. C.
for 2 h. The mixture was cooled to rt, filtered over celite,
concentrated, and purified by column chromatography (SiO2, 0-100%
EtOAc/hex) to yield
5-((4-chloro-2-formyl-5-((3'-(5-formyl-8-hydroxynaphthalen-2-yl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[2496] To a solution of
5-((4-chloro-2-formyl-5-((3'-(5-formyl-8-hydroxynaphthalen-2-yl)-2,2'-dim-
ethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
(60 mg, 0.092 mmol) and pyridine (0.02 mL, 0.3 mmol) in DCM (5 mL)
was added trifluoromethanesulfonic anhydride (0.02 mL, 0.1 mmol).
The mixture was stirred for 30 min, then poured over water (10 mL).
The aqueous layer was extracted with EtOAc (4.times.10 mL), and the
combined organics dried (MgSO.sub.4), concentrated, and purified by
column chromatography (SiO.sub.2, 0-90% EtOAc/hex) to yield
7-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-formylnaphthalen-1-yl
trifluoromethanesulfonate.
[2497] A vial was charged with Pd.sub.2(dba).sub.3 (1 mg, 0.001
mmol), tBuBrettPhos (2 mg, 0.005 mmol), and dioxane (1 mL). The
mixture was subjected to 3 vacuum/argon cycles, then heated to
120.degree. C. for 5 min. The solution was then cooled to rt.
[2498] A separate flask was charged with KCl (6 mg, 0.07 mmol), KF
(1 mg, 0.02 mmol),
7-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-formylnaphthalen-1-yl
trifluoromethanesulfonate (30 mg, 0.038 mmol), and dioxane (2 mL).
The mixture was subjected to 3 vacuum/argon cycles, and then the
catalyst solution was added. The resultant solution was stirred at
100.degree. C. for 16 h, then concentrated and purified by column
chromatography (SiO.sub.2, 0-75% EtOAc/hex) to yield
5-((4-chloro-5-((3'-(8-chloro-5-formylnaphthalen-2-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[2499]
(S)-4-(((6-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-
-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-4-chloronaphthalen-1-yl)methyl)amino)-3-hydroxybutanoic
acid was synthesized according to general reductive amination
procedure D. [M+1]=877.3. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.96 (d, J=2.0 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.38 (t,
J=2.0 Hz, 1H), 8.34-8.25 (m, 2H), 7.81-7.73 (m, 2H), 7.68 (d, J=7.8
Hz, 1H), 7.51 (s, 1H), 7.48 (dd, J=7.6, 1.4 Hz, 1H), 7.41-7.33 (m,
2H), 7.29 (t, J=7.6 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (s, 1H), 5.38
(s, 2H), 5.32 (s, 2H), 4.81 (s, 2H), 4.41 (dtd, J=9.4, 6.2, 3.0 Hz,
1H), 4.28-4.19 (m, 3H), 3.39 (dd, J=12.8, 3.1 Hz, 1H), 3.22-3.15
(m, 2H), 2.97 (dd, J=12.7, 9.8 Hz, 1H), 2.58 (d, J=6.3 Hz, 2H),
2.51 (d, J=6.3 Hz, 2H), 2.19 (s, 3H), 1.93 (s, 3H).
Example 360:
(S)-2-((4-((4''-(((2-(1H-imidazol-4-yl)ethyl)amino)methyl)-2,2'-dimethyl--
[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)met-
hoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00600##
[2501] A flask fitted with a Dean-Stark apparatus was charged with
4-bromobenzaldehyde (2.73 g, 14.8 mmol), toluenesulfonic acid (381
mg, 2 mmol), 1,3-propanediol (21.4 mL), and toluene (25 mL). The
mixture was heated to reflux for 3 h, then allowed to cool to rt,
diluted with EtOAc, and washed with a saturated solution of
NaHCO.sub.3. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated, and the residue purified by column chromatography
(SiO.sub.2, 0-50% EtOAc/hex) to yield
2-(4-bromophenyl)-1,3-dioxane.
[2502] A flask was charged with
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (1.00 g, 1.64 mmol), 2-(4-bromophenyl)-1,3-dioxane (1.20 g, 4.93
mmol), Na.sub.2CO.sub.3 (696 mg, 7 mmol), Pd XPhos G2 (62 mg, 0.82
mmol), dioxane (10 mL), and water (1 mL). The flask was subjected
to 3 vaccuum/argon cycles, then heated to 90.degree. C. for 5 h.
The mixture was cooled to rt, filtered over celite, concentrated,
and purified by column chromatography (SiO.sub.2, 0-100% EtOAc/hex)
to yield
5-((5-((4''-(1,3-dioxan-2-yl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-
methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile.
[2503]
(S)-2-((4-((4''-(1,3-dioxan-2-yl)-2,2'-dimethyl-[1,1':3',1''-terphe-
nyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)--
3-hydroxy-2-methylpropanoic acid was synthesized according to
general reductive amination procedure D.
[2504] To a solution of
(S)-2-((4-((4''-(1,3-dioxan-2-yl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-
-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydr-
oxy-2-methylpropanoic acid (800 mg, 1.07 mmol) in THF (10 mL) was
added 1 N HCl (5 mL, 5 mmol). The biphasic mixture was vigorously
stirred for 1 h, then concentrated in vacuo to yield
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-formyl-2,2'-dim-
ethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methy-
lpropanoic acid, which was carried forward without further
purification.
[2505]
(S)-2-((4-((4''-(((2-(1H-imidazol-4-yl)ethyl)amino)methyl)-2,2'-dim-
ethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3--
yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid was
synthesized according to general reductive amination procedure D.
[M+1]=785.4. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.98
(d, J=2.1 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.87 (d, J=1.4 Hz, 1H),
8.42 (t, J=2.1 Hz, 1H), 7.61-7.53 (m, 3H), 7.50-7.42 (m, 4H),
7.33-7.24 (m, 2H), 7.20 (dd, J=7.7, 1.4 Hz, 1H), 7.16-7.07 (m, 3H),
5.37 (s, 2H), 5.32 (s, 2H), 4.33 (s, 2H), 4.29 (s, 2H), 4.01 (d,
J=12.1 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.46 (t, J=7.0 Hz, 2H),
3.23 (t, J=7.7 Hz, 2H), 2.14 (s, 3H), 1.87 (s, 3H), 1.53 (s,
3H).
Example 361:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-((((1r,4r)-4-hy-
droxycyclohexyl)amino)methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00601##
[2507] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=789.5. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.0 Hz, 1H), 8.91 (d, J=1.9
Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.63-7.52 (m, 3H), 7.52-7.41 (m,
3H), 7.34-7.24 (m, 2H), 7.20 (dd, J=7.7, 1.4 Hz, 1H), 7.17-7.06 (m,
3H), 5.37 (s, 2H), 5.32 (s, 2H), 4.28 (d, J=3.5 Hz, 4H), 4.01 (d,
J=12.1 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.57 (td, J=10.7, 5.4 Hz,
1H), 3.16 (dtd, J=10.2, 7.0, 6.3, 3.0 Hz, 1H), 2.24 (d, J=12.3 Hz,
2H), 2.14 (s, 3H), 2.08 (d, J=12.6 Hz, 2H), 1.87 (s, 3H), 1.59-1.45
(m, 5H), 1.42-1.33 (m, 2H).
Example 362:
(S)-2-((4-((4''-(((2-acetamidoethyl)amino)methyl)-2,2'-dimethyl-[1,1':3',-
1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benz-
yl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00602##
[2509] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=776.5. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d, J=1.9
Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.51-7.37 (m,
3H), 7.35-7.24 (m, 2H), 7.20 (dd, J=7.7, 1.4 Hz, 1H), 7.18-7.04 (m,
3H), 5.37 (s, 2H), 5.32 (s, 2H), 4.39-4.20 (m, 4H), 4.01 (d, J=12.2
Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.53 (t, J=5.8 Hz, 2H), 3.22 (t,
J=5.8 Hz, 2H), 2.15 (s, 3H), 1.98 (s, 3H), 1.87 (s, 3H), 1.53 (s,
3H).
Example 363:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-4''--
(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)methoxy-
)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00603##
[2511] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=774.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d, J=1.9
Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.55 (s,
1H), 7.51-7.41 (m, 3H), 7.32 (t, J=7.6 Hz, 1H), 7.27 (t, J=7.6 Hz,
1H), 7.23-7.18 (m, 1H), 7.17-7.06 (m, 3H), 5.37 (s, 2H), 5.32 (s,
2H), 4.33 (d, J=2.0 Hz, 2H), 4.28 (s, 2H), 4.22 (tt, J=8.8, 4.5 Hz,
1H), 4.01 (d, J=12.1 Hz, 1H), 3.88-3.79 (m, 2H), 3.57 (dd, J=11.5,
4.2 Hz, 1H), 2.87 (dd, J=17.7, 8.8 Hz, 1H), 2.58 (dd, J=17.7, 5.0
Hz, 1H), 2.14 (s, 3H), 1.87 (s, 3H), 1.53 (s, 3H).
Example 364:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3''-(((2-hydroxyeth-
yl)amino)methyl)-2,2'-dimethyl-4''-(2-(pyridin-3-yl)ethoxy)-[1,1':3',1''-t-
erphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic
acid
##STR00604##
[2513] To a solution of 5-bromosalicaldehyde (500 mg, 2.49 mmol) in
DMF (8 mL) was added Cs.sub.2CO.sub.3 (973 mg, 3.00 mmol) and
4-(2-bromoethyl)pyridine (431 mg, 2.32 mmol). The mixture was
heated to 80.degree. C. for 12 h, then cooled to rt, diluted with
Et.sub.2O (50 mL), and washed with water (3.times.10 mL). The
organic layer was dried (MgSO4) and concentrated, and the residue
purified by column chromatography (SiO.sub.2, 0-100% EtOAc/hex) to
yield 5-bromo-2-(2-(pyridin-3-yl)ethoxy)benzaldehyde.
[2514] 2-((5-bromo-2-(2-(pyridin-3-ypethoxy)benzyl)amino)ethan-1-ol
was synthesized according to general reductive amination procedure
D.
[2515] A flask was charged with
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methypnicotinonitrile
(100 mg, 0.164 mmol),
2-((5-bromo-2-(2-(pyridin-3-yl)ethoxy)benzyl)amino)ethan-1-ol (231
mg, 0.657 mmol), Na.sub.2CO.sub.3 (139 mg, 1.35 mmol), Pd XPhos G2
(6 mg, 0.08 mmol), dioxane (2 mL), and water (0.2 mL). The flask
was subjected to 3 vaccuum/argon cycles, then heated to 90.degree.
C. for 12 h. The mixture was cooled to rt, filtered over celite,
concentrated, and purified by preparative HPLC to yield
5-((4-chloro-2-formyl-5-((3''-(((2-hydroxyethyl)amino)methyl)-2,2'-dimeth-
yl-4''-(2-(pyridin-3-ypethoxy)-[1,1':3',1''-terphenyl]-3-yl)methoxy)phenox-
y)methypnicotinonitrile.
[2516]
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3''-(((2-hydr-
oxyethyl)amino)methyl)-2,2'-dimethyl-4''-(2-(pyridin-3-yl)ethoxy)-[1,1':3'-
,1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic
acid was synthesized according to general reductive amination
procedure D. [M+1]=856.4. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.98 (d, J=2.1 Hz, 1H), 8.94 (s, 1H), 8.90 (d, J=2.0 Hz,
1H), 8.76 (d, J=5.6 Hz, 1H), 8.65 (dd, J=8.1, 1.7 Hz, 1H), 8.42 (t,
J=2.1 Hz, 1H), 8.04 (dd, J=8.1, 5.7 Hz, 1H), 7.55 (s, 1H),
7.49-7.38 (m, 3H), 7.32-7.18 (m, 4H), 7.15-7.05 (m, 3H), 5.37 (s,
2H), 5.32 (s, 2H), 4.51 (t, J=6.2 Hz, 2H), 4.29 (s, 2H), 4.26 (s,
2H), 4.01 (d, J=12.1 Hz, 1H), 3.87-3.76 (m, 3H), 3.48 (t, J=6.1 Hz,
2H), 3.15 (t, J=5.2 Hz, 2H), 2.13 (s, 3H), 1.88 (s, 3H), 1.53 (s,
3H).
Example 365:
5-((4-chloro-5-((2'-(fluoromethyl)-4''-(((2-hydroxyethyl)amino)methyl)-2--
methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-(((2-hydroxyethyl)amino)met-
hyl)phenoxy)methyl)nicotinonitrile
##STR00605##
[2518] To a solution of 2,6-dibromobenzaldehyde (1.00 g, 3.80 mmol)
in THF (10 mL) was added NaBH.sub.4 (215 mg, 5.69 mmol). The
mixture was stirred for 12 h, then poured over a saturated solution
of NH.sub.4Cl. The aqueous layer was extracted with EtOAc, and the
combined organics dried (MgSO.sub.4) and concentrated to yield
(2,6-dibromophenyl)methanol as a white solid (1.00 g, 99%) which
was carried forward without further purification.
[2519] A Teflon reaction tube was charged with
(2,6-dibromophenyl)methanol (1.00 g, 3.76 mmol) and DCM (10 mL).
The solution was cooled to 0.degree. C. and DAST (0.55 mL, 4.1
mmol) was added. The mixture was stirred for 10 min, then
NaHCO.sub.3 (saturated solution, 10 mL) was added. The aqueous
layer was extracted with DCM and the combined organics dried
(MgSO.sub.4) and concentrated. The residue was purified by column
chromatography (SiO.sub.2, 0-30% EtOAc/hex) to yield
1,3-dibromo-2-(fluoromethyl)benzene.
[2520] A flask was charged with
55-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (300 mg, 0.578
mmol), 1,3-dibromo-2-(fluoromethyl)benzene (465 mg, 1.74 mmol),
Na.sub.2CO.sub.3 (245 mg, 2.89 mmol), Pd(dppf)Cl.sub.2 (21 mg,
0.028 mmol), dioxane (4 mL), and water (0.4 mL). The flask was
subjected to 3 vaccuum/argon cycles, then heated to 90.degree. C.
for 12 h. The mixture was cooled to rt, filtered over celite,
concentrated, and purified by column chromatography (SiO.sub.2,
0-70% EtOAc/hex) to yield
5-((5-((3'-bromo-2'-(fluoromethyl)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-
-4-chloro-2-formylphenoxy)methyl)nicotinonitrile.
[2521] A flask was charged with
5-((5-((3'-bromo-2'-(fluoromethyl)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-
-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (270 mg, 0.466
mmol), bis(pinacolato)diboron (142 mg, 0.559 mmol), potassium
acetate (123 mg, 1.21 mmol), Pd(dppf)Cl.sub.2 (17 mg, 0.023 mmol),
and dioxane (2 mL). The mixture was subjected to three vacuum/argon
cycles, then stirred at 90.degree. C. for 3 h. The mixture was
cooled to rt, filtered over celite, concentrated and purified by
column chromatography (SiO.sub.2, 0-90% EtOAc/hex) to yield
5-((4-chloro-5-((2'-(fluoromethyl)-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)n-
icotinonitrile.
[2522] A flask was charged with
5-((4-chloro-5-((2'-(fluoromethyl)-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)n-
icotinonitrile (232 mg, 0.370 mmol), 4-bromobenzaldehyde (205 mg,
1.11 mmol), Na.sub.2CO.sub.3 (157 mg, 1.48 mmol), Pd(dppf)Cl.sub.2
(14 mg, 0.019 mmol), dioxane (4 mL), and water (0.4 mL). The flask
was subjected to 3 vaccuum/argon cycles, then heated to 90.degree.
C. for 12 h. The mixture was cooled to rt, filtered over celite,
concentrated, and purified by column chromatography (SiO.sub.2,
0-70% EtOAc/hex) to yield
5-((4-chloro-5-((2'-(fluoromethyl)-4''-formyl-2-methyl-[1,1':3',1''-terph-
enyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile.
[2523]
5-((4-chloro-5-((2'-(fluoromethyl)-4''-(((2-hydroxyethyl)amino)meth-
yl)-2-methyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-(((2-hydroxyethyl)ami-
no)methyl)phenoxy)methyl)nicotinonitrile was synthesized according
to general reductive amination procedure D. [M+1]=695.2. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.95 (d, J=1.9 Hz, 1H),
8.89 (d, J=1.8 Hz, 1H), 8.38 (t, J=2.0 Hz, 1H), 7.61 (d, J=8.3 Hz,
2H), 7.58-7.45 (m, 5H), 7.39 (d, J=7.7 Hz, 1H), 7.25 (t, J=7.7 Hz,
2H), 7.19 (d, J=7.4 Hz, 1H), 7.04 (s, 1H), 5.40-5.27 (m, 4H), 4.90
(td, J=38.7, 38.7, 10.7 Hz, 2H), 4.32 (s, 2H), 4.24 (s, 2H), 3.85
(t, J=5.3 Hz, 2H), 3.78 (t, J=5.8 Hz, 2H), 3.19 (t, J=5.1 Hz, 2H),
3.12 (t, J=5.8, 5.3 Hz, 2H), 2.12 (s, 3H).
Example 366:
5-((4-chloro-2-((dimethylamino)methyl)-5-((3'-(5-((dimethylamino)methyl)t-
hiophen-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)ni-
cotinonitrile
##STR00606##
[2525] A flask was charged with
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (104 mg, 0.171 mmol), 5-bromothiophene-2-carbaldehyde (0.06 mL,
0.5 mmol), Na.sub.2CO.sub.3 (72 mg, 0.68 mmol), Pd XPhos G2 (6 mg,
0.08 mmol), dioxane (2 mL), and water (0.2 mL). The flask was
subjected to 3 vaccuum/argon cycles, then heated to 90.degree. C.
for 3 h. The mixture was cooled to rt, filtered over celite,
concentrated, and purified by column chromatography (SiO.sub.2,
0-90% EtOAc/hex) to yield
5-((4-chloro-2-formyl-5-((3'-(5-formylthiophen-2-yl)-2,2'-dimethyl-[1,1'--
biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile.
[2526]
5-((4-chloro-2-((dimethylamino)methyl)-5-((3'-(5-((dimethylamino)me-
thyl)thiophen-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)met-
hyl)nicotinonitrile was synthesized according to general reductive
amination procedure D. [M+1]=651.2. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.96 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0
Hz, 1H), 8.37 (t, J=2.1 Hz, 1H), 7.54 (s, 1H), 7.48 (dd, J=7.7, 1.4
Hz, 1H), 7.40 (dd, J=7.8, 1.4 Hz, 1H), 7.35-7.24 (m, 3H), 7.18-7.05
(m, 4H), 5.39 (s, 2H), 5.32 (s, 2H), 4.58 (s, 2H), 4.30 (s, 2H),
2.92 (s, 6H), 2.83 (s, 6H), 2.12 (s, 3H), 2.05 (s, 3H).
Example 367:
5-((4-chloro-2-((((1S,2S)-2-hydroxycyclohexyl)amino)methyl)-5-((3''-(2-((-
2-hydroxyethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)me-
thoxy)phenoxy)methyl)nicotinonitrile
##STR00607##
[2528]
5-((4-chloro-5-((3''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1'-
'-terphenyl]-3-yl)methoxy)-2-((((1S,2S)-2-hydroxycyclohexyl)amino)methyl)p-
henoxy)methyl)nicotinonitrile was synthesized according to general
reductive amination procedure D.
[2529] To a solution of
5-((4-chloro-5-((3''-(2,2-diethoxyethoxy)-2,2'-dimethyl-[1,1':3',1''-terp-
henyl]-3-yl)methoxy)-2-((((1S,2S)-2-hydroxycyclohexyl)amino)methyl)phenoxy-
)methyl)nicotinonitrile (183 mg, 0.16 mmol) in dioxane (3 mL) was
added HCl (conc., 0.3 mL). The mixture was stirred for 3 h, then
concentrated to yield
5-((4-chloro-5-((2,2'-dimethyl-3''-(2-oxoethoxy)-[1,1':3',1''-te-
rphenyl]-3-yl)methoxy)-2-((((1S,2S)-2-hydroxycyclohexyl)amino)methyl)pheno-
xy)methyl)nicotinonitrile which was carried forward without further
purification.
[2530]
5-((4-chloro-2-((((1S,2S)-2-hydroxycyclohexyl)amino)methyl)-5-((3''-
-(2-((2-hydroxyethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-
-yl)methoxy)phenoxy)methyl)nicotinonitrile was synthesized
according to general reductive amination procedure D. [M+1]=761.3.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.97 (d, J=1.7 Hz,
1H), 8.92 (d, J=1.6 Hz, 1H), 8.40 (s, 1H), 7.50 (s, 1H), 7.46 (d,
J=7.4 Hz, 1H), 7.31-7.21 (m, 4H), 7.18 (dd, J=7.6, 1.2 Hz, 1H),
7.13 (d, J=7.6 Hz, 1H), 7.11-7.00 (m, 4H), 5.35 (s, 2H), 5.31 (s,
2H), 4.35 (t, 2H), 4.25 (d, J=13.1 Hz, 1H), 4.18-4.10 (m, 2H), 3.86
(t, 2H), 3.54 (t, 2H), 3.26 (t, 2H), 3.11 (dt, J=11.2, 3.5 Hz, 1H),
2.14 (s, 3H), 1.86 (s, 3H), 1.76-1.57 (m, 4H), 1.52-1.24 (m,
4H).
Example 368:
2-(1-((3''-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((1R,2S)-2-hyd-
roxycyclopentyl)amino)methyl)phenoxy)methyl)-2',2''-dimethyl-[1,1':3',1''--
terphenyl]-4-yl)methyl)azetidin-3-yl)acetic acid
##STR00608##
[2532] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=771.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (dd, J=11.8, 2.0 Hz, 2H), 8.38 (s,
1H), 7.58 (d, J=8.0 Hz, 2H), 7.50-7.44 (m, 3H), 7.34-7.06 (m, 7H),
5.34 (d, J=19.0 Hz, 3H), 4.57-4.47 (m, 2H), 4.29 (s, 3H), 4.18-4.05
(m, 3H), 3.48-3.34 (m, 3H), 3.28-3.21 (m, 2H), 3.12 (s, 1H),
3.05-2.94 (m, 2H), 2.79 (dd, J=17.5, 8.6 Hz, 2H), 2.47 (dd, J=17.5,
7.7 Hz, 2H), 2.14 (s, 3H), 1.87 (s, 3H).
Example 369:
(3S)-1-(5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((1R,2S)-2--
hydroxycyclopentyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphen-
yl]-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic
acid
##STR00609##
[2534] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=797.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (dd, J=10.5, 2.0 Hz, 2H), 8.39 (s,
1H), 7.66 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J=7.6 Hz, 1H),
7.39 (s, 1H), 7.34-7.07 (m, 7H), 5.34 (d, J=16.6 Hz, 4H), 5.00 (d,
J=7.6 Hz, 1H), 4.27 (d, J=13.1 Hz, 2H), 4.15 (d, J=13.2 Hz, 1H),
3.49-3.37 (m, 3H), 3.10 (d, J=17.7 Hz, 3H), 2.61 (s, 4H), 2.14 (s,
3H), 2.02 (s, 2H), 1.87 (s, 4H), 1.82-1.56 (m, 5H).
Example 370:
(3R)-1-(5-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydro-
xypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-y-
l)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid
##STR00610##
[2536] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=783.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=8.7, 2.0 Hz, 2H), 8.37 (s,
1H), 7.66 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J=7.6 Hz, 1H),
7.40 (s, 1H), 7.37-7.25 (m, 3H), 7.18 (dd, J=20.1, 7.4 Hz, 2H),
7.11 (d, J=4.5 Hz, 2H), 5.39 (s, 2H), 5.32 (s, 2H), 5.00 (d, J=7.7
Hz, 1H), 4.53 (s, 2H), 4.41 (s, 2H), 3.78-3.35 (m, 8H), 3.10 (d,
J=17.7 Hz, 2H), 2.63 (dd, J=15.4, 7.7 Hz, 2H), 2.49 (s, 1H), 2.14
(s, 3H), 2.04 (s, 1H), 1.88 (s, 3H).
Example 371:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-(-
1-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)-[1,1'-biphenyl]-3-yl)-
methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00611##
[2538] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=771.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.97 (s, 2H), 8.41 (s, 1H), 7.60-7.44 (m,
3H), 7.37 (s, 1H), 7.28 (dt, J=15.9, 7.4 Hz, 3H), 7.21-7.05 (m,
4H), 5.34 (d, J=17.9 Hz, 4H), 4.36-4.06 (m, 6H), 4.00 (d, J=12.1
Hz, 2H), 3.79 (d, J=12.2 Hz, 2H), 3.14-2.94 (m, 3H), 2.55 (s, 1H),
2.14 (s, 3H), 1.86 (s, 3H), 1.52 (s, 3H), 1.36 (d, J=7.0 Hz, 1H),
1.28 (d, J=6.6 Hz, 2H).
Example 372:
(3S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(1-(dimethylami-
no)-6-fluoro-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl-
)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00612##
[2540] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=763.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=11.3, 2.1 Hz, 2H), 8.37 (s,
1H), 7.51 (s, 1H), 7.49-7.33 (m, 4H), 7.33-7.19 (m, 3H), 7.16 (s,
1H), 7.08 (s, 1H), 5.37 (s, 2H), 5.31 (s, 2H), 5.06 (d, J=8.2 Hz,
1H), 4.23 (s, 3H), 3.24-3.15 (m, 2H), 3.09 (d, J=8.4 Hz, 1H), 2.97
(dd, J=12.8, 9.8 Hz, 2H), 2.91 (s, 2H), 2.76 (s, 2H), 2.69-2.56 (m,
2H), 2.51 (d, J=6.3 Hz, 3H), 2.13 (s, 3H), 1.82 (s, 3H).
Example 373:
5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(1-((S)-3-hydroxypy-
rrolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3--
yl)methoxy)phenoxy)methyl)nicotinonitrile
##STR00613##
[2542] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=729.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98-8.88 (m, 2H), 8.38 (s, 1H), 7.66 (d,
J=8.2 Hz, 1H), 7.53-7.43 (m, 2H), 7.38 (s, 1H), 7.34-7.07 (m, 7H),
5.48 (s, 4H), 5.37 (s, 2H), 5.31 (s, 2H), 5.08-4.96 (m, 2H),
4.61-4.51 (m, 2H), 4.23 (s, 2H), 3.77 (s, 3H), 3.47 (d, J=1.7 Hz,
2H), 3.10 (d, J=5.2 Hz, 3H), 2.14 (s, 3H), 1.88 (s, 3H).
Example 374:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-(1-(2-hydroxye-
thyl)pyrrolidin-2-yl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)b-
enzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00614##
[2544] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=775.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.90 (s, 2H), 7.63 (d, J=8.1 Hz, 2H),
7.57-7.47 (m, 3H), 7.31-7.07 (m, 6H), 5.34 (d, J=18.0 Hz, 4H), 4.26
(s, 2H), 3.98 (d, J=12.2 Hz, 2H), 3.81-3.67 (m, 4H), 3.47 (t, J=1.6
Hz, 2H), 3.12 (s, 2H), 2.37-2.28 (m, 3H), 2.15 (s, 3H), 1.89 (s,
3H), 1.50 (s, 3H).
Example 375:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(1-((2-hydroxye-
thyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00615##
[2546] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=775.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.0
Hz, 1H), 8.42 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.55 (s, 1H), 7.47
(d, J=7.4 Hz, 1H), 7.39-7.07 (m, 8H), 5.34 (d, J=17.0 Hz, 4H), 4.27
(s, 2H), 4.00 (d, J=12.1 Hz, 2H), 3.92 (s, 1H), 3.79 (d, J=12.2 Hz,
2H), 3.12 (t, J=1.7 Hz, 2H), 2.94 (s, 2H), 2.79 (s, 1H), 2.68-2.57
(m, 2H), 2.47 (s, 2H), 2.15 (s, 3H), 1.88 (s, 3H), 1.52 (s,
3H).
Example 376:
(2S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(dimethylami-
no)-2,3-dihydrobenzofuran-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy-
)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00616##
[2548] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=747.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.41 (s, 1H), 7.64 (d, J=7.9 Hz, 1H),
7.55 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.33-7.19 (m, 3H), 7.18-7.03
(m, 4H), 6.99 (s, 1H), 5.34 (d, J=16.8 Hz, 4H), 5.22 (d, J=7.2 Hz,
1H), 5.02 (d, J=12.6 Hz, 1H), 4.71 (d, J=12.1 Hz, 1H), 4.27 (s,
2H), 3.99 (d, J=12.2 Hz, 2H), 3.78 (d, J=12.1 Hz, 2H), 2.83 (s,
4H), 2.14 (s, 3H), 1.89 (s, 3H), 1.51 (s, 3H).
Example 377:
(2S,4S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((R)-1-(dimet-
hylamino)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)me-
thoxy)benzyl)-4-hydroxypyrrolidine-2-carboxylic acid
##STR00617##
[2550] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=757.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.97 (s, 1H), 8.92 (d, J=1.8 Hz, 1H),
8.42 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.49 (d, J=13.9 Hz, 2H),
7.41-7.08 (m, 8H), 5.40 (s, 1H), 5.31 (s, 1H), 5.04 (d, J=6.5 Hz,
1H), 4.46 (d, J=13.9 Hz, 2H), 4.37 (d, J=13.9 Hz, 1H), 4.20 (dd,
J=10.9, 3.8 Hz, 1H), 3.34 (s, 4H), 3.22 (dd, J=16.8, 8.7 Hz, 2H),
2.90 (s, 2H), 2.75 (s, 2H), 2.67-2.53 (m, 3H), 2.49 (d, J=8.4 Hz,
1H), 2.25 (d, J=12.9 Hz, 2H), 2.14 (s, 3H), 1.88 (s, 3H).
Example 378:
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((R)-1-(dimethyl-
amino)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)metho-
xy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00618##
[2552] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=745.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.98 (d, J=2.0 Hz, 1H), 8.91 (d, J=1.9
Hz, 1H), 8.41 (s, 1H), 7.62-7.54 (m, 2H), 7.47 (d, J=7.5 Hz, 1H),
7.40 (s, 1H), 7.36-7.05 (m, 7H), 5.34 (d, J=16.8 Hz, 4H), 5.04 (d,
J=8.7 Hz, 1H), 4.27 (s, 2H), 4.00 (d, J=12.1 Hz, 1H), 3.79 (d,
J=12.2 Hz, 1H), 3.26-3.18 (m, 1H), 2.90 (s, 2H), 2.75 (s, 2H),
2.62-2.43 (m, 3H), 2.15 (s, 3H), 1.88 (s, 3H), 1.52 (s, 3H).
Example 379:
5-((4-chloro-5-((2,2'-dimethyl-4''-(pyrrolidin-2-yl)-[1,1':3',1''-terphen-
yl]-3-yl)methoxy)-2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotino-
nitrile
##STR00619##
[2554] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=673.3. HPLC T.sub.R=4.87
min.
Example 380:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-((S)-1-(dimethy-
lamino)ethyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)am-
ino)-3-hydroxybutanoic acid
##STR00620##
[2556] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=733.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=12.0, 2.0 Hz, 2H), 8.37 (s,
1H), 7.57 (d, J=8.0 Hz, 2H), 7.53-7.42 (m, 4H), 7.35-7.19 (m, 3H),
7.17-7.05 (m, 3H), 5.38 (s, 2H), 5.31 (s, 2H), 4.37 (s, 2H), 4.23
(s, 3H), 3.20 (dd, J=12.7, 3.0 Hz, 2H), 3.00-2.94 (m, 1H), 2.90 (s,
6H), 2.51 (dd, J=6.3, 1.1 Hz, 2H), 2.14 (s, 3H), 1.89 (s, 3H).
Example 381:
(3S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(1-(dimethylami-
no)-2,3-dihydro-1H-inden-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-
benzyl)amino)-3-hydroxybutanoic acid
##STR00621##
[2558] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=745.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=12.6, 2.1 Hz, 2H), 8.37 (s,
1H), 7.58-7.42 (m, 3H), 7.29 (td, J=13.6, 7.0 Hz, 4H), 7.22-7.05
(m, 4H), 5.37 (s, 2H), 5.31 (s, 2H), 4.23 (s, 4H), 3.29-3.15 (m,
3H), 3.02 (ddd, J=37.3, 13.9, 8.8 Hz, 3H), 2.90 (s, 6H), 2.74-2.60
(m, 2H), 2.51 (dd, J=6.3, 1.1 Hz, 2H), 2.14 (s, 3H), 2.04-1.91 (m,
1H), 1.86 (s, 3H).
Example 382:
5-((4-chloro-2-((dimethylamino)methyl)-5-((3'-(6-((dimethylamino)methyl)p-
yridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nic-
otinonitrile
##STR00622##
[2560] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=646.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (dd, J=6.3, 2.0 Hz, 2H), 8.69 (s,
1H), 8.36 (d, J=2.2 Hz, 1H), 7.92 (dd, J=7.9, 2.2 Hz, 1H),
7.59-7.45 (m, 3H), 7.41-7.34 (m, 1H), 7.29 (t, J=7.9 Hz, 2H),
7.23-7.09 (m, 3H), 5.40 (s, 2H), 5.32 (s, 2H), 4.54 (s, 2H), 4.30
(s, 2H), 2.99 (s, 6H), 2.83 (s, 6H), 2.15 (s, 3H), 1.92 (s,
3H).
Example 383:
(S)-4-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4'-((dimethylamino)-
methyl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)benzyl)amino)-3-
-hydroxybutanoic acid
##STR00623##
[2562] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=719.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.95 (dd, J=12.0, 2.0 Hz, 2H), 8.35 (s,
1H), 7.57 (d, J=8.0 Hz, 2H), 7.53-7.43 (m, 4H), 7.37-7.19 (m, 3H),
7.19-7.00 (m, 3H), 5.40 (s, 2H), 5.31 (s, 2H), 4.36 (s, 2H), 4.23
(s, 3H), 3.20 (dd, J=12.7, 3.0 Hz, 1H), 3.01-2.94 (m, 1H), 2.90 (s,
5H), 2.51 (dd, J=6.3, 1.1 Hz, 2H), 2.10 (s, 3H), 1.90 (s, 3H).
Example 384:
(S)-4-((4-((4''-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2,2'-dimet-
hyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl-
)methoxy)benzyl)amino)-3-hydroxybutanoic acid
##STR00624##
[2564] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=793.3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (dd, J=11.8, 2.0 Hz, 2H), 8.38 (s,
1H), 7.59 (d, J=8.0 Hz, 2H), 7.51-7.45 (m, 3H), 7.35-7.06 (m, 7H),
5.38 (s, 2H), 5.31 (s, 2H), 4.42 (s, 2H), 4.23 (s, 3H), 4.06 (s,
1H), 3.74 (s, 1H), 3.42 (s, 1H), 3.20 (dd, J=12.8, 3.0 Hz, 2H),
3.02-2.92 (m, 2H), 2.51 (d, J=6.3 Hz, 2H), 2.14 (s, 3H), 1.89 (s,
3H).
Example 385:
(S)-4-((2-((3''-(((3-bromo-5-((((S)-3-carboxy-2-hydroxypropyl)amino)methy-
l)-6-((5-cyanopyridin-3-yl)methoxy)pyridin-2-yl)oxy)methyl)-2',2''-dimethy-
l-[1,1':3',1''-terphenyl]-4-yl)oxy)ethyl)amino)-3-hydroxybutanoic
acid
##STR00625##
[2566] The title compound was synthesized according to general
reductive amination procedure C. [M+1]=868.3. HPLC T.sub.R=4.98
min.
Example 386:
(S)-4-((4-((3'-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxybutanoic acid
##STR00626## ##STR00627##
[2568] 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate (1.149
g, 4.03 mmol) was added to a solution of 3-bromo-2-methylaniline
(500 mg, 2.69 mmol) and 4-(dimethylamino)pyridine (657 mg, 5.37
mmol) in dichloromethane (15 mL). After 14 hours saturated sodium
bicarbonate (15 mL) was added. The aqueous phase was extracted with
ethyl acetate (3.times.20 mL). The combined organic extracts were
washed with saturated sodium bicarbonate (25 mL) and brine (25 mL).
The organic phase was dried over sodium sulfate and the solvent was
removed under reduced pressure. The residue was subjected to flash
chromatography (0-100% ethyl acetate/hexanes). The fractions
containing product were combined and the solvent was removed under
reduced pressure, providing 1-azido-3-bromo-2-methylbenzene.
[2569] 1-Azido-3-bromo-2-methylbenzene (50 mg, 0.236 mmol) was
added to a mixture of tert-butyl prop-2-yn-1-ylcarbamate (73.2 mg,
0.472 mmol) and copper(I) thiophene-2-carboxylate (3.02 mg, 0.02
mmol) in tetrahydrofuran (1 mL). After 14 hours the solvent was
removed under reduced pressure. The residue was subjected to flash
chromatography (0-100% ethyl acetate/hexanes). The fractions
containing product were combined and the solvent was removed under
reduced pressure, tert-butyl
((1-(3-bromo-2-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate.
[2570]
5-((4-chloro-2-formyl-5-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile (80 mg,
0.154 mmol), tert-butyl
((1-(3-bromo-2-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate
(79.3 mg, 0.216 mmol), Tetrakis(triphenylphosphine)palladium (0)
(17.8 mg, 0.015 mmol), potassium carbonate (19 mg, 0.308 mmol) in
water (0.4 mL), and dimethoxyethane (4 mL) was degassed with argon
for 2 minutes. The above were combined and heated at 85.degree. C.
for 3 hours. The reaction was diluted with ethyl acetate (100 mL)
and washed with water (3.times.50 mL) and brine (50 mL). The
organic phase was dried over sodium sulfate and the solvent was
removed under reduced pressure. The residue was subjected to flash
chromatography (0-100% EtOAc/hexanes). The fractions containing
product and the solvent was removed under reduced pressure
providing tert-butyl
((1-(3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methy-
l)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-1,2,3-triazol-4-yl)methyl)carbam-
ate.
[2571]
(S)-4-((4-((3'-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-tri-
azol-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyan-
opyridin-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid was
synthesized according to general reductive amination procedure
G.
[2572] Trifluoroacetic acid (0.3 mL) was added to a solution
(S)-4-((4-((3'-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-
-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyrid-
in-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid (42 mg, 0.0537
mmol) in dichloromethane (0.7 mL) and After 20 minutes the reaction
was diluted with acetonitrile (5 mL) and co-evaporated until
.about.1 mL remained. The material was co-evaporated with
acetonitrile two more times. The residue was taken up in methanol
(0.5 mL) and water (0.5 mL). The solution was subjected to
preparative HPLC (eluant: 0.1% trifluoroacetic acid in
acetonitrile/water). The fractions containing product were combined
and subjected to lyophilization, providing
(S)-4-((4-((3'-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-
amino)-3-hydroxybutanoic acid. [M+1]=682.0. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.94 (m, 2H), 8.38 (s, 1H), 8.32 (s, 1H),
7.58-7.46 (m, 3H), 7.40 (ddd, J=10.5, 7.6, 1.5 Hz, 2H), 7.31 (t,
J=7.6 Hz, 1H), 7.22-7.13 (m, 1H), 7.09 (s, 1H), 5.39 (s, 2H), 5.32
(s, 2H), 4.36 (s, 2H), 4.24 (m, 3H), 3.20 (dd, J=12.7, 3.1 Hz, 1H),
3.05-2.91 (m, 1H), 2.52 (dd, J=6.2, 1.1 Hz, 2H), 2.15 (s, 3H), 1.82
(s, 3H).
Example 387:
(S)-4-((3-(4-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chl-
oro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)-1H-1,2,3-triazol-1-yl)propyl)amino)-3-hydroxybutanoic
acid
##STR00628##
[2574]
5-((4-chloro-2-formyl-5-((3'-(1-(3-hydroxypropyl)-1H-1,2,3-triazol--
4-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinoni-
trile was prepared analogously to Example 330.
[2575] Dess-martin periodinane was added to a solution of
5-((4-chloro-2-formyl-5-((3'-(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)--
2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
(70 mg, 0.115 mmol) in dichloromethane (4 mL). After 30 minutes the
reaction was diluted with ethyl acetate (25 mL) and washed with
saturated sodium bicarbonate (15 mL) and brine (15 mL). The organic
phase was dried over sodium sulfate and the solvent was removed
under reduced pressure, providing
5-((4-chloro-5-((2,2'-dimethyl-3'-(1-(3-oxopropyl)-1H-1,2,3-tri-
azol-4-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinoni-
trile.
[2576]
(S)-4-((3-(4-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-
-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1-
,1'-biphenyl]-3-yl)-1H-1,2,3-triazol-1-yl)propyl)amino)-3-hydroxybutanoic
acid was synthesized according to general reductive amination
procedure G. [M+1]=812.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.94 (m, 2H), 8.38 (s, 1H), 8.20 (s, 1H), 7.63-7.55 (m,
1H), 7.54-7.43 (m, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.6 Hz,
1H), 7.21-7.01 (m, 3H), 5.38 (s, 2H), 5.32 (s, 2H), 4.63 (t, J=6.8
Hz, 2H), 4.35-4.12 (m, 4H), 3.25-3.10 (m, 4H), 3.11-2.89 (m, 4H),
2.62-2.48 (m, 4H), 2.48-2.29 (m, 2H), 2.13 (s, 3H), 2.08 (s,
3H).
Example 388:
(S)-2-((4-(((4''-(2-(((S)-2-carboxy-1-hydroxypropan-2-yl)amino)ethoxy)-2,-
2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)oxy)methyl)-5-chloro-2-((5-cyanop-
yridin-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic
acid
##STR00629##
[2578] The title compound was synthesized according to general
reductive amination procedure D. [M+1]=823.2. .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.88 (s, 1H), 8.84 (s, 1H), 8.24 (s,
1H), 7.55 (s, 1H), 7.36-7.11 (m, 6H), 7.09-7.01 (m, 4H), 6.80 (d,
J=7.6 Hz, 1H), 5.28 (s, 2H), 5.21 (s, 2H), 4.33 (t, J=5.0 Hz, 2H),
4.28 (s, 2H), 3.95 (dd, J=18.4, 12.4 Hz, 2H), 3.79 (dd, J=18.9,
12.4 Hz, 2H), 3.50 (t, J=5.0 Hz, 2H), 1.95 (s, 3H), 1.88 (s, 3H),
1.54 (s, 3H), 1.49 (s, 3H).
Example 389:
(S)-4-((4-(((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlo-
ro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bip-
henyl]-3-yl)oxy)methyl)-5-chloro-2-methoxybenzyl)amino)-3-hydroxybutanoic
acid
##STR00630##
[2580] The title compound was synthesized according to general
reductive amination procedure A. [M+1]=887.1. .sup.1H (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.91 (dd, J=8.3, 2.0 Hz, 2H), 8.27
(t, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.46 (d, J=3.9 Hz, 2H), 7.34 (s,
1H), 7.27 (q, J=8.0 Hz, 2H), 7.13 (dd, J=7.7, 1.4 Hz, 1H),
7.10-7.05 (m, 1H), 6.95 (s, 1H), 6.81-6.74 (m, 1H), 5.32 (s, 2H),
5.25 (s, 2H), 5.23 (s, 2H), 4.36-4.09 (m, 6H), 3.87 (s, 3H),
3.17-3.06 (m, 4H), 2.79 (d, J=0.7 Hz, 3H), 2.48 (ddd, J=12.8, 6.3,
3.4 Hz, 4H), 2.07 (s, 3H).
Example 390:
(S)-4-((4-((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)benzyl)oxy)-2,2'-dimethyl-[1,1'-biphenyl-
]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-h-
ydroxybutanoic acid
##STR00631##
[2582] The title compound was synthesized according to general
reductive amination procedure A. [M+1]=989.1. .sup.1H (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.89 (d, J=21.5 Hz, 4H), 8.28 (s,
1H), 8.22 (s, 1H), 7.54 (s, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.46 (s,
1H), 7.35 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H),
7.15 (d, J=7.5 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.96 (s, 1H), 6.79
(d, J=7.6 Hz, 1H), 5.32 (s, 2H), 5.29 (s, 2H), 5.27 (s, 2H), 5.22
(s, 2H), 4.40-3.99 (m, 6H), 3.16 (ddd, J=17.9, 12.8, 3.1 Hz, 2H),
2.96 (ddd, J=17.2, 12.8, 9.7 Hz, 2H), 2.48 (td, J=6.7, 6.2, 4.1 Hz,
4H), 2.07 (s, 3H), 1.90 (s, 3H).
Example 391:
5-((4-chloro-2-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5-((4''-(2-(-
(2-hydroxyethyl)amino)ethoxy)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)m-
ethoxy)phenoxy)methyl)nicotinonitrile
##STR00632##
[2584] The title compound was synthesized according to general
reductive amination procedure A, followed by DCM/TFA Boc
deprotection. [M+1]=733.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.02 (dd, J=5.4, 2.1 Hz, 2H), 8.72 (s, 4H), 8.48 (t, J=2.1
Hz, 1H), 7.56 (s, 1H), 7.52-7.43 (m, 1H), 7.36-7.24 (m, 4H),
7.22-7.11 (m, 3H), 7.09-7.01 (m, 3H), 5.35 (s, 2H), 5.32 (d, J=2.3
Hz, 2H), 4.29 (t, J=5.1 Hz, 2H), 4.18 (d, J=5.6 Hz, 2H), 3.68 (t,
J=5.3 Hz, 2H), 3.40 (t, J=5.5 Hz, 2H), 3.15-3.07 (m, 2H), 2.99 (t,
J=5.6 Hz, 2H), 2.08 (s, 3H), 1.85 (s, 3H), 0.72-0.66 (m, 2H), 0.60
(t, J=3.3 Hz, 2H).
Example 392:
(S)-4-(((6-(((3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chl-
oro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-bi-
phenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00633##
[2586] The title compound was synthesized according to general
reductive amination procedure A. [M+1]=824.4. .sup.1H (400 MHz,
DMSO-d6) .delta. 9.04 (dd, J=5.6, 2.0 Hz, 2H), 8.99 (s, 2H), 8.71
(d, J=2.1 Hz, 1H), 8.62 (s, 2H), 8.49 (t, J=2.1 Hz, 1H), 8.01 (dd,
J=8.1, 2.2 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.50 (d,
J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.26-7.16 (m, 2H), 7.13-7.02
(m, 2H), 6.73 (d, J=7.5 Hz, 1H), 5.38 (s, 2H), 5.31 (dd, J=11.8,
3.0 Hz, 2H), 5.26 (d, J=3.1 Hz, 2H), 4.25 (s, 2H), 4.17 (d, J=15.3
Hz, 4H), 3.04 (d, J=27.4 Hz, 2H), 2.86 (s, 2H), 2.48-2.28 (m, 4H),
2.05 (s, 3H), 1.93 (s, 3H).
Example 393:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)amino)-3-hy-
droxybutanoic acid
##STR00634##
[2588] Step 1: Ethoxycarbonyl isothiocyanate (480 .mu.L, 4.07 mmol)
was added dropwise to 6-amino-5-chloropyridin-3-yl)methanol (550
mg, 3.47 mmol) dissolved in 1,4-dioxane (9 mL). The reaction
mixture was stirred at rt overnight. The precipitate was filtered
and washed with dichloromethane. The mother liquor was concentrated
and filtered again. The two crops of solids were combined and
dried. The product was dissolved in methanol (7 mL) and ethanol (7
mL) and treated with N,N-diisopropylethylamine (900 .mu.L, 5.17
mmol) and hydroxylamine hydrochloride (600 mg, 8.63 mmol). The
reaction mixture was heated at 50.degree. C. for 2 h. After cooling
to room temperature, the reaction mixture was concentrated and the
residue was used in the next step.
[2589] Step 2:
(2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridine-6-yl)methanol (690
mg, 3.47 mmol) suspended in acetonitrile (35 mL) was treated with
copper (II) bromide (1160 mg, 5.19 mmol) and tert-butyl nitrite
(990 .mu.L, 8.29 mmol). The reaction mixture was stirred at room
temperature for 3 h. The reaction mixture was concentrated. The
residue was suspended in ethyl acetate and washed with water. The
organic layer was concentrated and purified by column
chromatography to give
(2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridine-6-yl)methanol.
[2590] Step 3:
(2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridine-6-yl)methanol (500
mg, 1.91 mmol) dissolved in dichloromethane (20 mL) was treated
with Dess-Martin periodinane (848 mg, 2.00 mmol). The reaction
mixture was stirred at room temperature overnight. The reaction
mixture was quenched by adding saturated sodium thiosulfate
solution and then concentrated. The residue was dissolved in ethyl
acetate and washed with water. The organic layer was concentrated
and purified by column chromatography to give
2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde.
[2591] Step 4:
2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (70
mg, 0.27 mmol) and
5-((4-chloro-5-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitril-
e (96 mg, 0.16 mmol) suspended in 2-methyltetrahydrofuran (3 mL)
was treated with
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14
mg, 0.02 mmol) and 2 M sodium carbonate solution (240 .mu.L, 0.48
mmol). The reaction mixture was heated in the microwave at
110.degree. C. for 3 h. After cooling to room temperature, the
reaction mixture was concentrated. The residue was suspended in
ethyl acetate and washed with water. The organic layer was
concentrated and purified by column chromatography to give
5-((4-chloro-5-((3'-(8-chloro-6-formyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-
)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicot-
inonitrile.
[2592] Step 5:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)amino)-3-hy-
droxybutanoic acid was synthesized in the same manner as Procedure
C using (S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.01 (d, J=6.5 Hz, 4H), 8.46 (s, 2H), 7.97
(d, J=8.2 Hz, 2H), 7.56-7.47 (m, 4H), 7.42 (s, 5H), 7.30 (d, J=7.6
Hz, 3H), 7.24 (d, J=7.4 Hz, 3H), 7.16 (d, J=7.4 Hz, 4H), 6.49 (s,
3H), 5.34 (d, J=10.7 Hz, 6H), 2.52 (s, 2H), 2.26 (s, 3H), 2.07 (s,
3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C44H43Cl2N7O8: 868.3; found:
868.1.
Example 394:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00635##
[2594] Step 1: Methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate
(300 mg, 1.18 mmol) dissolved in diethyl ether (12 mL) and cooled
to 0.degree. C. was treated with lithium aluminum hydride (46 mg,
1.21 mmol). The reaction mixture was allowed to warm to room
temperature and stirred overnight. After cooling to 0.degree. C.
again, the reaction mixture was quenched by addition of sodium
sulfate decahydrate. The mixture was stirred for 20 min and
filtered. The filtrate was concentrated to give
(2-bromoimidazo[1,2-a]pyridin-6-yl)methanol.
[2595] Steps 2-4: Prepared in the same manner as step 3-5 of
Example 393. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd,
J=5.6, 2.0 Hz, 2H), 8.94 (s, 2H), 8.72 (s, 1H), 8.58 (s, 2H), 8.47
(t, J=2.1 Hz, 1H), 8.36 (s, 1H), 7.80-7.71 (m, 2H), 7.57 (s, 1H),
7.56-7.48 (m, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H),
7.19 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 5.59 (d, J=28.8 Hz, 4H),
5.41-5.30 (m, 3H), 4.24 (s, 3H), 4.12 (d, J=9.9 Hz, 4H), 3.06 (s,
4H), 2.85 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C.sub.45H.sub.45ClN.sub.6O.sub.8: 833.3; found:
833.3.
Example 395:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)-4-methylbenzo[d]thiazol-5-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00636##
[2597] Synthesized analogous to Example 393 using the appropriate
heterocyclic bromoaldehyde. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.02 (dd, J=6.0, 2.0 Hz, 2H), 8.90 (s, 2H), 8.57 (s, 2H),
8.46 (t, J=2.0 Hz, 1H), 7.57 (s, 1H), 7.51 (d, J=3.8 Hz, 2H), 7.48
(t, J=7.7 Hz, 1H), 7.31 (t, J=7.7 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H),
5.56 (s, 2H), 5.35 (d, J=10.1 Hz, 4H), 4.27 (s, 2H), 4.14 (d,
J=23.4 Hz, 5H), 3.00 (d, J=16.5 Hz, 2H), 2.85 (d, J=11.1 Hz, 3H),
2.69 (s, 3H), 2.40-2.33 (m, 3H), 2.25 (s, 3H), 2.08 (s, 3H).
LCMS-ESI+ (m/z): [M+H]+ calcd for
C.sub.46H.sub.46ClN.sub.5O.sub.8S: 864.3; found: 864.0.
Example 396:
(S)-4-(((2-(3-((S)-1-((5-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-
-chloro-6-((5-cyanopyridin-3-yl)methoxy)pyridin-2-yl)oxy)-2,3-dihydro-1H-i-
nden-4-yl)-2-methylphenyl)benzo[d]thiazol-6-yl)methyl)amino)-3-hydroxybuta-
noic acid
##STR00637##
[2599] Step 1:
(S)-5-(((2-((4-(3-bromo-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6--
chloro-4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile (40 mg, 0.07
mmol) dissolved in 1,4-dioxane (8 mL) was treated with bis
(pinacolato) diboron (27 mg, 0.11 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (6
mg, 0.007 mmol), and potassium acetate (21 mg, 0.21 mmol). The
reaction mixture was heated at 80.degree. C. overnight. After
cooling to room temperature, the reaction mixture was diluted with
ethyl acetate and washed with water. The organic layer was
concentrated and purified by column chromatography to
give(S)-5-(((5-chloro-3-formyl-6-((4-(2-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)pyridin-2-yl)ox-
y)methyl)nicotinonitrile.
[2600] Step 2: 2-bromobenzo[d]thiazole-6-carbaldehyde (25 mg, 0.10
mmol) and
(S)-5-(((5-chloro-3-formyl-6-((4-(2-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)pyridin-2-yl)ox-
y)methyl)nicotinonitrile (40 mg, 0.06 mmol) suspended in
2-methyltetrahydrofuran (2 mL) was treated with
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (6
mg, 0.007 mmol) and 2 M sodium carbonate solution (90 .mu.L, 0.18
mmol). The reaction mixture was heated in the microwave at
110.degree. C. for 90 min. After cooling to room temperature, the
reaction mixture was concentrated. The residue was suspended in
ethyl acetate and washed with water. The organic layer was
concentrated and purified by column chromatography to give
(S)-5-(((5-chloro-3-formyl-6-((4-(3-(6-formylbenzo[d]thiazol-2-yl)-2-meth-
ylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)pyridin-2-yl)oxy)methyl)nicotinoni-
trile.
[2601] Step 3:
(S)-4-(((2-(3-((S)-1-((5-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-
-chloro-6-((5-cyanopyridin-3-yl)methoxy)pyridin-2-yl)oxy)-2,3-dihydro-1H-i-
nden-4-yl)-2-methylphenyl)benzo[d]thiazol-6-yl)methyl)amino)-3-hydroxybuta-
noic acid was prepared according to general reductive amination
procedure C using (S)-4-amino-3-hydroxybutanoic acid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.02 (d, J=2.1 Hz, 1H), 8.69 (s,
2H), 8.45 (s, 1H), 8.28 (d, J=1.4 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H),
8.03 (s, 1H), 7.82-7.75 (m, 1H), 7.70 (dd, J=8.3, 1.7 Hz, 1H), 7.47
(t, J=7.6 Hz, 1H), 7.43-7.32 (m, 1H), 7.32-7.25 (m, 1H), 7.23 (d,
J=6.7 Hz, 1H), 6.51 (s, 1H), 5.58 (s, 4H), 4.32 (d, J=5.7 Hz, 3H),
4.17 (s, 5H), 3.07 (s, 3H), 2.88 (s, 3H), 2.69 (s, 1H), 2.39-2.34
(m, 2H), 2.31 (d, J=9.9 Hz, 5H), 1.95 (s, 2H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C.sub.45H.sub.43ClN.sub.6O.sub.8S: 863.3; found:
863.0.
Example 397:
(S)-4-(((7-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00638##
[2603] The title compound was prepared in the same manner as
Example 393 using 7-bromoimidazo[1,2-a]pyridine-2-carbaldehyde.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd, J=6.3, 2.0
Hz, 2H), 8.56 (s, 2H), 8.46 (t, J=2.1 Hz, 1H), 8.07 (s, 1H), 7.55
(d, J=14.3 Hz, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.32 (ddd, J=17.2,
14.8, 7.5 Hz, 4H), 6.49 (s, 3H), 5.54 (s, 3H), 5.34 (d, J=17.4 Hz,
4H), 4.30 (s, 2H), 4.13 (s, 5H), 3.09 (d, J=12.9 Hz, 2H), 2.91 (d,
J=60.1 Hz, 5H), 2.36 (dd, J=8.0, 6.1 Hz, 3H), 2.10 (s, 3H), 1.92
(s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for
C.sub.45H.sub.45ClN.sub.6O.sub.8: 833.3; found: 833.4.
Example 398:
(S)-4-(((2-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)quinolin-6-yl)methyl)amino)-3-hydroxybutanoic acid
##STR00639##
[2605] The title compound was prepared in the same manner as
Example 393 using 2-chloroquinoline-6-carbaldehyde. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.02 (dd, J=5.3, 2.1 Hz, 3H), 8.57
(s, 2H), 8.46 (dd, J=5.4, 3.3 Hz, 2H), 8.14 (d, J=1.9 Hz, 1H), 8.08
(d, J=8.7 Hz, 1H), 7.90 (dd, J=8.7, 1.9 Hz, 1H), 7.76 (d, J=8.5 Hz,
1H), 7.57 (s, 1H), 7.53-7.46 (m, 2H), 7.42 (t, J=7.5 Hz, 1H), 7.31
(t, J=7.6 Hz, 1H), 7.23-7.10 (m, 3H), 5.56 (s, 3H), 5.34 (d, J=13.5
Hz, 4H), 4.38 (s, 2H), 4.23-4.05 (m, 4H), 3.07 (s, 4H), 2.90 (s,
4H), 2.11 (s, 3H), 1.97 (s, 3H), 1.10 (d, J=6.1 Hz, 1H). LCMS-ESI+
(m/z): [M+H]+ calcd for C.sub.47H.sub.46ClN.sub.5O.sub.8: 844.3;
found: 844.3.
Example 399:
(S)-4-(((5-(3'-((4-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-2-chlor-
o-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biph-
enyl]-3-yl)benzo[d]thiazol-2-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00640##
[2607] The title compound was prepared in the same manner as
Example 393 using 5-bromobenzo[d]thiazole-2-carbaldehyde. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.44 (d, J=66.6 Hz, 2H), 9.02
(dd, J=6.2, 2.1 Hz, 2H), 8.58 (s, 2H), 8.24 (d, J=8.4 Hz, 1H), 8.01
(d, J=1.6 Hz, 1H), 7.60-7.43 (m, 3H), 7.41-7.23 (m, 3H), 7.22-7.06
(m, 3H), 5.55 (s, 2H), 5.34 (d, J=17.4 Hz, 4H), 4.77 (s, 2H), 4.12
(s, 5H), 3.24 (d, J=12.5 Hz, 2H), 2.98 (s, 3H), 2.83 (s, 2H), 2.36
(ddd, J=18.1, 15.5, 6.9 Hz, 2H), 2.11 (s, 3H), 1.88 (s, 3H).
LCMS-ESI+ (m/z): [M+H]+ calcd C.sub.45H.sub.44ClN.sub.5O.sub.8S:
850.3; found: 850.3.
[2608] The following compounds were prepared according to the
methods provided herein using the appropriate starting
material.
TABLE-US-00001 Example No. Structure 400
5-((4-chloro-5-((4''-((dimethylamino)methyl)-3''-(4-hydroxybut-1-yn-1--
yl)-2,2'- dimethyl-[1,1':3',1''-terphenyl]-3-yl)methoxy)-2-(((2-
hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
##STR00641## 401
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4''-((dimethylam-
ino)methyl)-
3''-(4-hydroxybut-1-yn-1-yl)-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-
yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
##STR00642## 402
2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)-
)bis(oxy))bis(5-
bromo-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(3-hyd-
roxy-2- methylpropanoic acid) ##STR00643## 404
(1S,1'S,2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-
diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-
diyl))bis(methylene))bis(azanediyl))bis(cyclohexan-1-ol)
##STR00644## 405
(1R,1'R,2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-
diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-
diyl))bis(methylene))bis(azanediyl))bis(cyclohexan-1-ol)
##STR00645## 406
(3S,3'S)-4,4'-(((2,2'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-
diyl)bis(methylene))bis(oxy))bis(4-((5-cyanopyridin-3-yl)methoxy)pyrimidi-
ne-5,2- diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00646## 407
(3R,3'R)-4,4'-(((6,6'-(((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bii-
ndene]-1,1'-
diyl)bis(oxy))bis(2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediy-
l))bis(3- hydroxybutanoic acid) ##STR00647## 408
N,N'-((((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-((5-cyanopyridin-3-y-
l)methoxy)-4,1-
phenylene))bis(methylene))bis(azanediyl))bis(ethane-2,1-diyl))diacetamide
##STR00648## 409
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-((5-cyanopyr-
idin-3-yl)methoxy)-
5,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00649## 410
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(2-methoxy-5,1-
phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00650## 411
[4,4'-biindoline]-1,1'-diylbis((3-(((2-hydroxyethyl)amino)methyl)pheny-
l)methanone) ##STR00651## 412
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(3,1-
phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00652## 413
(S)-4-hydroxy-1-(4-(1'-(4-(((R)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)-
-2-
methylbenzoyl)-[4,4'-biindoline]-1-carbonyl)-3-methylbenzyl)pyrrolidin-2-
one[4,4'-biindoline]-1,1'-diylbis(phenylmethanone) 414
[4,4'-biindoline]-1,1'-diylbis((4-(((2-hydroxyethyl)amino)methyl)pheny-
l)methanone) 415
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(4-methyl-3,1-
phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00653## 416
(S)-4-hydroxy-1-(3-(1'-(5-(((R)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)-
-2-
methylbenzoyl)-[4,4'-biindoline]-1-carbonyl)-4-methylbenzyl)pyrrolidin-2--
one 417
(S)-3-hydroxy-4-((3-(1'-(5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl-
)-2-
methylbenzoyl)-[4,4'-biindoline]-1-carbonyl)-4-methylbenzyl)amino)butanoi-
c acid 418
(3S,3'S)-4,4'-(((([4,4'-biindoline]-1,1'-dicarbonyl)bis(3-methyl-4,1-
phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic
acid) ##STR00654## 419
(S)-3-hydroxy-4-((4-(1'-(4-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl-
)-2-
methylbenzoyl)-[4,4'-biindoline]-1-carbonyl)-3-methylbenzyl)amino)butanoi-
c acid 420
1,1'-((([4,4'-biindoline]-1,1'-dicarbonyl)bis(3-methyl-4,1-
phenylene))bis(methylene))bis(pyrrolidin-2-one) ##STR00655## 422
(2R,2'R)-2,2'-(((6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-
diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxypyridine-6,3-
diyl))bis(methylene))bis(azanediyl))dipropanamide ##STR00656## 423
(3R,3'R)-4,4'-(((2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(ben-
zo[d]thiazole-6,2-
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00657##
TABLE-US-00002 Example No. Structure 425 ##STR00658## 426
##STR00659## 428 ##STR00660## 429 ##STR00661## 430 ##STR00662## 431
##STR00663## 432 ##STR00664## 433 ##STR00665## 434 ##STR00666## 435
##STR00667## 436 ##STR00668## 437 ##STR00669## 438 ##STR00670## 439
##STR00671## 440 ##STR00672## 441 ##STR00673## 442 ##STR00674## 443
##STR00675## 444 ##STR00676## 445 ##STR00677## 446 ##STR00678## 448
##STR00679## 449 ##STR00680## 450 ##STR00681## 451 ##STR00682## 452
##STR00683## 453 ##STR00684## 454 ##STR00685## 455 ##STR00686## 456
##STR00687## 457 ##STR00688## 458 ##STR00689## 459 ##STR00690##
TABLE-US-00003 ES/MS Example (m/z, No. Structure M + H.sup.+) 460
##STR00691## 875.03 461 ##STR00692## 859.06 463 ##STR00693## 737.17
464 ##STR00694## 796.31 465 ##STR00695## 813.17 466 ##STR00696##
814.21 467 ##STR00697## 921.2 468 ##STR00698## 873.9 469
##STR00699## 801.12 470 ##STR00700## 751.3 471 ##STR00701## 790.3
472 ##STR00702## 790.3 473 ##STR00703## 761.1 474 ##STR00704##
775.2 475 ##STR00705## 816.2 476 ##STR00706## 759.2 477
##STR00707## 775 478 ##STR00708## 1117.1 479 ##STR00709## 1117.1
480 ##STR00710## 937.2 481 ##STR00711## 1053.2 482 ##STR00712##
767.2 483 ##STR00713## 783.2 484 ##STR00714## 783.2 485
##STR00715## 859.3 486 ##STR00716## 779.2 487 ##STR00717## 745.98
488 ##STR00718## 773.942 489 ##STR00719## 773.946 490 ##STR00720##
759.991 491 ##STR00721## 759.933 497 ##STR00722## 783.164 498
##STR00723## 705.004 499 ##STR00724## 705.008 500 ##STR00725##
731.089 501 ##STR00726## 760.244 502 ##STR00727## 760.31 503
##STR00728## 730.131 504 ##STR00729## 761.175 505 ##STR00730##
761.175 506 ##STR00731## 721.033 507 ##STR00732## 721.087 508
##STR00733## 818.131 509 ##STR00734## 818.128 510 ##STR00735##
777.1 511 ##STR00736## 765.053 512 ##STR00737## 723.65 513
##STR00738## 687.67 514 ##STR00739## 869.62 515 ##STR00740## 892.19
516 ##STR00741## 872.26 517 ##STR00742## 818.12 518 ##STR00743##
818.1 519 ##STR00744## 830.12 520 ##STR00745## 830.07 521
##STR00746## 858.05 522 ##STR00747## 810.01 523 ##STR00748## 767.16
524 ##STR00749## 796.09 525 ##STR00750## 782.06 526 ##STR00751##
784.1 527 ##STR00752## 768.05 528 ##STR00753## 770.07 529
##STR00754## 756.04 540 ##STR00755## 869.99 541 ##STR00756## 900.02
542 ##STR00757## 797.93 543 ##STR00758## 858.11 544 ##STR00759##
867.01 545 ##STR00760## 840.91 546 ##STR00761## 857 547
##STR00762## 856.96 548 ##STR00763## 701.85 549 ##STR00764## 701.78
550 ##STR00765## 856.88 551 ##STR00766## 787.9 552 ##STR00767##
803.99 553 ##STR00768## 803.91 554 ##STR00769## 803.85 555
##STR00770## 788.07 556 ##STR00771## 843.19 557 ##STR00772## 803.28
558 ##STR00773## 846.09 559 ##STR00774## 848.05 560 ##STR00775##
818.05 561 ##STR00776## 808.02 562 ##STR00777## 907.7 563
##STR00778## 1120.94 564 ##STR00779## 741.2 565 ##STR00780## 895.02
566 ##STR00781## 894.96 567 ##STR00782## 867.01 568 ##STR00783##
856.21 569 ##STR00784## 844.15 570 ##STR00785## 812.06 571
##STR00786## 797.05 572 ##STR00787## 788.16 573 ##STR00788## 788.12
574 ##STR00789## 788.12 575 ##STR00790## 788.17 576 ##STR00791##
855.06 577 ##STR00792## 853.03 578 ##STR00793## 814 579
##STR00794## 800.2 580 ##STR00795## 786.1 581 ##STR00796## 766.2
582 ##STR00797## 757.3 583 ##STR00798## 823.2 584 ##STR00799## 811
585 ##STR00800## 787.1 586 ##STR00801## 977.2 587 ##STR00802##
789.2 588 ##STR00803## 761.136 589 ##STR00804## 761.195 590
##STR00805## 757.9 591 ##STR00806## 758.9 592 ##STR00807## 834.1
593 ##STR00808## 834.2 595 ##STR00809## 835.1
Intermediate 58:
2,2'-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane
##STR00810##
[2610] A mixture of 3-bromo-2-chlorophenol (73.5 g, 0.355 mol, 1.0
eq), B.sub.2Pin.sub.2 (98 g, 0.391 mol, 1.1 eq), KOAc (96.7 g,
0.987 mol, 2.78 eq) and Pd(dppf)Cl.sub.2-DCM (25.97 g, 35.5 mmol,
0.1 eq) were suspended in dioxane (1.2 L) was stirred at 80.degree.
C. for 15 h under positive pressure of nitrogen. The resulting
mixture was cooled to ambient temperature and filtered. The filter
cake was washed with dioxane (500 mL). The filtrates were
combined.
[2611] 3-bromo-2-chlorophenol (73.5 g, 0.355 mol, 1.0 eq),
K.sub.2CO.sub.3 (122 g, 0.888 mol, 2.5 eq) and Pd(dppf)Cl.sub.2-DCM
(8.8 g, 10.65 mmol, 0.03 eq) were added to the filtrate prepared
above. The reaction was stirred at 80.degree. C. for 8 h under
positive pressure of nitrogen. The resulting mixture was cooled to
ambient temperature and filtered. The filter cake was washed with
dioxane (500 mL). The filtrate were combined and concentrated. The
residue was dissolved with ethyl acetate (2 L). The solution was
washed with water, brine, dried over sodium sulfate and
concentrated. The crude was purified by silica gel chromatography
(PE:EA=5:1) to give 2,2'-dichloro-[1,1'-biphenyl]-3,3'-diol.
[2612] To a solution of compound 2 (63.8 g, 0.251 mol, 1.0 eq) and
DIPEA (121.5 g, 0.944 mol, 3.76 eq) in DCM (2 L) at 0.degree. C.
was added Tf.sub.2O (166 g, 0.590 mol, 2.35 eq) dropwise slowly.
Then the reaction was warmed to rt and stirred for 2 h. The pH of
the reaction solution was greater than 7. Water (2 L) was added.
The layers were separated, and the organic phase was washed with
aqueous solution NaHCO.sub.3, and brine, and dried over anhydrous
sodium sulfate and concentrated. The crude was purified by silica
gel chromatography, eluting with PE/DCM/EtOAc (1:1:0-1:1:0.2) to
give 2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl
bis(trifluoromethanesulfonate).
[2613] A mixture of 2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl
bis(trifluoromethanesulfonate) (150 g, 0.289 mol, 1.0 eq),
Bin.sub.2Pin.sub.2 (180 g, 0.722 mol, 2.5 eq) KOAc (113 g, 1.156
mol, 4.0 eq) and Pd(dppf)Cl.sub.2-DCM (31.72 g, 0.0434 mol, 0.15
eq) in dioxane (1.5 L) was stirred at 80.degree. C. for 15 h under
positive pressure of nitrogen. The resulting mixture was cooled to
ambient temperature. DCM (1.5 L) was added, and the mixture was
stirred for 15 min at rt. The mixture was filtered and the filter
cake was washed with DCM (500 mL). The filtrates were combined and
concentrated. The crude was purified by silica gel chromatography
(PE:EA, 10:1-5:1) to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.63 (d, J=6.7 Hz, 2H), 7.46-7.30 (m, 4H), 1.34
(s, 24H).
Intermediate 59:
6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde
##STR00811##
[2615] 6-chloro-2-methoxynicotinaldehyde (1.2 g, 7.01 mmol),
(3-bromo-2-chlorophenyl)boronic acid (1.5 g, 6.38 mmol), Potassium
Carbonate (1.76 g, 12.75 mmol), and
Tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), are
suspended in 30 mL of a 10:1 mixture of dioxane and water. The
mixture is sparged with argon gas for 10 minutes, and heated in a
95 C hot plate for 3 h. The solution is cooled to rt, and diluted
with dichloromethane (100 mL), water (50 mL), and brine (50 mL).
The organic layer was separated, and aqueous layer extracted
1.times. with dichloromethane (50 mL). The combined organics were
dried over Na2SO4, filtered, concentrated, and purified via column
chromatography with dichloromethane eluent (dry loaded, solubility
issues if DCM is not used). The fractions containing the product
are concentrated to yield the crude yellow solid that is
contaminated with unreacted 6-chloro-2-methoxynicotinaldehyde. The
yellow solid is crushed, and diluted with Et2O, sonicated, and
filtered. The filtrate is washed 2.times. with Et2O to give
6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.30 (s, 1H), 8.22 (d, J=7.7 Hz,
1H), 7.93 (dd, J=8.1, 1.5 Hz, 1H), 7.65 (dd, J=7.7, 1.5 Hz, 1H),
7.53-7.31 (m, 2H), 4.04 (s, 3H).
Intermediate 60:
6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-meth-
oxynicotinaldehyde
##STR00812##
[2617] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (720 mg,
2.2 mmol), Bis(pinacolato)diborane (615.85 mg, 2.43 mmol),
potassium acetate (605.85 mg, 6.17 mmol), and
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (182.27 mg, 0.22 mmol) was suspended in 20
mL of Dioxane. The resulting suspension was sparged with argon for
5 min. The reaction was sealed and stirred at 95 C for 6 h. The
reaction was diluted with EtOAc, and filtered through a plug of
celite. The filtrate was concentrated and purified by silica gel
chromatography, eluting with EtOAc (0-10%) in Hexanes to provide
6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-meth-
oxynicotinaldehyde. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.30 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 7.88-7.61 (m, 2H), 7.49 (t,
J=7.5 Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 4.04 (s, 3H), 1.34 (s,
12H).
Intermediate 61:
6-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde
##STR00813##
[2619]
6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)--
2-methoxynicotinaldehyde (400 mg, 1.07 mmol), Potassium Carbonate
(354.57 mg, 2.57 mmol),
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (88.5 mg, 0.11 mmol), and
1,3-dibromo-2-chlorobenzene (578.84 mg, 2.14 mmol) was suspended in
10 mL of a 9:1 mixture of Dioxane:water. The resulting suspension
was sparged with argon for 10 minutes, sealed, and stirred at 95 C
for 4 h. The suspension was cooled and diluted with EtOAc. The
organic layer was washed with water and brine. The combined
organics were dried over Na2SO4, concentrated, and purified by
silica gel chromatography, eluting with Hexane/EtOAc (0-10%). The
fractions were collected to afford
6-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.31 (s, 1H), 8.22 (d,
J=7.7 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.76 (dd, J=7.8, 1.7
Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.54-7.29 (m, 4H), 4.07 (s,
3H).
Intermediate 62:
6-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-b-
iphenyl]-3-yl)-2-methoxynicotinaldehyde
##STR00814##
[2621]
6-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinald-
ehyde (200 mg, 0.46 mmol), Bis(pinacolato)diborane (127.81 mg, 0.5
mmol), potassium acetate (125.73 mg, 1.28 mmol), and
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (37.83 mg, 0.05 mmol) was suspended in 5 mL
of Dioxane. The resulting suspension was sparged with argon for 5
min. The reaction was sealed and stirred at 95 C for 4 h. The
reaction was diluted with EtOAc, and filtered through a plug of
celite. The filtrate was concentrated and purified by silica gel
chromatography, eluting with EtOAc (0-10%) in Hexanes to provide
6-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-b-
iphenyl]-3-yl)-2-methoxynicotinaldehyde. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.31 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.71
(ddd, J=15.5, 7.2, 1.9 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.54-7.41
(m, 4H), 4.07 (s, 3H), 1.33 (s, 12H).
Example 596:
(S)-5-((((6-(3'-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-2,2'-dichloro-[1,1'-bi-
phenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one
##STR00815##
[2623] A mixture of tert-butyl
(2-(4-bromo-1H-pyrazol-1-yl)ethyl)carbamate (290 mg, 1 mmol),
6-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-b-
iphenyl]-3-yl)-2-methoxynicotinaldehyde (484 mg, 1 mmol), DMF (3
mL) and 2N potassium carbonate (0.5 mL) was purged with argon for
10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex with dichloromethane (41 mg, 0.05 mmol) was then added. The
resulting mixture was stirred at 90.degree. C. for 1 h. After
cooling, the mixture was partitioned between ethyl acetate and 3%
LiCl in water. The ethyl acetate layer was taken and concentrated.
The residue was purified by Combiflash (70% EtOAc in hexanes),
affording tert-butyl
(2-(4-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]--
3-yl)-1H-pyrazol-1-yl)ethyl)carbamate. [M+H].sup.+ 566.9.
[2624] tert-Butyl
(2-(4-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]--
3-yl)-1H-pyrazol-1-yl)ethyl)carbamate was then subjected to the
reductive amination using (S)-5-(aminomethyl)pyrrolidin-2-one and
sodium triacetoxyborohydride, affording tert-butyl
(S)-(2-(4-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)-
amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)ethyl)car-
bamate. [M+H].sup.+ 664.8.
[2625] To a solution of tert-butyl
(S)-(2-(4-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)-
amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)ethyl)car-
bamate (100 mg, 0.15 mmol) in dichloromethane (2 mL) was added
trifluoroacetic acid (1 mL). After stirring for 30 min. at room
temperature, the mixture was concentrated and the residue was
purified by reverse-phase HPLC, affording
(S)-5-((((6-(3'-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-2,2'-dichloro-[1,1'-bi-
phenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one
as the bisTFA salt. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.14 (d, J=0.8 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.88 (d, J=7.6 Hz,
1H), 7.69-7.59 (m, 2H), 7.50 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.7 Hz,
1H), 7.38-7.32 (m, 2H), 7.24 (dd, J=7.5, 1.7 Hz, 1H), 4.55-4.45 (m,
2H), 4.34 (dd, J=2.6 Hz, 2H), 4.09 (s, 3H), 4.06 (t, J=6.5 Hz, 1H),
3.48 (t, J=5.7 Hz, 2H), 3.25 (dd, J=6.2, 4.2 Hz, 2H), 2.52-2.30 (m,
3H), 1.99-1.84 (m, 1H). [M+H].sup.+ 565.1.
Example 597:
(S)-5-((((6-(2-chloro-3-(4-(6-methoxy-5-(((((S)-5-oxopyrrolidin-2-yl)meth-
yl)amino)methyl)pyridin-2-yl)thiophen-2-yl)phenyl)-2-methoxypyridin-3-yl)m-
ethyl)amino)methyl)pyrrolidin-2-one
##STR00816##
[2627] A 40 mL reaction vial, fitted with a stir bar, was charged
with
2-(4-bromothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.150 g), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde
(0.203 g), Pd(dppf) (0.018 g) and potassium carbonate (0.143 g).
DriSolv 1,4-Dioxane (5 mL) and distilled water (0.5 mL) were then
added by syringe, and the mixture de-gassed by bubbling argon for 5
min while mixing. The reaction vial was then sealed with a septum
cap and the reaction heated to 85.degree. C. using a heating block,
the reaction was monitored by LC/MS. Upon complete consumption of
starting material, saturated NaCl in water was added and the
reaction mixture was extracted three times with ethyl acetate. The
organic layers were collected, volatiles removed and crude mixture
purified by silica gel column chromatography. LCMS m/z 410.00
M+1.
[2628] A 40 mL screw cap vial, fitted with a stir bar, was charged
with
6-(3-(4-bromothiophen-2-yl)-2-chlorophenyl)-2-methoxynicotinaldehyde
(0.070 g), bis(pinacolato)diboron (0.065 g), potassium acetate
(0.034 g) and Pd(dppf) (0.007 g). DriSolv 1,4-Dioxane (2 mL) was
then added by syringe, and the mixture was de-gassed by bubbling
argon through for 5 min while mixing. The vial was then sealed and
the mixture heated to 85.degree. C., the reaction was monitored by
LC/MS and upon complete consumption of the starting material the
crude mixture was carried through to the next reaction without any
purification (boronic ester intermediate LCMS m/z 456.128 M+1). To
the previous reaction was added 6-chloro-2-methoxynicotinaldehyde
(0.059 g), Pd(PPh3)4 (0.020 g), potassium carbonate (0.047 g) and
distilled water (0.2 mL), the mixture was de-gassed by bubbling
argon through for 5 min while mixing. The vial was sealed with a
septum cap and the mixture heated to 85.degree. C. using a heating
block, the reaction was monitored by LC/MS. Upon complete
consumption of arylboronic ester a saturated solution of NaCl in
water was added to the reaction mixture in equal-volume to the
initial reaction volume. The resulting mixture was extracted three
times with ethyl acetate, the organic layers collected, volatiles
removed in vacuo and purified by silica gel column chromatography.
LCMS m/z 465.100 M+1.
[2629] A 20 mL reaction vial, fitted with a stir bar, was charged
with
6-(2-chloro-3-(4-(5-formyl-6-methoxypyridin-2-yl)thiophen-2-yl)phenyl)-2--
methoxynicotinaldehyde (0.028 g),
(S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (0.036 g)
N,N-diisopropyl-ethylamine (0.042 mL) and dimethylformamide (1 mL)
and allowed to mix for 0.5 h. Sodium triacetoxy-borohydride (0.064
g) was then added and the reaction allowed to mix overnight. The
next day the reaction was quenched with trifluoroacetic acid (1.205
mmol), filtered, diluted with a 1:4 solution DMF/water and purified
by HPLC to give
(S)-5-((((6-(2-chloro-3-(4-(6-methoxy-5-(((((S)-5-oxopyrrolidin-2-yl)meth-
yl)amino)methyl)pyridin-2-yl)thiophen-2-yl)phenyl)-2-methoxypyridin-3-yl)m-
ethyl)amino)methyl)pyrrolidin-2-one. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.23 (d, J=1.4 Hz, 1H), 7.93 (d, J=1.4
Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.68 (dd,
J=7.6, 1.9 Hz, 1H), 7.55 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.46 (m,
2H), 7.33 (d, J=7.5 Hz, 1H), 4.40-4.23 (m, 4H), 4.18-3.99 (m, 8H),
3.28-3.14 (m, 3H), 2.49-2.31 (m, 6H), 1.99-1.82 (m, 2H). ES/MS m/z:
661.281 M+1.
Example 598:
(S)-5-((((6-(2,2'-dichloro-3'-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)--
[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-
-2-one
##STR00817##
[2631] To a stirred solution of 5-Bromoindole (200 mg) in DMF at
room temperature was added NaH (2.2 equiv.). After gas evolution
ceased (2-chloroethyl)dimethylamine hydrochloride (1.2 equiv.) was
added. The reaction was stirred until complete consumption was
observed by LC/MS. The reaction was then diluted with water and
extracted 3.times.5 mL with EtOAc. The combined organic layers were
dried over sodium sulfate and concentrated in vacuo. The crude
material was subjected to column chromatography (0%-10%
MeOH/DCM+0.1% NEt.sub.3) to afford
2-(5-bromo-1H-indol-1-yl)-N,N-dimethylethan-1-amine.
[2632] 2-(5-bromo-1H-indol-1-yl)-N,N-dimethylethan-1-amine (1.2
equiv.), Pd(PPh.sub.3).sub.4 (0.1 equiv.), K.sub.2CO.sub.3 (2.0
equiv.), and
6-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-b-
iphenyl]-3-yl)-2-methoxynicotinaldehyde (40 mg, 1.0 equiv.) were
place in a vial. The vial was charged with a stir bar and sealed.
Dioxane (1 mL) and water (0.25 mL) were added via syringe. The vial
was then subjected to 4 cycles of evacuation followed by
back-filling with argon. The reaction vessel was then heated to
90.degree. C. for 2 hours. LC/MS indicated full consumption of
pinacol boronate. The reaction mixture was then diluted with water
(3 mL) and extracted 3.times.5 mL EtOAc. The combined organic
layers were dried over sodium sulfate and concentrated in vacuo.
The crude material was subjected to column chromatography (0%-10%
MeOH/DCM+0.1% NEt.sub.3) to afford
6-(2,2'-dichloro-3'-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)-[1,1'-biph-
enyl]-3-yl)-2-methoxynicotinaldehyde.
[2633] To a vial charged with
6-(2,2'-dichloro-3'-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)-[1,1'-biph-
enyl]-3-yl)-2-methoxynicotinaldehyde (20 mg, 1.0 equiv.),
(S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (3.0 equiv.), and
triethylamine (3.0 equiv.) was added 0.75 mL of DMF. To this slurry
was added sodium cyanoborohydride (5.0 equiv.). Upon complete
consumption of starting material according to LC/MS the reaction
mixture was diluted with a 5:1 DMF/water solution to a total volume
of 4 mL. Purification by reverse phase HPLC afforded
(S)-5-((((6-(2,2'-dichloro-3'-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)--
[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-
-2-one as a bis-TFA salt. ES/MS (m/z, M+H.sup.+): 642.2.
Example 599:
5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2-(3'-(5-((6-acetyl-2-
,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-
-[1,1'-biphenyl]-3-yl)isoindolin-1-one
##STR00818##
[2635] Into a flask containing 2-oxoindoline-5-carbaldehyde 1 (500
mg, 3.1 mmol) is added 1,3-dibromo-2-chlorobenzene (1677.51 mg,
6.21 mmol), along with cesium carbonate (2022 mg, 6.21 mmol),
N,N'-dimethylethylenediamine 99% (0.34 mL) 3.1 mmol) and dioxane
(15 mL). After flushing the reaction with nitrogen several times,
the reaction was bubbled with N.sub.2 through the resulting
suspension for 30 min before Copper(i) iodide (295 mg, 1.55 mmol)
was added. A reflux condenser was attached to the flask, and the
reaction mixture was heated at 105.degree. C. overnight. The
mixture was cooled to room temperature and filtered. The filtrate
was diluted with ethyl acetate (40 mL) and water (20 mL), and the
layers were separated. The aqueous layer was extracted with ethyl
acetate (50 mL), and the combined organic layers were washed with
brine (20 mL) and dried over sodium sulfate. The drying agent was
removed by filtration. The filtrate was concentrated under reduced
pressure, and the resulting residue was purified by flash column
chromatography (silica, 80:20 Hex/EtOAc) to provide
2-(3-bromo-2-chlorophenyl)-1-oxoisoindoline-5-carbaldehyde. MS
(ESI+) m/z 352.1 (M+H).
[2636] Into a microwave vial is placed
2-(3-bromo-2-chlorophenyl)-1-oxoisoindoline-5-carbaldehyde (250 mg,
0.71 mmol),
6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
-2-methoxynicotinaldehyde (293 mg, 0.78 mmol), Potassium Carbonate
(197 mg, 1.43 mmol), Tetrakis(triphenylphosphine)palladium(0) (82
mg, 0.07 mmol and dioxane/water (4:1, 10 mL). The mixture was
flushed with N.sub.2 and heated at 110.degree. C. for 1 hr. The
mixture was diluted with EtOAc and water. The organic layer was
separated, washed with brine and dried over MgSO.sub.4, filtered
and concentrated under reduced pressure before and the resulting
residue was purified by flash column chromatography (silica, 80:20
Hex/EtOAc) to provide
2-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl-
)-1-oxoisoindoline-5-carbaldehyde. MS (ESI+) m/z 517.31 (M+H).
[2637] The title compound was obtained using reductive amination
condition A (DCM/MeOH then Na(OAc).sub.3BH and AcOH) followed by
HPLC purification. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
7.97 (d, J=7.9 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.75 (s, 1H), 7.66
(ddd, J=6.0, 2.9, 1.7 Hz, 2H), 7.67-7.39 (m, 6H), 7.36 (d, J=7.5
Hz, 1H), 4.97 (s, 2H), 4.53 (s, 2H), 4.47-4.36 (m, 18H), 4.16 (s,
5H), 4.08 (s, 3H), 1.84 (s, 6H). .sup.19F NMR (376 MHz,
Methanol-d.sub.4) .delta. -77.63. MS (ESI+) m/z 765.15 (M+H).
[2638] The following compounds were prepared according to the
procedures described herein using the appropriate starting
material(s) and appropriate protecting group chemistry as
needed.
TABLE-US-00004 Exam- ES/MS ple (m/z, No. Structure M + H.sup.+) 600
##STR00819## 662.264 601 ##STR00820## 660.809 602 ##STR00821##
712.3 603 ##STR00822## 739.3 604 ##STR00823## 708.2 605
##STR00824## 711.4 606 ##STR00825## 628.2 607 ##STR00826## 628.2
608 ##STR00827## 628.2 609 ##STR00828## 642.2 (M.sup.+) 610
##STR00829## 628.9 611 ##STR00830## 603.2 612 ##STR00831## 613.1
613 ##STR00832## 599 614 ##STR00833## 722.2 615 ##STR00834## 616.1
616 ##STR00835## 616.1 617 ##STR00836## 560.2 618 ##STR00837##
722.2 619 ##STR00838## 698.2 620 ##STR00839## 592.1 621
##STR00840## 708.1 622 ##STR00841## 698.1 623 ##STR00842## 530 624
##STR00843## 529.9 625 ##STR00844## 529.6 626 ##STR00845## 797.65
627 ##STR00846## 541.2 629 ##STR00847## 636.33 630 ##STR00848##
573.27 631 ##STR00849## 737.16 632 ##STR00850## 713.12 633
##STR00851## 699.1 634 ##STR00852## 623.0 635 ##STR00853## 673.2
636 ##STR00854## 593.0
[2639] NMR data for select compounds is shown below.
TABLE-US-00005 Example No. NMR 600 1H NMR (400 MHz, Methanol-d4)
.delta. 8.70 (s, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 7.6
Hz, 1H), 7.74 (d, J = 1.3 Hz, 1H), 7.56 (ddd, J = 13.5, 7.5, 1.9
Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H),
4.51-4.28 (m, 4H), 4.10 (d, J = 18.6 Hz, 7H), 2.51-2.28 (m, 6H),
2.04-1.83 (m, 2H). 601 1H NMR (400 MHz, Methanol-d4) .delta. 7.93
(d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 3.9 Hz,
1H), 7.71 (dd, J = 7.6, 1.9 Hz, 1H), 7.63-7.46 (m, 3H), 7.41 (d, J
= 3.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 4.35 (dd, J = 24.8, 2.6
Hz, 4H), 4.20-4.01 (m, 7H), 3.01 (s, 1H), 2.88 (d, J = 0.8 Hz, 1H),
2.55-2.32 (m, 5H), 2.03-1.84 (m, 2H). 602 1H NMR (400 MHz,
Methanol-d4) .delta. 8.63 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.90
(d, J = 7.7 Hz, 2H), 7.66 (dd, J = 7.7, 1.7 Hz, 1H), 7.58 (q, J =
3.8, 3.0 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.44 (ddd, J = 7.7,
4.7, 2.4 Hz, 2H), 7.38 (d, J = 7.5 Hz, 1H), 4.64-4.53 (m, 2H),
4.40-4.29 (m, 2H), 4.11 (s, 3H), 4.06 (s, 2H), 3.98 (s, 3H),
3.29-3.21 (m, 3H), 2.49-2.30 (m, 6H), 1.92 (ddd, J = 10.5, 6.5, 2.8
Hz, 2H). 603 1H NMR (400 MHz, Methanol-d4) .delta. 7.98 (d, J = 8.4
Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.66
(dd, J = 7.7, 1.7 Hz, 1H), 7.58-7.50 (m, 4H), 7.46-7.41 (m, 2H),
7.37 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 1.1 Hz, 1H), 4.74-4.66 (m,
2H), 4.35 (d, J = 2.5 Hz, 2H), 4.10 (s, 5H), 3.80 (s, 3H),
3.49-3.34 (m, 2H), 3.27 (dd, J = 6.2, 4.2 Hz, 2H), 2.52-2.31 (m,
6H), 2.02-1.86 (m, 2H). 605 .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.89 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.64
(dd, J = 7.7, 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 3H), 7.51-7.47 (m,
2H), 7.42 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.34
(dd, J = 6.4, 3.0 Hz, 1H), 7.31 (dd, J = 8.2, 1.5 Hz, 1H),
4.56-4.45 (m, 2H), 4.35 (d, J = 2.7 Hz, 2H), 4.11 (s, 3H),
4.09-3.97 (m, 3H), 3.89 (s, 3H), 3.25 (ddd, J = 13.4, 6.0, 3.4 Hz,
4H), 2.38 (dtd, J = 16.9, 10.8, 9.9, 6.6 Hz, 7H), 1.99-1.84 (m,
2H). 611 .sup.1H (MeOH-d.sub.4, 400 MHz, d): 7.87 (d, 1H); 7.63
(dd, 1H); 7.62-7.57 (m, 3H); 7.54-7.45 (m, 3H); 7.42-7.33 (m, 4H);
5.25 (t, 1H); 4.70 (t, 1H); 4.35 (m, 2H); 4.09 (s, 3H); 4.05 (m,
2H); 3.25 (m, 2H); 3.04 (dt, 1H); 2.50-2.30 (m, 2H); 2.02-1.85 (m,
2H). 619 1H NMR (400 MHz, Methanol-d4) .delta. 8.61 (dd, J = 7.1,
1.0 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H),
7.69 (dd, J = 7.7, 1.7 Hz, 1H), 7.62-7.53 (m, 3H), 7.49-7.43 (m,
2H), 7.39 (d, J = 7.5 Hz, 1H), 7.25 (dd, J = 7.1, 1.7 Hz, 1H), 4.51
(d, J = 2.8 Hz, 2H), 4.37 (d, J = 2.6 Hz, 2H), 4.12 (s, 3H), 4.07
(dt, J = 13.3, 7.1 Hz, 2H), 3.32-3.21 (m, 4H), 2.52-2.28 (m, 6H),
2.05-1.84 (m, 2H). 631 1H NMR (400 MHz, Methanol-d4) .delta. 7.98
(d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H),
7.72-7.40 (m, 8H), 7.37 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 4.53 (d,
J = 31.4 Hz, 4H), 4.37 (d, J = 19.8 Hz, 8H), 4.08 (s, 3H),
3.37-3.28 (m, 2H), 2.50 (q, J = 6.4, 4.8 Hz, 4H), 2.44-2.35 (m,
4H). 633 1H NMR (400 MHz, DMSO-d6) .delta. 8.15 (s, 1H), 7.91-7.80
(m, 4H), 7.61 (s, 2H), 6.55 (s, 2H), 3.75 (p, J = 6.3 Hz, 2H), 3.58
(s, 3H), 3.30 (d, J = 7.1 Hz, 4H), 2.87 (qd, J = 12.9, 5.9 Hz, 4H),
2.55 (s, 3H), 2.27-2.08 (m, 7H), 1.77 (h, J = 8.8, 7.8 Hz, 3H),
1.17 (s, 2H). 634 1H NMR (400 MHz, DMSO-d6) .delta. 8.21-8.15 (m,
1H), 7.96 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 5.6 Hz, 2H), 7.65-7.60
(m, 2H), 7.53 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.34
(s, 1H), 6.55 (s, 1H), 5.27 (s, 2H), 4.31 (s, 2H), 4.21 (s, 2H),
4.05 (s, 2H), 3.99 (s, 3H), 3.69 (dd, J = 10.7, 5.4 Hz, 3H), 3.58
(s, 2H), 3.07 (s, 2H), 2.99 (s, 2H). 635 1H NMR (400 MHz, DMSO-d6)
.delta. 9.21 (s, 1H), 8.98 (s, 2H), 8.11 (s, 1H), 8.03 (d, J = 7.3
Hz, 1H), 7.65 (dd, J = 14.8, 7.5 Hz, 3H), 6.55 (s, 1H), 5.15 (s,
1H), 4.33 (s, 2H), 3.67 (s, 2H), 3.57 (d, J = 2.0 Hz, 3H), 3.05 (s,
2H), 2.87 (s, 2H). 636 1H NMR (400 MHz, DMSO-d6) .delta. 8.96 (s,
2H), 8.83 (s, 2H), 8.19 (dd, J = 6.1, 3.4 Hz, 1H), 8.07 (s, 1H),
7.95 (dd, J = 10.3, 8.1 Hz, 2H), 7.72 (dd, J = 6.7, 3.7 Hz, 3H),
7.68-7.59 (m, 2H), 7.53 (dd, J = 7.5, 1.7 Hz, 1H), 7.40 (d, J = 7.5
Hz, 1H), 6.55 (s, 1H), 5.29 (s, 2H), 4.36 (s, 2H), 4.22 (s, 2H),
3.99 (s, 3H), 3.70 (dt, J = 12.1, 5.1 Hz, 4H), 3.05 (d, J = 33.0
Hz, 4H).
Intermediate 63:
6-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxypyridine
##STR00855##
[2641] To a solution of aldehyde (3.5 g, 20.4 mmol) in 60 mL DCM at
0.degree. C. was added ethylenediamine (1.50 mL, 22.44 mmol)
dropwise. The solution was stirred at 0.degree. C. for 30 minutes,
then N-bromosuccinimide (3.99 g, 22.44 mmol) was added in one
portion, and the reaction mixture was stirred for 16 hours with
gradual warming to ambient temperature. Reaction was taken up in
DCM and stirred vigorously with 1:1 sat. sodium thiosulfate and
sat. sodium carbonate for 15 min. The organic later was dried with
MgSO.sub.4, filtered and concentrated to provide
6-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxypyridine.
Example 637:
(S)-4-(((5-chloro-6-(((S)-4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy-
)-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-(methylsulfon-
yl)pyridin-3-yl)methoxy)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid
##STR00856## ##STR00857##
[2643] To a solution of 4-hydroxy-indan-1-one in CH2Cl2 (500 mL)
was added imidazole. The mixture was stirred for 5 minutes, to
which was added portionwise tert-butyldimethylsilyl chloride while
cooling in an ice bath. The mixture was stirred for 16 hours at
room temperature and was diluted with EtOAc. The organic layer was
washed with citric acid, water and brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude residue was purified by column chromatography
(Hex-EA) to give 4-(tert-butyl-dimethyl-silanyloxy)-indan-1-one. 1H
NMR (400 MHz, CDCl3): .delta. 7.27 (d, 1H, J=7.5 Hz), 7.15 (t, 1H,
J=7.5 Hz), 6.89 (d, 1H, J=7.5 Hz), 2.93 (t, 2H, J=5.7 Hz), 2.57 (t,
2H, J=5.7 Hz), 0.81 (s, 9H), 0.15 (s, 6H).
[2644] To a 3000 mL rbf was added
(R)-(+)-2-methyl-CBS-oxazaborolidine (8.397 g, 30.29 mmol), Toluene
(30 mL) and borane-dimethylsulfide (105.35 mL, 1111 mmol) under N2.
The reaction was stirred at room temperature for 10 min then
diluted with DCM (240 mL) and cooled to -20.degree. C. A solution
of 4-bromo-2,3-dihydro-1H-inden-1-one (53.0 g, 202 mmol) in DCM
(240 mL) was added dropwise over 30 min while maintaining the
reaction temperature at -10.+-.5.degree. C. The reaction was
stirred for 2 h. Rxn quenched by the dropwise addition of MeOH (500
mL). Cooling bath was removed and reaction warmed to rt. About half
the rxn volume was distilled off using a short-path distillation
apparatus. All remaining solvent was then evaporated under reduced
pressure to give a solid which was purified by silica gel column
chromatography eluting with EA-Hex to provide
(S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-ol.
ES/MS m/z: [M-OH]+=247. 1H NMR (400 MHz, Chloroform-d) .delta. 7.13
(dt, J=15.3, 0.8 Hz, 1H), 7.02 (d, J=7.4 Hz, 1H), 6.70 (d, J=8.0
Hz, 1H), 5.23 (t, J=6.0 Hz, 1H), 3.00 (ddd, J=16.2, 8.6, 4.7 Hz,
1H), 2.79-2.66 (m, 1H), 2.46 (dddd, J=13.1, 8.3, 6.9, 4.7 Hz, 1H),
1.92 (dddd, J=13.6, 8.6, 6.3, 5.2 Hz, 1H), 1.00 (s, 9H), 0.20 (d,
J=1.8 Hz, 6H).
[2645] A solution of
(S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-ol (6.0
g, 22.7 mmol) and
6-chloro-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (11.7 g, 45.4
mmol), in toluene (40 mL) was degassed by vigorously bubbling N2
thru solution for 10 min. Then Pd(OAc)2 (1.02 g, 4.54 mmol),
t-BuXPhos (3.85 g, 9.07 mmol) and cesium carbonate (29.5 g, 90.8
mmol) were added and the bubbling continued for 5 min more. The
reaction was then stirred at 35 C for 48 h under N2. Rxn was cooled
to rt and diluted with DCM. Filtered thru celite and loaded
directly on silica gel column, eluting with Hex-DCM to provide
(S)-6-((4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)-2-
-(2-(trimethylsilyl)ethoxy)nicotinaldehyde. 1H NMR (400 MHz,
Chloroform-d) .delta. 10.29 (d, J=0.8 Hz, 1H), 8.92 (d, J=2.1 Hz,
1H), 8.86 (d, J=2.0 Hz, 1H), 8.16-8.04 (m, 2H), 7.10 (s, 1H), 7.10
(dt, J=15.5, 0.8 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.79-6.72 (m,
1H), 6.50-6.41 (m, 2H), 5.68-5.53 (m, 2H), 4.12 (q, J=7.1 Hz, 1H),
3.07 (ddd, J=16.3, 8.8, 5.2 Hz, 1H), 2.86 (ddd, J=16.3, 8.6, 5.5
Hz, 1H), 2.51 (dddd, J=13.9, 8.6, 7.1, 5.3 Hz, 1H), 2.14 (dddd,
J=13.9, 8.7, 5.5, 4.4 Hz, 1H), 2.04 (s, 1H), 1.32-1.19 (m, 2H),
1.01 (s, 9H), 0.23 (s, 6H).
[2646]
(S)-6-((4-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)-
oxy)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (4.69 g, 9.66
mmol) was taken up in 50 mL THF and cooled to -78 C. TBAF (9.66 mL,
9.66 mmol) was added dropwise and the reaction allowed to warm up
to 0 C over 30 min, providing a dark orange solution. AcOH (0.552
mL, 9,655 mmol) was added dropwise, removing most of the color.
Diluted with EtOAc and pH 5 citrate buffer. Organic layer was dried
(Na2SO4) and conc. Purification by silica gel chromatography
provided
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde. 1H NMR (400 MHz, Chloroform-d) .delta. 10.23
(d, J=0.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H),
7.07-6.96 (m, 1H), 6.78 (dd, J=7.9, 1.0 Hz, 1H), 6.53 (dd, J=7.1,
4.2 Hz, 1H), 6.34 (dd, J=8.4, 0.9 Hz, 1H), 5.20 (s, 1H), 4.66-4.57
(m, 2H), 3.10 (ddd, J=14.5, 8.7, 5.4 Hz, 1H), 2.89 (ddd, J=15.8,
8.7, 5.2 Hz, 1H), 2.66 (dddd, J=14.0, 8.6, 7.0, 5.4 Hz, 1H), 2.26
(dddd, J=13.9, 8.7, 5.2, 4.2 Hz, 1H), 0.91 (s, 2H), 0.08 (s,
9H).
[2647] A solution of
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde (5.00 g, 13 mmol) in 55 mL DCM was treated with
pyridine (2.76 mL, 34 mmol), DMAP (164 mg, 1.3 mmol) and TEA (3.75
mL, 27 mmol) was cooled to -78 C and treated dropwise with Tf2O
(2.50 mL, 15 mmol). Stirred for 15 min, then allowed to warm to rt.
After 1 h the reaction was diluted with EtOAc, washed with citric
acid soln, dried with Na2SO4 and concentrated. Purification by
silica chromatography (hex-DCM) provided
(S)-1-((5-formyl-6-(2-(trimethylsilyl)ethoxy)pyridin-2-yl)oxy)-2-
,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (6.42 g, 94%
yield). [M+H]=503.7. 1H NMR (400 MHz, Chloroform-d) .delta. 10.25
(d, J=0.8 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H),
7.33 (t, J=7.8 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.56 (dd, J=7.1,
5.0 Hz, 1H), 6.37 (dd, J=8.4, 0.8 Hz, 1H), 4.60 (td, J=8.2, 1.2 Hz,
2H), 3.27 (ddd, J=16.6, 8.9, 5.1 Hz, 1H), 3.12-2.99 (m, 1H), 2.72
(dddd, J=13.7, 8.5, 7.1, 5.1 Hz, 1H), 2.29 (dddd, J=13.8, 8.8, 6.1,
4.9 Hz, 1H), 1.55 (s, 1H), 1.24-1.18 (m, 2H), 0.07 (s, 9H).
.sup.19F NMR .delta. -74.10.
[2648] A solution of
(S)-6-((4-hydroxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(trimethylsilyl)eth-
oxy)nicotinaldehyde (6.42 g, 0.13 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.89
g, 15 mmol), Pd-dppf (0.932 g, 1.27 mmol) and KOAc (3.75 g, 38
mmol) in 55 mL dioxane was stirred at 90 C overnight. Reaction was
diluted with EtOAc, filtered thru celite and concentrated.
Purification of the filtrate derived material by silica
chromatography (DCM-hexanes) provided
(S)-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde. 1H NMR
(400 MHz, Chloroform-d) .delta. 10.24 (d, J=0.9 Hz, 1H), 8.03 (d,
J=8.3 Hz, 1H), 7.78 (dd, J=7.3, 1.3 Hz, 1H), 7.53 (d, J=7.6 Hz,
1H), 7.23 (d, J=7.4 Hz, 1H), 6.51 (dd, J=7.1, 4.3 Hz, 1H), 6.33
(dd, J=8.3, 0.9 Hz, 1H), 4.66-4.57 (m, 2H), 3.36 (ddd, J=17.2, 8.7,
5.7 Hz, 1H), 3.15 (ddd, J=17.2, 8.7, 5.6 Hz, 1H), 2.60 (dddd,
J=14.1, 8.6, 7.1, 5.6 Hz, 1H), 2.26-2.13 (m, 1H), 1.34 (s, 12H),
1.31-1.18 (m, 2H), 0.07 (s, 9H).
[2649] A solution of
(S)-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (3.20 g,
6.71 mmol), 1,3-dibromo-2-chlorobenzene (5.44 g, 20.1 mmol),
Pd-dppf (0.490 g, 0.67 mmol) and K.sub.2CO.sub.3 (2.34 g, 17 mmol)
in 60 mL dioxane and 6 mL water was stirred at 90 C for 5 h.
Reaction was diluted with EtOAc, dried with MgSO.sub.4 and filtered
thru celite and conc. Purification of the filtrate derived material
by silica chromatography (DCM-hexanes) provided
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy-
)-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde. 1H NMR (400 MHz,
Chloroform-d) .delta. 10.24 (d, J=0.8 Hz, 1H), 8.06 (d, J=8.4 Hz,
1H), 7.66 (dd, J=7.7, 1.9 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.33 (t,
J=7.6 Hz, 1H), 7.26-7.13 (m, 3H), 6.59 (d, J=16.5 Hz, 1H), 6.38 (s,
1H), 4.62 (t, J=8.3 Hz, 2H), 2.82 (tq, J=16.5, 8.5, 6.8 Hz, 1H),
2.68-2.59 (m, 2H), 2.24-2.15 (m, 1H), 1.30-1.18 (m, 3H), 0.07 (s,
9H).
[2650] A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-(2-(t-
rimethylsilyl)ethoxy)nicotinaldehyde (1.31 g, 2.41 mmol) in 6 mL
Chloroform and 3 mL DMF was treated with Palau-Cl
(2-chloro-1,3-bis(methoxycarbonyl)guanidine (Baran CBMG Reagent)
631 mg, 3.01 mmol) and TFA (37 uL, 0.48 mmol) as a 10% soln in DMF.
The reaction was stirred for 16 h at rt, then diluted with DCM and
treated with 10 mL sat thiosulfate and 20 mL NaHCO.sub.3. After
stirring vigorously for 10 min, the organic layer was separated,
dried with MgSO4, filtered and concentrated. Purification by column
chromatography (ISCO, elution with DCM-hexanes) provided
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde. 120 mg of starting
material was also obtained. 1H NMR (400 MHz, Chloroform-d) .delta.
10.20 (s, 1H), 8.09 (s, 1H), 7.66 (dd, J=7.7, 1.9 Hz, 1H), 7.51 (d,
J=7.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.29-7.14 (m, 1H), 7.20 (s,
2H), 6.58 (d, J=22.9 Hz, 1H), 4.61 (t, J=8.3 Hz, 2H), 2.94-2.77 (m,
2H), 2.69 (m, 2H), 2.28-2.20 (m, 1H), 1.27-1.17 (m, 2H), 0.07 (s,
9H).
[2651] A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (500 mg, 0.86 mmol)
in 6 mL DMF was treated with CsF (524 mg, 3.45 mmol) and stirred
for 1 h at 60.degree. C. Cooled to 0 C and treated with
K.sub.2CO.sub.3 (357 mg, 2.6 mmol),
3-(chloromethyl)-5-(methylsulfonyl)pyridine hydrochloride (251 mg,
1.04 mmol) and NaI (130 mg, 0.86 mmol). Allowed to warm to rt and
stir overnight. The reaction was partitioned between EtOAc and
water. Organic layer was washed with 2% LiCl, dried with sodium
sulfate, filtered and conc. Purification by column chromatography
(ISCO, elution with EtOAc-hexanes) provided
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H22BrCl2N2O5S: 648.97; found:
648.94.
[2652] A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)nicotinaldehyde (291
mg, 0.45 mmol) in 5 mL DMF and 0.5 mL H2O was treated with
2-(trimethylsilyl)ethyl
(2-hydroxyethyl)(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenox-
y)ethyl)carbamate (233 mg, 0.52 mmol), K2CO3 (186 mg, 1.4 mmol) and
Pd-dppf (33 mg, 0.045 mmol) and stirred for 16 h at 80.degree. C.
Cooled to rt and diluted with EtOAc, dried with sodium sulfate,
filtered and conc. Purification by column chromatography (ISCO,
elution with EtOAc-hexanes) provided 2-(trimethylsilyl)ethyl
(S)-(2-((2'-chloro-3'-(1-((3-chloro-5-formyl-6-((5-(methylsulfonyl)pyridi-
n-3-yl)methoxy)pyridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-[1,1'-biphenyl-
]-4-yl)oxy)ethyl)(2-hydroxyethyl)carbamate. LCMS-ESI+ (m/z): [M+H]+
calcd for C44H48Cl2N3O9SSi: 892.22; found: 891.83.
[2653] A solution of 2-(trimethylsilyl)ethyl
(S)-(2-((2'-chloro-3'-(1-((3-chloro-5-formyl-6-((5-(methylsulfonyl)pyridi-
n-3-yl)methoxy)pyridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-[1,1'-biphenyl-
]-4-yl)oxy)ethyl)(2-hydroxyethyl)carbamate (290 mg, 0.32 mmol) in 2
mL THF was treated with 1.0 M TBAF in THF (0.487 mL, 0.487 mmol)
and stirred for 18 h at 20.degree. C. The reaction was partitioned
between EtOAc and water. Organic layer was washed with water, dried
with sodium sulfate, filtered and concentrated to provide
(S)-5-chloro-6-((4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy)-[1,1'-b-
iphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-(methylsulfonyl)pyridi-
n-3-yl)methoxy)nicotinaldehyde. LCMS-ESI+ (m/z): [M+H]+ calcd for
C38H36Cl2N3O7S: 748.12; found: 748.03.
[2654]
(S)-4-(((5-chloro-6-(((S)-4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)-
ethoxy)-[1,1'-biphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-(methyl-
sulfonyl)pyridin-3-yl)methoxy)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic
acid was prepared from
(S)-5-chloro-6-((4-(2-chloro-4'-(2-((2-hydroxyethyl)amino)ethoxy)-[1,1'-b-
iphenyl]-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-(methylsulfonyl)pyridi-
n-3-yl)methoxy)nicotinaldehyde using general reductive amination
procedure D. 1H NMR (400 MHz, Methanol-d4) .delta. 9.03 (s, 2H),
8.50 (s, 1H), 7.90 (s, 1H), 7.54 (s, 4H), 7.45 (t, J=7.5 Hz, 1H),
7.41-7.32 (m, 2H), 7.29-7.18 (m, 3H), 6.52 (s, 1H), 5.70 (s, 2H),
4.29 (s, 2H), 4.18 (s, 2H), 3.27 (d, J=3.1 Hz, 1H), 3.17 (d, J=5.5
Hz, 3H), 3.07 (dd, J=12.7, 9.8 Hz, 1H), 2.95-2.87 (m, 2H), 2.76 (s,
1H), 2.57 (d, J=6.3 Hz, 3H), 2.10 (s, 1H). LCMS-ESI+ (m/z): [M+H]+
calcd for C.sub.42H.sub.45Cl.sub.2N.sub.4O.sub.9S: 851.22; found:
851.00.
Example 638:
(S)-2-(((2-(2-chloro-3-(1-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6--
methoxypyridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-[1,2,4]triazolo-
[1,5-a]pyridin-7-yl)methyl)amino)ethan-1-ol
##STR00858##
[2656] A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-(2-(trimethylsilyl)ethoxy)nicotinaldehyde (400 mg, 0.69 mmol)
in 3 mL DMF was treated with CsF (419 mg, 2.76 mmol) and stirred
for 1 h at 60.degree. C. Cooled to 0 C and treated with K2CO3 (286
mg, 2.07 mmol) and methyl iodide (64 .mu.L, 1.04 mmol). Allowed to
warm to rt and stir for 2 h. The reaction was partitioned between
EtOAc and water. Organic layer was washed with 2% LiCl, dried with
sodium sulfate, filtered and conc. Purification by column
chromatography (ISCO, elution with EtOAc-hexanes)
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-methoxynicotinaldehyde. LCMS-ESI+ (m/z): [M+H]+ calcd for
C.sub.22H.sub.17BrCl.sub.2NO.sub.3: 491.97; found: 491.83.
[2657] A solution of
(S)-6-((4-(3-bromo-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chlor-
o-2-methoxynicotinaldehyde (357 mg, 0.72 mmol) in 5 mL dioxane was
treated with inacoldiboron (221 mg, 0.87 mmol), Pd-dppf (53 mg,
0.073 mmol) and KOAc (213 mg, 2.2 mmol) and heated at 90 C for 1 h.
The reaction was diluted with EtOAc and filtered. Purification by
column chromatography (ISCO, elution with EtOAc-hexanes)
(S)-5-chloro-6-((4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxynicotinaldehyde.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H28BCl2NO5: 540.14; found:
540.32.
[2658] A solution of
(S)-5-chloro-6-((4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxynicotinaldehyde
(45 mg, 0.083 mmol),
2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde (26 mg, 0.115
mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)
dichloride (7 mg, 0.009 mmol) and sodium carbonate (120 .mu.L, 0.24
mmol, 2M solution in water). The reaction mixture was heated in the
microwave at 110.degree. C. for 45 min. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate
and washed with water and brine. The organic layer was dried over
sodium sulfate and filtered. The filtrate was concentrated and
purified by ISCO silica gel chromatography to give
(S)-2-(2-chloro-3-(1-((3-chloro-5-formyl-6-methoxypyridin-2-yl)ox-
y)-2,3-dihydro-1H-inden-4-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carb-
aldehyde.
[2659] Ethanolamine (15 .mu.L, 0.25 mmol) was first dissolved in
dimethyl sulfoxide (3 mL) and acetic acid (0.6 mL). After stirring
for 10 min,
(S)-2-(2-chloro-3-(1-((3-chloro-5-formyl-6-methoxypyridin-2-yl)oxy)-2,3-d-
ihydro-1H-inden-4-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde
(17 mg, 0.03 mmol) dissolved in dimethyl sulfoxide (1 mL) was then
added slowly dropwise. The reaction mixture was stirred at rt for 4
h before sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added.
After 1 h, the reaction was quenched by adding 400 .mu.L of
trifluoroacetic acid. Purification on reversed-phase HPLC
provided(S)-2-(((2-(2-chloro-3-(1-((3-chloro-5-(((2-hydroxyethyl)amino)me-
thyl)-6-methoxypyridin-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-[1,2,4]-
triazolo[1,5-a]pyridin-7-yl)methyl)amino)ethan-1-ol. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.15 (d, J=7.1 Hz, 2H), 8.70 (s,
2H), 8.07 (d, J=1.5 Hz, 1H), 7.99 (s, 1H), 7.94 (dd, J=7.3, 2.2 Hz,
1H), 7.60 (d, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.44-7.37 (m, 2H), 7.31
(dd, J=7.6, 1.2 Hz, 1H), 6.64 (s, 1H), 5.30 (d, J=21.2 Hz, 2H),
4.39 (s, 2H), 4.09 (s, 2H), 4.02 (s, 3H), 3.68 (dt, J=9.3, 4.6 Hz,
3H), 3.04 (d, J=19.4 Hz, 4H), 2.93-2.83 (m, 1H), 2.79-2.66 (m, 2H),
2.11 (d, J=19.3 Hz, 1H). ES/MS (m/z, M+H.sup.+): 648.9.
Example 639:
(3S,3'S)-4,4'-((((((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,-
1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00859##
[2661] A stirred mixture of 4-bromo-2,3-dihydro-1H-inden-1-one
(3.00 g, 14.2 mmol),
1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium
tetrafluoroborate (6.04 g, 17.1 mmol), and sulfuric acid (75.8
.mu.L, 1.42 mmol) in methanol (30 mL) was heated to 62.degree. C.
After 22 h, the resulting mixture was cooled to room temperature.
Ethyl acetate (50 mL) and diethyl ether (200 mL) were added. The
organic layer was washed with water (200 mL), was dried over
anhydrous magnesium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to
give 4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one.
[2662]
[N-[(1R,2R)-2-(Amino-.kappa.N)-1,2-diphenylethyl]-4-methylbenzenesu-
lfonamidato-.kappa.N]chloro[(1,2,3,4,5,6-q)-1-methyl-4-(1-methylethyl)benz-
ene]-ruthenium (21 mg, 0.033 mmol) was added to a stirred mixture
of 4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one (750 mg, 3.27 mmol),
formic acid (890 .mu.L, 24 mmol), triethylamine (2.7 mL, 20 mmol),
and dichloromethane (400 .mu.L) at room temperature. After 24 h,
diethyl ether (50 mL) was added. The organic layer was washed with
saturated aqueous sodium bicarbonate solution (2.times.30 mL), was
dried over anhydrous magnesium sulfate, was filtered, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (0 to 30% ethyl acetate
in hexanes) to give
(1S,2R)-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol.
[2663] Diisopropyl azodicarboxylate (572 .mu.L, 2.95 mmol) was
added over 2 min via syringe to a stirred mixture of
(1S,2R)-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol (455 mg, 1.97
mmol), 4-nitrobenzoic acid (494 mg, 2.95 mmol), and
triphenylphosphine (826 mg, 3.15 mmol) in tetrahydrofuran (10 mL)
at 0.degree. C. After 5 min, the resulting mixture was warmed to
room temperature. After 13 h, the resulting mixture was
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (0 to 20% ethyl acetate
in hexanes) to give
(1R,2R)-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl
4-nitrobenzoate.
[2664] A vigorously stirred mixture of
(1R,2R)-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl 4-nitrobenzoate
(287 mg, 0.754 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (230
mg, 0.905 mmol), potassium acetate (197 mg, 2.01 mmol), and
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg, 0.038
mmol) in 1,4-dioxane (7.0 mL) was heated to 95.degree. C. After 13
h, the resulting mixture was cooled to room temperature, was
filtered through celite, and was concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (0 to 12% ethyl acetate in hexanes) to give
(1R,2R)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihy-
dro-1H-inden-1-yl 4-nitrobenzoate.
[2665] A vigorously stirred mixture of
(1R,2R)-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl 4-nitrobenzoate
(287 mg, 0.754 mmol),
(1R,2R)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihy-
dro-1H-inden-1-yl 4-nitrobenzoate (322 mg, 0.754 mmol), saturated
aqueous sodium carbonate solution (943 .mu.L), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (59 mg, 0.075 mmol) in
1,4-dioxane (3.0 mL) was heated to 90.degree. C. After 5 h, the
resulting mixture was cooled to room temperature, and ethyl acetate
(60 mL) was added. The organic layer was washed with a mixture of
brine and water (2:1 v:v, 30 mL), was dried over anhydrous sodium
sulfate, was filtered, and was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (0 to 50% ethyl acetate in hexanes) to give a mixture of
(1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-
-1,1'-diyl bis(4-nitrobenzoate),
(1R,1'R,2R,2'R)-2,2'-difluoro-1'-hydroxy-2,2',3,3'-tetrahydro-1H,1'H-[4,4-
'-biinden]-1-yl 4-nitrobenzoate, and
(1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-
-1,1'-diol. The mixture was dissolved in tetrahydrofuran (15 mL)
and methanol (15 mL) and was stirred at room temperature. Aqueous
sodium hydroxide solution (1.0 M, 6.0 mL, 6.0 mmol) was added.
After 20 min, ethyl acetate (63 mL) and diethyl ether (63 mL) were
added. The organic layer was washed sequentially with water (100
mL), a mixture of saturated aqueous sodium bicarbonate solution and
water (1:1 v:v, 100 mL), and water (100 mL), was dried over
anhydrous magnesium sulfate, was filtered, and was concentrated
under reduced pressure to give
(1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-
-1,1'-diol.
[2666] A vigorously stirred mixture of
(1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-
-1,1'-diol (185 mg, 0.612 mmol), 6-chloro-2-methoxynicotinaldehyde
(420 mg, 2.45 mmol), cesium carbonate (917 mg, 2.82 mmol), and
[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-ami-
no-1,1'-biphenyl)]palladium(II) methanesulfonate (97 mg, 0.12 mmol)
in toluene (7.0 mL) was heated to 100.degree. C. After 14.5 h, the
resulting mixture was cooled to room temperature, was filtered
through celite, and was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(0 to 30% ethyl acetate in hexanes) to give
6,6'-(((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(2-methoxynicotinaldehyde).
[2667] Hydrogen chloride solution (4.0 M in 1,4-dioxane, 96.3
.mu.L, 0.385 mmol) was added via syringe to a stirred mixture of
6,6'-(((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(2-methoxynicotinaldehyde) (103 mg,
0.179 mmol) and 2-chloro-1,3-bis(methoxycarbonyl)guanidine (82.7
mg, 0.394 mmol) in acetonitrile (8.0 mL) and chloroform (8.0 mL) at
room temperature. After 40 min,
2-chloro-1,3-bis(methoxycarbonyl)guanidine (37.6 mg, 0.179 mmol)
was added. After 1 min, hydrogen chloride solution (4.0 M in
1,4-dioxane, 44.8 .mu.L, 0.179 mmol) was added via syringe. After
30 min, ethyl acetate (60 mL) was added. The organic layer was
washed sequentially with water (30 mL) and brine (30 mL), was dried
over anhydrous sodium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 30% ethyl acetate in hexanes) to
give
6,6'-(((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxynicotinaldehyde).
[2668] Sodium triacetoxyborohydride (126 mg, 0.596 mmol) was added
to a stirred mixture of
6,6'-(((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxynicotinaldehyde)
(38 mg, 0.060 mmol), (S)-4-amino-3-hydroxybutanoic acid (85.1 mg,
0.715 mmol), and acetic acid (0.20 mL) in dimethylsulfoxide (1.5
mL) at room temperature. After 45 min, trifluoroacetic acid (60
.mu.L) was added, and the resulting mixture was purified by reverse
phase preparative HPLC (0.1% trifluoroacetic acid in
acetonitrile/water) to give
(3S,3'S)-4,4'-((((((1R,1'R,2R,2'R)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,-
1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid).
ES/MS (m/z, M+H.sup.+): 847.2.
Example 640:
(3S,3'S)-4,4'-((((((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,-
1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)
##STR00860##
[2670] A stirred mixture of 4-chloro-2,3-dihydro-1H-inden-1-one
(3.00 g, 18.0 mmol),
1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium
tetrafluoroborate (7.66 g, 21.6 mmol), and sulfuric acid (96.0
.mu.L, 1.80 mmol) in methanol (40 mL) was heated to 65.degree. C.
After 18 h, the resulting mixture was cooled to room temperature.
Ethyl acetate (50 mL) and diethyl ether (200 mL) were added. The
organic layer was washed with water (200 mL), was dried over
anhydrous magnesium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to
give 4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one.
[2671]
[N-[(1S,2S)-2-(Amino-.kappa.N)-1,2-diphenylethyl]-4-methylbenzenesu-
lfonamidato-.kappa.N]chloro[(1,2,3,4,5,6-.eta.)-1-methyl-4-(1-methylethyl)-
benzene]-ruthenium (90.9 mg, 0.143 mmol) was added to a stirred
mixture of 4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one (2.64 g,
14.3 mmol), formic acid (3.88 mL, 103 mmol), triethylamine (12 mL,
86 mmol), and dichloromethane (1.5 mL) at room temperature. After
18 h, diethyl ether (150 mL) was added. The organic layer was
washed with saturated aqueous sodium bicarbonate solution
(2.times.90 mL), was dried over anhydrous magnesium sulfate, was
filtered, and was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (0 to 20%
ethyl acetate in hexanes) to give
(1R,2S)-4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-ol.
[2672] A vigorously stirred mixture of
(1R,2S)-4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-ol (1.00 g, 5.36
mmol), 6-chloro-2-methoxynicotinaldehyde (1.10 g, 6.43 mmol),
cesium carbonate (2.27 g, 6.97 mmol), and
[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-ami-
no-1,1'-biphenyl)]palladium(II) methanesulfonate (128 mg, 0.161
mmol) in toluene (8.0 mL) was heated to 105.degree. C. After 3.5 h,
the resulting mixture was cooled to room temperature, was filtered
through celite, and was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(0 to 20% ethyl acetate in hexanes) to give
6-(((1R,2S)-4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxynic-
otinaldehyde.
[2673] A vigorously stirred mixture of
6-(((1R,2S)-4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxynic-
otinaldehyde (312 mg, 0.970 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (123
mg, 0.485 mmol), saturated aqueous sodium carbonate solution (1.94
mL), and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (76 mg, 0.097 mmol) in
1,4-dioxane (9.0 mL) was heated to 100.degree. C. After 15 h, the
resulting mixture was cooled to room temperature, and ethyl acetate
(50 mL) was added. The organic layer was washed with a mixture of
brine and water (2:1 v:v, 30 mL), was filtered, and was
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (0 to 30% ethyl acetate
in hexanes) to give
6,6'-(((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(2-methoxynicotinaldehyde).
[2674] Hydrogen chloride solution (4.0 M in 1,4-dioxane, 136 .mu.L,
0.542 mmol) was added via syringe to a stirred mixture of
6,6'-(((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(2-methoxynicotinaldehyde) (144 mg,
0.252 mmol) and 2-chloro-1,3-bis(methoxycarbonyl)guanidine (116 mg,
0.555 mmol) in acetonitrile (8.0 mL) and chloroform (8.0 mL) at
room temperature. After 65 min,
2-chloro-1,3-bis(methoxycarbonyl)guanidine (29.1 mg, 0.139 mmol)
was added. After 1 min, hydrogen chloride solution (4.0 M in
1,4-dioxane, 31.5 .mu.L, 0.126 mmol) was added via syringe. After
15 min, ethyl acetate (60 mL) was added. The organic layer was
washed sequentially with water (30 mL) and brine (30 mL), was dried
over anhydrous sodium sulfate, was filtered, and was concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0 to 30% ethyl acetate in hexanes) to
give
6,6'-(((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxynicotinaldehyde).
[2675] Sodium triacetoxyborohydride (463 mg, 2.18 mmol) was added
to a stirred mixture of
6,6'-(((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-bi-
indene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxynicotinaldehyde)
(140 mg, 0.218 mmol), (S)-4-amino-3-hydroxybutanoic acid (156 mg,
1.31 mmol), and acetic acid (0.20 mL) in dimethylsulfoxide (1.5 mL)
at room temperature. After 60 min, trifluoroacetic acid (150 .mu.L)
was added, and the resulting mixture was purified by reverse phase
preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water)
to give
(3S,3'S)-4,4'-((((((1R,1'R,2S,2'S)-2,2'-difluoro-2,2',3,3'-tetrahydro-1H,-
1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-methoxypyridine-6,3--
diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid).
ES/MS (m/z, M+H.sup.+): 847.2.
[2676] The following compounds were prepared according to the
procedures described herein (e.g., according to Example 637 or 638)
using the appropriate starting material(s) and appropriate
protecting group chemistry as needed.
TABLE-US-00006 Exam- ES/MS ple (m/z, No. Structure M + H+) 641
##STR00861## 769.92 642 ##STR00862## 733.03 643 ##STR00863## 720.07
644 ##STR00864## 732.06 645 ##STR00865## 736.98 646 ##STR00866##
718.97 647 ##STR00867## 733.08 648 ##STR00868## 737.98 649
##STR00869## 750.9 650 ##STR00870## 756.03 651 ##STR00871## 757 652
##STR00872## 745.93 653 ##STR00873## 794.02 654 ##STR00874## 774
655 ##STR00875## 769.01 656 ##STR00876## 769.9 657 ##STR00877##
779.91 658 ##STR00878## 769.97 659 ##STR00879## 776.97 660
##STR00880## 851.05 661 ##STR00881## 763.96 662 ##STR00882## 841.93
663 ##STR00883## 841.88 664 ##STR00884## 789.23 665 ##STR00885##
860.97 666 ##STR00886## 877.03 667 ##STR00887## 808.07 668
##STR00888## 824.09 669 ##STR00889## 876.99 670 ##STR00890## 720.02
671 ##STR00891## 773.88 672 ##STR00892## 762.04 673 ##STR00893##
728.08 674 ##STR00894## 797.96 675 ##STR00895## 676 ##STR00896##
882.12 677 ##STR00897## 802.22 678 ##STR00898## 923.25 679
##STR00899## 1003.13 681 ##STR00900## 679.93 682 ##STR00901## 936
683 ##STR00902## 863.9 684 ##STR00903## 863.9 685 ##STR00904## 848
686 ##STR00905## 1063 687 ##STR00906## 1056.8 688 ##STR00907##
1088.9 689 ##STR00908## 1056.8 690 ##STR00909## 1063.5 691
##STR00910## 899.1 692 ##STR00911## 1121.7 693 ##STR00912## 1103.5
694 ##STR00913## 1121.3 695 ##STR00914## 751.1 696 ##STR00915##
750.8 697 ##STR00916## 860.0 (M + Na)+ 698 ##STR00917## 855.2 (M +
Na)+ 699 ##STR00918## 940 700 ##STR00919## 896.3 701 ##STR00920##
822.3 702 ##STR00921## 838.3 703 ##STR00922## 719.992 704
##STR00923## 718.945 705 ##STR00924## 719.956 706 ##STR00925##
718.918 707 ##STR00926## 733.933 708 ##STR00927## 732.974 709
##STR00928## 705.9 710 ##STR00929## 704.884 711 ##STR00930##
733.881 712 ##STR00931## 732.962 713 ##STR00932## 743.963 714
##STR00933## 757.982 715 ##STR00934## 729.004 716 ##STR00935##
700.996 717 ##STR00936## 700.961 718 ##STR00937## 686.973 719
##STR00938## 728.979 720 ##STR00939## 672.956 721 ##STR00940##
700.951 722 ##STR00941## 715.035 723 ##STR00942## 714.998 724
##STR00943## 715.028 725 ##STR00944## 714.965 726 ##STR00945##
756.972 727 ##STR00946## 749.9 728 ##STR00947## 750.001 729
##STR00948## 726.012 730 ##STR00949## 713.977 731 ##STR00950##
718.946 732 ##STR00951## 718.958 733 ##STR00952## 769.015 734
##STR00953## 744.933 735 ##STR00954## 812.906 736 ##STR00955##
788.853 737 ##STR00956## 807.022 738 ##STR00957## 763.09 739
##STR00958## 788.853 740 ##STR00959## 729.093 741 ##STR00960##
864.968 742 ##STR00961## 787.071 743 ##STR00962## 910.49 744
##STR00963## 838.88 745 ##STR00964## 794.76 746 ##STR00965## 760.86
747 ##STR00966## 896.48 748 ##STR00967## 818.59 749 ##STR00968##
774.74 750 ##STR00969## 740.48 751 ##STR00970## 987.2 752
##STR00971## 977.78 753 ##STR00972## 903.94 754 ##STR00973## 835.11
755 ##STR00974## 879.99 756 ##STR00975## 757.06 757 ##STR00976##
731.99 758 ##STR00977## 761.23 759 ##STR00978## 760.12 760
##STR00979## 789.08 761 ##STR00980## 774.14 762 ##STR00981## 776
763 ##STR00982## 760.14 764 ##STR00983## 774.13
765 ##STR00984## 760.09 766 ##STR00985## 786.09 767 ##STR00986##
773.02 768 ##STR00987## 746.98 769 ##STR00988## 745.93 770
##STR00989## 769.18 771 ##STR00990## 740.95 772 ##STR00991## 608.11
773 ##STR00992## 737.25 774 ##STR00993## 752.06 775 ##STR00994##
759.19 776 ##STR00995## 775.96 777 ##STR00996## 657.16 778
##STR00997## 672.11 779 ##STR00998## 733.15 780 ##STR00999## 737.03
781 ##STR01000## 752.06 782 ##STR01001## 751.94 783 ##STR01002##
613.89 784 ##STR01003## 693.84 785 ##STR01004## 748.08 786
##STR01005## 720.2 787 ##STR01006## 738.04 788 ##STR01007## 738.01
789 ##STR01008## 738.01 790 ##STR01009## 777.86 791 ##STR01010##
793.16 792 ##STR01011## 789.92 793 ##STR01012## 608.78 794
##STR01013## 688.75 795 ##STR01014## 750.2 796 ##STR01015## 756 797
##STR01016## 876.2 798 ##STR01017## 758.9 799 ##STR01018## 780.1
800 ##STR01019## 831.1 801 ##STR01020## 873.0 802 ##STR01021##
857.0 803 ##STR01022## 867.0
[2677] NMR data for select compounds is shown below.
TABLE-US-00007 Example No. NMR 637 1H NMR (400 MHz, Methanol-d4) d
9.03 (s, 2H), 8.50 (s, 1H), 7.90 (s, 1H), 7.54 (s, 4H), 7.45 (t, J
= 7.5 Hz, 1H), 7.41-7.32 (m, 2H), 7.29-7.18 (m, 3H), 6.52 (s, 1H),
5.70 (s, 2H), 4.29 (s, 2H), 4.18 (s, 2H), , 3.27 (d, J = 3.1 Hz,
1H), 3.17 (d, J = 5.5 Hz, 3H), 3.07 (dd, J = 12.7, 9.8 Hz, 1H),
2.95-2.87 (m, 2H), 2.76 (s, 1H), 2.57 (d, J = 6.3 Hz, 3H), 2.10 (s,
1H). 638 1H NMR (400 MHz, DMSO-d6) .delta. 9.15 (d, J = 7.1 Hz,
2H), 8.70 (s, 2H), 8.07 (d, J = 1.5 Hz, 1H), 7.99 (s, 1H), 7.94
(dd, J = 7.3, 2.2 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H),
7.44-7.37 (m, 2H), 7.31 (dd, J = 7.6, 1.2 Hz, 1H), 6.64 (s, 1H),
5.30 (d, J = 21.2 Hz, 2H), 4.39 (s, 2H), 4.09 (s, 2H), 4.02 (s,
3H), 3.68 (dt, J = 9.3, 4.6 Hz, 3H), 3.04 (d, J = 19.4 Hz, 4H),
2.93-2.83 (m, 1H), 2.79-2.66 (m, 2H), 2.11 (d, J = 19.3 Hz, 1H).
641 1H NMR (400 MHz, DMSO-d6) d 8.84 (s, 1H), 8.63 (s, 1H), 8.01
(s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 1H),
7.56 (d, J = 2.5 Hz, 1H), 7.55-7.45 (m, 2H), 7.38 (dd, J = 13.8,
7.3 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), , 4.33 (s,
2H), 4.21 (s, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.88 (d, J = 6.3 Hz,
1H), 3.42 (m, 6H), 3.10 (d, J = 26.0 Hz, 2H), 2.93-2.82 (m, 1H),
2.81-2.61 (m, 2H), 2.34-2.03 (m, 5H), 1.85-1.71 (m, 1H). 642 1H NMR
(400 MHz, Acetonitrile-d3) d 8.52 (d, J = 1.1 Hz, 1H), 7.84 (s,
1H), 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 7.63 (t, J = 7.1 Hz, 2H), 7.53
(s, 2H), 7.49-7.40 (m, 1H), 7.36 (d, J = 7.5 Hz, 1H), 6.72 (s, 1H),
4.47 (s, 2H), 4.41 (d, J = 2.9 Hz, 1H), 4.19 (s, 2H), 4.11 (s, 6H),
3.84 (d, J = 12.4 Hz, 1H), 3.68-3.53 (m, 1H), 3.11-2.62 (m, 5H),
2.40-2.00 (m, 2H), 2.00-1.62 (m, 3H), 1.57 (d, J = 1.2 Hz, 3H). 643
1H NMR (400 MHz, DMSO-d6) d 9.04 (s, 1H), 8.89 (s, 1H), 8.77-8.70
(m, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.69 (dd, J =
7.6, 1.9 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.47 (s, 2H), 7.37 (t,
J = 7.5 Hz, 1H), 7.29 (dd, J = 7.6, 1.2 Hz, 1H), 6.61 (d, J = 6.6
Hz, 1H), 5.54 (s, 2H), 4.36 (d, J = 6.4 Hz, 2H), 4.26 (d, J = 18.3
Hz, 2H), 4.04 (s, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 2.95-2.63 (m,
4H), 2.10 (s, 1H), 2.06-1.89 (m, 2H), 1.79 (td, J = 8.8, 8.1, 5.2
Hz, 4H), 1.78-1.61 (m, 3H), 1.60-1.47 (m, 2H). 644 1H NMR (400 MHz,
Acetonitrile-d3) ? 7.83 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 1.3 Hz,
1H), 7.62 (dd, J = 7.7, 1.8 Hz, 1H), 7.51 (td, J = 7.7, 4.5 Hz,
2H), 7.38 (q, J = 10.1, 7.7 Hz, 2H), 7.34-7.19 (m, 2H), 6.65 (s,
1H), 4.30 (t, J = 3.5 Hz, 1H), 4.29-4.16 (m, 2H), 4.11 (s, 2H),
4.01 (d, J = 12.6 Hz, 7H), 3.39 (td, J = 8.6, 4.8 Hz, 1H),
3.15-3.01 (m, 2H), 2.93 (s, 1H), 2.76 (m, 1H), 2.68 (dd, J = 14.5,
7.6 Hz, 1H), 2.41-2.25 (m, 4H), 2.17 (s, 2H), 2.05 (ddt, J = 12.2,
8.4, 4.5 Hz, 1H), 1.91-1.52 (m, 4H). 645 1H NMR (400 MHz,
Acetonitrile-d3) d 7.82 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.61
(dd, J = 7.6, 1.8 Hz, 1H), 7.51 (q, J = 7.8 Hz, 2H), 7.36 (t, J =
7.6 Hz, 1H), 7.32-7.24 (m, 3H), 6.65 (d, J = 6.8 Hz, 1H), 4.32-4.25
(m, 1H), 4.22 (d, J = 3.7 Hz, 2H), 4.11 (s, 2H), 4.01 (d, J = 14.6
Hz, 6H), 3.75 (d, J = 12.4 Hz, 1H), 3.39 (td, J = 8.7, 4.6 Hz, 1H),
2.92 (s, 1H), 2.83-2.55 (m, 4H), 2.23-2.10 (m, 1H), 2.10-2.00 (m,
1H), 1.90-1.66 (m, 2H), 1.66-1.52 (m, 1H), 1.48 (s, 3H). 650 1H NMR
(400 MHz, DMSO-d6) d 8.84 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.44
(s, 1H), 7.95 (s, 1H), 7.63-7.50 (m, 3H), 7.45 (dd, J = 7.5, 1.7
Hz, 1H), 7.44-7.32 (m, 2H), 7.31-7.24 (m, 2H), 6.61 (s, 1H), 5.55
(s, 1H), 5.30 (s, 2H), 4.23 (s, 3H), 4.04 (d, J = 5.4 Hz, 2H), 3.98
(s, 3H), 3.88 (d, J = 7.6 Hz, 1H), 3.31 (s, 1H), 3.13 (s, 1H), 3.06
(s, 1H), 2.91-2.84 (m, 1H), 2.82-2.61 (m, 2H), 2.26-2.07 (m, 4H),
1.99-1.89 (m, 1H), 1.84-1.60 (m, 5H), 1.53 (m, 1H). 651 1H NMR (400
MHz, DMSO-d6) d 8.93 (s, 1H), 8.74 (s, 2H), 8.45 (s, 1H), 8.06 (d,
J = 7.7 Hz, 1H), 7.95 (s, 1H), 7.70 (dd, J = 7.6, 1.8 Hz, 1H),
7.63-7.53 (m, 3H), 7.46 (s, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.29
(dd, J = 7.5, 1.2 Hz, 1H), 6.60 (d, J = 5.5 Hz, 1H), 5.55 (s, 1H),
5.29 (s, 2H), 4.25 (s, 3H), 4.04 (s, 2H), 3.98 (s, 3H), 3.89 (s,
1H), 3.32 (s, 1H), 3.16 (s, 1H), 3.09 (s, 1H), 2.88 (s, 1H),
2.80-2.67 (m, 3H), 2.26-2.07 (m, 2H), 2.01-1.89 (m, 1H), 1.78 (s,
4H), 1.83-1.63 (m, 2H), 1.53 (m, 1H). 652 1H NMR (400 MHz,
Chloroform-d) d 9.27 (s, 1H), 9.17 (s, 1H), 8.84 (s, 1H), 8.63 (s,
1H), 8.02 (s, 1H), 7.74 (dd, J = 7.6, 1.8 Hz, 1H), 7.71-7.56 (m,
3H), 7.52 (d, J = 9.8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.36-7.31
(m, 1H), 6.66 (d, J = 6.8 Hz, 1H), 4.50 (s, 2H), 4.14 (s, 2H), 4.07
(s, 3H), 4.04 (s, 3H), 3.98 (d, J = 6.5 Hz, 1H), 3.88 (m, 2H), 3.24
(s, 2H), 3.10 (s, 1H), 3.04 (s, 1H), 2.92 (s, 1H), 2.79 (d, J =
17.8 Hz, 1H), 2.71 (d, J = 19.0 Hz, 1H), 2.29-2.13 (m, 6H),
1.88-1.76 (m, 2H). 653 1H NMR (400 MHz, Chloroform-d) d 8.86 (d, J
= 22.3 Hz, 2H), 8.65 (s, 2H), 8.04 (s, 1H), 7.68-7.56 (m, 4H),
7.56-7.46 (m, 3H), 7.46-7.38 (m, 2H), 7.33 (d, J = 7.5 Hz, 2H),
6.78-6.58 (m, 1H), 5.36 (s, 2H), 4.45 (s, 2H), 4.29 (s, 2H), 4.15
(d, J = 5.0 Hz, 2H), 3.98-3.86 (m, 2H), 3.27-3.00 (m, 8H),
3.01-2.63 (m, 3H), 2.32-2.15 (m, 5H), 1.84 (td, J = 10.2, 5.2 Hz,
2H). 654 1H NMR (400 MHz, DMSO-d6) d 8.85 (s, 1H), 8.67 (s, 3H),
7.96 (s, 1H), 7.63-7.50 (m, 3H), 7.50-7.41 (m, 3H), 7.44-7.32 (m,
2H), 7.27 (d, J = 7.6 Hz, 2H), 6.60 (s, 1H), 5.59 (s, 1H), 5.30 (s,
2H), 4.23 (s, 2H), 4.16 (s, 1H), 4.09-4.03 (m, 2H), 3.98 (s, 3H),
3.89 (s, 1H), 3.13 (s, 1H), 3.05 (s, 2H), 2.88 (s, 2H), 2.87 (d, J
= 4.4 Hz, 1H), 2.80-2.70 (m, 1H), 2.69 (s, 1H), 2.51 (d, J = 4.9
Hz, 0H), 2.45 (s, 0H), 2.37 (dd, J = 15.9, 7.3 Hz, 1H), 2.26-2.07
(m, 4H), 1.78 (q, J = 9.8 Hz, 1H). 655 1H NMR (400 MHz,
Chloroform-d) d 8.86 (d, J = 22.3 Hz, 2H), 8.65 (s, 2H), 8.04 (s,
1H), 7.68-7.56 (m, 4H), 7.56-7.46 (m, 3H), 7.46-7.38 (m, 2H), 7.33
(d, J = 7.5 Hz, 2H), 6.78-6.58 (m, 1H), 5.36 (s, 2H), 4.29 (s, 2H),
4.15 (d, J = 5.0 Hz, 2H), 4.06 (s, 3H), 3.98-3.86 (m, 2H),
3.27-3.00 (m, 8H), 3.01-2.63 (m, 3H), 2.32-2.15 (m, 5H), 1.84 (td,
J = 10.2, 5.2 Hz, 2H). 658 1H NMR (400 MHz, DMSO-d6) d 8.83 (s,
2H), 8.64 (s, 2H), 8.10 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.62
(dd, J = 7.6, 1.8 Hz, 1H), 7.55 (dd, J = 10.0, 5.9 Hz, 3H), 7.47
(s, 2H), 7.38 (dd, J = 10.8, 7.1 Hz, 2H), 7.30 (d, J = 7.5 Hz, 1H),
6.68 (s, 1H), 5.40-5.26 (m, 2H), 4.21 (s, 2H), 4.12 (s, 2H), 3.97
(s, 3H), 3.89-3.81 (m, 2H), 3.14 (s, 1H), 3.07 (s, 2H), 3.01 (s,
1H), 2.97-2.71 (m, 3H), 2.27-2.03 (m, 5H), 1.77 (s, 2H). 659 1H NMR
(400 MHz, Methanol-d4) d 9.03 (s, 2H), 8.50 (s, 1H), 7.90 (s, 1H),
7.54 (s, 4H), 7.45 (t, J = 7.5 Hz, 1H), 7.41-7.32 (m, 2H),
7.29-7.18 (m, 3H), 6.52 (s, 1H), 5.70 (s, 2H), 4.29 (s, 2H), 4.18
(s, 2H), , 3.27 (d, J = 3.1 Hz, 1H), 3.17 (d, J = 5.5 Hz, 3H), 3.07
(dd, J = 12.7, 9.8 Hz, 1H), 2.95-2.87 (m, 2H), 2.76 (s, 1H), 2.57
(d, J = 6.3 Hz, 3H), 2.10 (s, 1H). 675 1H NMR (400 MHz,
Acetonitrile-d3) d 8.89 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 1.9 Hz,
1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.36-7.15 (m, 8H), 7.05 (d, J =
8.4 Hz, 2H), 6.53-6.39 (m, 1H), 5.58 (s, 2H), 4.39 (m, 1H), 4.29
(q, J = 6.6, 5.8 Hz, 3H), 4.23 (dd, J = 15.5, 1.7 Hz, 2H), 3.54 (s,
1H), 3.52-3.44 (m, 2H), 3.27 (dd, J = 12.9, 3.1 Hz, 1H), 3.21-3.05
(m, 3H), 3.00 (dd, J = 12.8, 9.8 Hz, 2H), 2.87 (d, J = 14.8 Hz,
1H), 2.72 (m, 2H), 2.63-2.44 (m, 6H), 2.02 (d, J = 8.1 Hz, 1H). 676
1H NMR (400 MHz, Acetonitrile-d3) d 8.90 (s, 1H), 8.80 (d, J = 2.0
Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.0, 1.2 Hz, 1H),
7.95 (s, 1H), 7.79 (dd, J = 7.8, 1.7 Hz, 1H), 7.47 (td, J = 7.6,
1.2 Hz, 1H), 7.37-7.12 (m, 9H), 7.09-7.02 (m, 2H), 6.46 (t, J = 5.9
Hz, 1H), 5.58 (s, 2H), 4.35-4.24 (m, 4H), 4.21 (d, J = 2.2 Hz, 2H),
3.28 (dd, J = 12.8, 3.0 Hz, 2H), 3.22-3.04 (m, 3H), 3.00 (dd, J =
12.8, 9.8 Hz, 2H), 2.94-2.81 (m, 1H), 2.72 (d, J = 7.7 Hz, 2H),
2.65-2.37 (m, 6H). 679 1H NMR (400 MHz, Acetonitrile-d3) d 8.85 (d,
J = 2.1 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.21 (t, J = 2.1 Hz,
1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.31 (t,
J = 7.5 Hz, 1H), 7.27-7.20 (m, 2H), 7.15 (dd, J = 5.4, 3.6 Hz, 1H),
6.62-6.54 (m, 1H), 6.39 (t, J = 5.9 Hz, 1H), 5.55 (s, 2H),
4.30-4.20 (m, 3H), 4.19 (s, 2H), 4.10 (s, 2H), 3.99 (s, 3H), 3.11
(ddd, J = 16.3, 12.9, 3.0 Hz, 2H), 3.02-2.76 (m, 4H), 2.69 (ddt, J
= 26.4, 13.1, 7.0 Hz, 3H), 2.57-2.42 (m, 4H), 2.41 (dt, J = 13.6,
6.0 Hz, 1H), 2.11 (ddt, J = 13.8, 9.1, 5.0 Hz, 1H). 683 1H NMR (400
MHz, Methanol-d4) d 8.96 (d, J = 2.1 Hz, 1H), 8.90-8.79 (m, 1H),
8.37 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 15.1 Hz, 2H), 7.60 (dd, J =
7.7, 1.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.45-7.39 (m, 1H), 7.36
(d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.24 (s, 2H), 6.54 (d, J = 23.0
Hz, 1H), 5.64 (s, 2H), 4.59-4.25 (m, 8H), 4.08 (s, 3H), 3.27-2.78
(m, 3H), 2.69-2.46 (m, 6H), 2.40 (dd, J = 8.2, 6.4 Hz, 2H),
2.20-2.01 (m, 2H). 684 1H NMR (400 MHz, Methanol-d4) d 8.99 (s,
1H), 8.84 (s, 1H), 8.40 (s, 1H), 7.95-7.84 (m, 2H), 7.60 (dd, J =
7.7, 1.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.44-7.33 (m, 2H), 7.28
(d, J = 19.1 Hz, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 5.63
(s, 2H), 4.65-4.26 (m, 8H), 4.15-4.04 (m, 4H), 4.00-3.80 (m, 2H),
3.03-2.67 (m, 1H), 2.54 (dt, J = 31.0, 7.2 Hz, 3H), 2.40 (dd, J =
8.1, 6.4 Hz, 2H), 2.10 (dq, J = 13.8, 6.9 Hz, 1H), 1.60 (s, 3H).
694 1H NMR (400 MHz, Methanol-d4) d 9.03 (dd, J = 5.5, 2.1 Hz, 4H),
8.50 (t, J = 2.1 Hz, 2H), 7.90 (s, 2H), 7.31-7.21 (m, 4H), 7.19
(dd, J = 5.8, 3.0 Hz, 2H), 6.50 (dd, J = 6.9, 5.0 Hz, 2H), 5.70 (s,
4H), 4.41-4.19 (m, 6H), 3.27 (d, J = 3.0 Hz, 2H), 3.18 (s, 6H),
3.08 (dd, J = 12.7, 9.8 Hz, 2H), 2.99-2.69 (m, 4H), 2.68-2.41 (m,
6H), 2.16-1.98 (m, 2H). 697 1H NMR (400 MHz, Methanol-d4) .delta.
7.98 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.60-7.25 (m, 6H),
7.24-7.16 (m, 1H), 6.67-6.57 (m, 1H), 4.42-4.30 (m, 2H), 4.30-4.15
(m, 2H), 4.10 (s, 3H), 4.09 (s, 3H), 4.09-3.76 (m, 3H), 3.30-3.20
(m, 2H), 3.08-2.52 (m, 2H), 2.52-2.31 (m, 4H), 2.27-2.08 (m, 1H),
1.99-1.84 (m, 1H). 1.59 (s, 3H). 700 1H NMR (400 MHz, Methanol-d4)
.delta. 8.99 (s, 1H), 8.83 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 8.5
Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.55-7.49 (m, 2H),
7.38 (td, J = 6.7, 2.5 Hz, 1H), 7.34-7.10 (m, 4H), 6.53 (q, J = 5.4
Hz, 1H), 5.65-5.57 (m, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 4.10 (s,
3H), 4.09-4.00 (m, 2H), 3.85 (d, J = 12.2 Hz, 1H), 3.29-3.21 (m,
2H), 2.99-2.62 (m, 2H), 2.62-2.49 (m, 1H), 2.49-2.30 (m, 3H),
2.17-2.03 (m, 1H), 1.97-1.85 (m, 1H), 1.58 (s, 3H). 703 1H NMR (400
MHz, Methanol-d4) .delta. 8.50 (s, 1H), 7.90 (s, 1H), 7.67 (dd, J =
7.6, 1.8 Hz, 1H), 7.63-7.31 (m, 4H), 7.28 (d, J = 7.4 Hz, 1H), 6.68
(d, J = 6.0 Hz, 1H), 4.83-4.06 (m, 14H), 4.00-2.10 (m, 14H). 704 1H
NMR (400 MHz, Methanol-d4) .delta. 7.90 (d, J = 7.1 Hz, 2H), 7.63
(dd, J = 7.7, 1.7 Hz, 1H), 7.57-7.31 (m, 5H), 7.27 (d, J = 7.4 Hz,
1H), 6.68 (d, J = 6.2 Hz, 1H), 4.59-4.01 (m, 14H), 4.00-2.11(m,
14H). 705 1H NMR (400 MHz, Methanol-d4) .delta. 8.51 (s, 1H), 7.90
(s, 1H), 7.67 (dd, J = 7.7, 1.8 Hz,
1H), 7.62-7.32 (m, 4H), 7.28 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 6.4
Hz, 1H), 4.75 (d, J = 28.8 Hz, 2H), 4.55-4.17 (m, 5H), 4.13 (s,
7H), 4.03-2.12 (m, 11H), 1.59 (d, J = 22.4 Hz, 3H). 706 1H NMR (400
MHz, Methanol-d4) .delta. 7.91 (d, J = 6.0 Hz, 2H), 7.63 (dd, J =
7.6, 1.8 Hz, 1H), 7.60-7.31 (m, 5H), 7.27 (d, J = 7.5 Hz, 1H), 6.68
(s, 1H), 4.60-4.32 (m, 4H), 4.23 (t, J = 10.4 Hz, 2H), 4.19-4.03
(m, 8H), 4.01-2.10 (m, 11H), 1.56 (s, 3H). 707 1H NMR (400 MHz,
Methanol-d4) .delta. 8.50 (s, 1H), 7.90 (s, 1H), 7.67 (d, J = 7.7
Hz, 1H), 7.55 (dd, J = 15.8, 7.8 Hz, 3H), 7.38 (t, J = 7.6 Hz, 1H),
7.28 (dd, J = 7.6, 1.2 Hz, 1H), 6.68 (s, 1H), 4.70 (d, J = 19.3 Hz,
2H), 4.49 (d, J = 10.5 Hz, 1H), 4.38 (s, 2H), 4.24-4.06 (m, 8H),
4.02 (d, J = 10.7 Hz, 1H), 3.97-2.15 (m, 13H), 1.36 (d, J = 32.1
Hz, 3H). 708 1H NMR (400 MHz, Methanol-d4) .delta. 7.89 (d, J = 8.9
Hz, 2H), 7.62 (dd, J = 6.0, 3.7 Hz, 1H), 7.58-7.31 (m, 5H), 7.27
(dd, J = 7.5, 1.2 Hz, 1H), 6.67 (s, 1H), 4.48 (d, J = 8.1 Hz, 2H),
4.38 (s, 2H), 4.23 (dd, J = 10.9, 4.6 Hz, 2H), 4.16-4.05 (m, 6H),
4.07-2.11 (m, 15H), 1.32 (d, J = 11.0 Hz, 3H). 709 1H NMR (400 MHz,
Methanol-d4) .delta. 8.51 (s, 1H), 7.90 (s, 1H), 7.67 (dd, J = 7.6,
1.8 Hz, 1H), 7.60-7.41 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 (d,
J = 7.4 Hz, 1H), 6.68 (s, 1H), 4.74 (d, J = 10.5 Hz, 4H), 4.36 (d,
J = 25.7 Hz, 4H), 4.13 (d, J = 1.1 Hz, 8H), 3.99-2.13 (m, 10H). 710
1H NMR (400 MHz, Methanol-d4) .delta. 7.91 (d, J = 7.0 Hz, 2H),
7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.58-7.30 (m, 5H), 7.27 (d, J = 7.4
Hz, 1H), 6.67 (s, 1H), 4.81-4.57 (m, 1H), 4.56-4.26 (m, 7H), 4.12
(d, J = 11.3 Hz, 8H), 4.01-2.14 (m, 10H). 711 1H NMR (400 MHz,
Methanol-d4) .delta. 8.55 (s, 1H), 7.90 (s, 1H), 7.68 (dd, J = 7.7,
1.8 Hz, 1H), 7.64-7.41 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 (d,
J = 7.5 Hz, 1H), 6.68 (s, 1H), 4.47 (s, 2H), 4.46-4.28 (m, 3H),
4.14 (d, J = 1.1 Hz, 6H), 4.04-2.12 (m, 18H). 712 1H NMR (400 MHz,
Methanol-d4) .delta. 7.89 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 7.7,
1.8 Hz, 1H), 7.59-7.19 (m, 6H), 6.68 (s, 1H), 4.47-4.30 (m, 3H),
4.28 (s, 2H), 4.12 (d, J = 9.6 Hz, 6H), 3.95-2.21 (m, 18H). 713 1H
NMR (400 MHz, Methanol-d4) .delta. 7.99-7.83 (m, 2H), 7.72-7.21 (m,
7H), 6.67 (s, 1H), 4.56-4.27 (m, 11H), 4.13 (d, J = 2.9 Hz, 6H),
3.77-3.62 (m, 1H), 3.13-2.15 (m, 9H). 714 1H NMR (400 MHz,
Methanol-d4) .delta. 7.90 (s, 2H), 7.68-7.21 (m, 7H), 6.68 (s, 1H),
4.58-4.25 (m, 8H), 4.13 (d, J = 7.3 Hz, 6H), 3.56 (d, J = 46.3 Hz,
4H), 3.14-2.15 (m, 11H). 715 1H NMR (400 MHz, Methanol-d4) .delta.
7.90 (s, 1H), 7.63 (d, J = 2.1 Hz, 4H), 7.59-7.17 (m, 6H), 6.68 (s,
1H), 4.55-4.25 (m, 4H), 4.13-3.99 (m, 4H), 3.94-3.82 (m, 1H),
3.31-3.20 (m, 2H), 3.22-1.52 (m, 16H). 721 1H NMR (400 MHz,
Methanol-d4) .delta. 7.86 (s, 1H), 7.63 (d, J = 2.5 Hz, 4H),
7.57-7.31 (m, 5H), 7.26 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H),
4.48-4.27 (m, 7H), 4.13 (s, 3H), 4.05 (d, J = 6.3 Hz, 1H), 3.72 (p,
J = 8.5 Hz, 1H), 3.31-3.20 (m, 2H), 3.16-1.84 (m, 9H). 722 1H NMR
(400 MHz, Methanol-d4) .delta. 7.90 (s, 1H), 7.63 (d, J = 2.1 Hz,
4H), 7.50 (t, J = 9.4 Hz, 2H), 7.38 (dd, J = 23.8, 7.6 Hz, 3H),
7.27 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 4.52-4.29 (m, 4H), 4.14 (s,
3H), 4.05 (d, J = 7.4 Hz, 1H), 3.95-3.45 (m, 4H), 3.31-3.20 (m,
2H), 3.17-2.62 (m, 4H), 2.55-2.34 (m, 4H), 2.24 (s, 2H), 2.02-1.85
(m, 1H). 723 1H NMR (400 MHz, Methanol-d4) .delta. 7.90 (s, 1H),
7.63 (d, J = 2.4 Hz, 4H), 7.51 (t, J = 9.4 Hz, 2H), 7.39 (dd, J =
23.7, 7.6 Hz, 3H), 7.27 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H),
4.49-4.27 (m, 4H), 4.14 (s, 3H), 4.05 (d, J = 6.8 Hz, 1H),
4.00-3.41 (m, 4H), 3.31-3.20 (m, 2H), 3.12-2.53 (m, 4H), 2.53-2.32
(m, 4H), 2.24 (s, 2H), 2.05-1.82 (m, 1H). 725 1H NMR (400 MHz,
Methanol-d4) .delta. 7.88 (s, 1H), 7.63 (s, 4H), 7.50 (t, J = 8.5
Hz, 2H), 7.46-7.32 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H),
4.49-4.30 (m, 4H), 4.18 (t, J = 8.1 Hz, 1H), 4.13 (s, 3H), 4.04 (d,
J = 6.8 Hz, 1H), 3.73-3.64 (m, 1H), 3.31-3.20 (m, 2H), 3.14-1.83(m,
13H). 726 1H NMR (400 MHz, Methanol-d4) .delta. 7.98-7.79 (m, 2H),
7.71-7.19 (m, 7H), 6.68 (s, 1H), 4.54-4.23 (m, 8H), 4.14 (d, J =
2.6 Hz, 7H), 3.33-3.21 (m, 2H), 3.14-2.63 (m, 3H), 2.45 (tt, J =
17.1, 9.7 Hz, 7H), 2.23 (s, 1H), 2.04-1.80 (m, 1H). 727 1H NMR (400
MHz, Methanol-d4) .delta. 8.00-7.83 (m, 2H), 7.71-7.58 (m, 1H),
7.60-7.19 (m, 6H), 6.68 (s, 1H), 4.37 (d, J = 2.6 Hz, 2H), 4.24 (s,
2H), 4.20-4.02 (m, 8H), 3.86 (d, J = 12.1 Hz, 1H), 3.33-3.20 (m,
2H), 3.15-2.66(m, 3H), 2.58-2.34 (m, 3H), 2.23 (s, 1H), 2.13-1.90
(m, 1H), 1.61 (s, 3H). 728 1H NMR (400 MHz, Methanol-d4) .delta.
7.91 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.69-7.59 (m, 1H),
7.60-7.19 (m, 6H), 6.68 (s, 1H), 4.43-4.27 (m, 3H), 4.22 (s, 2H),
4.13 (s, 7H), 3.53-3.49 (m, 1H), 3.33-3.19 (m, 2H), 3.16 (s, 1H),
3.14-2.67 (m, 3H), 2.58 (d, J = 6.3 Hz, 2H), 2.55-2.34 (m, 3H),
2.23 (s, 1H), 2.04-1.84 (m, 1H). 730 1H NMR (400 MHz, Methanol-d4)
.delta. 7.87 (s, 1H), 7.63 (d, J = 2.2 Hz, 4H), 7.57-7.21 (m, 6H),
6.68 (s, 1H), 4.45-4.31 (m, 2H), 4.25 (d, J = 2.7 Hz, 2H), 4.15 (s,
3H), 4.05 (t, J = 6.4 Hz, 2H), 3.30-3.20 (m, 4H), 3.11-2.64 (m,
3H), 2.55-2.34 (m, 6H), 2.23 (s, 1H), 1.95 (d, J = 13.0 Hz, 2H).
731 1H NMR (400 MHz, Methanol-d4) .delta. 7.88 (s, 1H), 7.70-7.16
(m, 10H), 6.68 (s, 1H), 4.36 (d, J = 2.2 Hz, 2H), 4.25 (s, 2H),
4.10 (d, J = 22.7 Hz, 5H), 3.88 (d, J = 12.1 Hz, 1H), 3.28 (d, J =
4.9 Hz, 1H), 3.14-2.62 (m, 3H), 2.56-2.32 (m, 3H), 2.23 (s, 1H),
2.03-1.88 (m, 1H), 1.63 (s, 3H). 732 1H NMR (400 MHz, Methanol-d4)
.delta. 7.85 (s, 1H), 7.63 (d, J = 2.0 Hz, 4H), 7.57-7.17 (m, 6H),
6.67 (s, 1H), 4.48-4.27 (m, 3H), 4.22 (s, 2H), 4.13 (s, 3H), 4.04
(d, J = 6.7 Hz, 1H), 3.33-3.22 (m, 4H), 3.11-2.64 (m, 3H), 2.59 (d,
J = 6.3 Hz, 2H), 2.56-2.30 (m, 3H), 2.23 (s, 1H), 2.02-1.81 (m,
1H). 734 1H NMR (400 MHz, Methanol-d4) .delta. 7.92 (d, J = 7.6 Hz,
1H), 7.87 (s, 1H), 7.63 (dd, J = 7.5, 1.7 Hz, 1H), 7.57-7.31 (m,
5H), 7.28 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 4.37 (d, J = 2.6 Hz,
2H), 4.25 (d, J = 2.5 Hz, 2H), 4.20-3.98 (m, 8H), 3.33-3.21 (m,
4H), 3.13-2.63 (m, 3H), 2.58-2.33 (m, 6H), 2.24 (s, 1H), 2.07-1.77
(m, 2H). 735 1H NMR (400 MHz, Methanol-d4) .delta. 7.98 (s, 1H),
7.90 (d, J = 7.4 Hz, 1H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.59-7.17
(m, 6H), 6.65 (s, 1H), 4.62-4.23 (m, 12H), 4.13 (d, J = 5.5 Hz,
6H), 3.10-2.65 (m, 3H), 2.68-2.32 (m, 8H), 2.22 (s, 1H). 736 1H NMR
(400 MHz, Methanol-d4) .delta. 8.01 (s, 1H), 7.92 (d, J = 7.6 Hz,
1H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.58-7.30 (m, 5H), 7.27 (d, J
= 7.5 Hz, 1H), 6.65 (s, 1H), 4.37 (d, J = 2.6 Hz, 2H), 4.25 (d, J =
2.4 Hz, 2H), 4.20-3.97 (m, 8H), 3.33-3.20 (m, 4H), 3.15-2.61 (m,
3H), 2.59-2.30 (m, 6H), 2.22 (s, 1H), 2.07-1.83 (m, 2H). 737 1H NMR
(400 MHz, Methanol-d4) .delta. 9.02 (d, J = 2.0 Hz, 1H), 8.87 (s,
1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.79 (d,
J = 8.2 Hz, 2H), 7.60-7.39 (m, 3H), 7.30 (d, J = 26.0 Hz, 3H), 6.57
(s, 1H), 5.66 (s, 2H), 4.35 (s, 2H), 4.17 (s, 4H), 4.11 (d, J =
12.2 Hz, 1H), 3.90 (d, J = 12.2 Hz, 1H), 2.85 (dd, J = 47.3, 25.8
Hz, 2H), 2.60 (d, J = 10.9 Hz, 1H), 2.13 (dq, J = 13.6, 6.7 Hz,
1H), 1.63 (s, 3H). 738 1H NMR (400 MHz, Methanol-d4) .delta. 9.02
(s, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.11-7.91 (m, 3H), 7.88-7.67
(m, 3H), 7.65-7.12 (m, 5H), 6.58 (s, 1H), 5.67 (s, 2H), 4.35 (s,
2H), 4.17 (s, 4H), 4.11 (d, J = 11.9 Hz, 1H), 3.89 (d, J = 12.2 Hz,
1H), 3.05-2.71 (m, 2H), 2.60 (s, 1H), 2.13 (d, J = 10.8 Hz, 1H),
1.63 (s, 3H). 739 1H NMR (400 MHz, Methanol-d4) .delta. 8.01 (s,
1H), 7.92 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H),
7.58-7.30 (m, 5H), 7.27 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 4.37 (d,
J = 2.6 Hz, 2H), 4.25 (d, J = 2.4 Hz, 2H), 4.20-3.97 (m, 8H),
3.33-3.20 (m, 4H), 3.15-2.61 (m, 3H), 2.59-2.30 (m, 6H), 2.22 (s,
1H), 2.07-1.83 (m, 2H). 741 1H NMR (400 MHz, Methanol-d4) .delta.
9.02 (d, J = 2.0 Hz, 1H), 8.89 (d, J = 12.1 Hz, 1H), 8.43 (s, 1H),
8.10 (s, 1H), 7.74-7.14 (m, 10H), 6.56 (s, 1H), 5.66 (s, 2H),
4.44-4.28 (m, 4H), 4.20-4.00 (m, 2H), 3.90 (d, J = 12.2 Hz, 1H),
3.27 (t, J = 5.8 Hz, 2H), 3.11-2.52 (m, 3H), 2.53-2.32 (m, 3H),
2.13 (dt, J = 13.1, 6.7 Hz, 1H), 1.94 (q, J = 6.9, 6.5 Hz, 1H),
1.63 (s, 3H). 743 1H NMR (400 MHz, Methanol-d4) .delta. 9.01 (s,
1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.11 (s, 1H), 7.92 (d, J = 7.5 Hz,
1H), 7.64 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.49-7.21
(m, 5H), 6.67-6.49 (m, 1H), 5.67 (s, 2H), 4.45-4.24 (m, 4H),
4.20-3.99 (m, 5H), 3.96-3.84 (m, 4H), 3.31-3.26 (m, 2H), 3.10-2.70
(m, 2H), 2.70-2.53 (m, 1H), 2.53-2.27 (m, 3H), 2.22-2.05 (m, 1H),
2.05-1.79 (m, 1H), 1.64 (s, 3H). 744 1H NMR (400 MHz, Methanol-d4)
.delta. 9.02 (s, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.30 (d, J = 8.0
Hz, 1H), 8.10 (s, 1H), 7.75-7.69 (m, 1H), 7.65-7.52 (m, 2H),
7.52-7.45 (m, 1H), 7.39-7.19 (m, 3H), 6.60-6.48 (m, 1H), 5.66 (s,
2H), 4.34 (s, 2H), 4.21 (s, 3H), 4.18-4.04 (m, 5H), 3.99-3.84 (m,
1H), 3.07-2.68 (m, 2H), 2.68-2.50 (m, 1H), 2.25-2.04 (m, 1H), 1.63
(s, 3H). 747 1H NMR (400 MHz, Methanol-d4) .delta. 9.02 (s, 1H),
8.87 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H),
7.63 (dd, J = 7.8, 1.9 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.48-7.17
(m, 5H), 6.56 (s, 1H), 5.66 (s, 2H), 4.45-4.29 (m, 4H), 4.18-4.01
(m, 5H), 3.95-3.84 (m, 1H), 3.30-3.25 (m, 2H), 3.06-2.67 (m, 2H),
2.67-2.53 (m, 1H), 2.53-2.33 (m, 3H), 2.20-2.07 (m, 1H), 2.01-1.84
(m, 1H), 1.64 (s, 3H). 748 1H NMR (400 MHz, Methanol-d4) .delta.
8.99 (d, J = 2.1 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H),
8.27 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.50 (dd, J = 7.6, 1.5 Hz,
1H), 7.46-7.35 (m, 2H), 7.34-7.13 (m, 4H), 6.59-6.48 (m, 1H),
5.69-5.57 (m, 2H), 4.32 (s, 2H), 4.16 (s, 3H), 4.12-4.04 (m, 5H),
3.87 (d, J = 12.2 Hz, 1H), 3.01-2.41 (m, 3H), 2.17 (d, J = 9.3 Hz,
3H), 2.14-2.01 (m, 1H), 1.60 (s, 3H). 749 1H NMR (400 MHz,
Methanol-d4) .delta. 8.99 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 2.0 Hz,
1H), 8.39 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.50
(dd, J = 7.7, 1.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.33-7.12 (m, 4H),
6.62-6.50 (m, 1H), 5.64 (s, 2H), 4.32 (s, 2H), 4.16 (s, 3H),
4.12-4.03 (m, 5H), 3.87 (d, J = 12.2 Hz, 1H), 2.98-2.44 (m, 3H),
2.27-2.03 (m, 4H), 1.61 (s, 3H). 753 1H NMR (400 MHz, Methanol-d4)
.delta. 8.21-8.18 (m, 2H), 8.12-8.05 (m, 2H), 7.37-7.03 (m, 10H),
6.46 (t, J = 6.4 Hz, 1H), 5.67-5.57 (m, 2H), 4.47-4.14 (m, 6H),
3.54 (t, J = 5.1 Hz, 2H), 3.40-3.32 (m, 2H), 3.19-3.03 (m, 2H),
2.97-2.60 (m, 2H), 2.60-2.41 (m, 5H), 2.10-1.99 (m, 1H), 1.96 (d, J
= 4.4 Hz, 3H). 757 1H NMR (400 MHz, Methanol-d4) .delta. 7.95-7.84
(m, 2H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H),
7.44-7.31 (m, 3H), 7.27 (d, J = 7.3 Hz, 1H), 6.66 (s, 1H),
4.41-4.29 (m, 7H), 4.13 (d, J = 0.9 Hz, 7H), 3.72 (q, J = 8.6 Hz,
1H), 3.37 (s, 1H), 3.28 (dd, J = 6.2, 3.7 Hz, 2H), 3.01 (s, 1H),
2.71 (d, J = 26.4 Hz, 2H), 2.51-2.35 (m, 3H), 2.22 (s, 1H),
2.00-1.89 (m, 1H). 758 1H NMR (400 MHz, Methanol-d4) .delta.
7.95-7.87 (m, 2H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (s, 2H),
7.48-7.33 (m, 3H), 7.27 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H),
4.43-4.32 (m, 2H), 4.31 (ddd, J = 9.0, 7.3, 2.0 Hz, 5H), 4.13 (s,
4H), 4.07 (q, J = 6.6 Hz, 1H), 3.71 (dd, J = 8.6, 2.6 Hz, 1H), 3.37
(s, 1H), 3.31-3.25 (m, 1H), 3.12 (s, 3H),
3.04-2.96 (m, 2H), 2.72 (d, J = 32.0 Hz, 3H), 2.51-2.35 (m, 2H),
2.27-2.17 (m, 3H), 2.00-1.88 (m, 2H). 759 1H NMR (400 MHz,
Methanol-d4) .delta. 7.95-7.87 (m, 2H), 7.63 (dd, J = 7.7, 1.8 Hz,
1H), 7.53 (d, J = 7.7 Hz, 2H), 7.48-7.35 (m, 3H), 7.27 (d, J = 7.4
Hz, 1H), 6.69 (s, 1H), 4.43-4.29 (m, 3H), 4.17-3.96 (m, 7H),
3.77-3.69 (m, 1H), 3.69-3.61 (m, 1H), 3.53 (d, J = 15.2 Hz, 1H),
3.28 (dd, J = 6.2, 3.8 Hz, 2H), 3.12 (s, 2H), 2.99 (d, J = 13.8 Hz,
1H), 2.87-2.70 (m, 2H), 2.51-2.35 (m, 3H), 2.23 (s, 2H), 2.12-2.03
(m, 1H), 1.99-1.86 (m, 2H), 1.85-1.72 (m, 1H), 1.66-1.58 (m, 1H).
761 1H NMR (400 MHz, Methanol-d4) .delta. 7.95-7.82 (m, 2H), 7.63
(dd, J = 7.6, 1.8 Hz, 1H), 7.52 (s, 2H), 7.39 (d, J = 7.5 Hz, 2H),
7.27 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 4.37 (d, J = 2.8 Hz, 2H),
4.35-4.22 (m, 2H), 4.18-4.04 (m, 6H), 3.62 (d, J = 12.1 Hz, 1H),
3.52 (d, J = 7.0 Hz, 1H), 3.37 (s, 1H), 3.29 (dd, J = 6.2, 3.7 Hz,
2H), 3.01 (t, J = 12.2 Hz, 2H), 2.84 (d, J = 12.4 Hz, 1H), 2.76 (s,
2H), 2.72-2.63 (m, 1H), 2.51-2.35 (m, 3H), 2.23 (d, J = 13.2 Hz,
2H), 2.03-1.89 (m, 2H), 1.80 (dd, J = 13.2, 2.7 Hz, 1H), 1.64-1.52
(m, 1H), 1.29 (s, 3H). 762 1H NMR (400 MHz, Methanol-d4) .delta.
7.95-7.87 (m, 2H), 7.66-7.59 (m, 1H), 7.53 (d, J = 7.6 Hz, 2H),
7.43-7.32 (m, 3H), 7.27 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H),
4.40-4.26 (m, 4H), 4.16-4.02 (m, 7H), 3.37 (s, 3H), 2.82-2.70 (m,
3H), 2.72-2.63 (m, 1H), 2.49-2.36 (m, 4H), 2.26-2.18 (m, 3H), 1.95
(ddd, J = 19.9, 16.9, 8.4 Hz, 5H). 763 1H NMR (400 MHz,
Methanol-d4) .delta. 7.91 (d, J = 7.8 Hz, 2H), 7.63 (dd, J = 7.7,
1.8 Hz, 1H), 7.52 (s, 3H), 7.43-7.33 (m, 2H), 7.27 (d, J = 7.6 Hz,
1H), 6.68 (s, 1H), 4.43-4.34 (m, 4H), 4.14 (d, J = 3.4 Hz, 6H),
4.07 (d, J = 8.5 Hz, 2H), 3.66 (s, 2H), 3.37 (s, 6H), 2.72 (d, J =
32.0 Hz, 1H), 2.49-2.36 (m, 2H), 2.23 (s, 2H), 1.94 (d, J = 7.7 Hz,
1H), 1.49 (d, J = 16.3 Hz, 4H). 764 1H NMR (400 MHz, Methanol-d4)
.delta. 7.96-7.85 (m, 2H), 7.63 (dd, J = 7.6, 1.8 Hz, 1H), 7.53 (d,
J = 7.1 Hz, 2H), 7.43-7.36 (m, 3H), 7.28 (d, J = 7.3 Hz, 1H), 6.68
(s, 1H), 4.43-4.31 (m, 3H), 4.15 (d, J = 16.4 Hz, 6H), 4.14-4.04
(m, 1H), 3.69 (s, 1H), 3.37 (s, 1H), 3.31-3.23 (m, 4H), 3.02 (d, J
= 5.3 Hz, 2H), 2.79-2.65 (m, 3H), 2.51-2.35 (m, 3H), 2.24 (s, 1H),
2.07-1.98 (m, 2H), 1.98-1.89 (m, 1H), 1.64-1.56 (m, 2H), 1.51-1.43
(m, 2H). 765 1H NMR (400 MHz, Methanol-d4) .delta. 7.91 (t, J = 6.9
Hz, 2H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (s, 2H), 7.38 (dd, J
= 13.8, 7.3 Hz, 3H), 7.27 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H),
4.43-4.29 (m, 4H), 4.13 (d, J = 3.0 Hz, 7H), 3.91 (s, 1H), 3.69 (s,
1H), 3.61 (d, J = 11.3 Hz, 1H), 3.29 (dd, J = 6.2, 3.7 Hz, 2H),
3.01 (d, J = 12.5 Hz, 2H), 2.81 (s, 6H), 2.61-2.51 (m, 1H),
2.51-2.35 (m, 3H), 2.23 (s, 1H), 1.32 (d, J = 7.3 Hz, 3H). 766 1H
NMR (400 MHz, Methanol-d4) .delta. 7.97-7.88 (m, 2H), 7.63 (dd, J =
7.7, 1.8 Hz, 1H), 7.52 (s, 2H), 7.44-7.33 (m, 3H), 7.27 (d, J = 7.6
Hz, 1H), 6.68 (s, 1H), 4.49-4.31 (m, 4H), 4.13 (s, 6H), 4.08 (t, J
= 6.6 Hz, 1H), 3.63 (d, J = 12.4 Hz, 1H), 3.38 (d, J = 7.8 Hz, 2H),
3.31-3.21 (m, 4H), 2.81-2.65 (m, 3H), 2.51-2.33 (m, 3H), 2.29-2.18
(m, 1H), 2.15-1.90 (m, 6H), 1.38-1.27 (m, 1H). 769 1H NMR (400 MHz,
Methanol-d4) .delta. 7.92 (d, J = 8.3 Hz, 2H), 7.67-7.60 (m, 1H),
7.52 (s, 2H), 7.49-7.33 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 6.69 (s,
1H), 4.37 (d, J = 2.7 Hz, 3H), 4.14 (d, J = 3.4 Hz, 7H), 3.95-3.83
(m, 1H), 3.81-3.74 (m, 1H), 3.63 (d, J = 8.8 Hz, 2H), 3.32-3.25 (m,
1H), 2.99 (dd, J = 13.1, 6.7 Hz, 2H), 2.81 (s, 2H), 2.79-2.65 (m,
2H), 2.61-2.52 (m, 1H), 2.49-2.35 (m, 3H), 2.23 (d, J = 12.3 Hz,
2H), 1.98-1.90 (m, 1H). 775 1H NMR (400 MHz, Methanol-d4) .delta.
8.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.95 (s, 1H), 7.68 (dd, J = 7.6,
1.8 Hz, 1H), 7.60-7.38 (m, 4H), 7.34 (t, J = 7.6 Hz, 1H), 7.29-7.21
(m, 1H), 6.62 (s, 1H), 4.33 (d, J = 18.8 Hz, 7H), 4.18 (s, 3H),
4.15 (s, 3H), 4.10 (d, J = 3.0 Hz, 7H), 3.07-2.61 (m, 3H), 2.20 (d,
J = 11.8 Hz, 1H), 1.85 (s, 3H). 779 1H NMR (400 MHz, Methanol-d4)
.delta. 8.29 (dd, J = 7.9, 1.3 Hz, 1H), 7.97 (s, 1H), 7.68 (dd, J =
7.6, 1.8 Hz, 1H), 7.63-7.29 (m, 6H), 7.25 (dd, J = 7.6, 1.2 Hz,
1H), 6.62 (s, 1H), 4.21 (d, J = 2.1 Hz, 2H), 4.18 (s, 3H), 4.10 (d,
J = 1.9 Hz, 7H), 4.04 (t, J = 6.1 Hz, 1H), 3.27-3.11 (m, 2H),
3.07-2.61 (m, 3H), 2.47-2.29 (m, 2H), 2.25-2.12 (m, 1H), 1.98-1.84
(m, 1H). 780 1H NMR (400 MHz, Methanol-d4) .delta. 7.98 (s, 1H),
7.85 (d, J = 8.2 Hz, 1H), 7.58-7.18 (m, 8H), 6.62 (s, 1H),
4.30-4.17 (m, 2H), 4.14-3.99 (m, 12H), 3.86 (d, J = 12.1 Hz, 1H),
3.10-2.58 (m, 3H), 2.19 (s, 1H), 1.61 (s, 3H). 781 1H NMR (400 MHz,
Methanol-d4) .delta. 8.32-8.23 (m, 1H), 7.98 (s, 1H), 7.68 (dd, J =
7.6, 1.8 Hz, 1H), 7.62-7.37 (m, 4H), 7.34 (t, J = 7.5 Hz, 1H), 7.24
(dd, J = 7.6, 1.1 Hz, 1H), 6.70-6.55 (m, 1H), 4.60-4.47 (m, 1H),
4.23 (d, J = 11.6 Hz, 3H), 4.18 (s, 4H), 4.09 (s, 4H), 4.05 (d, J =
12.1 Hz, 1H), 3.85 (dd, J = 12.1, 2.5 Hz, 1H), 3.68 (dd, J = 11.5,
7.9 Hz, 1H), 3.12-2.60 (m, 3H), 2.25-2.11 (m, 1H), 1.60 (d, J = 1.7
Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H). 782 1H NMR (400 MHz,
Methanol-d4) .delta. 8.27 (dd, J = 8.0, 1.1 Hz, 1H), 7.98 (s, 1H),
7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.62-7.38 (m, 4H), 7.34 (t, J = 7.5
Hz, 1H), 7.29-7.16 (m, 1H), 6.63 (s, 1H), 4.54 (ddd, J = 11.3, 7.8,
6.2 Hz, 1H), 4.28-4.21 (m, 3H), 4.18 (s, 3H), 4.06 (d, J = 21.7 Hz,
4H), 3.92-3.80 (m, 1H), 3.68 (dd, J = 11.5, 8.0 Hz, 1H), 3.17-2.60
(m, 3H), 2.19 (s, 1H), 1.60 (d, J = 1.2 Hz, 3H), 1.48 (d, J = 6.4
Hz, 3H). 785 1H NMR (400 MHz, Methanol-d4) .delta. 8.28 (d, J = 8.0
Hz, 1H), 8.00 (s, 1H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.62-7.22
(m, 5H), 6.63 (s, 1H), 4.48-4.25 (m, 1H), 4.18 (s, 3H), 4.10 (s,
5H), 4.06 (s, 3H), 3.89 (s, 1H), 3.34 (s, 5H), 3.18-2.61 (m, 3H),
2.42-1.54 (m, 6H). 786 1H NMR (400 MHz, Methanol-d4) .delta. 8.28
(d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H),
7.61-7.39 (m, 5H), 7.34 (t, J = 7.6 Hz, 1H), 7.28-7.20 (m, 1H),
6.62 (s, 1H), 4.17 (d, J = 6.5 Hz, 6H), 4.10 (d, J = 3.5 Hz, 8H),
3.16-2.60 (m, 3H), 2.19 (s, 1H), 1.66 (s, 6H). 787 1H NMR (400 MHz,
Methanol-d4) .delta. 8.29 (dd, J = 8.0, 1.2 Hz, 1H), 7.96 (s, 1H),
7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.60-7.39 (m, 4H), 7.34 (t, J = 7.6
Hz, 1H), 7.25 (dd, J = 7.6, 1.1 Hz, 1H), 6.62 (d, J = 6.3 Hz, 1H),
4.31 (dtd, J = 9.6, 6.3, 3.0 Hz, 1H), 4.18 (d, J = 4.7 Hz, 5H),
4.10 (d, J = 3.4 Hz, 7H), 3.23 (dd, J = 12.7, 3.0 Hz, 1H),
3.09-2.64 (m, 3H), 2.56 (d, J = 6.3 Hz, 2H), 2.19 (d, J = 10.0 Hz,
1H). 788 1H NMR (400 MHz, Methanol-d4) .delta. 8.28 (dd, J = 8.0,
1.0 Hz, 1H), 7.98 (s, 1H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H),
7.61-7.38 (m, 4H), 7.34 (t, J = 7.6 Hz, 1H), 7.29-7.20 (m, 1H),
6.62 (s, 1H), 4.22 (d, J = 6.2 Hz, 1H), 4.18 (s, 3H), 4.10 (d, J =
5.6 Hz, 7H), 4.06 (d, J = 12.1 Hz, 1H), 3.85 (d, J = 12.1 Hz, 1H),
3.11-2.60 (m, 3H), 2.19 (s, 1H), 1.60 (s, 3H). 789 1H NMR (400 MHz,
Methanol-d4) .delta. 8.28 (dt, J = 7.9, 1.0 Hz, 1H), 7.98 (s, 1H),
7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.61-7.39 (m, 4H), 7.34 (t, J = 7.6
Hz, 1H), 7.28-7.19 (m, 1H), 6.62 (s, 1H), 4.22 (d, J = 2.3 Hz, 2H),
4.18 (s, 4H), 4.10 (d, J = 5.6 Hz, 9H), 4.04 (s, 1H), 3.86 (d, J =
12.1 Hz, 1H), 3.14-2.62 (m, 1H), 2.19 (s, 1H), 1.60 (s, 3H). 790 1H
NMR (400 MHz, Methanol-d4) .delta. 7.97 (s, 1H), 7.66 (t, J = 7.9
Hz, 1H), 7.48 (dd, J = 7.5, 4.2 Hz, 2H), 7.44-7.28 (m, 4H), 7.23
(dd, J = 7.6, 1.1 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 4.42 (d, J =
1.8 Hz, 2H), 4.21 (d, J = 2.1 Hz, 2H), 4.10 (s, 3H), 4.04 (p, J =
5.9, 5.4 Hz, 2H), 3.31-3.25 (m, 5H), 3.07-2.61 (m, 2H), 2.51-2.28
(m, 6H), 2.17-1.82 (m, 4H). 792 1H NMR (400 MHz, Methanol-d4)
.delta. 7.97 (s, 1H), 7.56-7.29 (m, 5H), 7.26-7.17 (m, 2H), 7.12
(dd, J = 7.7, 1.4 Hz, 1H), 6.61 (d, J = 7.0 Hz, 1H), 4.41-4.28 (m,
2H), 4.21 (d, J = 2.1 Hz, 2H), 4.10 (s, 3H), 4.04 (dd, J = 7.4, 5.7
Hz, 1H), 3.97 (s, 3H), 3.27-3.12 (m, 4H), 3.07-2.56 (m, 3H),
2.48-2.29 (m, 6H), 2.17-1.90 (m, 5H). 797 1H NMR (400 MHz,
Methanol-d4) .delta. 8.18 (s, 2H), 8.07 (d, J = 16.7 Hz, 1H),
7.95-7.83 (m, 2H), 7.63-7.56 (m, 2H), 7.46 (dt, J = 19.9, 9.7 Hz,
2H), 7.35 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 6.7 Hz, 2H), 7.00 (s,
1H), 6.48 (s, 1H), 5.61 (s, 2H), 4.37-4.28 (m, 4H), 4.10 (d, J =
4.7 Hz, 3H), 3.29-3.22 (m, 1H), 3.13-3.02 (m, 1H), 2.88 (s, 1H),
2.79 (s, 1H), 2.58 (dd, J = 6.4, 4.4 Hz, 4H), 2.46-2.33 (m, 2H),
2.05 (d, J = 19.7 Hz, 1H), 1.91 (s, 2H), 1.32-1.26 (m, 1H). 798 1H
NMR (400 MHz, Methanol-d4) .delta. 7.87 (s, 1H), 7.60 (dd, J = 7.7,
1.8 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.47-7.33 (m, 2H), 7.26 (d,
J = 7.8 Hz, 2H), 6.67 (d, J = 6.2 Hz, 1H), 4.42 (s, 2H), 4.24 (d, J
= 2.3 Hz, 2H), 4.12 (d, J = 9.0 Hz, 6H), 4.06 (dt, J = 12.8, 6.5
Hz, 2H), 3.29-3.19 (m, 2H), 3.00 (dd, J = 31.1, 13.1 Hz, 1H),
2.92-2.70 (m, 2H), 2.68 (s, 1H), 2.54 (s, 3H), 2.52-2.34 (m, 6H),
2.25 (d, J = 15.3 Hz, 1H), 2.05-1.86 (m, 2H). 799 1H NMR (400 MHz,
DMSO-d6) .delta. 8.89 (d, J = 50.9 Hz, 2H), 8.66 (d, J = 29.3 Hz,
2H), 8.00 (s, 1H), 7.58 (d, J = 2.4 Hz, 3H), 7.49 (d, J = 3.7 Hz,
2H), 7.40 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 6.64 (d, J
= 6.8 Hz, 1H), 4.34 (s, 2H), 4.12 (d, J = 5.3 Hz, 2H), 4.03 (d, J =
4.0 Hz, 5H), 3.88 (dt, J = 13.0, 8.1 Hz, 3H), 3.28-2.96 (m, 5H),
2.96-2.65 (m, 4H), 2.25-2.13 (m, 5H), 1.88-1.74 (m, 2H). 800 1H NMR
(400 MHz, DMSO-d6) .delta. 9.05 (s, 1H), 8.99 (s, 2H), 8.84 (s,
1H), 8.68 (s, 2H), 8.49 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.84 (d,
J = 8.1 Hz, 1H), 7.63-7.51 (m, 3H), 7.45 (t, J = 9.9 Hz, 2H),
7.38-7.23 (m, 3H), 6.54 (d, J = 8.1 Hz, 1H), 6.48 (s, 1H), 5.60 (s,
2H), 4.24 (s, 4H), 4.01 (s, 3H), 3.90 (t, J = 6.6 Hz, 2H), 3.10 (s,
5H), 2.87 (s, 2H), 2.72 (s, 2H), 2.19 (tq, J = 12.3, 6.5 Hz, 6H).
801 1H NMR (400 MHz, DMSO-d6) .delta. 9.06 (d, J = 2.1 Hz, 1H),
9.00 (d, J = 1.9 Hz, 1H), 8.81 (s, 2H), 8.67 (s, 1H), 8.50 (s, 1H),
8.30 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.69-7.53 (m, 4H), 7.45
(d, J = 18.0 Hz, 2H), 7.33 (s, 2H), 7.26 (s, 1H), 6.55 (s, 2H),
5.62 (s, 2H), 4.85 (s, 3H), 4.22 (s, 3H), 3.88 (s, 3H), 2.25-2.10
(m, 5H), 1.98 (s, 2H), 1.79 (d, J = 22.4 Hz, 3H). 802 1H NMR (400
MHz, DMSO-d6) .delta. 9.21 (s, 1H), 9.03 (d, J = 21.4 Hz, 3H), 8.50
(s, 2H), 8.08 (s, 2H), 7.95 (d, J = 7.5 Hz, 2H), 7.88 (s, 2H), 7.60
(d, J = 10.1 Hz, 3H), 7.34 (d, J = 16.5 Hz, 3H), 6.54 (s, 2H), 5.63
(s, 2H), 4.37 (s, 2H), 4.23 (s, 2H), 3.87 (s, 3H), 3.58 (s, 4H),
2.19 (d, J = 7.9 Hz, 4H). 803 1H NMR (400 MHz, DMSO-d6) .delta.
9.16 (s, 1H), 8.99 (d, J = 23.2 Hz, 2H), 7.72 (s, 4H), 7.30 (d, J =
16.6 Hz, 2H), 6.50 (s, 3H), 5.51 (d, J = 52.9 Hz, 3H), 4.30 (s,
1H), 4.09 (d, J = 56.2 Hz, 4H), 2.92 (d, J = 40.3 Hz, 3H), 2.68 (d,
J = 6.3 Hz, 3H), 2.24-1.87 (m, 5H).
[2678] Biological Activity
[2679] PD-1/PD-L1 & CTLA/CD80 Biochemical Protein-Protein
Interaction Assay:
[2680] Compounds were tested in biochemical protein-protein
interaction assays to determine if they can specifically block the
interaction between the extracellular domains of PD-1/PD-L1 or
CTLA/CD80. Binding of the protein pairs is measured using a bead
based Amplified Luminescent Proximity Homogeneous Assay (ALPHA)
platform. Binding of each protein pair results in proximity of the
donor and acceptor beads which leads to an increase in ALPHA
signal. Disruption of the protein-protein interaction with a test
compound results in a decrease in ALPHA signal. Assays are
performed in 25 mM Hepes (pH 7.4), 150 mM NaCl, 3.4 mM EDTA, 0.005%
Tween 20, and 0.01% BSA. Final protein concentration in the assays
were 0.3 nM (His tagged PD-L1), 2.5 nM (biotinylated Fc-PD-1), 1 nM
(His tagged CTLA4) and 1 nM (biotinylated CD80). After an assay
reaction time of 60 minutes at 25.degree. C., binding was measured
with addition of 20 .mu.g/mL ALPHA assay acceptor beads (anti-His
coated) and 20 g/mL ALPHA assay donor beads (streptavidin coated).
IC.sub.50 values were calculated from the fit of the dose-response
curves to a four-parameter equation. Representative data are shown
below in Table 1.
TABLE-US-00008 TABLE 1 IC.sub.50 PD-L1-PD-1 Alpha IC.sub.50-mono
PD-L1-fcP-D1 Example (nM) 3 0.2 4 0.1 5 0.1 6 0.1 7 0.1 9 0.5 11
0.4 12 11.1 13 2.2 14 2.1 15 1250 16 0.1 17 0.3 18 16.2 19 1.1 20
12.6 21 17 22 34.9 23 40.6 24 41.7 25 20.9 26 16.2 27 2.3 28 12.7
29 0.8 32 0.3 33 0.4 34 0.4 35 15.6 36 21.6 38 2.8 39 166.6 40 0.1
41 0.2 42 0.3 58 0.3 59 0.1 60 2.3 61 0.7 66 0.4 67 1 68 10.3 69
14.2 70 10.6 71 26.5 72 8 73 56.1 84 0.9 106 0.4 113 0.6 114 0.5
119 0.8 120 2 121 1.4 126 0.1 127 0.2 132 0.3 137 0.6 138 1 139 5.1
141 3.6 147 0.3 150 0.5 151 2.2 154 3.8 155 0.2 156 2.3 157 0.2 158
2 159 0.5 160 0.6 161 2.8 162 0.2 163 0.6 164 0.2 165 5.8 166 2 167
2.2 177 0.1 178 0.2 180 4.6 181 3.3 186 18.8 187 0.6 188 0.3 199
187.8 200 138.3 201 31.2 202 3.2 203 1 204 25.7 205 6.9 206 0.2 207
2 208 1.4 213 1.6 214 0.2 215 1.26 219 0.2 220 2 221 1.5 222 0.3
223 34.6 224 1.8 238 0.9 239 8.1 240 0.4 241 0.6 242 0.2 243 0.2
245 0.6 246 1 248 0.2 250 63.6 251 2 252 0.3 253 4.6 254 20.8 257
24 258 6.3 259 22.7 261 120 262 1.5 263 1.8 265 3.2 267 1.1 269
12.3 271 56 272 2.5 273 200.2 275 153.9 276 77.8 277 124.8 280 0.3
281 8.7 283 0.8 287 456.6100 289 0.075 290 0.068 291 0.175 292
0.509 293 0.226 294 9.237 295 0.312 296 0.064 297 0.187 298 0.051
299 0.761 300 0.673 301 0.109 302 0.348 303 0.166 304 0.064 305
0.158 306 1.972 307 0.536 308 0.346 309 0.168 310 0.069 311 0.064
312 0.051 313 0.051 314 0.064 315 0.242 317 0.577 323 0.074 324
0.505 325 1.375 326 1.15 327 0.051 328 0.142 329 0.284 330 0.188
331 0.273 332 0.114 333 0.289 334 0.143 335 0.414 336 0.124 337
0.287 338 0.179 339 1.304 340 0.087 341 0.064 342 0.4 343 0.218 344
0.064 345 0.09 346 0.074 347 0.211 348 0.122 349 0.064 350 0.105
351 0.982 352 0.207 353 0.311 354 0.241 355 0.148 356 0.264 357
0.358 358 0.137 359 2.108 360 1.116 361 0.13 362 0.104 363 0.081
364 0.304 365 1.574 366 2.335 367 2.534 368 1.879 369 0.164 370
0.139 371 0.074 372 1.126 373 2.59 374 0.136 375 0.21 376 0.346 377
0.178 378 0.127 379 2.382 380 0.282 381 0.158 382 0.304 383 0.252
384 0.112 385 0.051 386 0.302 387 0.051 389 0.374 390 0.324 391
1.415 392 0.051 393 0.064 394 0.102 395 0.217 396 0.064 397 0.064
425 0.755 426 0.397 428 1.37
429 0.14 430 2.056 431 1.316 432 1.525 433 0.08 434 0.077 435 0.234
436 0.064 437 1.608 438 0.476 439 0.376 440 0.115 441 0.212 442
0.697 443 0.064 444 0.064 445 0.719 446 0.453 448 0.618 449 0.653
450 1.562 451 0.104 452 0.076 453 0.111 454 1.012 455 0.172 456
0.269 457 0.064 458 0.325 459 0.064 460 0.147 461 0.064 463 0.159
464 0.099 465 0.116 466 0.064 467 0.161 468 0.558 469 0.064 470
0.096 471 0.205 473 0.159 474 0.064 475 0.088 476 1.109 477 1.038
478 0.064 479 0.098 480 1.125 481 0.064 482 0.064 483 0.064 484
0.205 485 0.321 486 0.146 487 0.064 488 0.064 489 0.064 490 0.064
491 0.064 497 1.433 498 0.115 499 0.093 500 0.064 501 0.064 502
0.081 503 0.064 504 0.064 505 0.064 506 0.239 507 0.693 508 0.084
509 0.097 510 0.064 511 0.082 512 0.526 513 0.301 514 0.735 515
0.203 516 0.065 517 0.064 518 0.064 519 0.064 520 0.064 521 0.064
522 0.064 523 0.295 524 0.064 525 0.064 526 0.064 527 0.064 528
0.068 529 0.064 540 0.593 541 0.641 542 1.243 543 0.07 544 0.09 545
0.089 546 0.515 547 0.363 548 0.676 549 0.355 550 0.134 551 0.064
552 0.716 553 0.101 554 0.15 555 0.396 556 0.194 557 0.201 558
0.065 559 0.064 560 0.135 561 0.531 562 0.102 563 0.317 564 0.293
565 0.259 566 0.11 567 0.327 568 0.064 569 0.085 570 0.092 571
0.091 572 0.431 573 0.154 574 0.071 575 0.073 576 0.169 577 0.064
578 0.111 579 0.064 580 0.215 581 0.182 582 1.304 583 0.296 584
0.124 585 0.098 586 0.836 587 0.145 588 0.081 589 0.163 590 0.186
591 0.064 592 0.095 593 0.064 595 0.064 596 0.671 597 1.26 598
3.004 599 0.214 600 0.39 601 5.267 602 0.236 603 0.206 604 4.867
605 1.055 606 6.234 607 1.187 608 1.718 609 0.387 610 0.746 611
0.482 612 2.446 613 1.381 614 11.52 615 7.883 616 0.295 617 0.17
618 0.224 619 0.159 620 2.842 621 1.039 622 0.567 623 5.197 624
0.109 625 0.238 626 3.075 627 2.443 629 0.0640 630 0.0640 631 0.13
632 0.147 633 1.261 634 0.208 635 0.1 636 0.188 637 0.0640 638
0.0640 639 1.8540 640 1.0940 641 0.0640 642 2.3580 643 0.7340 644
1.9450 645 0.0640 646 6.2550 647 1.8850 648 0.0640 649 0.0640 650
0.2880 651 0.2970 652 0.1580 653 0.1700 654 0.0900 655 0.4040 656
0.2900 657 0.7950 658 0.2210 659 0.0640 660 0.0640 661 0.2560 662
0.1390 663 0.0640 664 2.6040 665 0.0640 666 0.0760 667 0.0640 668
0.0640 669 0.0640 670 1.7390 671 0.1590 672 0.0640 673 0.1540 674
0.0640 675 0.0640 676 0.0640 677 0.0630 678 0.1050 679 0.0580 681
8.9150 682 0.4210 683 0.1040 684 0.0640 685 0.5520 686 0.2820 687
0.6590 688 0.4120 689 0.0640 690 0.2800 691 2.3500 692 0.0510 693
0.5850 694 0.0510 695 0.0640 696 0.0990 697 0.0680 698 0.7040 699
0.1200 700 0.0640
701 0.8180 702 0.3160 703 0.0640 704 0.0640 705 0.0640 706 0.0640
707 0.0640 708 0.0640 709 0.0640 710 0.0640 711 0.0690 712 0.0640
713 0.0640 714 0.0640 715 0.0640 716 0.4030 717 0.5720 718 0.2420
719 0.0640 720 0.2620 721 0.0640 722 0.0640 723 0.0640 724 0.0640
725 0.0640 726 0.1250 727 0.0640 728 0.0640 729 0.9350 730 0.7400
731 0.0640 732 0.0740 733 0.2220 734 0.4630 735 0.3450 736 0.1530
737 0.0640 738 0.0640 739 0.0640 740 0.0640 741 0.0640 742 0.0640
743 0.3120 744 0.0640 745 0.0640 746 0.0640 747 0.0640 748 0.0640
749 0.0640 750 0.0640 751 4.5080 752 0.7790 753 0.0640 754 0.0910
755 0.1550 756 1.1610 757 0.0640 758 0.0640 759 0.0640 760 0.0640
761 0.0640 762 0.0640 763 0.0640 764 0.0640 765 0.0640 766 0.0640
767 0.0640 768 0.0640 769 0.0640 770 0.4180 771 0.0640 772 0.5520
773 0.6380 774 1.3120 775 0.2760 776 8.3100 777 0.0640 778 0.1130
779 0.3530 780 0.0640 781 0.0640 782 0.0640 783 0.2590 784 0.0640
785 0.0640 786 0.0640 787 0.0660 788 0.0640 789 0.0640 790 0.8650
791 2.8370 792 0.5340 793 1.7450 794 1.7340 795 0.0640 796 0.7620
797 0.0640 798 0.0640 799 0.3410 800 1.2940 801 9.6910 802 0.0840
803 0.0640
[2681] The above data shows that compounds of the present
disclosure are generally effective at blocking the PD-1/PD-L1
interaction.
EC.sub.50-CHO/PD-L1-Capture Assay:
[2682] Compounds were tested in a cell capture assay to determine
if they can specifically block the interaction between the
recombinant extracellular domain (ECD) of PD-1 and native
cell-bound PD-L1. Binding affinity of stable CHO cells
overexpressing PD-L1 with its cognate recombinant ligand coated on
plates was measured by counting the number of `captured` cells.
High-capacity streptavidin-coated plates were incubated with
biotylated-Fc-PD-1 for 2 hours in PBS. Unbound ligand was washed
out. CHO-PD-L1 cells (resuspended in PBS pH 7.4, 0.5 mM EDTA, and
2% bovine serum albumin) were pre-incubated for 1 hr with compound,
dispensed into each PD-1 ECD coated well and then incubated for 75
min at room temperature. To stop the capture assay, a
fixative/staining solution (final concentrations are 1.3%
glutaraldehyde and 1.67 .mu.M Draq5) was gently added to the cells
and incubated for 2 hrs at room temperature. Unbound cells were
then washed out and `captured` cells were enumerated using a
high-content microscopy system. EC.sub.50 values were calculated
from the fit of the dose-response curves to a four-parameter
equation. Representative data are shown below in Table 2.
TABLE-US-00009 TABLE 2 Example EC.sub.50-CHO/PD-L1- No. capture 1
381.5 2 1274.4 4 15.6 5 38.1 6 63.8 7 56 8 79.7 9 101.5 10 185 11
169.8 13 456.7 16 6 29 217.5 30 52.1 31 30.1 32 42.1 34 321.2 35
263.6 39 267.2 41 248.4 42 149.2 43 65.2 45 165.6 47 225.8 48 297.5
49 123.5 54 232.8 55 314.6 61 199.9 68 279.2 74 175.7 76 83.2 78
187.4 90 218.6 91 195.8 92 25.9 93 44.4 94 228.2 106 110.2 109 7.5
110 6.5 111 45.7 112 34.4 113 148.5 114 140.3 116 134.2 117 158.2
118 169.4 121 176.2 122 191.6 123 137.3 124 146.8 126 179.6 127
68.6 129 220.7 130 123.4 131 231 132 194.2 133 129.1 134 111.9 135
221.4 143 296.3 145 63.6 146 184.3 147 116.9 148 131.8 149 275.4
155 210.7 157 81.1 159 189.8 160 190.9 162 262.5 165 155.8 166 41.6
167 62.3 172 50.6 178 71.6 179 318.7 182 91.4 183 69.1 185 276.9
192 31.2 198 100.91 203 316.7 205 394 206 160.8 208 752 209 13.1
211 45.6 212 92.2 213 165.3 214 22.3 216 205.6 217 71.6 231 276.6
232 141.8 234 131.8 240 216.7 241 165.6 242 129.4 243 90.6 245
308.5 248 200.3 279 27.7 280 207.9 282 253.7 288 10.3
[2683] The above data shows that compounds of the present
disclosure are generally effective at inhibiting or specifically
blocking the interaction between the recombinant extracellular
domain (ECD) of PD-1 and native cell-bound PD-L1.
[2684] PD-1/PD-L1 NFAT Reporter Assay:
[2685] Compounds were tested in a functional co-culture reporter
assay in which TCR-mediated NFAT activity is inhibited by the
engagement of PD-1 with PD-L1. Blocking the PD-1/PD-L1 interaction
impairs PD-1 mediated blunting of TCR signaling and significantly
increases NFAT-mediated transcription of luciferase. CHO cells
expressing surface-bound anti-CD3 antibodies and PD-L1 (artificial
antigen presenting cells, aAPC-PD-L1) were first seeded overnight.
Jurkat cells overexpressing PD-1 and expressing a luciferase
construct under NFAT control are diluted in RPMI assay medium (RPMI
1640 with 2% FBS), mixed with compounds, and immediately seeded on
the monolayer of aAPC-PD-L1. The co-culture is then incubated for 6
hrs at 37.degree. C. Luciferase activity is assessed by adding the
ONE-Glo reagent and measuring luminescence with a plate reader.
EC.sub.50 values are calculated from the fit of the dose-response
curves to a four-parameter equation (Table 3).
[2686] PD-L1/PD-L1 Dimerization Biochemical Protein-Protein
Interaction Assay:
[2687] Compounds were tested in biochemical protein-protein
interaction assays to determine if they can specifically dimerize
the extracellular domains of PD-L1. Dimerization of the proteins
(His-tagged PD-L1 and FLAG-tagged PD-L1) is measured using a bead
based Amplified Luminescent Proximity Homogeneous Assay (ALPHA)
platform. Compound induced dimerization of PD-L1 results in
proximity of the donor and acceptor beads which leads to an
increase in ALPHA signal. Assays are performed in 25 mM Hepes (pH
7.4), 150 mM NaCl, 3.4 mM EDTA, 0.005% Tween 20, and 0.01% BSA.
Final protein concentration in the assays were 0.5 nM (His tagged
PD-L1) and 0.5 nM (FLAG tagged PD-L1). After an assay reaction time
of 2 hours at 25.degree. C., 20 .mu.g/mL (final assay
concentration) ALPHA assay acceptor beads (anti-His coated) were
added and incubated for 60 minutes at 25.degree. C. Binding was
measured following a final 60 minute incubation with 40 .mu.g/mL
(final assay concentration) ALPHA assay donor beads (anti-FLAG
coated). AC.sub.50 values were calculated from the fit of the
dose-response curves to a four-parameter equation (Table 3).
TABLE-US-00010 TABLE 3 AC.sub.50 PDL1 DimerAlpha EC.sub.50 NFAT Ex.
1 nM Luciferase 1 516 2 456 3 48 4 67.228 17 5 29 6 90.878 148 7
140.42 89 8 290 9 340 10 502 11 1100 12 653 13 4802 14 13076 15
5706 16 100.07 88 17 1607 18 50000 19 5136 20 1198 21 1372 22 2073
23 50000 24 1887 25 3763 26 18881 27 25293 28 663 29 244 30 369.04
50000 31 687 32 127 33 322 34 195 35 296 36 1070 37 894 38 2667 39
50000 40 176 41 188 42 123 43 10000 79 44 62 45 75 46 87 47 503 48
412 49 274 50 76 51 105 52 19786 53 722 54 997 55 1516 56 50000 57
351 58 822 59 1247 60 50000 61 6780 62 19476 63 50000 64 9781 65
3348 66 369.76 338 67 1317 68 553 69 1744 70 902 71 1030 72 2512 73
2618 74 10000 138 75 384 76 1056 77 50000 78 395 79 381 80 50000 81
50000 82 1706 83 1680 84 10003 85 9771 86 50000 87 50000 88 4146 89
670 90 10000 113 91 10000 523 92 170.13 63 93 145.16 127 94 210 95
639 96 912 97 28 98 70 99 157 100 482 101 1799 102 13240 103 14939
104 50000 105 50000 106 5271 107 35026 108 13867 109 112.6 662 110
194.34 354 111 129 112 183.78 286 113 193 114 186 115 50000 116 702
117 361.32 779 118 823 119 863 120 1302 121 74 122 79 123 198.44 75
124 10000 74 125 158 126 327 127 166.03 193 128 234 129 166.51 198
130 236.56 164 131 964 132 279.48 391 133 281.64 288 134 660 135
249.98 812 136 529 137 195.02 1453 138 392 139 23869 140 239 141
50000 142 235 143 395.15 217 144 205.78 201 145 362 146 334.48 2300
147 1202 148 124 149 668 150 50000 151 50000 152 594 153 329 154
50000 155 6487 156 34156 157 465 158 28121 159 538 160 139 161 310
162 236.19 160 163 343 164 500 165 352 166 139 167 10000 109 168
308 169 225 170 50000 171 7716 172 10000 139 173 50000 174 50000
175 808 176 2875 177 20608 178 10000 115 179 655 180 24816 181
30930 182 439 183 260.25 141 184 1390 185 195 186 1512 187 3201 188
1550 189 106 190 516 191 10000 60 192 267.46 197 193 132.45 99 194
1261 195 408 196 222.8 151 197 98 198 69 199 2151 200 893 201 1115
202 1919 203 696 204 927 205 1431 206 672 207 1547 208 10575 209
70.478 73 210 83.051 114 211 81.193 304 212 229.64 306 213 255.38
182 214 187.53 172 215 413 216 514 217 589 218 680 219 558 220 177
221 274 222 856 223 50000 224 24920 225 422.99 145 226 775 227 615
228 844 229 1222 230 821 231 962 232 313.88 331 233 11557 234 444
235 50000 236 5030 237 50000 238 2124 239 1118 240 366.95 108 241
275 242 288 243 393
244 390 245 3436 246 1200 247 776 248 540 249 50000 250 7492 251
25882 252 333 253 304 254 689 255 50000 256 758 257 657 258 419 259
511 260 463 261 3168 262 8621 263 36360 264 1293 265 7058 266 1381
267 8541 268 993 269 50000 270 50000 271 50000 272 37700 273 50000
274 1203 275 10367 276 2049 277 50000 278 50000 279 109.03 260 280
592 281 488 282 326.84 463 283 20893 284 1462 285 9688 286 232 287
958 288 57 289 10000 70 290 25.132 311 291 27.528 46 292 230.22 615
293 125.16 73 294 547.21 714 295 67.628 279 296 108.27 844 297
187.45 266 298 21 299 161.64 326 300 222.67 3720 301 95.867 1023
302 76.204 283 303 101.04 289 304 16.481 79 305 150.01 1765 306
291.81 547 307 598.97 702 308 203.4 373 309 102.96 240 310 120.6
215 311 75.526 104 312 143.95 97 313 91.301 152 314 188 315 1248
317 1179.2 1099 323 67.101 168 324 1023.6 894 325 633.12 2575 326
1211.6 439 327 114 328 241 146 329 289.72 466 330 209.33 1638 331
500.24 232 332 18.738 47 333 202.79 481 335 230.8 437 336 108.74
398 337 1924 338 140.24 1058 339 2216 340 27.769 217 341 38.336 284
342 118.42 447 343 81.128 158 344 55 475 345 228.95 552 346 181.34
214 347 124.8 142 348 80.408 381 349 62.843 320 350 252.44 527 351
168.24 235 352 56.314 105 353 214.6 153 354 341.99 1882 355 712 356
237.38 733 357 10000 202 358 100.37 2090 359 540.45 216 360 223.56
520 361 137.79 314 362 108.06 221 363 170.84 168 364 98.276 353 365
174.12 408 366 2842 367 227.46 376 368 274.21 118 369 57.569 107
370 81.369 577 371 78.017 210 372 425.11 860 373 168 339 374 164.76
788 375 173.05 389 376 770 377 231.43 262 378 191 379 153.36 415
380 184.26 652 381 143.98 219 382 334.26 1232 383 157.24 467 384
153.77 154 385 84 386 868 387 362 388 10000 225 389 119.85 306 390
97.456 120 391 242.51 305 392 232.4 351 393 84.033 118 394 130.25
435 395 89.645 151 396 37.94 105 397 709 398 728.01 1096 399 288.86
319 425 225.89 544 426 408.29 634 428 525.26 282 429 240.33 680 430
290.48 268 431 249.39 275 432 538.83 289 433 166.99 290 434 105.68
332 435 86.182 316 436 77.818 544 437 476.69 476 438 168.29 222 439
153.58 270 440 112.89 251 441 301.38 260 442 327.98 930 443 154.06
276 444 133.01 296 445 265.84 1493 446 457.95 315 448 902.63 1005
449 1493.4 2566 450 110.23 277 451 105.3 472 452 144.49 253 453
325.73 895 454 942.69 953 455 686.13 1544 456 182.03 1230 457
49.346 1557 458 138.59 429 459 89.904 1201 460 302.01 112 461
127.63 47 463 71.305 123 464 87.623 152 465 84.765 193 466 44.128
93 467 111.22 197 468 131.28 183 469 73.532 125 470 126.83 217 471
79.996 144 472 51 473 76.813 86 474 137.4 59 475 134.26 117 476
149.11 196 477 359.77 179 478 267.83 48 479 347.71 45 480 113.77
147 481 92.888 155 482 25.491 47 483 40.947 69 484 107.98 138 485
61.295 200 486 112 487 25.228 16 488 25.557 26 489 18.276 18 490
14.082 19 491 19.794 21 497 302.1 182 498 84.694 111 499 86.519 59
500 50.08 97 501 35.261 60 502 85.226 100 503 42.089 81 504 47.85
68 505 54.984 80 506 172.49 204 507 262.46 210 508 77.969 156 509
128.55 89 510 232.49 147 511 36.86 197 512 255.17 131 513 89.301 47
514 358.78 156 515 95 516 104.22 92 517 91.652 154 518 96.106 159
519 102.68 125 520 57.454 97 521 124.63 106 522 74.343 195 523
10000 129 524 67.668 39 525 34.846 27 526 73.609 110 527 69.901 46
528 63.33 89 529 56.181 165 540 126.03 103 541 70.351 93 542 135.98
197 543 49.676 187 544 17.344 109
545 24.445 145 546 39.174 109 547 20.054 51 548 74.563 197 549
54.558 177 550 47.657 163 551 12.434 100 552 74.724 152 553 17.727
70 554 39.501 148 555 23.089 84 556 37.72 86 557 137.33 135 558
33.558 51 559 18.667 53 560 77.784 163 561 193.04 146 562 126.34
162 563 564 80 565 73.433 112 566 39.38 86 567 68.718 85 568 44.311
65 569 128.37 74 570 56.457 115 571 155.58 126 572 452.86 129 573
215.25 120 574 55.956 72 575 40.589 34 576 24.313 32 577 9.732 16
578 37.182 135 579 34.754 191 580 231.43 200 581 60.308 158 582
346.58 147 583 38.272 180 584 38.566 149 585 182 586 181 587 324.37
45 588 206.48 50 589 164.01 89 590 134.21 140 591 22.717 20 592
107.3 172 593 124.18 113 595 77.049 65 596 415.02 169 597 310.22
231 598 480.36 1836 599 7925.6 50000 600 261.4 240 601 1125.1 748
602 124.08 242 603 235.05 158 604 934.65 552 605 351.78 130 606
557.85 50000 607 296.48 1732 608 214.46 50000 609 143.28 541 610
104.78 50000 611 408.3 223 612 728.92 50000 613 157.64 484 614
10000 50000 615 10000 50000 616 155.9 50000 617 264.72 50000 618
389.37 50000 619 118.12 187 620 10000 50000 621 10000 50000 622
10000 50000 623 10000 50000 624 20.923 50000 625 98.154 50000 626
10000 50000 627 480.39 50000 629 10000 251 630 10000 165 631 440.7
50000 632 313.61 2985 633 2841.4 2275 634 96.94 495 635 340.05
50000 636 83.554 180 637 20.779 90 638 23.809 429 639 942 640 50000
641 34.707 60 642 67.167 194 643 39.001 89 644 135.96 82 645 30.693
30 646 73.171 145 647 211.12 234 648 60.881 57 649 38.806 29 650
8.201 39 651 29.501 41 652 140.25 59 653 105.23 93 654 10.897 27
655 25.985 28 656 37.666 24 657 156.4 197 658 78.516 51 659 22.096
51 660 15.245 107 661 125.67 159 662 14.486 83 663 6.56 118 664
10000 50000 665 16.491 150 666 22.851 418 667 17.028 1893 668
16.485 886 669 17.179 637 670 74.789 50000 671 10000 235 672 24.53
435 673 398.99 583 674 11.32 44 675 95 676 62 677 180.38 145 678
253.53 264 679 100.56 64 681 50000 682 193.69 243 683 115.93 98 684
41.209 36 685 1822.3 625 686 136.97 46 687 3096.1 605 688 140.78
50000 689 114.12 139 690 80.795 287 691 193.17 443 692 198 693 120
694 96 695 21.64 26 696 16.885 12 697 51.001 50 698 111.18 152 699
24.684 136 700 22.122 43 701 332.27 3053 702 332.32 1311 703 24.212
11 704 66.777 11 705 60.582 20 706 42.831 14 707 39.298 31 708
38.593 34 709 49.36 21 710 54.611 22 711 102.77 69 712 32.999 12
713 69.421 25 714 66.315 26 715 7.886 35 716 15.094 343 717 16.161
484 718 70.434 704 719 32.67 110 720 94.892 558 721 18.996 14 722
16.05 47 723 35.134 41 724 21.158 120 725 14.262 88 726 81.94 76
727 15.841 27 728 14.976 25 729 48.994 652 730 40.706 100 731
15.975 26 732 2.694 14 733 129.31 120 734 45.993 36 735 104.09 95
736 18.388 22 737 8.231 80 738 8.059 72 739 3.815 10 740 53.577 288
741 3.104 12 742 42.007 32 743 82.234 50 744 9.532 44 745 19.203
113 746 103.63 143 747 5.356 10 748 10.056 24 749 16.809 77 750
72.114 222 751 181.6 355 752 82.454 471 753 35 754 434 755 39.227
139 756 6586 757 17.559 15 758 36.654 29 759 18.894 16 760 44.242
63 761 13.202 10 762 13.558 18 763 11.335 10 764 31.93 23 765
13.146 11 766 19.366 21 767 75.724 57 768 47.439 33 769 28.129 25
770 700.16 856 771 45.017 130 772 19.477 50000 773 10000 2100 774
2726.7 463 775 68.021 84 776 10000 1443 777 45.788 179 778 258.91
212 779 112.82 68 780 14.393 50 781 23.265 34 782 23.072 38 783
823.38 2987 784 28.933 182 785 16.139 66 786 12.246 86 787 35.352
58 788 11.785 39 789 17.884 58 790 75.688 84 791 205.9 175 792
22.685 40 793 186.83 1813 794 94.243 794 795 9.646 41 796 227.82
151 797 41.412 30 798 22.717 20
799 150.12 167 800 536.96 246 801 10000 50000 802 55.521 177 803
11.741 49
* * * * *