U.S. patent application number 15/398121 was filed with the patent office on 2017-07-06 for pyridine and pyridimine compounds as pi3k-gamma inhibitors.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Andrew W. Buesking, Andrew P. Combs, Nikoo Falahatpisheh, Lixin Shao, Stacey Shepard, Richard B. Sparks, Haisheng Wang.
Application Number | 20170190689 15/398121 |
Document ID | / |
Family ID | 57868380 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170190689 |
Kind Code |
A1 |
Sparks; Richard B. ; et
al. |
July 6, 2017 |
PYRIDINE AND PYRIDIMINE COMPOUNDS AS PI3K-GAMMA INHIBITORS
Abstract
The present disclosure provides compounds of Formula I, or
pharmaceutically acceptable salts thereof, that modulate the
activity of phosphoinositide 3-kinases-gamma (PI3K.gamma.) and are
useful in the treatment of diseases related to the activity of
PI3K.gamma. including, for example, autoimmune diseases, cancer,
cardiovascular diseases, and neurodegenerative diseases.
##STR00001##
Inventors: |
Sparks; Richard B.;
(Wilmington, DE) ; Shepard; Stacey; (Wilmington,
DE) ; Combs; Andrew P.; (Kennett Square, PA) ;
Buesking; Andrew W.; (Wilmington, DE) ; Shao;
Lixin; (Wilmington, DE) ; Wang; Haisheng;
(Hockessin, DE) ; Falahatpisheh; Nikoo;
(Wilmington, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
57868380 |
Appl. No.: |
15/398121 |
Filed: |
January 4, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62274942 |
Jan 5, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 491/107 20130101;
A61P 25/28 20180101; C07D 403/14 20130101; C07D 401/14 20130101;
C07D 487/08 20130101; C07D 405/14 20130101; C07D 487/10 20130101;
A61P 35/00 20180101; A61P 35/02 20180101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 487/08 20060101 C07D487/08; C07D 487/10 20060101
C07D487/10; C07D 405/14 20060101 C07D405/14; C07D 491/107 20060101
C07D491/107 |
Claims
1. A compound of Formula I: ##STR00412## or a pharmaceutically
acceptable salt or tautomer thereof, wherein: W is CH and V is CH;
or W is N and V is CH; or W is CH and V is N; X is CH, Y is N, and
Z is N or CR.sup.4; or X is N, Y is N or CR.sup.3, and Z is N or
CR.sup.4; provided that no more than two of X, Y and Z are N; ring
A is a monocyclic 4-6 membered azaheterocycloalkyl ring or a
monocyclic 5-6 membered azaheteroaryl ring, each of which has 1, 2,
or 3 nitrogen atoms as ring members; n is 0 or 1; R.sup.1 is
independently selected from halo, CN, NO.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11 groups;
R.sup.2 is halo, OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, cyano-C.sub.1-4 alkyl,
HO--C.sub.1-4 alkyl, C.sub.1-3 alkoxy-C.sub.1-4 alkyl, C.sub.1-6
alkylsulfonyl, or phenylsulfonyl, wherein the phenyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.g groups;
R.sup.3 and R.sup.4 are each independently selected from H, halo,
CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1OR.sup.d1, NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1 S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups; provided that when both R.sup.3 and R.sup.4 are
present, then one of R.sup.3 and R.sup.4 is selected from H, halo,
OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4
alkyl)amino, cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and
C.sub.1-3 alkoxy-C.sub.1-4 alkyl; alternatively R.sup.3 and
R.sup.4, taken together with the carbon atoms to which they are
attached form a monocyclic 4-7 membered cycloalkyl ring, a phenyl
ring, a monocyclic 4-6 membered heterocycloalkyl ring, or a
monocyclic 5-6 membered heteroaryl ring, each of which is
optionally substituted by 1, 2 or 3 independently selected R.sup.13
groups; each R.sup.11 is independently selected from halo, CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2OR.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
NR.sup.c2S(O)R.sup.b2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups; each R.sup.13 is independently selected
from halo, CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, OC(O)R.sup.b3,
OC(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3, NR.sup.c3OR.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR .sup.3C(O)OR.sup.a3,
NR.sup.c3C(O)NR.sup.c3R.sup.d3, NR.sup.c3S(O)R.sup.b3,
NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3 S(O).sub.2NR.sup.c3R.sup.d3,
S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups; Cy.sup.1a is selected from 3-10 membered
cycloalkyl and 4-10 membered heterocycloalkyl, each of which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups; each Cy is independently selected from 3-10
membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl,
and 4-10 membered heterocycloalkyl, each of which is optionally
substituted by 1, 2, 3, or 4 independently selected R.sup.11
groups; each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.13 groups; each
Cy.sup.2 is independently selected from 3-10 membered cycloalkyl,
6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered
heterocycloalkyl, each of which is optionally substituted by 1, 2,
3, or 4 independently selected R.sup.g groups; each Cy.sup.3 is
independently selected from 3-10 membered cycloalkyl, 6-10 membered
aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl,
each of which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.g groups; R.sup.a, R.sup.c, and
R.sup.d are each independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy, and
--C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.11 groups; R.sup.b is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy, and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.11 groups; alternatively, any R.sup.c and R.sup.d
attached to the same N atom, together with the N atom to which they
are attached, form a 4-10 membered heterocycloalkyl group or a 5-6
membered heteroaryl group, each optionally substituted with 1, 2,
or 3 independently selected R.sup.11 groups; R.sup.a1, R.sup.1, and
R.sup.d1 are each independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups; R.sup.b1 is independently
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups; or alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13 groups;
each R.sup.a2, R.sup.c2, and R.sup.d2 are independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.2, and --C.sub.1-4 alkylene-Cy.sup.2;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and C.sub.1-4 haloalkyl are each optionally substituted with 1, 2,
3, or 4 independently selected R.sup.g groups; each R.sup.b2 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.2, and --C.sub.1-4
alkylene-Cy.sup.2; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups; or alternatively, any R.sup.c2 and R.sup.d2 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g groups;
each R.sup.a3, R.sup.c3, and R.sup.d3 are independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.3, and --C.sub.1-4 alkylene-Cy.sup.3;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and C.sub.1-4 haloalkyl are each optionally substituted with 1, 2,
3, or 4 independently selected R.sup.g groups; each R.sup.b3 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.3, and --C.sub.1-4
alkylene-Cy.sup.3; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R groups; or
alternatively, any R.sup.c3 and R.sup.d3 attached to the same N
atom, together with the N atom to which they are attached, form a
4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g groups;
and each R.sup.g is independently selected from OH, NO.sub.2, CN,
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
2. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.c(O)OR.sup.b,
NR.sup.c(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups.
3-4. (canceled)
5. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.a, R.sup.c, and R.sup.d are each
independently selected from H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1 or 2 independently selected R.sup.11 groups; R.sup.b is
independently selected from C.sub.1-6 alkyl, Cy, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1 or 2 independently selected R.sup.11 groups; alternatively,
any R.sup.c and R.sup.d attached to the same N atom, together with
the N atom to which they are attached, form a 4-10 membered
heterocycloalkyl group, which is optionally substituted with 1 or 2
independently selected R.sup.11 groups.
6. (canceled)
7. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each Cy is independently 3-7 membered
cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered
heteroaryl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.11 groups.
8. (canceled)
9. The compound of claim 1, a pharmaceutically acceptable salt or
tautomer thereof, wherein each Cy is independently cyclopropyl,
cyclobutyl, cyclopentyl, ##STR00413## tetrahydrofuranyl,
tetrahydropyranyl, morpholinyl, or phenyl, each of which is
optionally substituted by 1 or 2 independently selected R.sup.11
groups.
10. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein Cy.sup.1a is 4-10 membered
heterocycloalkyl, which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.11 groups.
11-12. (canceled)
13. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each R.sup.11 is independently
selected from halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2OR.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups.
14-15. (canceled)
16. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each R.sup.a2, R.sup.c2, and R.sup.d2
are independently selected from H, C.sub.1-6 alkyl, Cy.sup.2;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.g groups; each R.sup.b2 is
independently selected from C.sub.1-6 alkyl and Cy.sup.2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.g groups; alternatively, any R.sup.c2
and R.sup.d2 attached to the same N atom, together with the N atom
to which they are attached, form a 5-6-membered heterocycloalkyl
group optionally substituted with 1 or 2 independently selected
R.sup.g groups.
17. (canceled)
18. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each Cy.sup.2 is independently
selected from 3-10 membered cycloalkyl, 6-10 membered aryl, and
4-10 membered heterocycloalkyl, each of which is optionally
substituted by 1, 2, 3, or 4 independently selected R.sup.g
groups.
19-22. (canceled)
23. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.2 is halo, OH, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino,
C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino, HO--C.sub.1-4
alkyl, or C.sub.1-3 alkoxy-C.sub.1-4 alkyl.
24-29. (canceled)
30. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.3 is selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, C(O)NR.sup.c1R.sup.d1, and
C(O)OR.sup.a1, wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.13
groups.
31. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.4 is selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1,
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
or 3 independently selected R.sup.13 groups.
32. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein R.sup.a1, R.sup.d, and R.sup.d1 are
each independently selected from H, C.sub.1-6 alkyl, Cy.sup.1, and
--C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.13 groups; R.sup.b1 are each independently selected from
C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1;
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
3, or 4 independently selected R.sup.13 groups; alternatively, any
R.sup.c1 and R.sup.d1 attached to the same N atom, together with
the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.13 groups.
33. (canceled)
34. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each Cy.sup.1 is independently
selected from 3-10 membered cycloalkyl, 4-6 membered
heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, each of
which is optionally substituted by 1, 2, 3, or 4 independently
selected R.sup.13 groups.
35. (canceled)
36. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each R.sup.13 is independently
selected from halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, NR.sup.c3R.sup.d3, NR.sup.3OR.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
NR.sup.c3C(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups.
37-38. (canceled)
39. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each R.sup.a3, R.sup.c3, and R.sup.d3
are independently selected from H and C.sub.1-6 alkyl; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; each R.sup.b3 is
independently selected from C.sub.1-6 alkyl, which is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups; alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups.
40. (canceled)
41. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each Cy.sup.3 is independently
selected from 3-7 membered cycloalkyl and 4-6 membered
heterocycloalkyl, each of which is optionally substituted by 1 or 2
independently selected R.sup.g groups.
42. (canceled)
43. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein each R.sup.g is independently selected
from OH, CN, halo, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, cyano-C.sub.1-3 alkyl, HO--C.sub.1-3
alkyl, amino, C.sub.1-6 alkylamino, and di(C.sub.1-6
alkyl)amino.
44. (canceled)
45. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ##STR00414##
46. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ##STR00415##
47. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ##STR00416##
48-50. (canceled)
51. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ring A is a monocyclic 5-6 membered
azaheterocycloalkyl ring or a 5-6 membered azaheteroaryl ring.
52. (canceled)
53. The compound of claim 51, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ring A is a pyrazole ring, a pyridine
ring, an imidazole ring, a tetrahydropyridine ring, a
dihydropyrrolyl ring, or a pyrrole ring.
54. (canceled)
55. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ##STR00417## ring A is a monocyclic
5-6 membered azaheterocycloalkyl ring or a 5-6 membered
azaheteroaryl ring; R.sup.1 is selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11 groups;
R.sup.2 is halo, OH, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, HO--C.sub.1-4 alkyl, or
C.sub.1-3 alkoxy-C.sub.1-4 alkyl; R.sup.3 and R.sup.4 are
independently selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1,
--C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1OR.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups; provided that when both R.sup.3 and R.sup.4 are
present, then one of R.sup.3 and R.sup.4 is selected from H, halo,
OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4
alkyl)amino, cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and
C.sub.1-3 alkoxy-C.sub.1-4 alkyl; and alternatively, R.sup.3 and
R.sup.4, taken together with the carbon atoms to which they are
attached form a monocyclic 4-7 membered cycloalkyl ring, a phenyl
ring, a monocyclic 4-6 membered heterocycloalkyl ring, or a
monocyclic 5-6 membered heteroaryl ring, each of which is
optionally substituted by 1, 2 or 3 independently selected R.sup.13
groups.
56. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein ##STR00418## ring A is a monocyclic
5-6 membered azaheterocycloalkyl ring or a 5-6 membered
azaheteroaryl ring; R.sup.1 is selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cOR.sup.d, NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11 groups;
R.sup.2 is halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamine,
di(C.sub.1-4 alkyl)amino, or C.sub.1-3 alkoxy-C.sub.1-4 alkyl;
R.sup.3 and R.sup.4 are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1 NR.sup.c1(O)R.sup.b1, NR.sup.c1C(O)OR.sup.b1,
NR.sup.c1(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups; provided that when both R.sup.3 and R.sup.4 are
present, then one of R.sup.3 and R.sup.4 is selected from H, halo,
OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4
alkyl)amino, cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and
C.sub.1-3 alkoxy-C.sub.1-4 alkyl; and alternatively, R.sup.3 and
R.sup.4, taken together with the carbon atoms to which they are
attached form a monocyclic 4-7 membered cycloalkyl ring, a phenyl
ring, a monocyclic 4-6 membered heterocycloalkyl ring, or a
monocyclic 5-6 membered heteroaryl ring, each of which is
optionally substituted by 1, 2 or 3 independently selected R.sup.13
groups.
57. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein: ##STR00419## W is CH and V is CH; or
W is N and V is CH; or W is CH and V is N; ring A is a pyrazole
ring, a pyridine ring, an imidazole ring, a tetrahydropyridine
ring, or a dihydropyrrolyl ring; R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1a, --C.sub.1-4
alkylene-Cy, OR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2R.sup.b, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are optionally substituted with 1, 2, or 3
independently selected R.sup.11 groups; R.sup.2 is C.sub.1-4 alkyl;
R.sup.3 and R.sup.4 are each independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1,
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
or 3 independently selected R.sup.13 groups; provided that when
both R.sup.3 and R.sup.4 are present, then one of R.sup.3 and
R.sup.4 is selected from H, C.sub.1-4 alkyl, and C.sub.1-4
haloalkyl; or alternatively, R.sup.3 and R.sup.4, taken together
with the carbon atoms to which they are attached form a monocyclic
4-7 membered cycloalkyl ring, and a phenyl ring each R.sup.11 is
independently selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2, OR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein said C.sub.1-6
alkyl is optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups; each R.sup.13 is selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, NR.sup.c3R.sup.d3, C(O)R.sup.b3,
NR.sup.c3C(O)OR.sup.a3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups; R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.11 groups; R.sup.b is independently
selected from C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.11 groups; or alternatively, any
R.sup.c and R.sup.d attached to the same N atom, together with the
N atom to which they are attached, form an azetidine ring, a
pyrrolidine ring, an azabiyclo[2.2.1]-heptane ring, a a piperidine
ring, a piperazine ring, a morpholine ring, an azepane ring, a
decahydroisoquinoline ring, a 2,8-diazaspiro[4.5]decan-1-one ring,
a 3-oxa-9-azaspiro[5.5]undecane ring, a 2-oxa-7-azaspiro[3.5]nonane
ring, or a 5-azaspiro[2.4]heptane ring, each of which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
R.sup.a1, R.sup.c1, and R.sup.d1 are each independently selected
from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups; R.sup.b1 are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups; or alternatively, any
R.sup.c1 and R.sup.d1 attached to the same N atom, together with
the N atom to which they are attached, form an azetidine ring, a
pyrrolidine ring, or a morpholine ring, each of which is optionally
substituted with 1, 2 or 3 independently selected R.sup.13 groups;
each R.sup.a3, R.sup.c3, and R.sup.d3 are independently selected
from H, C.sub.1-6 alkyl, and phenyl; wherein said C.sub.1-6 alkyl
is optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.g groups; each R.sup.b3 is independently selected from
C.sub.1-6 alkyl and phenyl; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.g groups; or alternatively, any R.sup.c3 and R.sup.d3
attached to the same N atom, together with the N atom to which they
are attached, form a morpholine ring; each Cy is independently
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ##STR00420##
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or phenyl, each
of which is optionally substituted by 1 or 2 independently selected
R.sup.11 groups; Cy.sup.1a is a pyrrolidine ring, a dihydropyrrole
ring, a morpholine ring, a piperidine ring, a piperazine ring, a
tetrahydrofuran ring, or a tetrahydropyran ring, each of which is
optionally substituted by 1 or 2 independently selected R.sup.11
groups; each Cy.sup.1 is independently cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, admantyl, indenyl, phenyl, piperidinyl,
morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl,
and pyridyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups; each Cy.sup.3 is
independently cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl,
or phenyl; n is 0 or 1; and each R.sup.g is independently selected
from OH, methoxy, and methyl.
58-59. (canceled)
60. The compound of claim 1, or a pharmaceutically acceptable salt
or tautomer thereof, wherein: ##STR00421## W is CH and V is CH; or
W is N and V is CH; or W is CH and V is N; ring A is a pyrazole
ring, a pyridine ring, an imidazole ring, a tetrahydropyridine
ring, or a dihydropyrrolyl ring; R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1a, --C.sub.1-4
alkylene-Cy, OR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2R.sup.b, and S(O).sub.2R.sup.b; wherein said
C.sub.1-6 alkyl and C.sub.1-4 haloalkyl are optionally substituted
with 1, 2, or 3 independently selected R.sup.11 groups; R.sup.2 is
C.sub.1-4 alkyl; R.sup.3 and R.sup.4 are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1,
--C.sub.1-4 alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1 wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3
independently selected R.sup.13 groups; provided that when both
R.sup.3 and R.sup.4 are present, then one of R.sup.3 and R.sup.4 is
selected from H, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
alternatively, R.sup.3 and R.sup.4, taken together with the carbon
atoms to which they are attached form a monocyclic 4-7 membered
cycloalkyl ring, and a phenyl ring each R.sup.11 is independently
selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl,
Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and
S(O).sub.2R.sup.b2; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups; each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups; R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1 or 2 independently selected R.sup.11 groups; R.sup.b is
independently selected from C.sub.1-6 alkyl, Cy.sup.1, and
--C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
alternatively, any R.sup.c and R.sup.d attached to the same N atom,
together with the N atom to which they are attached, form an
azetidine ring, a pyrrolidine ring, an azabiyclo[2.2.1]-heptane
ring, a a piperidine ring, a piperazine ring, a morpholine ring, an
azepane ring, a decahydroisoquinoline ring, a
2,8-diazaspiro[4.5]decan-1-one ring, a
3-oxa-9-azaspiro[5.5]undecane ring, a 2-oxa-7-azaspiro[3.5]nonane
ring, or a 5-azaspiro[2.4]heptane ring, each of which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
R.sup.a1, R.sup.c1, and R.sup.d1 are each independently selected
from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups; R.sup.bi are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups; alternatively, any R.sup.c1
and R.sup.d1 attached to the same N atom, together with the N atom
to which they are attached, form an azetidine ring, a pyrrolidine
ring, or a morpholine ring, each of which is optionally substituted
with 1, 2 or 3 independently selected R.sup.13 groups; each
R.sup.a3, R.sup.3, and R.sup.d3 are independently selected from H
and C.sub.1-6 alkyl; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups; each R.sup.b3 is independently selected from C.sub.1-6
alkyl; wherein said C.sub.1-6 alkyl is optionally substituted with
1, 2, 3, or 4 independently selected R.sup.g groups; alternatively,
any R.sup.c3 and R.sup.d3 attached to the same N atom, together
with the N atom to which they are attached, form a morpholine ring;
each Cy is independently cyclopropyl, cyclobutyl, cyclopentyl,
##STR00422## tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or
phenyl, each of which is optionally substituted by 1 or 2
independently selected R.sup.11 groups; Cy.sup.1a is a pyrrolidine
ring, a dihydropyrrole ring, a morpholine ring, a piperidine ring,
a piperazine ring, a tetrahydrofuran ring, or a tetrahydropyran
ring, each of which is optionally substituted by 1 or 2
independently selected R.sup.11 groups; each Cy.sup.1 is
independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
admantyl, indenyl, phenyl, piperidinyl, morpholinyl,
tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and pyridyl,
each of which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.13 groups; each Cy.sup.3 is
independently cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl,
or phenyl; n is 0 or 1; and each R.sup.g is independently selected
from OH, methoxy, and methyl.
61. The compound of claim 1, having Formula II: ##STR00423## or a
pharmaceutically acceptable salt or tautomer thereof.
62. The compound of claim 1, having Formula III: ##STR00424## or a
pharmaceutically acceptable salt or tautomer thereof.
63. The compound of claim 1, having Formula IV: ##STR00425## or a
pharmaceutically acceptable salt or tautomer thereof.
64. The compound of claim 1, having Formula V: ##STR00426## or a
pharmaceutically acceptable salt or tautomer thereof.
65-67. (canceled)
68. The compound of claim 1, wherein the compound is selected from:
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-phenyl-1H-imidazol-2-yl)pyrid-
ine;
4-(1-Benzyl-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
2-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzonitrile;
4-(1-(2-Chlorobenzyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyrid-
ine;
4-(1-Methyl-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
4-(3-Methyl-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
4-(1-Ethyl-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
4-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
2-(5-Phenyl-1H-imidazol-2-yl)-4-(1-propyl-1H-pyrazol-4-yl)pyridine;
4-(1-Methyl-1H-pyrazol-5-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
4-(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(5-phenyl-1H-imidazol--
2-yl)pyridine;
4-(1-Methyl-1H-imidazol-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine;
N-(2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)acetamide;
4-(2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
5-Methoxy-2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridine;
3-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzonitrile;
4-(1-(3-Chlorobenzyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyrid-
ine;
2-(5-Phenyl-1H-imidazol-2-yl)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)p-
yridine;
4-(2-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1--
yl)ethyl)morpholine; Methyl
2-((4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzoate; Methyl
3-((4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzoate; Methyl
4-((4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzoate;
2-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-y-
l)methyl)benzoic acid;
3-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzoic acid;
4-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzoic acid;
5-(4-Methylpiperazin-1-yl)-2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridine-
;
5-(Methylsulfonyl)-2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridine;
4-(2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-6-yl)morpholine;
4-((4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)-
benzonitrile;
4-(1-(Methylsulfonyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyrid-
ine;
4-(1-(Ethylsulfonyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)py-
ridine;
4-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazo-
l-2-yl)pyridine;
2-(5-Phenyl-1H-imidazol-2-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol--
4-yl)pyridine;
2-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)acetamid-
e;
N,N-Dimethyl-2-(4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazo-
l-1-yl)acetamide;
2-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)-1-(pyrr-
olidin-1-yl)ethanone;
1-Morpholino-2-(4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol--
1-yl)ethanone;
3-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)propanen-
itrile;
3-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)p-
ropanamide;
4-(1-(Cyclopentylsulfonyl)-1H-pyrazol-4-yl)-2-(5-phenyl-1H-imidazol-2-yl)-
pyridine; Ethyl
3-(4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)propanoa-
te;
2-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)aceto-
nitrile;
3-(4-(2-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl)-
propanoic acid;
N-Methyl-3-(4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-1-yl-
)propanamide;
N-cyclopentyl-3-(4-(2-(5-phenyl-1H-imidazol-2-yl)pyridin-4-yl)-1H-pyrazol-
-1-yl)propanamide;
2-(5-Phenyl-1H-imidazol-2-yl)-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl-
)pyridine; 5-(5-Methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine;
N-Ethyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine;
5-(5-Methoxy-3,4'-bipyridin-2'-yl)-N-pentyl-1H-imidazol-2-amine;
N-Isobutyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine;
N-(Cyclobutylmethyl)-5-(5-methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-ami-
ne;
N-Butyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-4H-1,2,4-triazol-3-amine;
N-Isopropyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-4H-1,2,4-triazol-3-amine;
5-(5-Methoxy-3,4'-bipyridin-2'-yl)-N-methyl-4H-1,2,4-triazol-3-amine;
5-(5-Methoxy-3,4'-bipyridin-2'-yl)-N-phenyl-4H-1,2,4-triazol-3-amine;
5-Methoxy-2'-(5-phenyl-4H-1,2,4-triazol-3-yl)-3,4'-bipyridine;
5-Methoxy-2'-(4H-1,2,4-triazol-3-yl)-3,4'-bipyridine;
5-Methoxy-2'-(5-methyl-4H-1,2,4-triazol-3-yl)-3,4'-bipyridine;
5-Methoxy-2'-(2-phenyl-1H-imidazol-5-yl)-3,4'-bipyridine;
N-[2-(5-Methoxy-3,4'-bipyridin-2'-yl)-4-methyl-1H-imidazol-5-yl]
acetamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine;
5-Methoxy-2'-(5-methyl-1H-imidazol-2-yl)-3,4'-bipyridine;
2-(5-Methoxy-3,4'-bipyridin-2'-yl)-1,4,5,6-tetrahydrocyclopenta[d]imidazo-
le;
5-Methoxy-2'-(5-(trifluoromethyl)-1H-imidazol-2-yl)-3,4'-bipyridine;
Ethyl
2-(5-methoxy-3,4'-bipyridin-2'-yl)-5-(trifluoromethyl)-1H-imidazole-
-4-carboxylate;
2-(5-Methoxy-3,4'-bipyridin-2'-yl)-5-(trifluoromethyl)-1H-imidazole-4-car-
boxylic acid;
5-Methoxy-2'-(4-methyl-5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridine;
4-(2-(5-Methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-5-yl)-N,N-dimethylbenze-
nesulfonamide;
2'-(5-Isopropyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine;
2'-(5-Ethyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine;
2'-(5-Cyclopropyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine;
5-Methoxy-2'-(5-(pyridin-2-yl)-1H-imidazol-2-yl)-3,4'-bipyridine;
2'-(5-tert-Butyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine;
2-[4-(5-Methoxypyridin-3-yl)pyrimidin-2-yl]-1H-benzimidazole;
2-[6-(5-Methoxypyridin-3-yl)pyrimidin-4-yl]-1H-benzimidazole;
2'-(5-Methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine;
4-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
4-(2'-(5-(Trifluoromethyl)-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholi-
ne;
4-(2'-(5-Ethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
4-(2'-(5-Isopropyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
4-(2'-(5-Cyclopropyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
4-(2'-(5-Cyclobutyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morpholine;
4-(2'-(5-Cyclopropyl-4-methyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morph-
oline;
4-(2'-(5-Ethyl-4-methyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)morph-
oline;
2'-(5-Cyclohexyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridi-
ne;
2'-(5-Methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
5-(Methylsulfonyl)-2'-(5-(trifluoromethyl)-1H-imidazol-2-yl)-3,4'-bipyrid-
ine;
2'-(5-Ethyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Isopropyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Cyclopropyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Cyclobutyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Cyclopentyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Benzyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine;
2'-(5-Cyclopropyl-4-methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipy-
ridine;
2'-(5-Ethyl-4-methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bip-
yridine;
5-(Methylsulfonyl)-2'-(5-(pyridin-2-yl)-1H-imidazol-2-yl)-3,4'-bi-
pyridine;
5-Methyl-2-(5-(methylsulfonyl)-3,4'-bipyridin-2'-yl)-1H-imidazol-
e-4-carboxylic acid;
4-Cyclohexyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-5-am-
ine;
2'-[4-(Difluoromethyl)-5-methyl-1H-imidazol-2-yl]-5-(methylsulfonyl)--
3,4'-bipyridine;
[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]
methanol;
2-[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidaz-
ol-4-yl]ethanol;
1-[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]et-
hanol; Methyl
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxy-
late; tert-Butyl
[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbamate;
2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine; tert-Butyl
[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbamate;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine;
N-[2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]
ethanesulfonamide;
2-Methoxy-N-[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]acetamide-
; N-(2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
2-Chloro-N-(2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
3-Chloro-N-(2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
4-Chloro-N-(2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
3-Cyano-N-(2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
4-Cyano-N-(2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)benzamide;
N-(2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)cyclopentanecarboxa-
mide;
N-Ethyl-N-[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]urea;
Ethyl 2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-ylcarbamate;
2'-(5-Phenyl-1H-imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-3,4'-bi-
pyridin-5-amine;
2'-(5-Phenyl-1H-imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-3,4'-bipyridi-
n-5-amine;
N-(1-Methylpiperidin-4-yl)-2'-(5-phenyl-1H-imidazol-2-yl)-3,4'--
bipyridin-5-amine;
N-((1-Methylpiperidin-4-yl)methyl)-2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bi-
pyridin-5-amine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-3,4-
'-bipyridin-5-amine;
(S)-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-hydroxypyr-
rolidin-1-yl)methanone;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(4-methylpiperazi-
n-1-yl)methanone;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(morpholino)metha-
none;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(3-(dimethylamino)propyl)-3,4'--
bipyridine-5-carboxamide;
4-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbonyl)piperazi-
ne-1-carboxamide;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(pyrrolidin-1-yl)-
methanone;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-hydr-
oxyazetidin-1-yl)methanone;
1-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbonyl)azetidin-
e-3-carbonitrile;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-hydroxypiperid-
in-1-yl)methanone;
(R)-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-fluoropyrr-
olidin-1-yl)methanone;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-oxa-9-azaspiro-
[5.5]undecan-9-yl)methanone;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-isopropyl-3,4'-bipyridine-5-carboxam-
ide;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(4-(1-methylp-
iperidin-4-yl)piperazin-1-yl)methanone;
1-(4-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbonyl)piper-
azin-1-yl)ethanone;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-3,4'-bipy-
ridine-5-carboxamide;
(R)-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-(dimethyla-
mino)pyrrolidin-1-yl)methanone;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-
,4'-bipyridine-5-carboxamide;
(R)-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-hydroxypyr-
rolidin-1-yl)methanone;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)--
3,4'-bipyridine-5-carboxamide;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(2-oxa-7-azaspiro-
[3,5]nonan-7-yl)methanone;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(2-methoxyethyl)-3,4'-bipyridine-5-c-
arboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-((tetrahydrofuran-2-yl)methyl)-3,4'--
bipyridine-5-carboxamide;
1-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbonyl)pyrrolid-
in-3-one;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-(2-hy-
droxyethyl)pyrrolidin-1-yl)methanone;
(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-(pyridin-2-yl)-
pyrrolidin-1-yl)methanone;
2-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbonyl)-6-methy-
l-2,6-diazaspiro[3.4]octan-5-one;
((3R,4R)-1-{[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbo-
nyl}-4-methylpyrrolidin-3-yl)methanol;
5-[(3,3-Difluoropyrrolidin-1-yl)carbonyl]-2'-(4,5-dimethyl-1H-imidazol-2--
yl)-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-methoxypyrrolidin-1-yl)carbonyl]-
-3,4'-bipyridine; Methyl
1-{[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbonyl}pyrro-
lidine-3-carboxylate;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-[(3R)-tetrahydrofuran-3-yl]-3,4'-bip-
yridine-5-carboxamide;
1-{[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbonyl}piper-
idin-4-ol;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-{[3-(trifluoromethyl)pyrro-
lidin-1-yl]carbonyl}-3,4'-bipyridine;
5-(7-Azabicyclo[2.2.1]hept-7-ylcarbonyl)-2'-(4,5-dimethyl-1H-imidazol-2-y-
l)-3,4'-bipyridine;
1-{[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbonyl}-3-me-
thylpyrrolidin-3-ol;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-phenylpyrrolidin-1-yl)carbonyl]--
3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-pyridin-4-ylpyrrolidin-1-yl)carb-
onyl]-3,4'-bipyridine;
1-{[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbonyl}pyrro-
lidine-3-carbonitrile;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-{[2-(trifluoromethyl)azetidin-1-yl]c-
arbonyl}-3,4'-bipyridine;
5-[(3,3-Dimethylazetidin-1-yl)carbonyl]-2'-(4,5-dimethyl-1H-imidazol-2-yl-
)-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(4-phenylpiperidin-1-yl)carbonyl]-3-
,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(4aR,8aS)-octahydroisoquinolin-2(1H-
)-ylcarbonyl]-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-phenylpiperidin-1-yl)carbonyl]-3-
,4'-bipyridine;
5-[(4-Benzylpiperidin-1-yl)carbonyl]-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3-
,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(2-methylpiperidin-1-yl)carbonyl]-3-
,4'-bipyridine;
5-(Azetidin-1-ylcarbonyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyrid-
ine;
N-Benzyl-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carboxa-
mide;
N-Benzyl-2'-(4,5-dimethyl-1H-imidazol-2-yl)-N-methyl-3,4'-bipyridine-
-5-carboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-methyl-N-phenyl-3,4'-bipyridine-5-ca-
rboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-[(1S)-1-phenylethyl]-3,4'--
bipyridine-5-carboxamide;
4-Benzyl-1-{[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbo-
nyl}piperidin-4-ol;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-pyrazin-2-ylpyrrolidin-1-yl)carb-
onyl]-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-ethyl-N-methyl-3,4'-bipyridine-5-car-
boxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-methoxyazetidin-1-yl)ca-
rbonyl]-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(4-methyl-1,4-diazepan-1-yl)carbony-
l]-3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(2-hydroxyethyl)-N-methyl-3,4'-bipyr-
idine-5-carboxamide;
N-(Cyclopropylmethyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine--
5-carboxamide;
N-(Cyanomethyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-N-methyl-3,4'-bipyridi-
ne-5-carboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(2-methoxyethyl)-N-methyl-3,4'-bipyr-
idine-5-carboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-{[1-(hydroxymethyl)cyclopropyl]methy-
l}-N-methyl-3,4'-bipyridine-5-carboxamide;
N-(Cyclobutylmethyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-
-carboxamide;
N-(Cyclopentylmethyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine--
5-carboxamide;
N-(tert-Butyl)-2-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carbox-
amide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(3-hydroxypropyl)-N-methyl-3,4-
'-bipyridine-5-carboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-methyl-N-propyl-3,4'-bipyridine-5-ca-
rboxamide;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[(3-ethylpyrrolidin-1-yl)c-
arbonyl]-3,4'-bipyridine;
5-(5-Azaspiro[2.4]hept-5-ylcarbonyl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3-
,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1,2,5,6-tetrahydro--
3,4'-bipyridine;
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-[1-(phenylsulfonyl)piperidin-3-yl]pyr-
idine; 1-(4-(2-(4,5-Dimethyl-1H-imidazol-2-yl)pyridin-4-yl)-5,
6-dihydropyridin-1(2H)-yl)ethanone;
1-(3-(2-(4,5-Dimethyl-1H-imidazol-2-yl)pyridin-4-yl)-5,
6-dihydropyridin-1 (2H)-yl)ethanone;
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-(1-(methylsulfonyl)-1,2,5,6-tetrahydr-
opyridin-3-yl)pyridine;
4-(1-(4-Chlorophenylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(4,5-dime-
thyl-1H-imidazol-2-yl)pyridine;
(3-(2-(4,5-Dimethyl-1H-imidazol-2-yl)pyridin-4-yl)-5,6-dihydropyridin-1(2-
H)-yl)(phenyl)methanone;
4-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(4,5-dimethyl-1H-imidazol-2-
-yl)pyridine;
4-(1-(4-Chlorobenzyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(4,5-dimethyl-1H--
imidazol-2-yl)pyridine;
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-(1-((tetrahydro-2H-pyran-4-yl)methyl)-
-1,2, 5,6-tetrahydropyridin-3-yl)pyridine;
1-(3-(2-(4,5-Dimethyl-1H-imidazol-2-yl)pyridin-4-yl)-2,5-dihydro-1H-pyrro-
l-1-yl)ethanone;
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-(1-(methylsulfonyl)-2,5-dihydro-1H-py-
rrol-3-yl)pyridine;
4-(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)-2-(4,5-dimethyl-1H-imidazol-2-yl)-
pyridine;
4-(1-(4-Chlorobenzyl)-2,5-dihydro-1H-pyrrol-3-yl)-2-(4,5-dimethy-
l-1H-imidazol-2-yl)pyridine;
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-(1-((tetrahydro-2H-pyran-4-yl)methyl)-
-2,5-dihydro-1H-pyrrol-3-yl)pyridine;
(3R)-1-[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]pyrrolidin-
-3-ol;
(3S)-1-[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]pyrr-
olidin-3-ol;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-phenyl-3,4'-bipyridin-5-amine;
5-Chloro-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine;
tert-Butyl
3-[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]-2,5-dihydro-1H-
-pyrrole-1-carboxylate;
5-(2,5-Dihydro-1H-pyrrol-3-yl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bi-
pyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[1-(methylsulfonyl)-2,5-dih-
ydro-1H-pyrrol-3-yl]-3,4'-bipyridine;
1-(3-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)-2,5-dihydro-
-1H-pyrrol-1-yl)ethanone; Methyl
3-(2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)-2,5-dihydro-1H-
-pyrrole-1-carboxylate;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[1-(methylsulfonyl)pyrrolidin-3-yl]--
3,4'-bipyridine; Ethyl
5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-4-carbo-
xylate;
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole--
4-carboxylic acid;
N-Cyclopentyl-5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imi-
dazole-4-carboxamide;
2'-[5-Methyl-4-(morpholin-4-ylcarbonyl)-1H-imidazol-2-yl]-5-(methylsulfon-
yl)-3,4'-bipyridine;
(3R)-1-({5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-
-4-yl}carbonyl)pyrrolidin-3-ol;
(3S)-1-({5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-
-4-yl}carbonyl)pyrrolidin-3-ol;
1-({5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-4-yl-
}carbonyl)azetidin-3-ol;
1-({5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-4-yl-
}carbonyl)azetidine-3-carbonitrile;
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-4-carbo-
xamide;
N,5-Dimethyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidaz-
ole-4-carboxamide;
N,N,5-Trimethyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole--
4-carboxamide;
N-Ethyl-5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-
-4-carboxamide;
N-Isopropyl-5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imida-
zole-4-carboxamide;
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-N-(tetrahydro-2H-pyr-
an-4-yl)-1H-imidazole-4-carboxamide;
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-N-[(3S)-tetrahydrofu-
ran-3-yl]-1H-imidazole-4-carboxamide;
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-N-[(3R)-tetrahydrofu-
ran-3-yl]-1H-imidazole-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxy-
lic acid;
N-Cyclopentyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-
-1H-imidazole-4-carboxamide;
N-Isopropyl-N,5-dimethyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imi-
dazole-4-carboxamide;
N-Ethyl-N,5-dimethyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazo-
le-4-carboxamide;
N,5-Dimethyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-(tetrahydrofuran-
-3-yl)-1H-imidazole-4-carboxamide;
2'-(5-Methyl-4-{[3-(trifluoromethyl)azetidin-1-yl]carbonyl})-1H-imidazol--
2-yl)-5-morpholin-4-yl-3,4'-bipyridine;
2'-{4-[(3-Methoxyazetidin-1-yl)carbonyl]-5-methyl-1H-imidazol-2-yl}-5-mor-
pholin-4-yl-3,4'-bipyridine; tert-Butyl
(1-{[5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]-
carbonyl}azetidin-3-yl)carbamate;
N-Cyclohexyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidaz-
ole-4-carboxamide;
N-(tert-Butyl)-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imid-
azole-4-carboxamide;
2'-{4-[(3,3-Dimethylazetidin-1-yl)carbonyl]-5-methyl-1H-imidazol-2-yl}-5--
morpholin-4-yl-3,4'-bipyridine;
N-Isopropyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazo-
le-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-(tetrahydro-2H-pyran-
-4-yl)-1H-imidazole-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-[(3R)-tetrahydrofura-
n-3-yl]-1H-imidazole-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-[(3S)-tetrahydrofura-
n-3-yl]-1H-imidazole-4-carboxamide;
N-Benzyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole--
4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-[(1S)-1-phenylethyl]-
-1H-imidazole-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-[(1R)-1-phenylethyl]-
-1H-imidazole-4-carboxamide;
N-[(1R)-2-Methoxy-1-phenylethyl]-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyri-
din-2'-yl)-1H-imidazole-4-carboxamide; N-[(1 S)-2-Methoxy-1-phenyl
ethyl]-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4--
carboxamide;
N-[1-(3-Fluorophenyl)ethyl]-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2-
'-yl)-1H-imidazole-4-carboxamide;
N-2-Adamantyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imida-
zole-4-carboxamide; N-[(3S)-1-Benzylpyrrolidin-3-yl]-S
-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxam-
ide;
N-[(3R)-1-Benzylpyrrolidin-3-yl]-5-methyl-2-(5-morpholin-4-yl-3,4'-bi-
pyridin-2'-yl)-1H-imidazole-4-carboxamide;
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-N-(tetrahydro-2H-thiop-
yran-4-yl)-1H-imidazole-4-carboxamide;
N-(2,3-Dihydro-1H-inden-2-yl)-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-
-2'-yl)-1H-imidazole-4-carboxamide;
N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]m-
ethyl}tetrahydro-2H-pyran-4-amine;
N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]
methyl}cyclopentanamine;
N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]
methyl}propan-2-amine;
(3S)--N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol--
4-yl]methyl}tetrahydrofuran-3-amine;
(3R)--N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol--
4-yl]methyl}tetrahydrofuran-3-amine;
N-Methyl-1-[5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazo-
l-4-yl]methanamine;
N,N-Dimethyl-1-[5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imi-
dazol-4-yl]methanamine;
2-Methoxy-N-{[5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imida-
zol-4-yl]methyl}ethanamine;
3-Methoxy-N-{[5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imida-
zol-4-yl]methyl}propan-1-amine;
2'-[5-Methyl-4-(morpholin-4-ylmethyl)-1H-imidazol-2-yl]-5-morpholin-4-yl--
3,4'-bipyridine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]methanol;
4-(1-(4-Chlorobenzyl)-1H-pyrazol-4-yl)-2-(4,5-dimethyl-1H-imidazol-2-yl)p-
yridine; and
(2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-N-[(3S)--
tetrahydrofuran-3-yl]-1H-imidazole-4-carboxamide; or a
pharmaceutically acceptable salt or tautomer of any of the
aforementioned.
69. The compound of claim 1, wherein the compound is selected from:
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(tetrahydrofuran-3-ylmethyl)-3,4'-bi-
pyridin-5-amine;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-N-(1-phenylethyl)-3,4'-bipyridin-5-ami-
ne;
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-{[(3S)-3-methoxypyrrolidin-1-yl]c-
arbonyl}-3,4'-bipyridine;
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N,5-dimethyl-1H-im-
idazole-4-carboxamide;
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-1H-imidaz-
ole-4-carbonitrile;
N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-2'-(4-methyl-1H-imidazol-2-yl)-[-
3,4'-bipyridine]-5-sulfonamide;
N-((1r,4r)-4-Hydroxycyclohexyl)-2'-(4-methyl-1H-imidazol-2-yl)-[3,4'-bipy-
ridine]-5-sulfonamide;
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-{4-[1-(methylsulfonyl)pyrrolidin-
-3-yl]-1H-imidazol-2-yl}pyridine;
2-[4-(1-Acetylpyrrolidin-3-yl)-1H-imidazol-2-yl]-4-[1-(4-chlorobenzyl)-1H-
-pyrazol-4-yl]pyridine;
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-{4-[1-(phenylsulfonyl)pyrrolidin-
-3-yl]-1H-imidazol-2-yl}pyridine;
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-pyrrolidin-3-yl-1H-imidazol-2-
-yl)pyridine;
N-(2-Methoxyphenyl)-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-
-imidazol-4-amine; and
N-[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]py-
ridazin-4-amine; or a pharmaceutically acceptable salt or tautomer
of any of the aforementioned.
70. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or tautomer thereof, and a
pharmaceutically acceptable excipient or carrier.
71. A method of inhibiting the activity of PI3K.gamma. kinase,
comprising contacting the PI3K.gamma. kinase with a compound of
claim 1, or a pharmaceutically acceptable salt or tautomer
thereof.
72-73. (canceled)
74. A method of treating a disease or disorder in a patient,
wherein said disease or disorder is associated with abnormal
expression or activity of PI3K.gamma. kinase, comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1, or a pharmaceutically acceptable salt or
tautomer thereof.
75. (canceled)
76. The method of claim 74, wherein disease or disorder is lung
cancer, melanoma, pancreatic cancer, breast cancer, prostate
cancer, liver cancer, color cancer, endometrial cancer, bladder
cancer, skin cancer, cancer of the uterus, renal cancer, gastric
cancer, or sarcoma.
77. The method of claim 76, wherein the sarcoma is Askin's tumor,
sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant
hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar
soft part sarcoma, angiosarcoma, cystosarcoma phyllodes,
dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small
round cell tumor, epithelioid sarcoma, extraskeletal
chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,
gastrointestinal stromal tumor (GIST), hemangiopericytoma,
hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,
lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath
tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial
sarcoma, or undifferentiated pleomorphic sarcoma.
78. The method of claim 74, wherein the disease or disorder is
acute myeloid leukemia, acute monocytic leukemia, small
lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic
myelogenous leukemia (CML), multiple myeloma, T-cell actute
lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large
granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm
(PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic
lymphoma.
79. The method of claim 78, wherein the mature (peripheral) t-cell
neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular
lymphocytic leukemia, aggressive NK-cell leukemia, mycosis
fungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell
type), enteropathy type T-cell lymphoma, adult T-cell
leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma.
80. The method of claim 78, wherein the anaplastic large cell
lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.
81. The method of claim 74, wherein the disease or disorder is
Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid
leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell
leukemia, Mantle cell lymphoma, small lymphocytic lymphoma,
follicular lymphoma, lymphoplasmacytic lymphoma, extranodal
marginal zone lymphoma, Waldenstrom's macroglobulinemia,
prolymphocytic leukemia, acute lymphoblastic leukemia,
myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma,
mediastinal (thymic) large B-cell lymphoma, lymphomatoid
granulomatosis, splenic marginal zone lymphoma, primary effusion
lymphoma, intravascular large B-cell lymphoma, plasma cell
leukemia, extramedullary plasmacytoma, smouldering myeloma,
monoclonal gammopathy of undetermined significance (MGUS), or
diffuse large B cell lymphoma.
82. The method of claim 81, wherein non-Hodgkin's lymphoma (NHL) is
relapsed NHL, refractory NHL, recucurrent follicular NHL, indolent
NHL (iNHL), or aggressive NHL (aNHL).
83. The method of claim 81, wherein the diffuse large B cell
lymphoma is activated B-cell like (ABC) diffuse large B cell
lymphoma, or germinal center B cell (GCB) diffuse large B cell
lymphoma.
84. The method of claim 81, wherein the Burkitt's lymphoma is
endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or
Burkitt's-like lymphoma.
85. The method of claim 74, wherein the disease or disorder is
rheumatoid arthritis, multiple sclerosis, systemic lupus
erythematous, asthma, allergy, pancreatitis, psoriasis,
anaphylaxis, glomerulonephritis, inflammatory bowel disease,
thrombosis, meningitis, encephalitis, diabetic retinopathy, benign
prostatic hypertrophy, myasthenia gravis, Sjogren's syndrome,
osteoarthritis, restenosis, or atherosclerosis.
86. The method of claim 74, wherein the disease or disorder is
heart hypertropy, cardiac myocyte dysfunction, chronic obstructive
pulmonary disease (COPD), elevated blood pressure, ischemia,
ischemia-reperfusion, vasoconstriction, anemia, bacterial
infection, viral infection, graft rejection, kidney disease,
anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal
muscle hypertrophy, angiogenesis, sepsis, graft rejection,
glomerulosclerosis, progressive renal fibrosis, idiopathic
thrombocytopenic purpura (ITP), autoimmune hemolytic anemia,
vasculitis, systemic lupus erythematosus, lupus nephritis,
pemphigus, or membranous nephropathy.
87. The method of claim 86, wherein the idiopathic thrombocytopenic
purpura (ITP) is relapsed ITP or refractory ITP.
88. The method of claim 86, wherein the vasculitis is Behcet's
disease, Cogan's syndrome, giant cell arteritis, polymyalgia
rheumatica (PMR), Takayasu's arteritis, Buerger's disease, central
nervous system vasculitis, Kawasaki disease, polyarteritis nodosa,
Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis,
Henoch-Schonlein purpura (HSP), hypersensitivity vasculitis,
microscopic polyangiitis, Wegener's granulomatosis, or
anti-neutrophil cytoplasm antibody associated (ANCA) systemic
vasculitis (AASV).
89. The method of claim 74, wherein the disease or disorder is
Alzheimer's disease, central nervous system trauma, or stroke.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Ser. No.
62/274,942, filed Jan. 5, 2016, the disclosure of which is
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure provides pyridine and pyrimidine
compounds that modulate the activity of phosphoinositide
3-kinases-gamma (PI3K.gamma.) and are useful in the treatment of
diseases related to the activity of PI3K.gamma. including, for
example, autoimmune diseases, cancer, cardiovascular diseases, and
neurodegenerative diseases.
BACKGROUND
[0003] The phosphoinositide 3-kinases (PI3Ks) belong to a large
family of lipid signaling kinases that phosphorylate
phosphoinositides at the D3 position of the inositol ring (Cantley,
Science, 2002, 296(5573):1655-7). PI3Ks are divided into three
classes (class I, II, and III) according to their structure,
regulation and substrate specificity. Class I PI3Ks, which include
PI3K.alpha., PI3K.beta., PI3K.gamma., and PI3K.delta. are a family
of dual specificity lipid and protein kinases that catalyze the
phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP.sub.2)
giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP.sub.3).
PIP.sub.3 functions as a second messenger that controls a number of
cellular processes, including growth, survival, adhesion and
migration. All four class I PI3K isoforms exist as heterodimers
composed of a catalytic subunit (p110) and a tightly associated
regulatory subunit that controls their expression, activation, and
subcellular localization. PI3K.alpha., PI3K.beta. and PI3K.delta.
associate with a regulatory subunit known as p85 and are activated
by growth factors and cytokines through a tyrosine kinase-dependent
mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62)
whereas PI3K.gamma. associates with two regulatory subunits (p101
and p84) and its activation is driven by the activation of
G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,
160(1):89-99). PI3K.alpha. and PI3K.beta..quadrature. are
ubiquitously expressed. In contrast, PI3K.gamma. and PI3K.delta.
are predominantly expressed in leukocytes (Vanhaesebroeck, et al.,
Trends Biochem Sci., 2005, 30(4):194-204).
[0004] Expression of PI3K.gamma. is mainly restricted to
hematopoietic system, although it can be also detected at lower
level in endothelium, heart and brain. PI3K.gamma. knock-out or
kinase dead knock in mice are normal and fertile and do not present
any overt adverse phenotypes. Analysis at the cellular level
indicates that PI3K.gamma. is required for GPCR ligand-induced
PtdINs (3,4,5)P3 production, chemotaxis and respiratory burst in
neutrophils. PI3K.gamma.-null macrophages and dendritic cell
exhibit reduced migration towards various chemoattractants. T-cells
deficient in PI3K.gamma. show impaired cytokine production in
response to anti-CD3 or Con A stimulation. PI3K.gamma. working
downstream of adenosine A3A receptor is critical for sustained
degranulation of mast cells induced by FC.epsilon.RI cross-linking
with IgE. PI3K.gamma. is also essential for survival of eosinophils
(Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)
[0005] Given its unique expression pattern and cellular functions,
the potential role of PI3K.gamma. in various autoimmune and
inflammatory disease models has been investigated with genetic and
pharmacological tools. In asthma and allergy models,
PI3K.gamma..sup.-/- mice or mice treated with PI3K.gamma. inhibitor
showed a defective capacity to mount contact hypersensitivity and
delayed-type hypersensitivity reactions. In these models,
PI3K.gamma. was shown to be important for recruitment of
neutrophils and eosinopohils to airways and degranulation of mast
cells (see e.g. Laffargue et al., Immunity, 2002, 16, 441-451;
Prete et al., The EMBO Journal, 2004, 23, 3505-3515; Pinho et al.,
L. Leukocyte Biology, 2005, 77, 800-810; Thomas et al., Eur. J.
Immunol. 2005, 35, 1283-1291; Doukas et al., J. Pharmacol. Exp
Ther. 2009, 328, 758-765).
[0006] In two different acute pancreatitis models, genetic ablation
of PI3K.gamma. significantly reduced the extent of acinar cell
injury/necrosis and neutrophil infiltration without any impact on
secretive function of isolated pancreatic acini (Lupia et al., Am.
J. Pathology, 2004, 165, 2003-2011). PI3K.gamma..sup.-/- mice were
largely protected in four different models of rheumatoid arthritis
(CIA, .alpha.-CII-IA, K/BxN serum transfer and TNF transgenic) and
PI3K.gamma. inhibition suppressed the progression of joint
inflammation and damage in the CIA and .alpha.-CII-IA models (see
e.g., Camps et al., Nat. Medicine, 2005, 11, 939-943; Randis et
al., Eur. J. Immunol, 2008, 38, 1215-1224; Hayer et al., FASB J.,
2009, 4288-4298). In the MRL-lpr mouse model of human systemic
lupus erythematous, inhibition of PI3K.gamma. reduced
glomerulonephritis and prolonged life span (Barber et al., Nat.
Medicine, 2005, 9, 933-935).
[0007] There is evidence suggesting that chronic inflammation due
to infiltration by myeloid-derived cells is a key component in the
progression of neurodegeneration diseases, such as Alzheimer's
disease (AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005,
289, C264-C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In
line with this suggestion, PI3K.gamma. inhibition was shown to
attenuate A.beta.(1-40)-induced accumulation of activated
astrocytes and microglia in the hippocampus and prevent the
peptide-induced congnitive deficits and synaptic dysfunction in a
mouse model of AD (Passos et al., Brain Behav. Immun. 2010, 24,
493-501). PI3K.gamma. deficiency or inhibition also was shown to
delay onset and alleviate symptoms in experimental autoimmune
encephalomyelitis in mice, a mouse model of human multiple
sclerosis, which is another form of neurodegeneration disease (see
e.g., Rodrigues et al., J. Neuroimmunol. 2010, 222, 90-94; Berod et
al., Euro. J. Immunol. 2011, 41, 833-844; Comerford et al., PLOS
one, 2012, 7, e45095; Li et al., Neuroscience, 2013, 253,
89-99).
[0008] Chronic inflammation has been formally recognized as one of
the hallmarks for many different types of cancers. Accordingly,
selective anti-inflammatory drugs represent a novel class of
anti-cancer therapies (Hanahan and Weinberg, Cell, 2011, 144,
646-674). Since PI3K.gamma. is reported to mediate various
inflammatory processes, its role as an immune oncology target has
also been investigated. A recent study reported that PI3K.gamma.
deficiency suppressed tumor growth in the syngeneic models of lung
cancer, pancreatic cancer and melanoma (LLC, PAN02 and B16).
PI3K.gamma. deficiency or inhibition also inhibited tumor growth in
a spontaneous breast cancer model (Schmid et al., Cancer Cell,
2011, 19, 715-727). A further study reported that PI3K.gamma.
deficiency could ameliorate inflammation and tumor growth in mice
having colitis-associated colon cancer, (Gonzalez-Garcia et al.,
Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic
analysis indicates that tumor infiltration by CD11b.sup.+ myeloid
cells can cause protumorigenic inflammation at tumor sites and
PI3K.gamma. in the myeloid cells is critical in mediating signaling
of various chemoattractants in bring the cells to the tumor (Schmid
et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that
PI3K.gamma. is also required for differentiation of naive myeloid
cells into M2 macrophages at tumor sites. M2 macrophages promote
tumor growth and progression by secreting immunosuppressive factors
such arginase 1, which depletes the tumor microenvironment of
arginine, thereby promoting T-cell death and NK cell inhibition
(Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract, 411;
Kaneda et al., Cancer Res., 74 (Suppl 19: Abstract 3650)).
[0009] In addition to its potential role in promoting
protumorigenic microenvironment, PI3K.gamma. may play a direct role
in cancer cells. PI3K.gamma. is reported to be required for
signaling from the Kaposi's sarcoma-associated herpevirus encoded
vGPCR oncogene and tumor growth in a mouse model of sarcoma (Martin
et al., Cancer Cell, 2011, 19, 805-813). PI3K.gamma. was also
suggested to be required for growth of T-ALL (Subramanjam et al.,
Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells (Falasca and
Maffucci, Frontiers in Physiology, 2014, 5, 1-10). Moreover, in a
survey of driver mutations in pancreatic cancer, PI3K.gamma. gene
was found to contain second highest scoring predicted driven
mutation (R839C) among the set of genes not previously identified
as a driver in pancreatic cancer (Carter et al., Cancer Biol. Ther.
2010, 10, 582-587).
[0010] Finally, PI3K.gamma. deficiency also has been reported to
offer protection to experimental animals in different
cardiovascular disease models. For examples, lack of PI3K.gamma.
would reduce angiotension-evoked smooth muscle contraction and,
therefore, protect mice from angiotension-induced hypertension
(Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). In rigorous
animal myocardial infarction models, PI3K.gamma. inhibition
provided potent cardioprotection, reducing infarct development and
preserving myocardial function (Doukas et al., Proc. Natl. Acad.
Sci. USA, 2006, 103, 19866-19871).
[0011] For these reasons, there is a need to develop new
PI3K.gamma. inhibitors that can be used for the treatment of
diseases such as cancer, autoimmune disorders, and inflammatory and
cardiac diseases. This application is directed to this need and
others.
SUMMARY
[0012] The present disclosure relates to, inter alia, compounds of
Formula I:
##STR00002##
wherein X, Y, Z, V, W, A, R.sup.1, R.sup.2, and n are described
herein.
[0013] The present disclosure further provides pharmaceutical
compositions comprising a compound of Formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0014] The present disclosure further provides methods of
inhibiting an activity of PI3K.gamma. kinase comprising contacting
the kinase with a compound of Formula I, or a pharmaceutically
acceptable salt thereof.
[0015] The present disclosure further provides methods of treating
a disease or a disorder associated with abnormal PI3K.gamma. kinase
expression or activity in a patient by administering to a patient a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
[0016] The present disclosure further provides a compound of
Formula I, or a pharmaceutically acceptable salt thereof, for use
in any of the methods described herein.
[0017] The present disclosure further provides use of a compound of
Formula I, or a pharmaceutically acceptable salt thereof, for the
preparation of a medicament for use in any of the methods described
herein.
DETAILED DESCRIPTION
[0018] The present disclosure provides, inter alia, a compound of
Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof or tautomer thereof,
wherein:
[0019] W is CH and V is CH; or
[0020] W is N and V is CH; or
[0021] W is CH and V is N;
[0022] X is CH, Y is N, and Z is N or CR.sup.4; or
[0023] X is N, Y is N or CR.sup.3, and Z is N or CR.sup.4;
[0024] provided that no more than two of X, Y and Z are N;
[0025] ring A is a monocyclic 4-6 membered azaheterocycloalkyl ring
or a monocyclic 5-6 membered azaheteroaryl ring, each of which has
1, 2, or 3 nitrogen ring members;
[0026] n is 0 or 1;
[0027] R.sup.1 is independently selected from halo, CN, NO.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0028] R.sup.2 is halo, OH, CN, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, cyano-C.sub.1-4 alkyl,
HO--C.sub.1-4 alkyl, C.sub.1-3 alkoxy-C.sub.1-4 alkyl, C.sub.1-6
alkylsulfonyl, or phenylsulfonyl, wherein the phenyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.g
groups;
[0029] R.sup.3 and R.sup.4 are each independently selected from H,
halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1,
OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1OR.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0030] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl;
[0031] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups;
[0032] each R.sup.11 is independently selected from halo, CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2OR.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
NR.sup.c2S(O)R.sup.b2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups;
[0033] each R.sup.13 is independently selected from halo, CN,
NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4 alkylene-Cy.sup.3,
OR.sup.a3, SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, OC(O)R.sup.b3, OC(O)NR.sup.c3R.sup.d3,
NR.sup.c3R.sup.d3, NR.sup.c3OR.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.c3C(O)OR.sup.a3, NR.sup.c3C(O)NR.sup.c3R.sup.d3,
NR.sup.c3S(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2NR.sup.e3R.sup.d3, S(O)R.sup.b3,
S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups;
[0034] Cy.sup.1a is selected from 3-10 membered cycloalkyl and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.11 groups;
[0035] each Cy is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.11 groups;
[0036] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.13 groups;
[0037] each Cy.sup.2 is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.g groups;
[0038] each Cy.sup.3 is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.g groups;
[0039] R.sup.a, R, and R.sup.d is independently selected from H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy, and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.11 groups;
[0040] R.sup.b is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy, and
--C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0041] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-10 membered heterocycloalkyl group or a 5-6 membered heteroaryl
group, each optionally substituted with 1, 2, or 3 independently
selected R.sup.11 groups;
[0042] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0043] R.sup.b1 is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups; or
[0044] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0045] each R.sup.a2, R.sup.c2, and R.sup.d2 are independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.2, and --C.sub.1-4
alkylene-Cy.sup.2; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0046] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.2, and --C.sub.1-4 alkylene-Cy.sup.2; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; or
[0047] alternatively, any R.sup.c2 and R.sup.d2 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0048] each R.sup.a3, R.sup.c3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.3, and --C.sub.1-4
alkylene-Cy.sup.3; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0049] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.3, and --C.sub.1-4 alkylene-Cy.sup.3; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; or
[0050] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g groups;
and
[0051] each R.sup.g is independently selected from OH, NO.sub.2,
CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamoyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
[0052] In some embodiments, the compound is a compound of Formula
I, or a pharmaceutically acceptable salt thereof.
[0053] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.1 is selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups.
[0054] In some embodiments, R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1a, --C.sub.1-4
alkylene-Cy, OR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are optionally substituted with 1, 2, or 3
independently selected R.sup.11 groups.
[0055] In some embodiments, R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1a, --C.sub.1-4
alkylene-Cy, OR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2R.sup.b, and S(O).sub.2R.sup.b; wherein said
C.sub.1-6 alkyl and C.sub.1-4 haloalkyl are optionally substituted
with 1, 2, or 3 independently selected R.sup.11 groups.
[0056] In some embodiments, R.sup.1 is selected from halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1a, --C.sub.1-4
alkylene-Cy, OR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b
NR.sup.c(O)OR.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2R.sup.b, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are optionally substituted with 1, 2, or 3
independently selected R.sup.11 groups.
[0057] In some embodiments, R.sup.1 is C.sub.1-6 alkyl, Cy.sup.1a,
--C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b, or
S(O).sub.2R.sup.b.
[0058] In some embodiments, R.sup.1 is C.sub.1-6 alkyl, Cy.sup.1a,
OCH.sub.3, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
NHR.sup.d, NHC(O)R.sup.b, or S(O).sub.2R.sup.b.
[0059] In some embodiments, R.sup.1 is methyl, ethyl, OCH.sub.3,
morpholinyl, S(O).sub.2R.sup.b, C(O)R.sup.b, or
C(O)NR.sup.cR.sup.d. In some embodiments, R.sup.1 is OCH.sub.3. In
some embodiments, R.sup.1 is morpholinyl. In some embodiments,
R.sup.1 is SO.sub.2CH.sub.3. In some embodiments, R.sup.1 is
C(O)R.sup.b, where R.sup.b is C.sub.1-6 alkyl or Cy. In some
embodiments, R.sup.1 is C(O)NR.sup.cR.sup.d, where R.sup.c and
R.sup.d are independently selected from H, C.sub.1-6 alkyl, and Cy,
or R and R.sup.d together with the N atom to which they are
attached, a 4-6 membered heterocycloalkyl group or a 5-6 membered
heteroaryl group.
[0060] In some embodiments, R.sup.1 is C.sub.1-6 alkyl, optionally
substituted by 1, 2, or 3 independently selected R.sup.11
groups.
[0061] In some embodiments, R.sup.1 is
S(O).sub.2NR.sup.cR.sup.d.
[0062] In some embodiments, R.sup.a, R.sup.c, and R.sup.d are each
independently selected from H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1 or 2 independently selected R.sup.11 groups; R.sup.b is
independently selected from C.sub.1-6 alkyl, Cy, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1 or 2 independently selected R.sup.11 groups; alternatively,
any R and R.sup.d attached to the same N atom, together with the N
atom to which they are attached, form a 4-10 membered
heterocycloalkyl group, which is optionally substituted with 1 or 2
independently selected R.sup.11 groups.
[0063] In some embodiments, R.sup.c and R.sup.d attached to the
same N atom, together with the N atom to which they are attached,
form an azetidine ring, a pyrrolidine ring, an
azabiyclo[2.2.1]-heptane ring, a a piperidine ring, a piperazine
ring, a morpholine ring, an azepane ring, a decahydroisoquinoline
ring, a 2,8-diazaspiro[4.5]decan-1-one ring, a
3-oxa-9-azaspiro[5.5]undecane ring, a 2-oxa-7-azaspiro[3.5]nonane
ring, or a 5-azaspiro[2.4]heptane ring, each of which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups.
[0064] In some embodiments, each Cy is independently 3-7 membered
cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered
heteroaryl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.11 groups.
[0065] In some embodiments, each Cy is independently 3-7 membered
cycloalkyl, 4-6 membered heterocycloalkyl, or phenyl, each of which
is optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups.
[0066] In some embodiment, each Cy is independently cyclopropyl,
cyclobutyl, cyclopentyl,
##STR00004##
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or phenyl, each
of which is optionally substituted by 1 or 2 independently selected
R.sup.11 groups.
[0067] In some embodiments, each Cy is 4-6 membered
heterocycloalkyl, which is optionally substituted by 1 or 2
independently selected R.sup.11 groups.
[0068] In some embodiments, each Cy is independently 3-7 membered
cycloalkyl, which is optionally substituted by 1 or 2 independently
selected R.sup.11 groups.
[0069] In some embodiments, each Cy is phenyl, which is optionally
substituted by 1 or 2 independently selected R.sup.11 groups.
[0070] In some embodiments, each Cy is independently 4-10 membered
heterocycloalkyl, which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.11 groups. In some embodiments, Cy is
morpholinyl.
[0071] In some embodiments, Cy.sup.1a is 4-10 membered
heterocycloalkyl, which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.11 groups.
[0072] In some embodiments, Cy.sup.1a is 5-6 membered
heterocycloalkyl, which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.11 groups.
[0073] In some embodiments, Cy.sup.1a is a pyrrolidine ring, a
dihydropyrrole ring, a morpholine ring, a piperidine ring, a
piperazine ring, a tetrahydrofuran ring, or a tetrahydropyran ring,
each of which is optionally substituted by 1 or 2 independently
selected R.sup.11 groups.
[0074] In some embodiments, each R.sup.11 is independently selected
from halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2OR.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups.
[0075] In some embodiments, each R.sup.11 is independently selected
from halo, CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2,
--C.sub.1-4 alkylene-Cy.sup.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2R.sup.d2,
NR.sup.c2OR.sup.d2, NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.g groups.
[0076] In some embodiments, each R.sup.11 is independently selected
from halo, CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2,
--C.sub.1-4 alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and
S(O).sub.2R.sup.b2; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups.
[0077] In some embodiments, each R.sup.a2, R.sup.c2, and R.sup.d2
are independently selected from H, C.sub.1-6 alkyl, Cy.sup.2;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.g groups; each R.sup.b2 is
independently selected from C.sub.1-6 alkyl and Cy.sup.2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.g groups; alternatively, any R.sup.c2
and R.sup.d2 attached to the same N atom, together with the N atom
to which they are attached, form a 5-6-membered heterocycloalkyl
group optionally substituted with 1 or 2 independently selected
R.sup.g groups.
[0078] In some embodiments, any R.sup.c2 and R.sup.d2 attached to
the same N atom, together with the N atom to which they are
attached, form a pyrrolidine or a morpholine ring, each of which is
optionally substituted with 1 or 2 independently selected R.sup.g
groups.
[0079] In some embodiments, each R.sup.11 is independently
Cy.sup.2.
[0080] In some embodiments, each Cy.sup.2 is independently 6-10
membered aryl.
[0081] In some embodiments, each Cy.sup.2 is independently 4-10
membered heterocycloalkyl.
[0082] In some embodiments, each Cy.sup.2 is independently selected
from 3-10 membered cycloalkyl, 6-10 membered aryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.g groups.
[0083] In some embodiments, each Cy.sup.2 is independently selected
from 3-7 membered cycloalkyl, phenyl, and 4-6 membered
heterocycloalkyl, each of which is optionally substituted by 1 or 2
independently selected R.sup.g groups.
[0084] In some embodiments, each Cy.sup.2 is independently phenyl,
cyclopentyl, piperidinyl, morpholinyl, pyridyl, or pyrazinyl.
[0085] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), n is 1.
[0086] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), n is 0.
[0087] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.2 is halo, OH, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino,
C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino, HO--C.sub.1-4
alkyl, or C.sub.1-3 alkoxy-C.sub.1-4 alkyl.
[0088] In some embodiments, R.sup.2 is halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino,
C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino, or C.sub.1-3
alkoxy-C.sub.1-4 alkyl.
[0089] In some embodiments, R.sup.2 is halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, or
C.sub.1-3 alkoxy-C.sub.1-4 alkyl.
[0090] In some embodiments, R.sup.2 is C.sub.1-4 alkyl, or
C.sub.1-4 haloalkyl.
[0091] In some embodiments, R.sup.2 is C.sub.1-4 alkyl.
[0092] In some embodiments, R.sup.2 is methyl.
[0093] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.3 and R.sup.4 are each independently
selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1OR.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1, wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, or 3
independently selected R.sup.13 groups;
[0094] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl;
[0095] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups.
[0096] In some embodiments, R.sup.3 and R.sup.4 are each
independently selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1,
--C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.b1
NR.sup.c1C(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0097] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0098] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring or a phenyl ring, each of which is
optionally substituted by 1, 2 or 3 independently selected R.sup.13
groups.
[0099] In some embodiments, R.sup.3 and R.sup.4 are each
independently selected from H, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and
NR.sup.c1C(O)R.sup.b1 wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.13
groups;
[0100] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0101] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring or a phenyl ring.
[0102] In some embodiments, R.sup.3 and R.sup.4 are each
independently selected from H, CN, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and
NR.sup.c1C(O)R.sup.b1 wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.13
groups;
[0103] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0104] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring or a phenyl ring.
[0105] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.3 is selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, C(O)NR.sup.c1R.sup.d1, and
C(O)OR.sup.a1, wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.13
groups.
[0106] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.3 is selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, C(O)NR.sup.c1R.sup.d1, and
C(O)OR.sup.a1, wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 independently selected R.sup.13
groups.
[0107] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), R.sup.4 is selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1,
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
or 3 independently selected R.sup.13 groups.
[0108] In some embodiments, R.sup.3 is H or C.sub.1-4 alkyl, and
R.sup.4 is C.sub.1-6 alkyl or Cy.sup.1.
[0109] In some embodiments, R.sup.3 is H or methyl, and R.sup.4 is
methyl or phenyl.
[0110] In some embodiments, R.sup.3 is H and R.sup.4 is phenyl.
[0111] In some embodiments, R.sup.3 is methyl and R.sup.4 is
methyl.
[0112] In some embodiments, R.sup.3 and R.sup.4, taken together
with the carbon atoms to which they are attached form a phenyl
ring.
[0113] In some embodiments, R.sup.3 and R.sup.4, taken together
with the carbon atoms to which they are attached form a cyclopentyl
ring.
[0114] In some embodiments, R.sup.3 is H, C.sub.1-6 alkyl or
C(O)NR.sup.c1R.sup.d1
[0115] In some embodiments, R.sup.3 is H or methyl.
[0116] In some embodiments, R.sup.3 is C(O)NR.sup.c1R.sup.d1
[0117] In some embodiments, R.sup.3 is C(O)NR.sup.c1R.sup.d1, where
R.sup.o1 and R.sup.d1 are independently selected from H, C.sub.1-6
alkyl, and Cy.sup.1, or R.sup.c1 and R.sup.d1 together with the N
atom to which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group.
[0118] In some embodiments, R.sup.3 is H, C.sub.1-6 alkyl,
C(O)OR.sup.b1, or C(O)NR.sup.cR.sup.d1
[0119] In some embodiments, R.sup.3 is H or methyl.
[0120] In some embodiments, R.sup.3 is C(O)OR.sup.b1
[0121] In some embodiments, R.sup.3 is CN.
[0122] In some embodiments, R.sup.a1, R.sup.c1, and R.sup.d1 are
each independently selected from H, C.sub.1-6 alkyl, Cy.sup.1, and
--C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.13 groups; R.sup.b1 are each independently selected from
C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1;
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
3, or 4 independently selected R.sup.13 groups; alternatively, any
R.sup.c1 and R.sup.d1 attached to the same N atom, together with
the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.13 groups.
[0123] In some embodiments, any R.sup.c1 and R.sup.d1 attached to
the same N atom, together with the N atom to which they are
attached, form an azetidine ring, a pyrrolidine ring, or a
morpholine ring, each of which is optionally substituted with 1, 2
or 3 independently selected R.sup.13 groups.
[0124] In some embodiments, each Cy.sup.1 is independently selected
from 3-10 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6
membered heteroaryl, and phenyl, each of which is optionally
substituted by 1, 2, 3, or 4 independently selected R.sup.13
groups.
[0125] In some embodiments, each Cy.sup.1 is independently
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, admantyl,
indenyl, phenyl, piperidinyl, morpholinyl, tetrahydrofuranyl,
tetrahydropyranyl, thiomorpholinyl, and pyridyl, each of which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.13 groups.
[0126] In some embodiments, each Cy.sup.1 is independently 4-10
membered heterocycloalkyl, which is optionally substituted by 1, 2,
3, or 4 independently selected R.sup.13 groups.
[0127] In some embodiments, each Cy.sup.1 is independently 4-6
membered heterocycloalkyl, which is optionally substituted by 1, 2,
3, or 4 independently selected R.sup.13 groups
[0128] In some embodiments, each Cy.sup.1 is independently
azetidinyl, pyrrolidinyl, or morpholinyl.
[0129] In some embodiments, each Cy.sup.1 is independently 3-10
membered cycloalkyl, which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups.
[0130] In some embodiments, each Cy.sup.1 is independently 6-10
membered aryl, which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.13 groups.
[0131] In some embodiments, each Cy.sup.1 is independently phenyl,
pyridyl, cyclopropyl, cyclopentyl, or cyclohexyl.
[0132] In some embodiments, R.sup.4 is methyl, ethyl, CF.sub.3,
phenyl, or NHR.sup.d1.
[0133] In some embodiments, R.sup.4 is methyl.
[0134] In some embodiments, R.sup.4 is CF.sub.3.
[0135] In some embodiments, R.sup.4 is phenyl.
[0136] In some embodiments, R.sup.4 is NHR.sup.d1, wherein R.sup.d1
is selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are each optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups.
[0137] In some embodiments, R.sup.4 is NHR.sup.d1, wherein R.sup.d1
is selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1,
and --C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.13 groups.
[0138] In some embodiments, R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1, or NR.sup.c1R.sup.d1.
[0139] In some embodiments, each R.sup.13 is independently selected
from halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, NR.sup.c3R.sup.d3, NR.sup.c3OR.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
NR.sup.c3C(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups.
[0140] In some embodiments, each R.sup.13 is independently selected
from halo, CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.3,
--C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3,
NR.sup.c3OR.sup.d3, NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
and NR.sup.c3C(O)NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups.
[0141] In some embodiments, each R.sup.13 is selected from halo,
CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, NR.sup.c3R.sup.d3,
NR.sup.c3C(O)OR.sup.a3, and S(O).sub.2NR.sup.c3R.sup.d3; wherein
said C.sub.1-6 alkyl is optionally substituted by 1 or 2
independently selected R.sup.g groups.
[0142] In some embodiments, each R.sup.13 is selected from halo,
CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, NR.sup.c3R.sup.d3,
NR.sup.3C(O)OR.sup.a3, C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
S(O).sub.2R.sup.b3, and S(O).sub.2NR.sup.c3R.sup.d3; wherein said
C.sub.1-6 alkyl is optionally substituted by 1 or 2 independently
selected R.sup.g groups.
[0143] In some embodiments, each R.sup.a3, R.sup.c3, and R.sup.d3
are independently selected from H and C.sub.1-6 alkyl; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; each R.sup.b3 is
independently selected from C.sub.1-6 alkyl, which isoptionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups; alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups.
[0144] In some embodiments, any R.sup.c3 and R.sup.d3 attached to
the same N atom, together with the N atom to which they are
attached, form a morpholine ring.
[0145] In some embodiments, each Cy.sup.3 is independently selected
from 3-7 membered cycloalkyl and 4-6 membered heterocycloalkyl,
each of which is optionally substituted by 1 or 2 independently
selected R.sup.g groups.
[0146] In some embodiments, each Cy.sup.3 is independently
cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl, or
phenyl.
[0147] In some embodiments, each R.sup.g is independently selected
from OH, CN, halo, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, cyano-C.sub.1-3 alkyl, HO--C.sub.1-3
alkyl, amino, C.sub.1-6 alkylamino, and di(C.sub.1-6
alkyl)amino.
[0148] In some embodiments, each R.sup.g is independently selected
from OH, methoxy, and methyl.
##STR00005##
[0149] In some embodiments,
##STR00006##
[0150] In some embodiments,
##STR00007##
[0151] In some embodiments, W is CH and V is CH. In some
embodiments, W is N and V is CH. In some embodiments, W is CH and V
is N.
[0152] In some embodiments of compounds provided herein (e.g.,
compounds of Formula I), ring A is a monocyclic 5-6 membered
azaheterocycloalkyl ring or a 5-6 membered azaheteroaryl ring.
[0153] In some embodiments, ring A is a monocyclic 5-6 membered
azaheteroaryl ring.
[0154] In some embodiments, ring A is a pyrazole ring, a pyridine
ring, an imidazole ring, a tetrahydropyridine ring, a
dihydropyrrolyl ring, or a pyrrole ring. In some embodiments, ring
A is a pyrazole ring, a pyridine ring, an imidazole ring, a
tetrahydropyridine ring, or a dihydropyrrolyl ring. In some
embodiments, ring A is a pyrazole ring or a pyridine ring. In some
embodiments, ring A is a tetrahydropyridine ring or a
dihydropyrrolyl ring. In some embodiments, ring A is pyrazol-3-yl,
pyrazol-5-yl, imidazol-2-yl, pyridin-3-yl, piperidin-3-yl,
1,2,5,6-tetrahydropyridin-4-yl, or 2,5-dihydropyrrol-3-yl.
[0155] In some embodiments:
##STR00008##
[0156] ring A is a monocyclic 5-6 membered azaheterocycloalkyl ring
or a 5-6 membered azaheteroaryl ring;
[0157] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1a,
--C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d1, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0158] R.sup.2 is halo, OH, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, HO--C.sub.1-4 alkyl, or
C.sub.1-3 alkoxy-C.sub.1-4 alkyl;
[0159] R.sup.3 and R.sup.4 are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1OR.sup.d1,
NR.sup.c1C(O)R.sup.b1 NR.sup.c1C(O)OR.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0160] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl; and
[0161] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups.
[0162] In some embodiments:
##STR00009##
[0163] ring A is a monocyclic 5-6 membered azaheterocycloalkyl ring
or a 5-6 membered azaheteroaryl ring;
[0164] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1a,
--C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cOR.sup.d, NR.sup.cC(O)R.sup.b, NR.sup.c(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0165] R.sup.2 is halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, or C.sub.1-3 alkoxy-C.sub.1-4
alkyl;
[0166] R.sup.3 and R.sup.4 are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1, NR.sup.cC(O)OR.sup.b1,
NR.sup.c1(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0167] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl; and
[0168] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups.
[0169] In some embodiments:
##STR00010##
[0170] W is CH and V is CH; or
[0171] W is N and V is CH; or
[0172] W is CH and V is N;
[0173] ring A is a monocyclic 5-6 membered azaheterocycloalkyl ring
or a 5-6 membered azaheteroaryl ring;
[0174] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1a,
--C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cOR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0175] R.sup.2 is halo, OH, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, HO--C.sub.1-4 alkyl, or
C.sub.1-3 alkoxy-C.sub.1-4 alkyl;
[0176] R.sup.3 and R.sup.4 are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1OR.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0177] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl;
[0178] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups;
[0179] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2, OR.sup.a2,
SR.sup.2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2OR.sup.d2, NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups;
[0180] each R.sup.13 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.3, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, 5,
NR.sup.c3R.sup.d3, NR.sup.c3OR.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.c3C(O)OR.sup.a3, NR.sup.c3C(O)NR.sup.c3R.sup.d3,
S(O).sub.2R.sup.b3, and S(O).sub.2NR.sup.c3R.sup.d3; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.g groups;
[0181] each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3, and
S(O).sub.2NR.sup.e3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0182] R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy, and
--C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0183] R.sup.b is independently selected from C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, Cy, and --C.sub.1-4 alkylene-Cy; wherein said
C.sub.1-6 alkyl is optionally substituted with 1 or 2 independently
selected R.sup.11 groups;
[0184] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-10 membered heterocycloalkyl group, which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0185] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1,
and --C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.13 groups;
[0186] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0187] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0188] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, and C.sub.1-4 haloalkyl; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0189] each R.sup.b3 is independently selected from C.sub.1-6 alkyl
and C.sub.1-4 haloalkyl; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0190] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0191] each Cy is independently 3-7 membered cycloalkyl, 4-6
membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, each
of which is optionally substituted by 1, 2, 3, or 4 independently
selected R.sup.11 group;
[0192] Cy.sup.1a is 3-7 membered cycloalkyl, 4-6 membered
heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0193] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl,
and phenyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0194] each Cy.sup.3 is independently selected from -7 membered
cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered
heteroaryl, each of which is optionally substituted by 1 or 2
independently selected R.sup.g groups;
[0195] n is 0 or 1; and
[0196] each R.sup.g is independently selected from OH, NO.sub.2,
CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamoyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
[0197] In some embodiments:
##STR00011##
[0198] W is CH and V is CH; or
[0199] W is N and V is CH; or
[0200] W is CH and V is N;
[0201] ring A is a monocyclic 5-6 membered azaheterocycloalkyl ring
or a 5-6 membered azaheteroaryl ring;
[0202] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, Cy.sup.1a,
--C.sub.1-4 alkylene-Cy, OR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cOR.sup.d, NR.sup.cC(O)R.sup.b, NR.sup.c(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0203] R.sup.2 is halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4
alkylamine, di(C.sub.1-4 alkyl)amino, or C.sub.1-3 alkoxy-C.sub.1-4
alkyl;
[0204] R.sup.3 and R.sup.4 are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
haloalkyl, Cy.sup.1, --C.sub.1-4 alkylene-Cy.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1(O)R.sup.b1, NR.sup.cC(O)OR.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-4 haloalkyl are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.13 groups;
[0205] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, halo, OH, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, amino, C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amino,
cyano-C.sub.1-4 alkyl, HO--C.sub.1-4 alkyl, and C.sub.1-3
alkoxy-C.sub.1-4 alkyl;
[0206] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups;
[0207] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2R.sup.d2,
NR.sup.2OR.sup.d2, NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.g groups;
[0208] each R.sup.13 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, NR.sup.c3R.sup.d3, NR.sup.3OR.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3, and
NR.sup.c3C(O)NR.sup.c3R.sup.d3, wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0209] R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy, and
--C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0210] R.sup.b is independently selected from C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, Cy, and --C.sub.1-4 alkylene-Cy; wherein said
C.sub.1-6 alkyl is optionally substituted with 1 or 2 independently
selected R.sup.11 groups;
[0211] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-10 membered heterocycloalkyl group, which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0212] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1,
and --C.sub.1-4 alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.13 groups;
[0213] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0214] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0215] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, and C.sub.1-4 haloalkyl; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0216] each R.sup.b3 is independently selected from C.sub.1-6 alkyl
and C.sub.1-4 haloalkyl; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0217] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0218] each Cy is independently 3-7 membered cycloalkyl, 4-6
membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, each
of which is optionally substituted by 1, 2, 3, or 4 independently
selected R.sup.11 group;
[0219] Cy.sup.1a is 3-7 membered cycloalkyl, 4-6 membered
heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0220] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl,
and phenyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0221] each Cy.sup.3 is independently selected from 3-7 membered
cycloalkyl and 4-6 membered heterocycloalkyl, each of which is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0222] n is 0 or 1; and
[0223] each R.sup.g is independently selected from OH, CN, halo,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino,
C.sub.1-6 alkylamino, and di(C.sub.1-6 alkyl)amino.
[0224] In some embodiments:
##STR00012##
[0225] ring A is a pyrazole ring, a pyridine ring, an imidazole
ring, a tetrahydropyridine ring, or a dihydropyrrolyl ring;
[0226] W is CH and V is CH; or
[0227] W is N and V is CH; or
[0228] W is CH and V is N;
[0229] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
S(O).sub.2R.sup.b, and and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.1-6 alkyl and C.sub.1-4 haloalkyl are optionally substituted
with 1, 2, or 3 independently selected R.sup.11 groups;
[0230] R.sup.2 is C.sub.1-4 alkyl;
[0231] R.sup.3 and R.sup.4 are each independently selected from H,
CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a,
NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1 wherein said C.sub.1-6
alkyl is optionally substituted with 1, 2, or 3 independently
selected R.sup.13 groups;
[0232] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0233] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, and a phenyl ring
[0234] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0235] each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
S(O).sub.2R.sup.b3, and S(O).sub.2NR.sup.c3R.sup.d3; wherein said
C.sub.1-6 alkyl is optionally substituted by 1 or 2 independently
selected R.sup.g groups;
[0236] R.sup.a, R, and R.sup.d are each independently selected from
H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy; wherein said
C.sub.1-6 alkyl is optionally substituted with 1 or 2 independently
selected R.sup.11 groups;
[0237] R.sup.b is independently selected from C.sub.1-6 alkyl, Cy,
and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is
optionally substituted with 1 or 2 independently selected R.sup.11
groups;
[0238] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-10 membered heterocycloalkyl group, which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0239] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0240] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups;
[0241] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0242] each R.sup.a3, R.sup.c3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, and phenyl; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0243] each R.sup.b3 is independently selected from C.sub.1-6 alkyl
and phenyl; wherein said C.sub.1-6 alkyl is optionally substituted
with 1, 2, 3, or 4 independently selected R.sup.g groups;
[0244] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0245] each Cy is independently 3-7 membered cycloalkyl, 4-6
membered heterocycloalkyl, or phenyl, each of which is optionally
substituted by 1, 2, 3, or 4 independently selected R.sup.11
group;
[0246] Cy.sup.1a is 5-6 membered heterocycloalkyl, which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0247] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl,
and phenyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0248] each Cy.sup.3 is independently selected from 3-7 membered
cycloalkyl and 4-6 membered heterocycloalkyl, each of which is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0249] n is 0 or 1; and
[0250] each R.sup.g is independently selected from OH, C.sub.1-3
alkoxy, and C.sub.1-3 alkyl.
[0251] In some embodiments:
##STR00013##
[0252] W is CH and V is CH; or
[0253] W is N and V is CH; or
[0254] W is CH and V is N;
[0255] ring A is a pyrazole ring, a pyridine ring, an imidazole
ring, a tetrahydropyridine ring, or a dihydropyrrolyl ring;
[0256] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.1-6 alkyl and C.sub.1-4 haloalkyl are optionally substituted
with 1, 2, or 3 independently selected R.sup.11 groups;
[0257] R.sup.2 is C.sub.1-4 alkyl;
[0258] R.sup.3 and R.sup.4 are each independently selected from H,
CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1,
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
or 3 independently selected R.sup.13 groups;
[0259] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0260] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, and a phenyl ring
[0261] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0262] each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
S(O).sub.2R.sup.b3, and S(O).sub.2NR.sup.c3R.sup.d3; wherein said
C.sub.1-6 alkyl is optionally substituted by 1 or 2 independently
selected R.sup.g groups;
[0263] R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.11 groups;
[0264] R.sup.b is independently selected from C.sub.1-6 alkyl, Cy,
and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is
optionally substituted with 1 or 2 independently selected R.sup.11
groups;
[0265] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form
an azetidine ring, a pyrrolidine ring, an azabiyclo[2.2.1]-heptane
ring, a a piperidine ring, a piperazine ring, a morpholine ring, an
azepane ring, a decahydroisoquinoline ring, a
2,8-diazaspiro[4.5]decan-1-one ring, a
3-oxa-9-azaspiro[5.5]undecane ring, a 2-oxa-7-azaspiro[3.5]nonane
ring, or a 5-azaspiro[2.4]heptane ring, each of which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0266] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0267] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups;
[0268] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form an azetidine ring, a pyrrolidine ring, or a morpholine ring,
each of which is optionally substituted with 1, 2 or 3
independently selected R.sup.13 groups;
[0269] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, and phenyl; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0270] each R.sup.b3 is independently selected from C.sub.1-6 alkyl
and phenyl; wherein said C.sub.1-6 alkyl is optionally substituted
with 1, 2, 3, or 4 independently selected R.sup.g groups;
[0271] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a morpholine ring;
[0272] each Cy is independently cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl,
##STR00014##
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or phenyl, each
of which is optionally substituted by 1 or 2 independently selected
R.sup.11 groups;
[0273] Cy.sup.1a is a pyrrolidine ring, a dihydropyrrole ring, a
morpholine ring, a piperidine ring, a piperazine ring, a
tetrahydrofuran ring, or a tetrahydropyran ring, each of which is
optionally substituted by 1 or 2 independently selected R.sup.11
groups;
[0274] each Cy.sup.1 is independently cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, admantyl, indenyl, phenyl, piperidinyl,
morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl,
and pyridyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0275] each Cy.sup.3 is independently cyclopentyl,
tetrahydrofuranyl, or tetrahydropyranyl, or phenyl;
[0276] n is 0 or 1; and
[0277] each R.sup.g is independently selected from OH, methoxy, and
methyl.
[0278] In some embodiments:
##STR00015##
[0279] ring A is a pyrazole ring, a pyridine ring, an imidazole
ring, a tetrahydropyridine ring, or a dihydropyrrolyl ring;
[0280] W is CH and V is CH; or
[0281] W is N and V is CH; or
[0282] W is CH and V is N;
[0283] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2R.sup.b; wherein said C.sub.1-6 alkyl and C.sub.1-4
haloalkyl are optionally substituted with 1, 2, or 3 independently
selected R.sup.11 groups;
[0284] R.sup.2 is C.sub.1-4 alkyl;
[0285] R.sup.3 and R.sup.4 are each independently selected from H,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1 wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3
independently selected R.sup.13 groups;
[0286] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0287] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, and a phenyl ring
[0288] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0289] each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0290] R.sup.a, R.sup.c, and R.sup.d are each independently
selected from H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy;
wherein said C.sub.1-6 alkyl is optionally substituted with 1 or 2
independently selected R.sup.11 groups;
[0291] R.sup.b is independently selected from C.sub.1-6 alkyl, Cy,
and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is
optionally substituted with 1 or 2 independently selected R.sup.11
groups;
[0292] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-10 membered heterocycloalkyl group, which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0293] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0294] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups;
[0295] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0296] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H and C.sub.1-6 alkyl; wherein said C.sub.1-6 alkyl
is optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.g groups;
[0297] each R.sup.b3 is independently selected from C.sub.1-6
alkyl; wherein said C.sub.1-6 alkyl is optionally substituted with
1, 2, 3, or 4 independently selected R.sup.g groups;
[0298] alternatively, any R.sup.o3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0299] each Cy is independently 3-7 membered cycloalkyl, 4-6
membered heterocycloalkyl, or phenyl, each of which is optionally
substituted by 1, 2, 3, or 4 independently selected R.sup.11
group;
[0300] Cy.sup.1a is 5-6 membered heterocycloalkyl, which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0301] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl,
and phenyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0302] each Cy.sup.3 is independently selected from 3-7 membered
cycloalkyl and 4-6 membered heterocycloalkyl, each of which is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0303] n is 0 or 1; and
[0304] each R.sup.g is independently selected from OH, C.sub.1-3
alkoxy, and C.sub.1-3 alkyl.
[0305] In some embodiments:
##STR00016##
[0306] W is CH and V is CH; or
[0307] W is N and V is CH; or
[0308] W is CH and V is N;
[0309] ring A is a pyrazole ring, a pyridine ring, an imidazole
ring, a tetrahydropyridine ring, or a dihydropyrrolyl ring;
[0310] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2R.sup.b; wherein said C.sub.1-6 alkyl and C.sub.1-4
haloalkyl are optionally substituted with 1, 2, or 3 independently
selected R.sup.11 groups;
[0311] R.sup.2 is C.sub.1-4 alkyl;
[0312] R.sup.3 and R.sup.4 are each independently selected from H,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1 wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3
independently selected R.sup.13 groups;
[0313] provided that when both R.sup.3 and R.sup.4 are present,
then one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-4
alkyl, and C.sub.1-4 haloalkyl;
[0314] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, and a phenyl ring
[0315] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, --C.sub.1-4
alkylene-Cy.sup.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein
said C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups;
[0316] each R.sup.13 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, --C.sub.1-4 alkylene-Cy.sup.3, OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3, and
S(O).sub.2NR.sup.e3R.sup.d3; wherein said C.sub.1-6 alkyl is
optionally substituted by 1 or 2 independently selected R.sup.g
groups;
[0317] R.sup.a, R, and R.sup.d are each independently selected from
H, C.sub.1-6 alkyl, Cy, and --C.sub.1-4 alkylene-Cy; wherein said
C.sub.1-6 alkyl is optionally substituted with 1 or 2 independently
selected R.sup.11 groups;
[0318] R.sup.b is independently selected from C.sub.1-6 alkyl, Cy,
and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is
optionally substituted with 1 or 2 independently selected R.sup.11
groups;
[0319] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form
an azetidine ring, a pyrrolidine ring, an azabiyclo[2.2.1]-heptane
ring, a a piperidine ring, a piperazine ring, a morpholine ring, an
azepane ring, a decahydroisoquinoline ring, a
2,8-diazaspiro[4.5]decan-1-one ring, a
3-oxa-9-azaspiro[5.5]undecane ring, a 2-oxa-7-azaspiro[3.5]nonane
ring, or a 5-azaspiro[2.4]heptane ring, each of which is optionally
substituted with 1 or 2 independently selected R.sup.11 groups;
[0320] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy; wherein said C.sub.1-6 alkyl is optionally substituted
with 1, 2, 3, or 4 independently selected R.sup.13 groups;
[0321] R.sup.b1 are each independently selected from C.sub.1-6
alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy.sup.1; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.13 groups;
[0322] alternatively, any R.sup.c1 and R.sup.d1 attached to the
same N atom, together with the N atom to which they are attached,
form an azetidine ring, a pyrrolidine ring, or a morpholine ring,
each of which is optionally substituted with 1, 2 or 3
independently selected R.sup.13 groups;
[0323] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H and C.sub.1-6 alkyl; wherein said C.sub.1-6 alkyl
is optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.g groups;
[0324] each R.sup.b3 is independently selected from C.sub.1-6
alkyl; wherein said C.sub.1-6 alkyl is optionally substituted with
1, 2, 3, or 4 independently selected R.sup.g groups;
[0325] alternatively, any R.sup.c3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a morpholine ring;
[0326] each Cy is independently cyclopropyl, cyclobutyl,
cyclopentyl,
##STR00017##
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or phenyl, each
of which is optionally substituted by 1 or 2 independently selected
R.sup.11 groups;
[0327] Cy.sup.1a is a pyrrolidine ring, a dihydropyrrole ring, a
morpholine ring, a piperidine ring, a piperazine ring, a
tetrahydrofuran ring, or a tetrahydropyran ring, each of which is
optionally substituted by 1 or 2 independently selected R.sup.11
groups;
[0328] each Cy.sup.1 is independently cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, admantyl, indenyl, phenyl, piperidinyl,
morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl,
and pyridyl, each of which is optionally substituted by 1, 2, 3, or
4 independently selected R.sup.13 groups;
[0329] each Cy.sup.3 is independently cyclopentyl,
tetrahydrofuranyl, or tetrahydropyranyl, or phenyl;
[0330] n is 0 or 1; and
[0331] each R.sup.g is independently selected from OH, methoxy, and
methyl.
[0332] In some embodiments:
##STR00018##
[0333] W is CH and V is CH;
[0334] ring A is a pyrazolyl or pyridyl;
[0335] R.sup.1 is selected from halo, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, Cy.sup.1a, --C.sub.1-4 alkylene-Cy, OR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2R.sup.b; wherein said C.sub.1-6 alkyl and C.sub.1-4
haloalkyl are optionally substituted with 1, 2, or 3 independently
selected R.sup.11 groups;
[0336] R.sup.2 is C.sub.1-4 alkyl or C.sub.1-4 haloalkyl;
[0337] one of R.sup.3 and R.sup.4 is selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.1, --C.sub.1-4
alkylene-Cy.sup.1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1, wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3
independently selected R.sup.13 groups;
[0338] and the other of R.sup.3 and R.sup.4 is selected from H,
halo, OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamine,
di(C.sub.1-4 alkyl)amino, cyano-C.sub.1-4 alkyl, HO--C.sub.1-4
alkyl, or C.sub.1-3 alkoxy-C.sub.1-4 alkyl;
[0339] alternatively, R.sup.3 and R.sup.4, taken together with the
carbon atoms to which they are attached form a monocyclic 4-7
membered cycloalkyl ring, a phenyl ring, a monocyclic 4-6 membered
heterocycloalkyl ring, or a monocyclic 5-6 membered heteroaryl
ring, each of which is optionally substituted by 1, 2 or 3
independently selected R.sup.13 groups;
[0340] each R.sup.11 is independently selected from halo, CN,
C.sub.1-6 alkyl, Cy.sup.2, --C.sub.1-4 alkylene-Cy.sup.2,
OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2R.sup.d2, and S(O).sub.2R.sup.b2; wherein said C.sub.1-6
alkyl is optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.g groups;
[0341] each R.sup.13 is independently selected from halo, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, Cy.sup.3, --C.sub.1-4
alkylene-Cy.sup.3, OR.sup.a3, C(O)R.sup.b3, C(O)OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
and S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl are each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.g groups;
[0342] Cy.sup.1a is selected from 4-10 membered heterocycloalkyl,
which is optionally substituted by 1, 2, 3, or 4 independently
selected R.sup.11 groups;
[0343] each Cy is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, and 4-10 membered heterocycloalkyl,
each of which is optionally substituted by 1, 2, 3, or 4
independently selected R.sup.13 groups;
[0344] each Cy.sup.1 is independently selected from 3-10 membered
cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10
membered heterocycloalkyl, each of which is optionally substituted
by 1, 2, 3, or 4 independently selected R.sup.13 groups;
[0345] each Cy.sup.2 is independently selected from 6-10 membered
aryl and 4-10 membered heterocycloalkyl, each of which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.g groups;
[0346] each Cy.sup.3 is independently selected from 3-10 membered
cycloalkyl and 4-10 membered heterocycloalkyl, each of which is
optionally substituted by 1, 2, 3, or 4 independently selected
R.sup.g groups;
[0347] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4 alkylene-Cy;
wherein said C.sub.1-6 alkyl is optionally substituted with 1, 2,
3, or 4 independently selected R.sup.11 groups;
[0348] each R.sup.b is independently selected from C.sub.1-6 alkyl,
Cy, and --C.sub.1-4 alkylene-Cy; wherein said C.sub.1-6 alkyl is
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.11 groups;
[0349] alternatively, any R.sup.c and R.sup.d attached to the same
N atom, together with the N atom to which they are attached, form a
4-6 membered heterocycloalkyl group, which is optionally
substituted with 1, 2, or 3 independently selected R.sup.11
groups;
[0350] R.sup.a1, R.sup.c1, and R.sup.d1 are each independently
selected from H, C.sub.1-6 alkyl, Cy.sup.1, and --C.sub.1-4
alkylene-Cy.sup.1; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.13
groups;
[0351] R.sup.b1 is independently selected from Cy.sup.1, and
--C.sub.1-4 alkylene-Cy.sup.1; or
[0352] alternatively, any R.sup.c and R.sup.d1 attached to the same
N atom, together with the N atom to which they are attached, form a
4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.13
groups;
[0353] each R.sup.a2, R.sup.c2, and R.sup.d2 are independently
selected from H, C.sub.1-6 alkyl, Cy.sup.2, and --C.sub.1-4
alkylene-Cy.sup.2; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0354] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, Cy.sup.2, and --C.sub.1-4
alkylene-Cy.sup.2; wherein said C.sub.1-6 alkyl and C.sub.1-4
haloalkyl are each optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; or
[0355] alternatively, any R.sup.c2 and R.sup.d2 attached to the
same N atom, together with the N atom to which they are attached,
form a 5- or 6-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g
groups;
[0356] each R.sup.a3, R.sup.3, and R.sup.d3 are independently
selected from H, C.sub.1-6 alkyl, Cy.sup.3, and --C.sub.1-4
alkylene-Cy.sup.3; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.g
groups;
[0357] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, Cy.sup.3, and --C.sub.1-4 alkylene-Cy.sup.3; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, 3, or 4
independently selected R.sup.g groups; or
[0358] alternatively, any R.sup.o3 and R.sup.d3 attached to the
same N atom, together with the N atom to which they are attached,
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 independently selected R.sup.g groups;
and
[0359] each R.sup.g is independently selected from OH, CN, halo,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy.
[0360] In any of the previous embodiments, the compound is a
compound of Formula II:
##STR00019##
or a pharmaceutically acceptable salt thereof.
[0361] In any of the previous embodiments, the compound is a
compound of Formula III:
##STR00020##
or a pharmaceutically acceptable salt thereof.
[0362] In any of the previous embodiments, the compound is a
compound of Formula IV:
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0363] In any of the previous embodiments, the compound is a
compound of Formula V:
##STR00022##
or a pharmaceutically acceptable salt thereof.
[0364] In any of the previous embodiments, the compound is a
compound of Formula IIa, Formula IIb, or Formula IIc:
##STR00023##
or a pharmaceutically acceptable salt thereof.
[0365] In any of the previous embodiments, the compound is a
compound of Formula IIa1, Formula IIa2, or Formula IIa3:
##STR00024##
or a pharmaceutically acceptable salt thereof.
[0366] In any of the previous embodiments, the compound is a
compound of Formula IIb1:
##STR00025##
or a pharmaceutically acceptable salt thereof.
[0367] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single
embodiment, can also be provided separately or in any suitable
subcombination.
[0368] The term "n-membered" where n is an integer typically
describes the number of ring-forming atoms in a moiety where the
number of ring-forming atoms is n. For example, piperidinyl is an
example of a 6-membered heterocycloalkyl ring, pyrazolyl is an
example of a 5-membered heteroaryl ring, pyridyl is an example of a
6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is
an example of a 10-membered cycloalkyl group.
[0369] As used herein, the phrase "optionally substituted" means
unsubstituted or substituted. The substituents are independently
selected, and substitution may be at any chemically accessible
position. As used herein, the term "substituted" means that a
hydrogen atom is removed and replaced by a substituent. A single
divalent substituent, e.g., oxo, can replace two hydrogen atoms. It
is to be understood that substitution at a given atom is limited by
valency.
[0370] Throughout the definitions, the term "C.sub.n-m" indicates a
range which includes the endpoints, wherein n and m are integers
and indicate the number of carbons. Examples include C.sub.1-4,
C.sub.1-6, and the like.
[0371] As used herein, the term "C.sub.n-m alkyl", employed alone
or in combination with other terms, refers to a saturated
hydrocarbon group that may be straight-chain or branched, having n
to m carbons. Examples of alkyl moieties include, but are not
limited to, chemical groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher
homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,
1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl
group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,
from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
[0372] As used herein, "C.sub.n-m alkenyl" refers to an alkyl group
having one or more double carbon-carbon bonds and having n to m
carbons. Example alkenyl groups include, but are not limited to,
ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the
like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to
4, or 2 to 3 carbon atoms.
[0373] As used herein, "C.sub.n-m alkynyl" refers to an alkyl group
having one or more triple carbon-carbon bonds and having n to m
carbons. Example alkynyl groups include, but are not limited to,
ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some
embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3
carbon atoms.
[0374] As used herein, the term "C.sub.n-m alkylene", employed
alone or in combination with other terms, refers to a divalent
alkyl linking group having n to m carbons. Examples of alkylene
groups include, but are not limited to, ethan-1,1-diyl,
ethan-1,2-diyl, propan-1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl,
butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,
2-methyl-propan-1,3-diyl, and the like. In some embodiments, the
alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or
1 to 2 carbon atoms.
[0375] As used herein, the term "C.sub.n-m alkoxy", employed alone
or in combination with other terms, refers to a group of formula
--O-alkyl, wherein the alkyl group has n to m carbons. Example
alkoxy groups include, but are not limited to, methoxy, ethoxy,
propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy
and tert-butoxy), and the like. In some embodiments, the alkyl
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0376] As used herein, the term "C.sub.n-m alkylamino" refers to a
group of formula --NH(alkyl), wherein the alkyl group has n to m
carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to
4, or 1 to 3 carbon atoms. Examples of alkylamino groups include,
but are not limited to, N-methylamino, N-ethylamino, N-propylamino
(e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g.,
N-(n-butyl)amino and N-(tert-butyl)amino), and the like.
[0377] As used herein, the term "C.sub.n-m alkoxycarbonyl" refers
to a group of formula --C(O)O-alkyl, wherein the alkyl group has n
to m carbon atoms. In some embodiments, the alkyl group has 1 to 6,
1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups
include, but are not limited to, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl),
butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl),
and the like.
[0378] As used herein, the term "C.sub.n-m alkylcarbonyl" refers to
a group of formula --C(O)-- alkyl, wherein the alkyl group has n to
m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1
to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups
include, but are not limited to, methylcarbonyl, ethylcarbonyl,
propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl),
butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and
the like.
[0379] As used herein, the term "C.sub.n-m alkylcarbonylamino"
refers to a group of formula --NHC(O)-alkyl, wherein the alkyl
group has n to m carbon atoms. In some embodiments, the alkyl group
has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0380] As used herein, the term "C.sub.n-m alkylsulfonylamino"
refers to a group of formula --NHS(O).sub.2-alkyl, wherein the
alkyl group has n to m carbon atoms. In some embodiments, the alkyl
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0381] As used herein, the term "aminosulfonyl" refers to a group
of formula --S(O).sub.2NH.sub.2.
[0382] As used herein, the term "C.sub.n-m alkylaminosulfonyl"
refers to a group of formula --S(O).sub.2NH(alkyl), wherein the
alkyl group has n to m carbon atoms. In some embodiments, the alkyl
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0383] As used herein, the term "di(C.sub.n-m alkyl)aminosulfonyl"
refers to a group of formula --S(O).sub.2N(alkyl).sub.2, wherein
each alkyl group independently has n to m carbon atoms. In some
embodiments, each alkyl group has, independently, 1 to 6, 1 to 4,
or 1 to 3 carbon atoms.
[0384] As used herein, the term "aminosulfonylamino" refers to a
group of formula --NHS(O).sub.2NH.sub.2.
[0385] As used herein, the term "C.sub.n-m alkylaminosulfonylamino"
refers to a group of formula --NHS(O).sub.2NH(alkyl), wherein the
alkyl group has n to m carbon atoms. In some embodiments, the alkyl
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0386] As used herein, the term "di(C.sub.n-m
alkyl)aminosulfonylamino" refers to a group of formula
--NHS(O).sub.2N(alkyl).sub.2, wherein each alkyl group
independently has n to m carbon atoms. In some embodiments, each
alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0387] As used herein, the term "aminocarbonylamino", employed
alone or in combination with other terms, refers to a group of
formula --NHC(O)NH.sub.2.
[0388] As used herein, the term "C.sub.n-m alkylaminocarbonylamino"
refers to a group of formula --NHC(O)NH(alkyl), wherein the alkyl
group has n to m carbon atoms. In some embodiments, the alkyl group
has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0389] As used herein, the term "di(C.sub.n-m
alkyl)aminocarbonylamino" refers to a group of formula
--NHC(O)N(alkyl).sub.2, wherein each alkyl group independently has
n to m carbon atoms. In some embodiments, each alkyl group has,
independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0390] As used herein, the term "C.sub.n-m alkylcarbamyl" refers to
a group of formula --C(O)--NH(alkyl), wherein the alkyl group has n
to m carbon atoms. In some embodiments, the alkyl group has 1 to 6,
1 to 4, or 1 to 3 carbon atoms.
[0391] As used herein, the term "thio" refers to a group of formula
--SH.
[0392] As used herein, the term "C.sub.n-m alkylthio" refers to a
group of formula --S-alkyl, wherein the alkyl group has n to m
carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to
4, or 1 to 3 carbon atoms.
[0393] As used herein, the term "C.sub.n-m alkylsulfinyl" refers to
a group of formula --S(O)-- alkyl, wherein the alkyl group has n to
m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1
to 4, or 1 to 3 carbon atoms.
[0394] As used herein, the term "C.sub.n-m alkylsulfonyl" refers to
a group of formula --S(O).sub.2-alkyl, wherein the alkyl group has
n to m carbon atoms. In some embodiments, the alkyl group has 1 to
6, 1 to 4, or 1 to 3 carbon atoms.
[0395] As used herein, the term "amino" refers to a group of
formula --NH.sub.2.
[0396] As used herein, the term "aryl," employed alone or in
combination with other terms, refers to an aromatic hydrocarbon
group, which may be monocyclic or polycyclic (e.g., having 2, 3 or
4 fused rings). The term "C.sub.n-m aryl" refers to an aryl group
having from n to m ring carbon atoms. Aryl groups include, e.g.,
phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and
the like. In some embodiments, aryl groups have from 6 to 10 carbon
atoms. In some embodiments, the aryl group is phenyl or
naphtyl.
[0397] As used herein, the term "carbamyl" to a group of formula
--C(O)NH.sub.2.
[0398] As used herein, the term "carbonyl", employed alone or in
combination with other terms, refers to a --C(.dbd.O)-- group,
which may also be written as C(O).
[0399] As used herein, the term "carboxy" refers to a --C(O)OH
group.
[0400] As used herein, the term "cyano-C.sub.1-3 alkyl" refers to a
group of formula --(C.sub.1-3 alkylene)-CN.
[0401] As used herein, the term "HO--C.sub.1-3 alkyl" refers to a
group of formula --(C.sub.1-3 alkylene)-OH.
[0402] As used herein, the term "di(C.sub.n-m-alkyl)amino" refers
to a group of formula --N(alkyl).sub.2, wherein the two alkyl
groups each has, independently, n to m carbon atoms. In some
embodiments, each alkyl group independently has 1 to 6, 1 to 4, or
1 to 3 carbon atoms.
[0403] As used herein, the term "di(C.sub.n-m-alkyl)carbamyl"
refers to a group of formula --C(O)N(alkyl).sub.2, wherein the two
alkyl groups each has, independently, n to m carbon atoms. In some
embodiments, each alkyl group independently has 1 to 6, 1 to 4, or
1 to 3 carbon atoms.
[0404] As used herein, "halo" refers to F, Cl, Br, or I. In some
embodiments, a halo is F, Cl, or Br.
[0405] As used herein, "C.sub.n-m haloalkoxy" refers to a group of
formula --O-haloalkyl having n to m carbon atoms. An example
haloalkoxy group is OCF.sub.3. In some embodiments, the haloalkoxy
group is fluorinated only. In some embodiments, the alkyl group has
1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0406] As used herein, the term "C.sub.n-m haloalkyl", employed
alone or in combination with other terms, refers to an alkyl group
having from one halogen atom to 2s+1 halogen atoms which may be the
same or different, where "s" is the number of carbon atoms in the
alkyl group, wherein the alkyl group has n to m carbon atoms. In
some embodiments, the haloalkyl group is fluorinated only. In some
embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0407] As used herein, "cycloalkyl" refers to non-aromatic cyclic
hydrocarbons including cyclized alkyl and/or alkenyl groups.
Cycloalkyl groups can include mono- or polycyclic (e.g., having 2,
3 or 4 fused rings) groups and spirocycles. Ring-forming carbon
atoms of a cycloalkyl group can be optionally substituted by oxo or
sulfido (e.g., C(O) or C(S)).
[0408] Also included in the definition of cycloalkyl are moieties
that have one or more aromatic rings fused (i.e., having a bond in
common with) to the cycloalkyl ring, for example, benzo or thienyl
derivatives of cyclopentane, cyclohexane, and the like. A
cycloalkyl group containing a fused aromatic ring can be attached
through any ring-forming atom including a ring-forming atom of the
fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8,
9, or 10 ring-forming carbons (C.sub.3-10). In some embodiments,
the cycloalkyl is a C.sub.3-10 monocyclic or bicyclic cyclocalkyl.
In some embodiments, the cycloalkyl is a C.sub.3-7 monocyclic
cyclocalkyl. Example cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl,
norpinyl, norcarnyl, and the like. In some embodiments, cycloalkyl
is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0409] As used herein, "heteroaryl" refers to a monocyclic or
polycyclic aromatic heterocycle having at least one heteroatom ring
member selected from sulfur, oxygen, and nitrogen. In some
embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring
members independently selected from nitrogen, sulfur and oxygen. In
some embodiments, any ring-forming N in a heteroaryl moiety can be
an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered
monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom
ring members independently selected from nitrogen, sulfur and
oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic
heteroaryl having 1 or 2 heteroatom ring members independently
selected from nitrogen, sulfur and oxygen.
[0410] In some embodiments, the heteroaryl is a five-membered or
six-membereted heteroaryl ring. A five-membered heteroaryl ring is
a heteroaryl with a ring having five ring atoms wherein one or more
(e.g., 1, 2, or 3) ring atoms are independently selected from N, O,
and S. Exemplary five-membered ring heteroaryls are thienyl, furyl,
pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and
1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl
with a ring having six ring atoms wherein one or more (e.g., 1, 2,
or 3) ring atoms are independently selected from N, O, and S.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,
pyrimidinyl, triazinyl and pyridazinyl.
[0411] As used herein, "heterocycloalkyl" refers to non-aromatic
monocyclic or polycyclic heterocycles having one or more
ring-forming heteroatoms selected from O, N, or S. Included in
heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl groups. Heterocycloalkyl groups can
also include spirocycles. Example heterocycloalkyl groups include
pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran,
oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,
tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,
thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like.
Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl
group can be optionally substituted by oxo or sulfido (e.g., C(O),
S(O), C(S), or S(O).sub.2, etc.). The heterocycloalkyl group can be
attached through a ring-forming carbon atom or a ring-forming
heteroatom. In some embodiments, the heterocycloalkyl group
contains 0 to 3 double bonds. In some embodiments, the
heterocycloalkyl group contains 0 to 2 double bonds. Also included
in the definition of heterocycloalkyl are moieties that have one or
more aromatic rings fused (i.e., having a bond in common with) to
the cycloalkyl ring, for example, benzo or thienyl derivatives of
piperidine, morpholine, azepine, etc. A heterocycloalkyl group
containing a fused aromatic ring can be attached through any
ring-forming atom including a ring-forming atom of the fused
aromatic ring. In some embodiments, the heterocycloalkyl is a
monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur and having
one or more oxidized ring members. In some embodiments, the
heterocycloalkyl is a monocyclic or bicyclic 4-10 membered
heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur and having one or more
oxidized ring members.
[0412] As used herein, 4-6 membered azaheterocycloalkyl ring is a
monocyclic 4-6 membered heterocycloalkyl ring, having 1, 2, or 3
nitrogen atoms as ring members and optionally having 1-2 additional
heteroatoms independently selected from N, O, and S, provided
valency rules are observed.
[0413] As used herein, 5-6 membered azaheterocycloaryl ring is a
monocyclic 5-6 membered heteroaryl ring, having 1, 2, or 3 nitrogen
atoms as ring members and optionally having 1-2 additional
heteroatoms independently selected from N, O, and S, provided
valency rules are observed and the ring remains aromatic.
[0414] As used herein, the term "oxo" refers to an oxygen atom as a
divalent substituent, forming a carbonyl group when attached to a
carbon (e.g., C.dbd.O), or attached to a heteroatom forming a
sulfoxide or sulfone group.
[0415] At certain places, the definitions or embodiments refer to
specific rings (e.g., an azetidine ring, a pyridine ring, etc.).
Unless otherwise indicated, these rings can be attached to any ring
member provided that the valency of the atom is not exceeded. For
example, an azetidine ring may be attached at any position of the
ring, whereas a pyridin-3-yl ring is attached at the
3-position.
[0416] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present disclosure that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically inactive starting materials
are known in the art, such as by resolution of racemic mixtures or
by stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present disclosure. Cis and trans geometric
isomers of the compounds of the present disclosure are described
and may be isolated as a mixture of isomers or as separated
isomeric forms. In some embodiments, the compound has the
(R)-configuration. In some embodiments, the compound has the
(S)-configuration.
[0417] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are, for
example, optically active acids, such as the D and L forms of
tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids such as 0-camphorsulfonic acid. Other
resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of .alpha.-methylbenzylamine
(e.g., S and R forms, or diastereomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,
cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
[0418] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0419] Compounds provided herein also include tautomeric forms.
Tautomeric forms result from the swapping of a single bond with an
adjacent double bond together with the concomitant migration of a
proton. Tautomeric forms include prototropic tautomers which are
isomeric protonation states having the same empirical formula and
total charge. Example prototropic tautomers include ketone-enol
pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine
pairs, and annular forms where a proton can occupy two or more
positions of a heterocyclic system, for example, 1H- and
3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole,
and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or
sterically locked into one form by appropriate substitution.
[0420] All compounds, and pharmaceutically acceptable salts
thereof, can be found together with other substances such as water
and solvents (e.g. hydrates and solvates) or can be isolated.
[0421] In some embodiments, preparation of compounds can involve
the addition of acids or bases to affect, for example, catalysis of
a desired reaction or formation of salt forms such as acid addition
salts.
[0422] Example acids can be inorganic or organic acids and include,
but are not limited to, strong and weak acids. Some example acids
include hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid,
methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid,
and nitric acid. Some weak acids include, but are not limited to
acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric
acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid,
nonanoic acid, and decanoic acid.
[0423] Example bases include lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, potassium
carbonate, and sodium bicarbonate. Some example strong bases
include, but are not limited to, hydroxide, alkoxides, metal
amides, metal hydrides, metal dialkylamides and arylamines,
wherein; alkoxides include lithium, sodium and potassium salts of
methyl, ethyl and t-butyl oxides; metal amides include sodium
amide, potassium amide and lithium amide; metal hydrides include
sodium hydride, potassium hydride and lithium hydride; and metal
dialkylamides include lithium, sodium, and potassium salts of
methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,
trimethylsilyl and cyclohexyl substituted amides.
[0424] In some embodiments, the compounds provided herein, or salts
thereof, are substantially isolated. By "substantially isolated" is
meant that the compound is at least partially or substantially
separated from the environment in which it was formed or detected.
Partial separation can include, for example, a composition enriched
in the compounds provided herein. Substantial separation can
include compositions containing at least about 50%, at least about
60%, at least about 70%, at least about 80%, at least about 90%, at
least about 95%, at least about 97%, or at least about 99% by
weight of the compounds provided herein, or salt thereof. Methods
for isolating compounds and their salts are routine in the art.
[0425] The term "compound" as used herein is meant to include all
stereoisomers, geometric isomers, tautomers, and isotopes of the
structures depicted. Compounds herein identified by name or
structure as one particular tautomeric form are intended to include
other tautomeric forms unless otherwise specified.
[0426] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0427] The present application also includes pharmaceutically
acceptable salts of the compounds described herein. The present
disclosure also includes pharmaceutically acceptable salts of the
compounds described herein. As used herein, "pharmaceutically
acceptable salts" refers to derivatives of the disclosed compounds
wherein the parent compound is modified by converting an existing
acid or base moiety to its salt form. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts of the present
disclosure include the conventional non-toxic salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. The pharmaceutically acceptable salts of the present
disclosure can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or
butanol) or acetonitrile (ACN) are preferred. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17th ed.,
Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of
Pharmaceutical Science, 66, 2 (1977), each of which is incorporated
herein by reference in its entirety.
Synthesis
[0428] As will be appreciated, the compounds provided herein,
including salts thereof, can be prepared using known organic
synthesis techniques and can be synthesized according to any of
numerous possible synthetic routes.
[0429] Compounds described herein, wherein W and Y are N, C--H, or
C--R.sup.4, can be prepared as shown in Scheme 1. Halo-containing
starting materials (1-1) can be reacted with M-Cy, where M is a
boronic acid, boronic ester, or an appropriately substituted metal
such as Sn(Bu).sub.4 or Zn, under standard Suzuki conditions or
standard Stille conditions (e.g., in the presence of a palladium(0)
catalyst, such as tetrakis(triphenylphosphine)palladium(0) or
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) and a base (e.g., a bicarbonate or carbonate base, or CsF) or
standard Negishi conditions (e.g., in the presence of a
palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)), to give derivative 1-2.
The nitrile of intermediate 1-2 can be converted to a substituted
imidazole as shown in 1-3 via several routes, some of which are
outlined in Scheme 2. The order of steps can be reversed, such that
imidazole formation to furnish 1-4 (by methods such as shown in
Scheme 2) can precede the coupling to R.sup.1. In this case, the NH
of the heterocycle (1-4) can be optionally protected (e.g., SEM-Cl
and base) to give a N-protected derivative (1-5) which can be
coupled with M-Cy as described for the transformation from 1-1 to
1-2 above, to provide 1-6, which upon N-deprotection (e.g.,
reaction with a strong acid, such as TFA) will furnish compounds
1-3. This and all subsequent preparations in the Schemes can be
contemplated as potentially proceeding by either route, the choice
of which may be dictated by the compatibility of functional groups
present in the intermediates. Alternatively, conversion of
halide-containing intermediates such as 1-1 or 1-5 to a metal M
(e.g., M is B(OR).sub.2, SnR.sub.3, Zn) under standard conditions
can give intermediates that can undergo Suzuki, Stille or Negishi
couplings with appropriate halo-derivatives Cy-X as alternative
ways to access compounds shown in 1-2 or 1-6. Where the nitrile is
not present in starting material 1-1, it can be installed from a
halo-substituent (such as Cl) at the same position in intermediate
1-2 via Negishi coupling with Zn(CN).sub.2 (e.g., in the presence
of a Pd(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)).
##STR00026##
[0430] Useful methods for formation of the imidazole are outlined
in Scheme 2, in which both nitriles and carboxylic acids serve as
useful starting materials. Nitrile 2-1 can be converted to an
imidate (e.g., by reacting with catalytic sodium methoxide in an
alcohol or by reacting with HCl in an alcohol) and the intermediate
imidate can be reacted with an amino ketal or amino acetal (2-2) in
the presence of acid (e.g., AcOH or HCl) and heat to form imidazole
2-3. Alternatively, the intermediate imidate can be reacted with
NH.sub.4Cl to afford an amidine, which can be alkylated with
.alpha.-halo ketones (2-4) in the presence of base (e.g.,
KHCO.sub.3, or K.sub.2CO.sub.3) in a solvent such as an alcohol, or
preferably, DMF, to furnish imidazole 2-3. The imidate intermediate
formed by reacting nitrile 2-1 with catalytic sodium methoxide can
be treated with a diamine (2-5) (e.g., a phenylenediamine
derivative) and cyclized under acidic conditions and heat to afford
imidazole 2-3. Alternatively, carboxylic acid 2-6 can be coupled to
a diamine (2-5) in the presence of a coupling reagent (e.g., HATU
and the like) and base (e.g., Hunig's Base or triethylamine). The
intermediate amide can be cyclized to imidazole 2-3 by heating in
acid (e.g., AcOH). Carboxylic acid 2-6 can also be reacted with
.alpha.-halo ketones (2-4) in the presence of base (e.g.,
K.sub.2CO.sub.3) to afford an ester intermediate that can be heated
in the presence of NH.sub.4OAc to afford imidazole 2-3. The
imidazole formations may be carried out with R=Cy or alternatively,
with R.dbd.X (halo).
##STR00027## ##STR00028## ##STR00029##
[0431] When Cy contains a nucleophilic functional group (e.g.,
illustrated using pyrazole), further transformations may be carried
out as shown in Scheme 3. For example, alkylation of suitably
protected intermediate 3-1 with R.sup.5-LG, where LG is a suitable
leaving group, can be carried out in the presence of base (e.g.,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaH, KOtBu,
etc.) to afford, after N-deprotection, the alkylated product 3-2.
Similarly, reacting with sulfonyl chlorides in the presence of
base, followed by N-deprotection, forms product 3-3. Reacting an
acidic nucleophilic functional group (e.g., pyrazole 3-1) with an
alcohol R.sup.5--OH under standard Mitsunobu conditions (e.g.,
diethylazodicarboxylate and triphenylphosphine), followed by
N-deprotection, provides an alternative route to products 3-2.
Compounds such as 3-5 can be formed by reacting 3-1 with a Michael
acceptor (3-4) (e.g., an acrylate ester or acrylonitrile) in the
presence of base (e.g., carbonate base or DBU) to form, after
N-deprotection, 3-5. Where desired, if R.sup.5 of the alkylated
product contains a manipulatable functional group, further
transformations (e.g., hydrolysis, amide formation, reduction,
alkylation, acylation, sulfonylation) are possible. Similar
transformations may be carried out on suitable electron withdrawing
groups (EWG, e.g. CO.sub.2R, CN) of Michael adducts 3-5.
[0432] Alternative heterocycles may be installed in the compounds
provided herein as shown in Schemes 4 to 7. In Scheme 4, a
regioselective cross-coupling can be achieved with M-Cy at the
4-position of pyridine 4-1. This can be achieved by reacting M-Cy,
where M is a boronic acid, boronic ester, or an appropriately
substituted metal such as Sn(Bu).sub.4 or Zn, under standard Suzuki
conditions or standard Stille conditions (e.g., in the presence of
a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) and a base (e.g., a bicarbonate or carbonate base, or CsF) or
standard Negishi conditions (e.g., in the presence of a
palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)), to give derivative 4-2.
The desired heterocycle (e.g., imidazole isomer 4-3) can be coupled
under Suzuki, Stille or Negishi conditions as described above to
afford (on subsequent N-deprotection) compounds 4-4.
##STR00030## ##STR00031##
##STR00032##
[0433] Compounds containing an amino-imidazole such as 5-5 can be
accessed synthetically by reacting an .alpha.-halo ketone (5-1)
with 2-aminopyrimidine to form intermediate 5-2. After coupling
with M-Cy under standard Suzuki, Stille or Negishi conditions to
afford 5-3, the aminoimidazole moiety can be liberated by reaction
with hydrazine hydrate at elevated temperature (e.g., about
100.degree. C.) to afford 5-4. The amine of 5-4 can be alkylated by
reaction of the amine with an aldehyde (e.g., R.sup.9CHO) in the
presence of a reducing agent (e.g., sodium cyanoborohydride or
sodium triacetoxyborohydride) to give 5-5.
##STR00033##
[0434] Compounds of provided herein containing an aminotriazole can
be prepared by reacting an ester (6-2, prepared by Suzuki, Stille
or Negishi coupling of 6-1 with M-Cy) with hydrazine hydrate at
elevated temperature to form an acyl hydrazide 6-3.
[0435] Intermediate 6-3 can be reacted with an alkylated thiourea
(6-5) in the presence of heat and base (e.g., 2,6-lutidine) to
afford aminotriazole product 6-6. When unavailable commercially,
the requisite reactant 6-5 can be prepared by alkylating available
thiourea 6-4 with methyl iodide.
##STR00034##
[0436] As shown in Scheme 7, triazoles can be formed from 7-2 by
reacting the imidate intermediate derived therefrom (by treatment
of the nitrile with catalytic sodium methoxide) with an acyl
hydrazide (7-3) at elevated temperature to furnish triazoles
7-4.
##STR00035##
[0437] Compounds of provided herein containing imidazoles can be
further functionalized as shown, for example, in Schemes 8 and 9.
For example, an imidazole such as 8-1, containing an
unfunctionalized carbon, can be nitrated (e.g., using HNO.sub.3 in
H.sub.2SO.sub.4) to provide nitro derivative 8-2, which can be
reduced (e.g., using iron in AcOH or in aq. HCl and alcoholic
solvent) to amino derivative 8-3. If R=Cy is not anticipated to be
robust to the conditions, the synthesis may be carried out with
R.dbd.X (halo), and the desired cyclic group (Cy) introduced by
Suzuki, Stille, or Negishi conditions on intermediate 8-2.
##STR00036##
[0438] Compounds of provided herein, 9-3, wherein R.sup.2 contains
a carbonyl group (e.g., ester or aldehyde) may be prepared as shown
in Scheme 9. Imidazole 9-1, containing an unfunctionalized carbon,
can be treated with a halogenating reagent (e.g., N-iodosuccinimide
or N-bromosuccinimide) to form intermediate 9-2. Subjection of an
optionally protected intermediate 9-2 to a Pd-catalyzed
cross-coupling reaction (e.g., CO insertion) can furnish
intermediates 9-3, containing an ester or an aldehyde which may be
further manipulated, for example, as shown in Scheme 10.
Alternative transformations from the iodo-intermediate 9-2 are
possible, such as Suzuki, Stille and Negishi couplings.
##STR00037##
[0439] Following conversion of halo-containing derivative 10-1
(e.g., X.dbd.I or Br) to ester intermediate 10-2, using carbon
monoxide in the presence of methanol and a Pd catalyst (e.g.,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1)), basic hydrolysis (e.g., aq.
NaOH in THF and an alcohol) can be carried out. The resulting
carboxylic acid can be coupled with amines R.sup.11R.sup.12NH to
form amides 10-3 under standard coupling conditions (e.g., HATU in
the presence of Hunig's base or triethylamine). If the CO insertion
on 10-1 is carried out in the absence of alcohol and in the
presence of triethylsilane, aldehydes 10-4 can be prepared. The
aldehyde can be converted to amines (10-5) by reductive amination
with R.sup.11R.sup.12NH in the presence of a reducing agent (e.g.,
sodium cyanoborohydride, sodium triacetoxyborohydride). Numerous
other functional group transformations can be carried out on
intermediates such as 10-4, such as Grignard addition, reduction,
and fluorination (e.g., with Deoxo-Fluor.RTM.).
##STR00038##
[0440] Further transformations can also be carried out on
intermediates wherein Cy contains nucleophilic functionality, for
example, an amine as in 11-1. As shown in Scheme 11, intermediate
11-1 can be treated with reagents R.sup.13-L-X (where L is a linker
and X is a suitable leaving group; e.g., acyl chlorides, sulfonyl
chlorides, chloroformates) in the presence of base (e.g.,
triethylamine) to provide amides, sulfonamides, and carbamates of
11-2, respectively. Reaction of 11-1 with R.sup.13NCO (an
isocyanate) affords ureas, and reductive amination with R.sup.13CHO
in the presence of a reducing agent (e.g., sodium cyanoborohydride,
sodium triacetoxyborohydride) affords alkylated amines.
##STR00039##
[0441] An alternative synthetic route for functionalizing Cy is
illustrated in Scheme 12. A suitably protected halo-containing
intermediate 12-1 (e.g., X.sup.1.dbd.Br) can be coupled with a
chloro-containing boronic acid or ester under Suzuki coupling
conditions to provide 12-2. The chloro-containing intermediate 12-2
can be coupled with an amine R.sup.11R.sup.12NH by heating under
Buchwald/Hartwig conditions (e.g., in the presence of a palladium
catalyst, such as .sup.tBuBrettPhos Pd G3, and a base (e.g., an
alkoxide base or carbonate base)) to give derivative 12-3.
##STR00040##
[0442] Similar chloro-containing intermediates (13-2), bearing
nitrile as a precursor to later imidazole formation, find utility
in Suzuki, Stille, or Negishi couplings to afford groups R.sup.14
(e.g., heterocyclyl) which are C-linked in 13-3. In the case that
M-R.sup.14 is a heterocycle (where M is H and is attached to the
amine nitrogen of amine-containing heterocycle R.sup.14), coupling
to the halide of 13-2 can be performed by heating under
Buchwald/Hartwig conditions (e.g., in the presence of a palladium
catalyst, such as .sup.tBuBrettPhos Pd G3, and a base (e.g., an
alkoxide base or a carbonate base)) to give a derivative 13-4, in
which R.sup.14 is N-linked to the pyridine. Where R.sup.14 contains
suitable functionality, further functional group manipulations can
be carried out as desired and as outlined in examples set forth in
the other Schemes.
##STR00041##
[0443] Further transformations can also be carried out on
intermediates that contain carboxylate functionality on Cy, such as
14-1. The ester can be hydrolyzed (e.g., with aq. NaOH) and coupled
with amines R.sup.11R.sup.12NH under standard conditions (e.g.,
HATU and Hunig's base) to provide amides (14-2). Reduction to the
alcohol can be carried out (e.g., using DIBAL), which can be
followed by numerous subsequent transformations. For example,
re-oxidation to the aldehyde (e.g., using Dess-Martin periodinane)
can provide intermediate 14-3. Among other possible
transformations, the aldehyde (14-3) can undergo reductive
amination to afford amines (14-4) by reaction with
R.sup.11R.sup.12NH and a reducing agent (e.g., sodium
cyanoborohydride, sodium triacetoxyborohydride).
[0444] When M-Cy of Scheme 1 is a partially saturated heterocycle,
further synthetic transformations can be carried out on the coupled
product as shown in Scheme 15. After N-deprotection of 15-1, the
amine 15-2 can be converted to functionalized products 15-3. For
example, 15-2 can be acylated or sulfonylated by reacting with
R.sup.13-L-X (where L is a linker and X is a suitable leaving group
(e.g., acyl chlorides, sulfonyl chlorides, chloroformates) in the
presence of a suitable base, to afford amide, sulfonamide, or
carbamate products. Alternatively, products such as ureas can be
formed by reacting with isocyanates R.sup.13NCO, and alkylated
products can be formed by reductive amination with aldehydes
R.sup.13CHO in the presence of reducing agents. The double bond of
the heterocyclic ring can be hydrogenated to afford the fully
saturated compound 15-4 by reacting with H.sub.2 over a catalyst
(e.g., Palladim on Carbon). Similar transformations can be applied
to heterocyclic rings installed by Suzuki coupling elsewhere on the
compounds provided herein.
##STR00042##
##STR00043##
[0445] The reactions for preparing compounds described herein can
be carried out in suitable solvents which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially non-reactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, (e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature). A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected by the skilled artisan.
[0446] The expressions, "ambient temperature" and "room
temperature" or "rt" as used herein, are understood in the art, and
refer generally to a temperature, e.g. a reaction temperature, that
is about the temperature of the room in which the reaction is
carried out, for example, a temperature from about 20.degree. C. to
about 30.degree. C.
[0447] Preparation of compounds described herein can involve the
protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example,
in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd Ed., Wiley & Sons, Inc., New York
(1999).
[0448] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC), liquid chromatography-mass spectroscopy
(LCMS), or thin layer chromatography (TLC).
[0449] Compounds can be purified by those skilled in the art by a
variety of methods, including high performance liquid
chromatography (HPLC) and normal phase silica chromatography.
Methods of Use
[0450] The compounds or salts described herein inhibit activity of
PI3K.gamma. kinase. Accordingly, the compounds or salts described
herein can be used in methods of inhibiting PI3K.gamma. kinase by
contacting the kinase with any one or more of the compounds, salts,
or compositions described herein. In some embodiments, the
compounds or salts can be used in methods of inhibiting activity of
PI3K.gamma. in an individual in need of said inhibition by
administering an inhibiting amount of a compound or salt thereof
described herein. In some embodiments, the contacting is in vivo.
In some embodiments, the contacting is ex vivo.
[0451] In some embodiments, the PI3K.gamma. includes a mutation. A
mutation can be a replacement of one amino acid for another, or a
deletion of one or more amino acids. In such embodiments, the
mutation can be present in the kinase domain of the
PI3K.gamma..
[0452] In some embodiments, the compound or salt further inhibits
PI3K.delta..
[0453] The compounds or salts described herein can be selective. By
"selective" is meant that the compound binds to or inhibits
PI3K.gamma. with greater affinity or potency, respectively,
compared to at least one other kinase. In some embodiments, the
compounds provided herein are selective inhibitors of PI3K.gamma.
over PI3K.delta., PI3K.alpha., and PI3K.beta.. In some embodiments,
the compounds provided herein are selective inhibitors of
PI3K.gamma. over PI3K.alpha. and PI3K.beta.. In some embodiments,
selectivity can be at least about 2-fold, 3-fold, 5-fold, 10-fold,
20-fold, 50 fold, or 100 fold over PI3K.delta. as measured by the
assays described herein. In some embodiments, selectivity can be
tested at the K.sub.m ATP concentration of each enzyme. In some
embodiments, the selectivity of compounds provided herein can be
determined by cellular assays associated with particular PI3K
kinase activity.
[0454] Another aspect of the present disclosure pertains to methods
of treating a kinase PI3K.gamma.-associated disease or disorder in
an individual (e.g., patient) by administering to the individual in
need of such treatment a therapeutically effective amount or dose
of one or more compounds provided herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition thereof. A
PI3K.gamma.-associated disease or disorder can include any disease,
disorder or condition that is directly or indirectly linked to
expression or activity of the PI3K.gamma., including overexpression
and/or abnormal activity levels.
[0455] In some embodiments, the disease or disorder is an
autoimmune disease or disorder, cancer, cardiovascular disease, or
neurodegenerative disease.
[0456] In some embodiments, the disease or disorder is lung cancer
(e.g., non-small cell lung cancer), melanoma, pancreatic cancer,
breast cancer, prostate cancer, liver cancer, color cancer,
endometrial cancer, bladder cancer, skin cancer, cancer of the
uterus, renal cancer, gastric cancer, or sarcoma. In some
embodiments, the sarcoma is Askin's tumor, sarcoma botryoides,
chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma,
malignant schwannoma, osteosarcoma, alveolar soft part sarcoma,
angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma
protuberans, desmoid tumor, desmoplastic small round cell tumor,
epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal
osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST),
hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma,
leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma,
malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma,
rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic
sarcoma.
[0457] In some embodiments, the disease or disorder is acute
myeloid leukemia (e.g., acute monocytic leukemia), small
lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic
myelogenous leukemia (CML), multiple myeloma, T-cell actute
lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large
granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm
(PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic
lymphoma. In some embodiments, the mature (peripheral) t-cell
neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular
lymphocytic leukemia, aggressive NK-cell leukemia, mycosis
fungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell
type), enteropathy type T-cell lymphoma, adult T-cell
leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma In some
embodiments, the anaplastic large cell lymphoma (ALCL) is systemic
ALCL or primary cutaneous ALCL.
[0458] In some embodiments, the disease or disorder is Burkitt's
lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia,
non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia,
Mantle cell lymphoma, small lymphocytic lymphoma, follicular
lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone
lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia,
acute lymphoblastic leukemia, myelofibrosis, mucosa-associated
lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell
lymphoma, lymphomatoid granulomatosis, splenic marginal zone
lymphoma, primary effusion lymphoma, intravascular large B-cell
lymphoma, plasma cell leukemia, extramedullary plasmacytoma,
smouldering myeloma (aka asymptomatic myeloma), monoclonal
gammopathy of undetermined significance (MGUS), or diffuse large B
cell lymphoma.
[0459] In some embodiments, the non-Hodgkin's lymphoma (NHL) is
relapsed NHL, refractory NHL, recucurrent follicular NHL, indolent
NHL (iNHL), or aggressive NHL (aNHL).
[0460] In some embodiments, the diffuse large B cell lymphoma is
activated B-cell like (ABC) diffuse large B cell lymphoma, or
germinal center B cell (GCB) diffuse large B cell lymphoma.
[0461] In some embodiments, the Burkitt's lymphoma is endemic
Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like
lymphoma
[0462] In some embodiments, the disease or disorder is rheumatoid
arthritis, multiple sclerosis, systemic lupus erythematous, asthma,
allergy, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis,
inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis), thrombosis, meningitis, encephalitis, diabetic
retinopathy, benign prostatic hypertrophy, myasthenia gravis,
Sjogren's syndrome, osteoarthritis, restenosis, or
atherosclerosis.
[0463] In some embodiments, disease or disorder is heart
hypertropy, cardiac myocyte dysfunction, chronic obstructive
pulmonary disease (COPD), elevated blood pressure, ischemia,
ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic
anemia, aplastic anemia, or pure red cell anemia), bacterial
infection, viral infection, graft rejection, kidney disease,
anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal
muscle hypertrophy, angiogenesis, sepsis, graft rejection,
glomerulosclerosis, progressive renal fibrosis, idiopathic
thrombocytopenic purpura (ITP), autoimmune hemolytic anemia,
vasculitis, systemic lupus erythematosus, lupus nephritis,
pemphigus, or membranous nephropathy.
[0464] In some embodiments, the disease or disorder is Alzheimer's
disease, central nervous system trauma, or stroke.
[0465] In some embodiments, the idiopathic thrombocytopenic purpura
(ITP) is relapsed ITP or refractory ITP.
[0466] In some embodiments, the vasculitis is Behcet's disease,
Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica
(PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis
obliterans), central nervous system vasculitis, Kawasaki disease,
polyarteritis nodosa, Churg-Strauss syndrome, mixed
cryoglobulinemia vasculitis (essential or hepatitis C virus
(HCV)-induced), Henoch-Scho{umlaut over (n)}lein purpura (HSP),
hypersensitivity vasculitis, microscopic polyangiitis, Wegener's
granulomatosis, or anti-neutrophil cytoplasm antibody associated
(ANCA) systemic vasculitis (AASV).
[0467] The present disclosure further provides a compound described
herein, or a pharmaceutically acceptable salt thereof, for use in
any of the methods described herein.
[0468] The present disclosure further provides use of a compound
described herein, or a pharmaceutically acceptable salt thereof,
for the preparation of a medicament for use in any of the methods
described herein.
[0469] As used herein, the term "contacting" refers to the bringing
together of indicated moieties in an in vitro system or an in vivo
system. For example, "contacting" a PI3K with a compound of the
disclosure includes the administration of a compound of the present
disclosure to an individual or patient, such as a human, having a
PI3K, as well as, for example, introducing a compound of the
disclosure into a sample containing a cellular or purified
preparation containing the PI3K.
[0470] As used herein, the term "individual" or "patient," used
interchangeably, refers to any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans.
[0471] As used herein, the phrase "therapeutically effective
amount" refers to the amount of active compound or pharmaceutical
agent that elicits the biological or medicinal response that is
being sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician.
[0472] As used herein, the term "treating" or "treatment" can refer
to one or more of (1) inhibiting the disease; for example,
inhibiting a disease, condition or disorder in an individual who is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology); and (2) ameliorating the
disease; for example, ameliorating a disease, condition or disorder
in an individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (i.e.,
reversing the pathology and/or symptomatology) such as decreasing
the severity of disease.
Combination Therapies
[0473] One or more additional pharmaceutical agents such as, for
example, chemotherapeutics, anti-inflammatory agents, steroids,
immunosuppressants, immune-oncology agents, metabolic enzyme
inhibitors, chemokine receptor inhibitors, and phosphatase
inhibitors, as well as Akt1, Akt2, Akt3, TGF-.beta.R, PKA, PKG,
PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,
HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF.alpha.R, PDGF.beta.R,
CSFIR, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4,
Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,
EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK,
ABL, ALK, B-Raf, Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR,
PDGFR, cKit, IGF-1R, RAF and FAK kinase inhibitors such as, for
example, those described in WO 2006/056399. Other agents such as
therapeutic antibodies can be used in combination with the
compounds provided herein for treatment of PI3K-associated
diseases, disorders or conditions. The one or more additional
pharmaceutical agents can be administered to a patient
simultaneously or sequentially.
[0474] In some embodiments, the compounds of the present disclosure
can be combined with one or more of the following inhibitors for
the treatment of cancer and/or diseases or indications as described
herein. Non-limiting examples of inhibitors that can be combined
with the compounds of the present disclosure for treatment of
cancer and/or diseases or indications as described herein include
an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828,
INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,
ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,
epacadostat and NLG919), an LSD1 inhibitor (e.g., INCB59872 and
INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g.,
INCB50797 and INCB50465), a Pim inhibitor, a CSF1R inhibitor, a TAM
receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis
inhibitor, an interleukin receptor inhibitor, bromo and extra
terminal family members inhibitors (for example, bromodomain
inhibitors or BET inhibitors such as INCB54329 and INCB57643) and
an adenosine receptor antagonist or combinations thereof.
[0475] In some embodiments, the compound or salt described herein
is administered with a PI3K.delta. inhibitor. In some embodiments,
the compound or salt described herein is administered with a JAK
inhibitor. In some embodiments, the compound or salt described
herein is administered with a JAK1 or JAK2 inhibitor (e.g.,
baricitinib or ruxolitinib). In some embodiments, the compound or
salt described herein is administered with a JAK1 inhibitor. In
some embodiments, the compound or salt described herein is
administered with a JAK1 inhibitor, which is selective over
JAK2.
[0476] Example antibodies for use in combination therapy include
but are not limited to Trastuzumab (e.g. anti-HER2), Ranibizumab
(e.g. anti-VEGF-A), Bevacizumab (trade name Avastin, e.g.
anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g.
anti-EGFR), Rituxan (anti-CD20) and antibodies directed to
c-MET.
[0477] One or more of the following agents may be used in
combination with the compounds provided herein and are presented as
a non-limiting list: a cytostatic agent, cisplatin, doxorubicin,
taxotere, taxol, etoposide, irinotecan, camptostar, topotecan,
paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,
methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777,
L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR,
Gleevec.TM., intron, ara-C, adriamycin, cytoxan, gemcitabine,
Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil,
Pipobroman, Triethylenemelamine, Triethyl enethiophosphoramine,
Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine,
Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine,
Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN.TM.,
Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,
Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,
Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase,
Teniposide 17.alpha.-Ethinylestradiol, Diethylstilbestrol,
Testosterone, Prednisone, Fluoxymesterone, Dromostanolone
propionate, Testolactone, Megestrolacetate, Methylprednisolone,
Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,
goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,
Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,
Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,
Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,
Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal,
Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole,
Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225,
Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib,
dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine,
didox, trimidox, amidox, 3-AP, and MDL-101,731.
[0478] Additional examples of chemotherapeutics include proteosome
inhibitors (e.g., bortezomib), thalidomide, revlimid, and
DNA-damaging agents such as melphalan, doxorubicin,
cyclophosphamide, vincristine, etoposide, carmustine, and the
like.
[0479] Example steroids include corticosteroids such as
dexamethasone or prednisone.
[0480] Example Bcr-Abl inhibitors include the compounds, and
pharmaceutically acceptable salts thereof, of the genera and
species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and
U.S. Ser. No. 60/578,491.
[0481] Example suitable Flt-3 inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
03/037347, WO 03/099771, and WO 04/046120.
[0482] Example suitable RAF inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 00/09495 and
WO 05/028444.
[0483] Example suitable FAK inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO
04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO
01/014402.
[0484] In some embodiments, the compounds provided herein can be
used in combination with one or more other kinase inhibitors
including imatinib, particularly for treating patients resistant to
imatinib or other kinase inhibitors.
[0485] In some embodiments, the compounds provided herein can be
used in combination with a chemotherapeutic in the treatment of
cancer, and may improve the treatment response as compared to the
response to the chemotherapeutic agent alone, without exacerbation
of its toxic effects. In some embodiments, the compounds provided
herein can be used in combination with a chemotherapeutic provided
herein. For example, additional pharmaceutical agents used in the
treatment of multiple myeloma, can include, without limitation,
melphalan, melphalan plus prednisone [MP], doxorubicin,
dexamethasone, and Velcade (bortezomib). Further additional agents
used in the treatment of multiple myeloma include Bcr-Abl, Flt-3,
RAF and FAK kinase inhibitors. Additive or synergistic effects are
desirable outcomes of combining a PI3K inhibitor of the present
disclosure with an additional agent.
[0486] In some embodiments, the compounds provided herein can be
used in combination with a targeted agent provided herein.
[0487] In some embodiments, the compounds provided herein can be
used in combination with one or more immune-oncology agents. In
some embodiments, the immune-oncology agent is selected from the
group consisting of CTLA4, PD1, and PDL biologics.
[0488] In some embodiments, the compounds provided herein can be
used in combination with one or more metabolic enzyme inhibitors.
In some embodiments, the metabolic enzyme inhibitor is an inhibitor
of IDO1, TDO, or arginase.
[0489] In some embodiments, the compounds provided herein can be
used in combination with one or more immune checkpoint inhibitors.
Exemplary immune checkpoint inhibitors include inhibitors against
immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96,
CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,
arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4,
BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some
embodiments, the immune checkpoint molecule is a stimulatory
checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40,
GITR and CD137. In some embodiments, the immune checkpoint molecule
is an inhibitory checkpoint molecule selected from A2AR, B7-H3,
B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some
embodiments, the compounds provided herein can be used in
combination with one or more agents selected from KIR inhibitors,
TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4
inhibitors and TGFR beta inhibitors.
[0490] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0491] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal
antibody. In some embodiments, the anti-PD-1 monoclonal antibody is
nivolumab, pembrolizumab (also known as MK-3475), pidilizumab,
SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1
monoclonal antibody is nivolumab or pembrolizumab. In some
embodiments, the anti-PD1 antibody is pembrolizumab.
[0492] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal
antibody. In some embodiments, the anti-PD-L1 monoclonal antibody
is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or
MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal
antibody is MPDL3280A or MEDI4736.
[0493] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
In some embodiments, the anti-CTLA-4 antibody is ipilimumab.
[0494] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In
some embodiments, the anti-LAG3 antibody is BMS-986016 or
LAG525.
[0495] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In
some embodiments, the anti-GITR antibody is TRX518 or MK-4166.
[0496] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or
OX40L fusion protein. In some embodiments, the anti-OX40 antibody
is MEDI0562. In some embodiments, the OX40L fusion protein is
MEDI6383.
[0497] Compounds of the present disclosure can be used in
combination with one or more agents for the treatment of diseases
such as cancer. In some embodiments, the agent is an alkylating
agent, a proteasome inhibitor, a corticosteroid, or an
immunomodulatory agent. Examples of an alkylating agent include
cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some
embodiments, the proteasome inhibitor is carfilzomib. In some
embodiments, the corticosteroid is dexamethasone (DEX). In some
embodiments, the immunomodulatory agent is lenalidomide (LEN) or
pomalidomide (POM).
[0498] The agents can be combined with the present compound in a
single or continuous dosage form, or the agents can be administered
simultaneously or sequentially as separate dosage forms.
[0499] In some embodiments, a corticosteroid such as dexamethasone
is administered to a patient in combination with the compounds
provided herein where the dexamethasone is administered
intermittently as opposed to continuously.
[0500] In some further embodiments, combinations of the compounds
provided herein with other therapeutic agents can be administered
to a patient prior to, during, and/or after a bone marrow
transplant or stem cell transplant.
Pharmaceutical Formulations and Dosage Forms
[0501] When employed as pharmaceuticals, the compounds provided
herein can be administered in the form of pharmaceutical
compositions. These compositions can be prepared in a manner well
known in the pharmaceutical art, and can be administered by a
variety of routes, depending upon whether local or systemic
treatment is desired and upon the area to be treated.
Administration may be topical (including transdermal, epidermal,
ophthalmic and to mucous membranes including intranasal, vaginal
and rectal delivery), pulmonary (e.g., by inhalation or
insufflation of powders or aerosols, including by nebulizer;
intratracheal or intranasal), oral or parenteral. Parenteral
administration includes intravenous, intraarterial, subcutaneous,
intraperitoneal intramuscular or injection or infusion; or
intracranial, e.g., intrathecal or intraventricular,
administration. Parenteral administration can be in the form of a
single bolus dose, or may be, for example, by a continuous
perfusion pump. Pharmaceutical compositions and formulations for
topical administration may include transdermal patches, ointments,
lotions, creams, gels, drops, suppositories, sprays, liquids and
powders. Conventional pharmaceutical carriers, aqueous, powder or
oily bases, thickeners and the like may be necessary or
desirable.
[0502] This disclosure also includes pharmaceutical compositions
which contain, as the active ingredient, the compound of the
disclosure or a pharmaceutically acceptable salt thereof, in
combination with one or more pharmaceutically acceptable carriers
(excipients). In some embodiments, the composition is suitable for
topical administration. In making the compositions of the
disclosure, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, for example, a capsule, sachet, paper, or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, 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 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[0503] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
[0504] The compounds provided herein may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nanoparticulate) preparations of the compounds of
the disclosure can be prepared by processes known in the art, e.g.,
see International App. No. WO 2002/000196.
[0505] 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, 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.
The compositions provided herein can 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.
[0506] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1000 mg (1 g), more
usually about 100 to about 500 mg, of the active ingredient. The
term "unit dosage forms" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[0507] In some embodiments, the compositions of the invention
contain from about 5 to about 50 mg of the active ingredient. One
having ordinary skill in the art will appreciate that this embodies
compositions containing about 5 to about 10, about 10 to about 15,
about 15 to about 20, about 20 to about 25, about 25 to about 30,
about 30 to about 35, about 35 to about 40, about 40 to about 45,
or about 45 to about 50 mg of the active ingredient.
[0508] In some embodiments, the compositions of the invention
contain from about 50 to about 500 mg of the active ingredient. One
having ordinary skill in the art will appreciate that this embodies
compositions containing about 50 to about 100, about 100 to about
150, about 150 to about 200, about 200 to about 250, about 250 to
about 300, about 350 to about 400, or about 450 to about 500 mg of
the active ingredient.
[0509] In some embodiments, the compositions of the invention
contain from about 500 to about 1000 mg of the active ingredient.
One having ordinary skill in the art will appreciate that this
embodies compositions containing about 500 to about 550, about 550
to about 600, about 600 to about 650, about 650 to about 700, about
700 to about 750, about 750 to about 800, about 800 to about 850,
about 850 to about 900, about 900 to about 950, or about 950 to
about 1000 mg of the active ingredient.
[0510] Similar dosages may be used of the compounds described
herein in the methods and uses of the invention.
[0511] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0512] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present disclosure. When
referring to these preformulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, about 0.1 to about 1000 mg of the active ingredient of the
present disclosure.
[0513] The tablets or pills of the present disclosure can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can 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.
[0514] The liquid forms in which the compounds and compositions of
the present disclosure can be incorporated for administration
orally or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0515] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions can be nebulized
by use of inert gases. Nebulized solutions may be breathed directly
from the nebulizing device or the nebulizing device can be attached
to a face mask, tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions can be
administered orally or nasally from devices which deliver the
formulation in an appropriate manner.
[0516] Topical formulations can contain one or more conventional
carriers. In some embodiments, ointments can contain water and one
or more hydrophobic carriers selected from, for example, liquid
paraffin, polyoxyethylene alkyl ether, propylene glycol, white
Vaseline, and the like. Carrier compositions of creams can be based
on water in combination with glycerol and one or more other
components, e.g. glycerinemonostearate, PEG-glycerinemonostearate
and cetylstearyl alcohol. Gels can be formulated using isopropyl
alcohol and water, suitably in combination with other components
such as, for example, glycerol, hydroxyethyl cellulose, and the
like. In some embodiments, topical formulations contain at least
about 0.1, at least about 0.25, at least about 0.5, at least about
1, at least about 2, or at least about 5 wt % of the compound of
the invention. The topical formulations can be suitably packaged in
tubes of, for example, 100 g which are optionally associated with
instructions for the treatment of the select indication, e.g.,
psoriasis or other skin condition.
[0517] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the
like.
[0518] In therapeutic applications, compositions can be
administered to a patient already suffering from a disease in an
amount sufficient to cure or at least partially arrest the symptoms
of the disease and its complications. Effective doses will depend
on the disease condition being treated as well as by the judgment
of the attending clinician depending upon factors such as the
severity of the disease, the age, weight and general condition of
the patient, and the like.
[0519] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0520] The therapeutic dosage of a compound of the present
invention can vary according to, for example, the particular use
for which the treatment is made, the manner of administration of
the compound, the health and condition of the patient, and the
judgment of the prescribing physician. The proportion or
concentration of a compound of the invention in a pharmaceutical
composition can vary depending upon a number of factors including
dosage, chemical characteristics (e.g., hydrophobicity), and the
route of administration. For example, the compounds provided herein
can be provided in an aqueous physiological buffer solution
containing about 0.1 to about 10% w/v of the compound for
parenteral administration. Some typical dose ranges are from about
1 .quadrature.g/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100
mg/kg of body weight per day. The dosage is likely to depend on
such variables as the type and extent of progression of the disease
or disorder, the overall health status of the particular patient,
the relative biological efficacy of the compound selected,
formulation of the excipient, and its route of administration.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0521] The compositions of the invention can further include one or
more additional pharmaceutical agents such as a chemotherapeutic,
steroid, anti-inflammatory compound, or immunosuppressant, examples
of which are listed herein.
Labeled Compounds and Assay Methods
[0522] Another aspect of the present disclosure relates to labeled
compounds of the present disclosure (radio-labeled,
fluorescent-labeled, etc.) that would be useful not only in imaging
techniques but also in assays, both in vitro and in vivo, for
localizing and quantitating PI3K in tissue samples, including
human, and for identifying PI3K ligands by inhibition binding of a
labeled compound. Accordingly, the present disclosure includes PI3K
assays that contain such labeled compounds.
[0523] The present disclosure further includes isotopically-labeled
compounds of the present disclosure. An "isotopically" or
"radio-labeled" compound is a compound of the invention where one
or more atoms are replaced or substituted by an atom having an
atomic mass or mass number different from the atomic mass or mass
number typically found in nature (i.e., naturally occurring).
Suitable radionuclides that may be incorporated in compounds of the
present disclosure include but are not limited to .sup.2H (also
written as D for deuterium), .sup.3H (also written as T for
tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl,
.sup.82Br, .sup.75Br, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I,
.sup.125I and .sup.131I. The radionuclide that is incorporated in
the instant radio-labeled compounds will depend on the specific
application of that radio-labeled compound. For example, for in
vitro PI3K labeling and competition assays, compounds that
incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I,
.sup.35S or will generally be most useful. For radio-imaging
applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I,
.sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[0524] It is understood that a "radio-labeled" or "labeled
compound" is a compound that has incorporated at least one
radionuclide. In some embodiments the radionuclide is selected from
the group consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and
.sup.82Br.
[0525] The present disclosure can further include synthetic methods
for incorporating radio-isotopes into compounds provided herein.
Synthetic methods for incorporating radio-isotopes into organic
compounds are well known in the art, and an ordinary skill in the
art will readily recognize the methods applicable for the compounds
of invention.
[0526] A labeled compound of the invention can be used in a
screening assay to identify/evaluate compounds. For example, a
newly synthesized or identified compound (i.e., test compound)
which is labeled can be evaluated for its ability to bind a PI3K by
monitoring its concentration variation when contacting with the
PI3K, through tracking of the labeling. For example, a test
compound (labeled) can be evaluated for its ability to reduce
binding of another compound which is known to bind to a PI3K (i.e.,
standard compound). Accordingly, the ability of a test compound to
compete with the standard compound for binding to the PI3K directly
correlates to its binding affinity. Conversely, in some other
screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the
labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound,
and the relative binding affinity of the test compound is thus
ascertained.
Kits
[0527] The present disclosure also includes pharmaceutical kits
useful, for example, in the treatment or prevention of
PI3K-associated diseases or disorders, such as cancer, which
include one or more containers containing a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention. Such kits can further include, if
desired, one or more of various conventional pharmaceutical kit
components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc.,
as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities
of the components to be administered, guidelines for
administration, and/or guidelines for mixing the components, can
also be included in the kit.
[0528] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results. The compounds of the
Examples have been found to be PI3K.gamma. inhibitors according to
at least one assay described herein.
EXAMPLES
[0529] Preparatory LC-MS purifications of some of the compounds
prepared were performed on Waters mass directed fractionation
systems. The basic equipment setup, protocols, and control software
for the operation of these systems have been described in detail in
the literature (see e.g. "Two-Pump At Column Dilution Configuration
for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002);
"Optimizing Preparative LC-MS Configurations and Methods for
Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty,
G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and
"Preparative LC-MS Purification: Improved Compound Specific Method
Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi.
Chem., 6, 874-883 (2004)). The compounds separated were typically
subjected to analytical liquid chromatography mass spectrometry
(LCMS) for purity analysis under the following conditions:
Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire.TM.
C.sub.18 5 .mu.m, 2.1.times.50 mm, Buffers:mobile phase A:0.025%
TFA in water and mobile phase B: acetonitrile; gradient 2% to 80%
of B in 3 minutes with flow rate 2.0 mL/minute.
[0530] Some of the compounds prepared were also separated on a
preparative scale by reverse-phase high performance liquid
chromatography (RP-HPLC) with MS detector or flash chromatography
(silica gel) as indicated in the Examples. Typical preparative
reverse-phase high performance liquid chromatography (RP-HPLC)
column conditions are as follows:
[0531] pH 2 purifications: Waters Sunfire.TM. C.sub.18 5 .mu.m,
19.times.100 mm column, eluting with mobile phase A: 0.1% TFA
(trifluoroacetic acid) in water and mobile phase B: acetonitrile;
the flow rate was 30 mL/minute, the separating gradient was
optimized for each compound using the Compound Specific Method
Optimization protocol as described in the literature (see e.g.
"Preparative LCMS Purification: Improved Compound Specific Method
Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb.
Chem., 6, 874-883 (2004)). Typically, the flow rate used with the
30.times.100 mm column was 60 mL/minute.
[0532] pH 10 purifications: Waters XBridge C.sub.18 5 .mu.m,
19.times.100 mm column, eluting with mobile phase A: 0.15%
NH.sub.4OH in water and mobile phase B: acetonitrile; the flow rate
was 30 mL/minute, the separating gradient was optimized for each
compound using the Compound Specific Method Optimization protocol
as described in the literature (see e.g. "Preparative LCMS
Purification: Improved Compound Specific Method Optimization", K.
Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883
(2004)). Typically, the flow rate used with 30.times.100 mm column
was 60 mL/minute.
[0533] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified
to yield essentially the same results.
Example 1.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-phenyl-1H-imidazol--
2-yl)pyridine trifluoroacetate salt
##STR00044##
[0534] Step 1. 4-Bromo-2-(5-phenyl-1H-imidazol-2-yl)pyridine
##STR00045##
[0536] 4-Bromopyridine-2-carboxylic acid (7.11 g, 35.2 mmol,
Combi-Blocks) and 2-bromoacetophenone (7.0 g, 35 mmol, Aldrich)
were dissolved in DMF (100. mL), and N,N-diisopropylethylamine (12
mL, 70. mmol) was added. After stirring for 1 hour, the mixture was
diluted with water, and the aqueous mixture was extracted with
three portions of ethyl acetate (EtOAc). The combined organic
extracts were washed sequentially with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford intermediate
2-oxo-2-phenylethyl 4-bromopicolinate. LCMS(M+H).sup.+: 320.0,
322.0. This intermediate was dissolved in AcOH (150 mL), and
treated with NH.sub.4OAc (41 g, 530 mmol) at 130.degree. C. for 1
hour. The mixture was cooled to room temperature and most of the
AcOH was removed in vacuo. The residue was then diluted with an
ice-cold solution of NaHCO.sub.3 and the aqueous mixture was
extracted with three portions of EtOAc. The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product was triturated with DCM and
isolated by filtration. Yield: 2.9 g, 27%.
[0537] LCMS(M+H).sup.+: 300.1, 302.1.
Step 2.
4-Bromo-2-(4-phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidaz-
ol-2-yl)pyridine
##STR00046##
[0539] A solution of 4-bromo-2-(5-phenyl-1H-imidazol-2-yl)pyridine
(1.4 g, 4.7 mmol, from Step 1) in THF (60 mL) at 0.degree. C. was
treated with 1.0 M KO.sup.tBu in THF (6.5 mL, 6.5 mmol) and the
reaction was stirred at 0.degree. C. for 30 minutes. The reaction
mixture was treated with [.beta.-(trimethylsilyl)ethoxy]methyl
chloride (1.2 mL, 6.5 mmol, Aldrich) and stirred at 0.degree. C.
for 30 minutes. Aq. NH.sub.4Cl solution was poured into the cold
reaction mixture and after stirring for 30 minutes, the aqueous
mixture was extracted with EtOAc. The extract was washed with
water, followed by brine. The solution was dried over sodium
sulfate, filtered and concentrated. The product was purified by
flash chromatography, eluting with a gradient from 0-10% EtOAc in
hexanes. The major isomer, first to elute, was collected. Yield:
1.23 g, 61%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.68 (br,
1H), 8.42 (d, 1H), 7.96-7.88 (m, 2H), 7.55 (s, 1H), 7.51-7.41 (m,
3H), 7.38-7.29 (m, 1H), 6.08 (s, 2H), 3.66-3.59 (m, 2H), 0.97-0.91
(m, 2H), -0.04 (s, 9H);
[0540] LCMS (M+H).sup.+: 430.1/432.1.
Step 3.
2-(4-Phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-
-4-(1H-pyrazol-4-yl)pyridine
##STR00047##
[0542] A degassed mixture of 4-bromo-2-(4-phenyl-1-{[2-(trimethyl
silyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine (0.30 g, 0.70 mmol,
from Step 2),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (190
mg, 0.98 mmol, Aldrich), Na.sub.2CO.sub.3 (220 mg, 2.1 mmol) and
tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.070 mmol) in
1,4-dioxane (10 mL) and water (3.0 mL) was heated to 140.degree. C.
in the microwave for 20 min. Upon cooling to room temperature, the
reaction mixture was diluted with water and the aqueous mixture was
extracted with EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-50% EtOAc in hexanes.
[0543] Yield: 0.175 g, 60%. LCMS (M+H).sup.+: 418.3.
Step 4.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-phenyl-1H-imidazol-2-y-
l)pyridine trifluoroacetate salt
[0544] A mixture of
2-(4-Phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-(1H--
pyrazol-4-yl)pyridine (13 mg, 0.031 mmol, from Step 3) in DMF (0.45
mL) was treated with K.sub.2CO.sub.3 (26 mg, 0.19 mmol) and
1-(bromomethyl)-4-chlorobenzene (7.7 mg, 0.037 mmol, Aldrich).
After 1 hour, the reaction mixture was diluted with water and the
aqueous mixture was extracted with EtOAc. The extract was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
dissolved in trifluoroacetic acid (TFA, 0.45 mL, 5.9 mmol) and
stirred at 40.degree. C. for 20 minutes. The TFA was removed in
vacuo and the residue was dissolved in methanol (MeOH) and purified
by preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). Yield:
8.9 mg. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.66 (d, J=5.3
Hz, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.04 (br, 1H),
7.98-7.90 (m, 2H), 7.74 (d, J=4.7 Hz, 1H), 7.52-7.42 (m, 4H),
7.42-7.29 (m, 3H), 5.45 (s, 2H); LCMS (M+H).sup.+: 412.1.
[0545] Examples 5-14, 16-21, 25-26, 30-35, 37, 40-41, and 43
through 60 were synthesized according to the procedure of Example 1
and the data are listed in Table 1. Examples 5-7, 10, 12, 20-21,
26, 30-35, 43 and 56 were prepared via alkylations as described by
Example 1 and Scheme 3. Examples 48-51 were prepared via alkylation
and subsequent hydrolysis and amide formation. Examples 44-46, and
54 were prepared by sulfonylation as described in Scheme 3.
Examples 25, 47 and 60 were prepared via Mitsunobu alkylation as
shown in Scheme 3. Aza-Michael addition was used to prepare
Examples 52 and 55, as shown in Scheme 3. Aza-Michael addition
followed by hydrolysis (to Example 57) and amide formation was used
to prepare Examples 53 and 58-59.
TABLE-US-00001 TABLE 1 ##STR00048## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 5 4-(1-Benzyl-1H- pyrazol-4-yl)-2-(5-
phenyl-1H-imidazol- 2-yl)pyridine trifluoroacetate salt
##STR00049## 378.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.68
(d, J = 5.3 Hz, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 8.12
(s, 1H), 7.99-7.91 (m, 2H), 7.78 (dd, J = 5.2, 1.4 Hz, 1H), 7.51
(t, J = 7.6 Hz, 2H), 7.43- 7.36(m, 3H), 7.36- 7.29 (m, 3H), 5.44
(s, 2H) 6 2-((4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H-
pyrazol-1- yl)methyl)benzonitrile trifluoroacetate salt
##STR00050## 403.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.70
(d, J = 5.3 Hz, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10
(s, 1H), 7.97-7.94 (m, 2H), 7.93 (dd, J = 7.8, 1.0 Hz, 1H), 7.79
(dd, J = 5.2, 1.4 Hz, 1H), 7.74 (td, J = 7.7, 1.3 Hz, 1H), 7.57
(td, J = 7.7, 1.0 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.43- 7.36 (m,
2H), 5.66 (s, 2H) 7 4-(1-(2- Chlorobenzyl)-1H- pyrazol-4-yl)-2-(5-
phenyl-1H-imidazol- 2-yl)pyridine trifluoroacetate salt
##STR00051## 412.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.69
(d, J = 5.3 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10
(s, 1H), 8.00-7.91 (m, 2H), 7.80 (dd, J = 5.2, 1.3 Hz, 1H),
7.56-7.45 (m, 3H), 7.45-7.33 (m, 3H), 7.20 (dd, J = 7.1, 2.2 Hz,
1H), 5.55 (s, 2H) 8 4-(1-Methyl-1H- pyrazol-4-yl)-2-(5-
phenyl-1H-imidazol- 2-yl)pyridine trifluoroacetate salt
##STR00052## 302.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.65
(d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 8.06
(s, 1H), 7.98-7.92 (m, 2H), 7.73 (dd, J = 5.2, 1.5 Hz, 1H),
7.52-7.43 (m, 2H), 7.41-7.33 (m, 1H), 3.94 (s, 3H) 9
4-(3-Methyl-1H- pyrazol-4-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00053## 302.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.70 (d, J = 5.3 Hz, 1H), 8.36 (d,
J = 0.9 Hz, 1H), 8.13 (s, 1H), 8.12 (s, 1H), 8.00-7.90 (m, 2H),
7.69 (dd, J = 5.3, 1.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.44-7.34 (m,
1H), 2.55 (s, 3H) 10 4-(1-Ethyl-1H- pyrazol-4-yl)-2-(5-
phenyl-1H-imidazol- 2-yl)pyridine trifluoroacetate salt
##STR00054## 316.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.66
(d, J = 5.3 Hz, 1H), 8.54 (s, 1H), 8.43 (d, J = 0.7 Hz, 1H), 8.14
(d, J = 0.5 Hz, 1H), 8.07 (s, 1H), 7.98-7.90 (m, 2H), 7.74 (dd, J =
5.3, 1.6 Hz, 1H), 7.53- 7.44 (m, 2H), 7.42- 7.31 (m, 1H), 4.22 (q,
J = 7.3 Hz, 2H), 1.45 (t, J = 7.3 Hz, 3H) 11 4-(3,5-Dimethyl-1H-
pyrazol-4-yl)-2-(5- phenyl-1H-imidazol- 2- yl)pyridinetrifluoro-
acetate salt ##STR00055## 316.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.74 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 0.7 Hz, 1H), 8.15
(s, 1H), 7.98-7.86 (m, 2H), 7.54 (dd, J = 5.2, 1.5 Hz, 1H), 7.53-
7.46 (m, 2H), 7.43- 7.37 (m, 1H), 2.36 (s, 6H) 12 2-(5-Phenyl-1H-
imidazol-2-yl)-4-(1- propyl-1H-pyrazol-4- yl)pyridine
trifluoroacetate salt ##STR00056## 330.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.66 (d, J = 5.3 Hz, 1H), 8.53 (s, 1H), 8.42
(s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.99-7.91 (m, 2H), 7.74 (dd, J
= 5.2, 1.5 Hz, 1H), 7.52-7.42 (m, 2H), 7.42-7.31 (m, 1H), 4.15 (t,
J = 6.9 Hz, 2H), 1.86 (h, J = 7.2 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H)
13 4-(1-Methyl-1H- pyrazol-5-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00057## 302.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.85 (d, J = 5.2 Hz, 1H), 8.39 (s,
1H), 8.14 (s, 1H), 7.99- 7.86 (m, 2H), 7.78 (dd, J = 5.1, 1.6 Hz,
1H), 7.61 (d, J = 1.9 Hz, 1H), 7.55-7.44 (m, 2H), 7.44-7.33 (m,
1H), 6.75 (d, J = 1.9 Hz, 1H), 4.03 (s, 3H) 14 4-(1-Methyl-3-
(trifluoromethyl)-1H- pyrazol-5-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00058## 370.1 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.89 (d, J = 5.1 Hz, 1H), 8.41 (s,
1H), 8.09 (s, 1H), 7.99- 7.91 (m, 2H), 7.82 (dd, J = 5.1, 1.5 Hz,
1H), 7.52-7.45 (m, 2H), 7.43-7.31 (m, 1H), 7.25 (s, 1H), 4.10 (s,
3H) 16 4-(1-Methyl-1H- imidazol-2-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00059## 302.2 .sup.1H NMR
(400 MHz, CD.sub.3CN) .delta. 12.09 (br s, 3H), 8.90 (d, J = 5.1
Hz, 1H), 8.83 (s, 1H), 7.96-7.89 (m, 2H), 7.83 (dd, J = 5.1, 1.6
Hz, 1H), 7.81 (s, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8
Hz, 1H), 7.53-7.48 (m, 2H), 7.48-7.42 (m, 1H), 3.99 (s, 3H) 17
N-(2'-(5-Phenyl-1H- imidazol-2-yl)-3,4'- bipyridin-5- yl)acetamide
trifluoroacetate salt ##STR00060## 356.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 10.48 (s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.84
(d, J = 2.2 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.60 (t, J = 1.9 Hz,
1H), 8.57 (s, 1H), 8.13 (s, 1H), 7.99-7.93 (m, 2H), 7.91 (dd, J =
5.1, 1.3 Hz 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.43- 7.32 (m, 1H), 2.15
(s, 3H) 18 4-(2'-(5-Phenyl-1H- imidazol-2-yl)-3,4'- bipyridin-5-
yl)morpholine trifluoroacetate salt ##STR00061## 384.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.85 (d, J = 5.2 Hz, 1H), 8.60 (d,
J = 1.5 Hz, 1H), 8.59 (s, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.08 (s,
1H), 8.01-7.92 (m, 4H), 7.49 (t, J = 7.7 Hz, 2H), 7.42-7.33 (m,
1H), 3.90-3.63 (m, 4H), 3.47-3.19 (m, 4H) 19 5-Methoxy-2'-(5-
phenyl-1H-imidazol- 2-yl)-3,4'-bipyridine trifluoroacetate salt
##STR00062## 329.1 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.88
(d, J = 5.2 Hz, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.65 (s, 1H), 8.50
(d, J = 2.7 Hz, 1H), 8.17 (s, 1H), 8.04 (dd, J = 5.1, 1.4 Hz, 1H),
7.99- 7.94 (m, 2H), 7.93- 7.87 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H),
7.41 (t, J = 7.4 Hz, 1H), 3.99 (s, 3H) 20 3-((4-(2-(5-Phenyl-
1H-imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1-
yl)methyl)benzonitrile trifluoroacetate salt ##STR00063## 403.1
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.71- 8.64 (m, 2H),
8.42 (s, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.98-7.91 (m, 2H),
7.85-7.78 (m, 2H), 7.76 (dd, J = 5.2, 1.4 Hz, 1H), 7.68- 7.58 (m,
2H), 7.52- 7.46 (m, 2H), 7.40- 7.34 (m, 1H), 5.52 (s, 2H) 21
4-(1-(3- Chlorobenzyl)-1H- pyrazol-4-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00064## 412.1 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.68 (d, J = 5.3 Hz, 1H), 8.66 (s,
1H), 8.43 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.98-7.93 (m, 2H),
7.77 (dd, J = 5.2, 1.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.46-
7.35 (m, 4H), 7.29 (dt, J = 6.6, 2.0 Hz, 1H), 5.46 (s, 2H) 25
2-(5-Phenyl-1H- imidazol-2-yl)-4-(1- (piperidin-4-yl)-1H-
pyrazol-4-yl)pyridine trifluoroacetate salt ##STR00065## 371.2
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.91 (br d, J = 9.4 Hz,
1H), 8.69 (d, J = 5.2 Hz, 1H), 8.67-8.55 (m, 2H), 8.48 (s, 1H),
8.22 (s, 1H), 8.09 (s, 1H), 8.01-7.92 (m, 2H), 7.80 (dd, J = 5.2,
1.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H),
4.60 (tt, J = 10.6, 3.8 Hz, 1H), 3.46 (d, J = 12.6 Hz, 2H), 3.15
(q, J = 11.6 Hz, 2H), 2.36-2.25 (m, 2H), 2.25-2.10 (m, 2H) 26
4-(2-(4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H-
pyrazol-1- yl)ethyl)morpholine trifluoroacetate salt ##STR00066##
401.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.71 (d, J = 5.2
Hz, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H),
8.00-7.93 (m, 2H), 7.78 (dd, J = 5.2, 1.5 Hz, 1H), 7.50 (t, J = 7.6
Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 4.67 (t, J = 6.4 Hz, 2H), 3.84
(br s, 4H), 3.72 (t, J = 6.4 Hz, 2H), 3.32 (br s, 4H) 30 Methyl
2-((4-(2-(5- phenyl-1H-imidazol- 2-yl)pyridin-4-yl)- 1H-pyrazol-1-
yl)methyl)benzoate trifluoroacetate salt ##STR00067## 436.2 .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.68 (d, J = 5.2 Hz, 1H), 8.60
(s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.99-7.90 (m,
3H), 7.78 (d, J = 4.5 Hz, 1H), 7.60 (td, J = 7.6, 1.2 Hz, 1H),
7.54- 7.42 (m, 3H), 7.38 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.8 Hz,
1H), 5.80 (s, 2H), 3.89 (s, 3H) 31 Methyl 3-((4-(2-(5-
phenyl-1H-imidazol- 2-yl)pyridin-4-yl)- 1H-pyrazol-1-
yl)methyl)benzoate trifluoroacetate salt ##STR00068## 436.2 .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.71- 8.63 (m, 2H), 8.42 (s,
1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.99-7.88 (m, 4H), 7.78-7.70 (m,
1H), 7.67-7.60 (m, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7
Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 5.53 (s, 2H), 3.86 (s, 3H) 32
Methyl 4-((4-(2-(5- phenyl-1H-imidazol- 2-yl)pyridin-4-yl)-
1H-pyrazol-1- yl)methyl)benzoate trifluoroacetate salt ##STR00069##
436 2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.68 (s, 1H),
8.65 (d, J = 5.3 Hz, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 8.02- 7.89
(m, 5H), 7.75- 7.69 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.42 (d, J =
8.3 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 5.54 (s, 2H), 3.84 (s, 3H)
33 2-((4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H-
pyrazol-1- yl)methyl)benzoic acid trifluoroacetate salt
##STR00070## 422.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.67
(d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.06
(s, 1H), 7.99-7.93 (m, 3H), 7.78-7.74 (m, 1H), 7.56 (td, J = 7.6,
1.3 Hz, 1H), 7.51-7.41 (m, 3H), 7.37 (t, J = 7.4 Hz, 1H), 6.92 (d,
J = 7.7 Hz, 1H), 5.83 (s, 2H) 34 3-((4-(2-(5-Phenyl- 1H-imidazol-2-
yl)pyridin-4-yl)-1H- pyrazol-1- yl)methyl)benzoic acid
trifluoroacetate salt ##STR00071## 422.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.69 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.41
(s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.98-7.93 (m, 2H), 7.93-7.86
(m, 2H), 7.75 (dd, J = 5.4, 1.2 Hz, 1H), 7.63- 7.55 (m, 1H), 7.56-
7.42 (m, 3H), 7.36 (t, J = 7.4 Hz, 1H), 5.52 (s, 2H) 35
4-((4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1-
yl)methyl)benzoic acid trifluoroacetate salt ##STR00072## 422.2
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.68 (s, 1H), 8.66 (d,
J = 5.3 Hz, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H),
7.98-7.90 (m, 4H), 7.74 (d, J = 4.8 Hz, 1H), 7.48 (t, J = 7.6 Hz,
2H), 7.41 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 5.53 (s,
2H) 37 5-(4- Methylpiperazin-1- yl)-2'-(5-phenyl-1H-
imidazol-2-yl)-3,4'- bipyridine trifluoroacetate salt ##STR00073##
397.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.20 (br s, 1H),
8.80 (d, J = 1.9 Hz, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H),
8.21 (dd, J = 9.0, 2.2 Hz, 1H), 8.17(s, 1H), 8.00-7.87 (m, 3H),
7.52 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.18 (d, J =
9.0 Hz, 1H), 4.57 (br m, 2H), 3.46 (br m, J = 84.8 Hz, 2H), 3.26
(br m, 2H), 3.12 (br m, 2H), 2.88 (s,
3H) 40 5-(Methylsulfonyl)- 2'-(5-phenyl-1H- imidazol-2-yl)-3,4'-
bipyridine trifluoroacetate salt ##STR00074## 377.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 9.45 (d, J = 2.1 Hz, 1H), 9.24 (d,
J = 2.0 Hz, 1H), 8.93 (d, J = 5.1 Hz, 1H), 8.80 (t, J = 2.1 Hz,
1H), 8.71 (s, 1H), 8.17 (s, 1H), 8.13 (dd, J = 5.1, 1.4 Hz, 1H),
8.00- 7.90 (m, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz,
1H), 3.47 (s, 3H) 41 4-(2'-(5-Phenyl-1H- imidazol-2-yl)-3,4'-
bipyridin-6- yl)morpholine trifluoroacetate salt ##STR00075## 384.2
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.81- 8.74 (m, 2H),
8.63 (s, 1H), 8.25 (s, 1H), 8.15 (dd, J = 9.0, 2.1 Hz, 1H),
8.02-7.90 (m, 3H), 7.54 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.3 Hz,
1H), 7.07 (d, J = 9.0 Hz, 1H), 3.77- 3.69 (m, 4H), 3.65- 3.58 (m,
4H) 43 4-((4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H-
pyrazol-1- yl)methyl)benzonitrile trifluoroacetate salt
##STR00076## 403.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.70- 8.66 (m, 2H), 8.42 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H),
7.98-7.91 (m, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.79- 7.73 (m, 1H),
7.54- 7.42 (m, 4H), 7.38 (t, J = 7.3 Hz, 1H), 5.57 (s, 2H) 44 4-(1-
(Methylsulfonyl)-1H- pyrazol-4-yl)-2-(5- phenyl-1H-imidazol-
2-yl)pyridine trifluoroacetate salt ##STR00077## 366 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 9.14 (s, 1H), 8.71 (s, 1H), 8.66
(d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 7.96- 7.92 (m, 2H), 7.86- 7.78
(m, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 6.9 Hz, 1H), 3.65
(s, 3H) 45 4-(1-(Ethylsulfonyl)- 1H-pyrazol-4-yl)-2- (5-phenyl-1H-
imidazol-2- yl)pyridine trifluoroacetate salt ##STR00078## 380.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.88 (s, 1H), 8.76 (br s,
1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.91-7.78 (m, 4H), 7.52 (t, J =
7.5 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 3.69 (q, J = 7.3 Hz, 2H),
1.27 (t, J = 7.3 Hz, 3H) 46 4-(1- (Cyclopropylsulfonyl)-
1H-pyrazol-4-yl)-2- (5-phenyl-1H- imidazol-2- yl)pyridine
trifluoroacetate salt ##STR00079## 392.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.14 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.68
(s, 1H), 8.51 (s, 1H), 8.00- 7.92 (m, 3H), 7.90 (d, J = 4.5 Hz,
1H), 7.46 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.1 Hz, 1H), 3.30-3.16
(m, 1H), 1.39-1.32 (m, 2H), 1.30-1.19 (m, 2H) 47 2-(5-Phenyl-1H-
imidazol-2-yl)-4-(1- (tetrahydro-2H- pyran-4-yl)-1H-
pyrazol-4-yl)pyridine trifluoroacetate salt ##STR00080## 372.1
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.65 (d, J = 5.3 Hz,
1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.95
(d, J = 7.4 Hz, 2H), 7.74 (d, J = 4.1 Hz, 1H), 7.48 (t, J = 7.5 Hz,
2H), 7.36 (t, J = 7.2 Hz, 1H), 4.60- 4.39(m, 1H), 4.10- 3.84 (m,
2H), 3.62- 3.32(m, 2H), 2.12- 1.80 (m, 4H) 48 2-(4-(2-(5-Phenyl-
1H-imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1- yl)acetamide
trifluoroacetate salt ##STR00081## 345.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.67 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.42
(s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.76
(d, J = 4.0 Hz, 1H), 7.63 (s, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.37
(t, , J = 7.2 Hz, 1H), 7.34 (s, 1H), 4.87 (s, 2H) 49
N,N-Dimethyl-2-(4- (2-(5-phenyl-1H- imidazol-2-
yl)pyridin-4-yl)-1H- pyrazol-1- yl)acetamide trifluoroacetate salt
##STR00082## 373.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.69
(d, J = 5.3 Hz, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 8.13
(s, 1H), 8.00-7.93 (m, 2H), 7.79 (dd, J = 5.2, 1.1 Hz, 1H), 7.51
(t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 5.24 (s, 2H), 3.08
(s, 3H), 2.89 (s, 3H) 50 2-(4-(2-(5-Phenyl- 1H-imidazol-2-
yl)pyridin-4-yl)-1H- pyrazol-1-yl)-1- (pyrrolidin-1- yl)ethanone
trifluoroacetate salt ##STR00083## 399.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.69 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.44
(s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.79
(d, J = 5.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz,
1H), 5.14 (s, 2H), 3.54 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz,
2H), 1.94 (p, J = 6.8 Hz, 2H), 1.81 (p, J = 6.7 Hz, 2H) 51
1-Morpholino-2-(4- (2-(5-phenyl-1H- imidazol-2-
yl)pyridin-4-yl)-1H- pyrazol-1-yl)ethanone trifluoroacetate salt
##STR00084## 415.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.71
(d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.16 (s, 2H), 7.97
(d, J = 7.5 Hz, 2H), 7.81 (d, J = 4.4 Hz, 1H), 7.52 (t, J = 7.5 Hz,
2H), 7.42 (t, J = 7.3 Hz, 1H), 5.29 (s, 2H), 3.69- 3.64 (m, 2H),
3.63- 3.59 (m, 2H), 3.59- 3.53 (m, 2H), 3.52- 3.39 (m, 2H) 52
3-(4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1-
yl)propanenitrile trifluoroacetate salt ##STR00085## 341.2 .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.69 (d, J = 5.2 Hz, 1H), 8.62
(s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 7.4
Hz, 2H), 7.76 (d, J = 4.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.38
(t, J = 7.2 Hz, 1H), 4.51 (t, J = 6.4 Hz, 2H), 3.17 (t, J = 6.3 Hz,
2H) 53 3-(4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H-
pyrazol-1- yl)propanamide ##STR00086## 359.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.66 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.41
(s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.75
(d, J = 5.0 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.43 (s, 1H), 7.39
(t, J = 7.4 Hz, 1H), 6.92 (s, 1H), 4.40 (t, J = 6.7 Hz, 2H), 2.71
(t, J = 6.7 Hz, 2H) 54 4-(1- (Cyclopentylsulfonyl)-
1H-pyrazol-4-yl)-2- (5-phenyl-1H- imidazol-2- yl)pyridine
trifluoroacetate salt ##STR00087## 420.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.17 (s, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.69
(s, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 8.02-7.87 (m, 3H), 7.51 (t, J
= 7.6 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.29 (ddd, J = 15.4, 8.7,
6.7 Hz, 1H), 2.09-1.87 (m, 4H), 1.67-1.43 (m, 4H) 55 Ethyl
3-(4-(2-(5- phenyl-1H-imidazol- 2-yl)pyridin-4-yl)- 1H-pyrazol-1-
yl)propanoate trifluoroacetate salt ##STR00088## 388.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.68 (d, J = 5.3 Hz, 1H), 8.62 (s,
1H), 8.55 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 7.4 Hz,
2H), 7.77 (d, J = 4.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.40 (t, J
= 7.4 Hz, 1H), 4.45 (t, J = 6.6 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H),
2.96 (t, J = 6.6 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H) 56
2-(4-(2-(5-Phenyl- 1H-imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1-
yl)acetonitrile trifluoroacetate salt ##STR00089## 327.1 .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.71 (d, J = 5.2 Hz, 1H), 8.64
(s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 7.5
Hz, 2H), 7.83-7.75 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.39 (t, J =
7.3 Hz, 1H), 5.63 (s, 2H) 57 3-(4-(2-(5-Phenyl- 1H-imidazol-2-
yl)pyridin-4-yl)-1H- pyrazol-1- yl)propanoic acid trifluoroacetate
salt ##STR00090## 360.1 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.66 (d, J = 5.2 Hz, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H),
8.06 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.74 (d, J = 4.7 Hz, 1H),
7.49 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 4.41 (t, J =
6.6 Hz, 2H), 2.89 (t, J = 6.7 Hz, 2H) 58 N-Methyl-3-(4-(2-(5-
phenyl-1H-imidazol- 2-yl)pyridin-4-yl)- 1H-pyrazol-1-
yl)propanamide trifluoroacetate salt ##STR00091## 373.2 .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.63 (d, J = 5.0 Hz, 1H), 8.47 (s,
1H), 8.37 (s, 1H), 8.15 (s, 1H), 8.01-7.92 (m, 3H), 7.93-7.86 (m,
1H), 7.70 (d, J = 4.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.34 (t, J
= 7.4 Hz, 1H), 4.41 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H),
2.57 (d, J = 4.6 Hz, 3H) 59 N-cyclopentyl-3-(4- (2-(5-phenyl-1H-
imidazol-2- yl)pyridin-4-yl)-1H- pyrazol-1- yl)propanamide
trifluoroacetate salt ##STR00092## 427.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.67 (d, J = 5.3 Hz, 1H), 8.51 (s, 1H), 8.45
(s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.98 (d, J = 7.5 Hz, 2H), 7.91
(d, J = 7.3 Hz, 1H), 7.74 (d, J = 4.6 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.39 (t, J = 7.2 Hz, 1H), 4.41 (t, J 6.7 Hz, 2H), 4.03-3.90
(m, 1H), 2.68 (t, J = 6.7 Hz, 2H), 1.80-1.64 (m, 2H), 1.64-1.50 (m,
2H), 1.50-1.36 (m, 2H), 1.37-1.20 (m, 2H) 60 2-(5-Phenyl-1H-
imidazol-2-yl)-4-(1- (tetrahydrofuran-3- yl)-1H-pyrazol-4-
yl)pyridine trifluoroacetate salt, racemic mixture prepared
##STR00093## 358.1 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.87
(s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.19
(s, 1H), 8.08 (s, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.81-7.75 (m, 1H),
7.50 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 5.16-5.07 (m,
1H), 4.09-3.94 (m, 3H), 3.87 (td, J = 8.4, 5.6 Hz, 1H), 2.50- 2.40
(m, 1H), 2.40- 2.30 (m, 1H)
Example 61.
5-(5-Methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine
##STR00094##
[0546] Step 1. 2-(4-Chloropyridin-2-yl)imidazo[1,2-a]pyrimidine
##STR00095##
[0548] 2-Bromo-1-(4-chloropyridin-2-yl)ethanone (0.050 g, 0.21
mmol, J&W Pharmlab), 2-amino-pyrimidine (0.020 g, 0.21 mmol,
Aldrich), and 4-dimethylaminopyridine (0.001 g, 0.01 mmol) were
combined in CH.sub.3CN (1 mL) and heated in a microwave reactor to
100.degree. C. for 30 minutes. Upon cooling, the reaction mixture
was diluted with CH.sub.3CN and water and purified by preparative
HPLC (C-18 column eluting with a water:acetonitrile gradient
buffered at pH 10 with 0.15% ammonium hydroxide). Yield: 0.032 g,
65%.
[0549] LCMS(M+H).sup.+: 231.1.
Step 2. 2'-Imidazo[1,2-a]pyrimidin-2-yl-5-methoxy-3,4'-bipyridine
trifluoroacetate salt
##STR00096##
[0551] A mixture of
2-(4-chloropyridin-2-yl)imidazo[1,2-a]pyrimidine (0.032 g, 0.14
mmol, from Step 1),
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(0.033 g, 0.14 mmol, Aldrich) and CsF (0.063 g, 0.42 mmol) in
1,4-dioxane (1 mL) and water (0.5 mL was degassed by a stream of
nitrogen bubbled through the solution subsurface for 10 minutes).
4-(di-tert-Butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.015 g, 0.021 mmol, Aldrich) was added and the mixture was
sealed and heated to 90.degree. C. for 3 hours. Upon cooling to
room temperature, the reaction mixture was diluted with water,
CH.sub.3CN, and MeOH for purification by preparative HPLC (C-18
column eluting with a water:acetonitrile gradient buffered at pH 2
with 0.1% trifluoroacetic acid). Yield: 43 mg. LCMS (M+H).sup.+:
304.1.
Step 3. 5-(5-Methoxy-3,4-bipyridin-2'-yl)-1H-imidazol-2-amine
[0552] 2'-Imidazo[1,2-a]pyrimidin-2-yl-5-methoxy-3,4'-bipyridine
trifluoroacetate salt (0.043 g, 0.067 mmol, from Step 2) and
hydrazine hydrate (0.023 g, 0.47 mmol) in CH.sub.3CN (0.5 mL) was
heated to 100.degree. C. in the microwave for 10 minutes. The
product was purified by preparative HPLC (C-18 column eluting with
a water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). Yield: 5 mg, 30%.
[0553] .sup.1H NMR (400 MHz, CD3OD) .delta. 8.64 (d, J=5.2 Hz, 1H),
8.57 (d, J=1.8 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H), 8.09-8.03 (m, 1H),
7.80 (dd, J=2.6, 1.9 Hz, 1H), 7.62 (dd, J=5.2, 1.7 Hz, 1H), 7.54
(s, 1H), 4.01 (s, 3H); LCMS(M+H).sup.+: 268.1.
Example 62.
N-Ethyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine
trifluoroacetate salt
##STR00097##
[0555] 5-(5-Methoxy-3,4'-bipyridin-2'-yl)-1H-imidazol-2-amine
(0.030 g, 0.11 mmol, from Example 61) was stirred with acetaldehyde
(8 .mu.L, 0.1 mmol) in MeOH (0.20 mL) and NaCNBH.sub.3 (0.014 g,
0.22 mmol) and 3A molecular sieves were added. The reaction was
stirred for 72 h. Additional NaCNBH.sub.3 (0.014 g, 0.22 mmol) was
added and the reaction was continued for 8 hours. The reaction was
quenched by the addition of water and was purified by preparative
HPLC (C-18 column eluting with a water:acetonitrile gradient
buffered at pH 2 with 0.1% trifluoroacetic acid). Yield: 10 mg.
[0556] .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 12.57 (s, 1H),
8.74 (d, J=1.6 Hz, 1H), 8.70 (d, J=5.2 Hz, 1H), 8.46 (d, J=2.7 Hz,
1H), 8.28 (s, 1H), 7.97 (t, J=5.7 Hz, 1H), 7.90 (s, 1H), 7.89-7.86
(m, 1H), 7.80 (dd, J=5.2, 1.4 Hz, 1H), 3.97 (s, 3H), 3.39 (dq,
J=7.0 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H); LCMS (M+H).sup.+: 296.2.
[0557] Examples 63 through 65 were synthesized according to the
procedure of Example 62 and the data are listed in Table 2.
TABLE-US-00002 TABLE 2 ##STR00098## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 63 5-(5-Methoxy-3,4'- bipyridin-2'-yl)-N-
pentyl-1H-imidazol-2- amine trifluoroacetate salt ##STR00099##
338.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 12.45 (s, 1H),
8.73 (d, J = 1.8 Hz, 1H), 8.70 (d, J = 5.3 Hz, 1H), 8.45 (d, J =
2.7 Hz, 1H), 8.28 (s, 1H), 7.94-7.88 (m, 2H), 7.88-7.86 (m, 1H),
7.80 (dd, J = 5.3, 1.6 Hz, 1H), 3.97 (s, 3H), 3.34 (q, J = 6.7 Hz,
2H), 1.67-1.44 (m, 2H), 1.42-1.19 (m, 4H), 1.00-0.67 (m, 3H) 64
N-Isobutyl-5-(5- methoxy-3,4'-bipyridin- 2'-yl)-1H-imidazol-2-
amine trifluoroacetate ##STR00100## 324.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 12.38 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.70
(d, J = salt 5.2 Hz, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.29 8.26 (m,
1H), 7.94 (t, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.88-7.85 (m, 1H),
7.81 (dd, J = 5.2, 1.5 Hz, 1H), 3.97 (s, 3H), 3.19 (t, J = 6.7 Hz,
2H), 2.03-1.69 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H) 65
N-(Cyclobutylmethyl)- 5-(5-methoxy-3,4'- bipyridin-2'-yl)-1H-
imidazol-2-amine ##STR00101## 336.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 12.47 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.70
(d, J = trifluoroacetate salt 5.3 Hz, 1H), 8.45 (d, J = 2.7 Hz,
1H), 8.29 8.24 (m, 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.88 (s, 1H),
7.88-7.86 (m, 1H), 7.80 (dd, J = 5.3, 1.5 Hz, 1H), 3.97 (s,
3H),3.41 (t, J = 6.6 Hz, 2H), 2.64-2.53 (m, 1H), 2.11-1.97 (m, 2H),
1.94-1.80 (m, 2H), 1.80-1.66 (m, 2H)
Example 66.
N-Butyl-5-(5-methoxy-3,4'-bipyridin-2'-yl)-4H-1,2,4-triazol-3-amine
trifluoroacetate salt
##STR00102##
[0558] Step 1. Methyl 5-methoxy-3,4-bipyridine-2-carboxylate
##STR00103##
[0560] A degassed mixture of methyl 4-bromopyridine-2-carboxylate
(2.0 g, 9.2 mmol, Combi-Blocks),
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(2.2 g, 9.2 mmol, Aldrich), CsF (4 g, 30 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.65 g, 0.92 mmol, Aldrich) in 1,4-dioxane (20 mL) and water
(7 mL) was heated to 120.degree. C. for 3.5 hours. The layers were
separated and the organic layer was diluted with EtOAc and dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes. Yield: 1.64 g, 73%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.83 (d, J=5.0 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H),
8.41 (d, J=2.7 Hz, 1H), 8.36 (d, J=1.7 Hz, 1H), 7.69 (dd, J=5.0,
1.8 Hz, 1H), 7.46-7.42 (m, 1H), 4.05 (s, 3H), 3.95 (s, 3H);
LCMS(M+H).sup.+: 245.1.
Step 2. 5-Methoxy-3,4'-bipyridine-2-carbohydrazide
##STR00104##
[0562] A mixture of methyl 5-methoxy-3,4'-bipyridine-2'-carboxylate
(0.250 g, 1.02 mmol, from Step 1) and hydrazine hydrate (0.299 mL,
6.14 mmol) in MeOH (2.5 mL) was heated in an oil bath at 70.degree.
C. for 4 hours. Upon cooling to room temperature, the solid product
was isolated by filtration, rinsed with a small amount of MeOH, and
air dried. Yield: 0.19 g, 76%. .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 9.96 (t, J=4.2 Hz, 1H), 8.71 (dd, J=5.1, 0.6 Hz, 1H), 8.63
(d, J=1.8 Hz, 1H), 8.41 (d, J=2.8 Hz, 1H), 8.29 (dd, J=1.8, 0.6 Hz,
1H), 7.98 (dd, J=5.1, 1.9 Hz, 1H), 7.81 (dd, J=2.7, 2.0 Hz, 1H),
4.60 (d, J=4.6 Hz, 2H), 3.95 (s, 3H); LCMS(M+H).sup.+: 245.0.
Step 3.
N-Butyl-5-(5-methoxy-3,4-bipyridin-2'-yl)-4H-1,2,4-triazol-3-amine
trifluoroacetate salt
[0563] To N-butylthiourea (0.019 g, 0.15 mmol) in DCM (0.3 mL) was
added MeI (23 .mu.L, 0.37 mmol) and the reaction mixture was heated
to 40.degree. C. for 1 hour. The solvent was evaporated under a
stream of nitrogen. Acetonitrile (0.6 mL) was added, followed by
5-methoxy-3,4'-bipyridine-2'-carbohydrazide (0.030 g, 0.12 mmol,
from Step 2) and 2,6-lutidine (0.057 mL, 0.49 mmol). The reaction
mixture was heated in a sealed vial to 90.degree. C. for 14 hours,
then at 120.degree. C. for 1 hour. The product was purified by
preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). Yield: 9
mg. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.82 (d, J=5.2 Hz,
1H), 8.68 (d, J=1.7 Hz, 1H), 8.46 (d, J=2.7 Hz, 1H), 8.38-8.32 (m,
1H), 8.00 (dd, J=5.2, 1.6 Hz, 1H), 7.91-7.83 (m, 1H), 7.55 (br s,
1H), 6.86 (br s, 1H), 3.97 (s, 3H), 3.30 (t, J=7.2 Hz, 2H), 1.57
(p, J=7.4 Hz, 2H), 1.48-1.19 (m, 2H), 0.95-0.85 (m, 3H); LCMS
(M+H).sup.+: 325.2.
[0564] Examples 67, 68, and 70 were synthesized according to the
procedure of Example 66 and the data are listed in Table 3.
TABLE-US-00003 TABLE 3 ##STR00105## Ex. No. Name R = MS (M +
H).sup.+ .sup.1H NMR 67 N-Isopropyl-5-(5- methoxy-3,4'-
bipyridin-2'-yl)-4H- 1,2,4-triazol-3- amine trifluoroacetate salt
##STR00106## 311.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.81
(d, J = 5.2 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 2.7 Hz,
1H), 8.36-8.31 (m, 1H), 7.99 (dd, J = 5.3, 1.6 Hz, 1H), 7.88-7.85
(m, 1H), 3.97 (s, 3H), 3.84 (hept, J = 5.8 Hz, 1H), 1.23 (d, J =
6.4 Hz, 6H) 68 5-(5-Methoxy-3,4'- bipyridin-2'-yl)-N-
methyl-4H-1,2,4- triazol-3-amine trifluoroacetate salt ##STR00107##
283.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.83 (d, J = 5.3
Hz, 1H), 8.69 (d, J = 1.7 Hz, 1H), 8.46 (d, J = 2.7 Hz, 1H),
8.40-8.36 (m, 1H), 8.01 (dd, J = 5.2, 1.5 Hz, 1H), 7.90- 7.87 (m,
1H), 3.97 (s, 3H), 2.93 (s, 3H) 70 5-(5-Methoxy-3,4'-
bipyridin-2'-yl)-N- phenyl-4H-1,2,4- triazol-3-amine
trifluoroacetate salt ##STR00108## 345.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.78 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 1.8 Hz,
1H), 8.55 (d, J = 1.2 Hz, 1H), 8.46 (d, J = 2.7 Hz, 1H), 8.01-7.99
(m, 1H), 7.96 (dd, J = 5.4, 1.8 Hz, 1H), 7.55-7.49 (m, 2H),
7.35-7.28 (m, 2H), 7.02-6.95 (m, 1H), 4.03 (s, 3H)
Example 71.
5-Methoxy-2'-(5-phenyl-4H-1,2,4-triazol-3-yl)-3,4'-bipyridine
##STR00109##
[0565] Step 1. 5-Methoxy-3,4'-bipyridine-2-carbonitrile
##STR00110##
[0567] A degassed mixture of 4-bromopyridine-2-carbonitrile (1.0 g,
5.5 mmol, Synthonix),
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(1.3 g, 5.4 mmol, Aldrich), CsF (2 g, 20 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.38 g, 0.54 mmol) in 1,4-dioxane (10 mL) and water (3 mL)
was heated to 120.degree. C. for 2 hours. Upon cooling, ethyl
acetate and water were added into the reaction mixture and the
solid product was isolated by filtration and dried under vacuum at
40.degree. C. to afford 0.84 g of product. The filtrate, which
contained product, was washed with water, followed by brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated to afford crude
product which was purified by trituration with DCM overnight and
filtered to afford an additional 0.12 g of product. Combined yield:
0.96 g, 84%. LCMS (M+H).sup.+: 212.1.
Step 2.
5-Methoxy-2-(5-phenyl-4H-1,2,4-triazol-3-yl)-3,4-bipyridine
[0568] A suspension of 5-methoxy-3,4'-bipyridine-2'-carbonitrile
(30.0 mg, 0.142 mmol, from Step 1) and sodium methoxide (25 wt % in
MeOH, 30.0 .mu.L, 0.13 mmol) in MeOH (1 mL) was stirred for 2
hours. To about 1/3 of the reaction mixture was added
benzohydrazide (13 mg, 0.095 mmol, Aldrich) and the mixture was
heated to reflux overnight. The product was diluted with MeOH and
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). Yield: 9.5 mg, 60%. .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.83 (d, J=5.0 Hz, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.45
(d, J=2.3 Hz, 1H), 8.15 (d, J=7.3 Hz, 2H), 7.96-7.92 (m, 1H),
7.90-7.83 (m, 1H), 7.52 (t, J=7.3 Hz, 2H), 7.49-7.43 (m, 1H); LCMS
(M+H).sup.+: 330.1.
[0569] Examples 72 through 73 were synthesized according to the
procedure of Example 71 and the data are listed in Table 4.
TABLE-US-00004 TABLE 4 ##STR00111## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 72 5-Methoxy-2'- H 254.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) (4H-1,2,4-triazol- .delta. 8.72 (d, J = 5.2 Hz, 1H),
8.63 3-yl)-3,4'- (d, J = 1.7 Hz, 1H), 8.42 (d, J = bipyridine 2.7
Hz, 1H), 8.39-8.35 (m, 1H), 8.15 (s, 1H), 7.82-7.75 (m, 2H), 3.96
(s, 3H) 73 5-Methoxy-2'-(5- CH.sub.3 268.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) methyl-4H-1,2,4- .delta. 8.77(d, J = 5.1 Hz, 1H),
8.64 triazol-3-yl)-3,4'- (d, J = 1.3 Hz, 1H), 8.42 (d, J =
bipyridine 2.7 Hz, 1H), 8.34 (s, 1H), 7.87 (d, J = 4.3 Hz, 1H),
7.84-7.72 (m, 1H), 3.96 (s, 3H), 2.40 (s, 3H)
Example 74.
5-Methoxy-2'-(2-phenyl-1H-imidazol-5-yl)-3,4'-bipyridine
##STR00112##
[0570] Step 1. 2'-Chloro-5-methoxy-3,4'-bipyridine
##STR00113##
[0572] A degassed mixture of 4-bromo-2-chloropyridine (0.74 g, 3.8
mmol, Aldrich),
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi- ne
(0.90 g, 3.8 mmol, Aldrich), CsF (2 g, 10 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.27 g, 0.38 mmol, Aldrich) in 1,4-dioxane (10 mL) and
H.sub.2O (3 mL) was heated to 90.degree. C. for 2 hours. Upon
cooling, ethyl acetate and water were added and a precipitate
formed. This mixture was stirred overnight and the solid product
was isolated by filtration and dried under vacuum at 40.degree. C.
overnight to afford 0.35 g of product. The layers of the filtrate
were separated and the organic solution was washed with water,
followed by brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude solid was triturated with DCM and isolated
by filtration to afford a further 0.17 g of product. Yield: 0.52 g,
62%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.66 (d, J=1.8 Hz,
1H), 8.52 (d, J=5.2 Hz, 1H), 8.42 (d, J=2.8 Hz, 1H), 8.03-8.00 (m,
1H), 7.88 (dd, J=5.2, 1.6 Hz, 1H), 7.85-7.82 (m, 1H); LCMS
(M+H).sup.+: 221.1.
Step 2. 5-Methoxy-2-(2-phenyl-1H-imidazol-5-yl)-3,4-bipyridine
[0573] To a suspension of 4-bromo-2-phenyl-1H-imidazole (0.49 g,
2.2 mmol, Matrix) in DCM (6 mL) was added di-tert-butyldicarbonate
(0.53 g, 2.4 mmol) and 4-dimethylaminopyridine (DMAP, 0.026 g, 0.21
mmol). After 20 minutes, solvent was removed in vacuo. The residue
was partitioned between EtOAc and water and the organic layer was
washed twice with saturated NH.sub.4Cl and once with brine. The
organic solution was dried over sodium sulfate, filtered, and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-20% EtOAc in hexanes. Yield: 0.52 g,
73%.
[0574] A solution of the Boc-protected bromo-2-phenylimidazole
(0.20 g, 0.62 mmol) in THF (4 mL) at 0.degree. C. was treated with
.sup.iPrMgCl--LiCl complex in THF (1.3 M, 0.71 mL, 0.93 mmol). The
reaction mixture was warmed to room temperature over 1 hour and was
stirred at room temperature for an additional 2.5 hours. Additional
.sup.iPrMgCl--LiCl complex in THF (1.3 M, 0.50 mL, 0.65 mmol) was
added. After 2 hours, the reaction mixture was cooled to 0.degree.
C. and trimethylborate (190 .mu.L, 1.7 mmol) was added. The
reaction mixture was stirred overnight with warming to room
temperature. The reaction mixture was then quenched with water and
extracted with EtOAc. The organic layer was washed with water,
followed by brine, dried over sodium sulfate, filtered, and
concentrated. The product was purified using preparative HPLC (C-18
column eluting with a water:acetonitrile gradient buffered at pH 2
with 0.1% trifluoroacetic acid) and used in the coupling reaction
below.
[0575] A degassed mixture of 2'-chloro-5-methoxy-3,4'-bipyridine,
potassium acetate (13.0 mg, 0.132 mmol, from Step 1),
(2-phenyl-1H-imidazol-4-yl)boronic acid trifluoroacetate (7.8 mg,
0.026 mmol, prepared above) and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (2.3 mg, 0.0032 mmol, Aldrich) in 1,4-dioxane (0.3 mL) and
H.sub.2O (0.1 mL) was heated to 120.degree. C. for 2 hours. The
product was purified by preparative HPLC (C-18 column eluting with
a water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). Yield: 4.4 mg, 52%. .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 12.91 (br s, 1H), 8.69-8.60 (m, 2H), 8.43 (d, J=2.5 Hz,
1H), 8.30-8.23 (m, 1H), 8.10 (d, J=7.4 Hz, 2H), 7.91 (s, 1H),
7.83-7.78 (m, 1H), 7.67-7.58 (m, 1H), 7.49 (t, J=7.6 Hz, 2H),
7.43-7.36 (m, 1H), 3.97 (s, 3H); LCMS (M+H).sup.+: 329.1.
Example 75.
N-[2-(5-Methoxy-3,4'-bipyridin-2'-yl)-4-methyl-1H-imidazol-5-yl]acetamide
##STR00114##
[0576] Step 1. 4-Bromo-2-(4-methyl-1H-imidazol-2-yl)pyridine
##STR00115##
[0578] To 4-bromopyridine-2-carbonitrile (0.500 g, 2.73 mmol,
Synthonix) in MeOH (3 mL) was added sodium methoxide (25 wt % in
MeOH, 0.050 mL, 0.24 mmol, Aldrich) and the reaction mixture was
heated at 40.degree. C. for 1 hour. Upon cooling to room
temperature, 1,1-diethoxypropan-2-amine (0.40 g, 2.7 mmol,
AstaTech) and AcOH (0.3 mL) were added. The reaction mixture was
heated in an oil bath held at 100.degree. C. for 30 minutes. The
reaction mixture was removed from the bath, MeOH (1.5 mL) and 6 N
HCl (1.25 mL, 7.50 mmol) were added, and heating was resumed at
70.degree. C. for 5 hours. Upon cooling to room temperature,
solvent was removed via rotary evaporation. Potassium carbonate in
water was added to adjust the pH to 10 and the precipitated product
was stirred for 1 hour and isolated by filtration and air dried.
Yield: 0.57 g, 88%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
12.65 (br s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H),
7.58 (dd, J=5.3, 1.9 Hz, 1H), 6.88 (s, 1H), 2.21 (s, 3H); LCMS
(M+H).sup.+: 238.0/240.0.
Step 2. 4-Bromo-2-(4-methyl-5-nitro-1H-imidazol-2-yl)pyridine
##STR00116##
[0580] A solution of 4-bromo-2-(4-methyl-1H-imidazol-2-yl)pyridine
(0.300 g, 1.26 mmol, from Step 1) in HNO.sub.3 (1 mL) and
H.sub.2SO.sub.4 (1 mL) was stirred at ambient temperature
overnight. The reaction mixture was added to a solution of sat'd
NaHCO.sub.3.
[0581] The yellow solid formed was isolated by filtration and air
dried and used without further purification. Yield: 0.14 g, 39%
yield. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.54 (d, J=5.3
Hz, 1H), 8.20 (s, 1H), 7.73 (d, J=3.9 Hz, 1H), 2.60 (s, 3H); LCMS
(M+H).sup.+: 283.0/285.0.
Step 3.
N-[2-(5-Methoxy-3,4'-bipyridin-2'-yl)-4-methyl-1H-imidazol-5-yl]ac-
etamide
[0582] A mixture of
4-bromo-2-(4-methyl-5-nitro-1H-imidazol-2-yl)pyridine (0.14 g, 0.49
mmol, from Step 2) in AcOH (6 mL) was treated with iron powder (0.2
g, 4 mmol) and the mixture was heated at 60.degree. C. for 2 hours.
The reaction mixture was filtered and the acetic acid was removed
from the filtrate via rotary evaporation. The residue was dissolved
in MeOH, filtered, and purified by preparative HPLC (C-18 column
eluting with a water:methanol gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). The product as the trifluoroacetate salt
(0.120 g) and
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(0.19 g, 0.81 mmol, Aldrich) were combined with CsF (0.18 g, 1.2
mmol) in 1,4-dioxane (4 mL) and H.sub.2O (1 mL). The mixture was
degassed.
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiu-
m (0.058 g, 0.081 mmol, Aldrich) was added and the reaction mixture
was sealed and heated at 90.degree. C. for 5 hours. Upon cooling to
room temperature, the reaction mixture was diluted with MeCN,
filtered, and purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid), followed by further purification via
preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 10 with 0.15% ammonium hydroxide).
[0583] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.66 (d, J=5.2 Hz,
1H), 8.56 (s, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.30 (s, 1H), 7.79 (br
m, 1H), 7.66-7.60 (m, 1H), 3.98 (s, 3H), 2.21 (s, 3H), 2.15 (s,
3H); LCMS(M+H).sup.+: 324.2.
Example 76.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-methoxy-3,4'-bipyridine
##STR00117##
[0584] Step 1. 5-Methoxy-3,4'-bipyridine-2-carboximidamide
##STR00118##
[0586] To a suspension of 5-methoxy-3,4'-bipyridine-2'-carbonitrile
(0.50 g, 2.4 mmol, prepared as in Example 71, Step 1) in MeOH (4.5
mL) was added sodium methoxide (25 wt % in MeOH, 0.50 mL, 2.2 mmol)
and the reaction was stirred for 4.5 hours. Ammonium chloride (0.15
g, 2.8 mmol) was added and the reaction mixture was stirred at room
temperature overnight. Methanol (1 mL) was added and the reaction
mixture was heated to 60.degree. C. for 4 hours. Additional
NH.sub.4Cl (35 mg, 0.65 mmol) was added and heating at 60.degree.
C. was continued overnight. The methanol was then removed via
rotary evaporation. The crude solid was stirred with EtOAc:H.sub.2O
(1:1, 20 mL) for 5 hours. The solid product was isolated by
filtration and dried under vacuum at 40.degree. C. to afford 0.24 g
of product. The filtrate was concentrated to dryness via rotary
evaporation and the solid was stirred with EtOAc:H.sub.2O (2:1, 6
mL) overnight. Additional solid product formed was again isolated
by filtration and dried under vacuum at 40.degree. C. to afford
0.27 g of product. Combined yield: 0.51 g, 93%. LCMS (M+H).sup.+:
229.1.
Step 2.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-methoxy-3,4-bipyridine
[0587] To a suspension of
5-methoxy-3,4'-bipyridine-2'-carboximidamide (10.0 mg, 0.044 mmol,
from Step 1) in THF (0.3 mL) was added KHCO.sub.3 (0.021 g, 0.21
mmol), followed by 3-bromo-2-butanone (5.0 .mu.L, 0.066 mmol) and
H.sub.2O (75 .mu.L). The reaction mixture was heated in a sealed
vial at 100.degree. C. for 2 hours, then at 90.degree. C.
overnight. The product was purified via preparative HPLC (C-18
column eluting with a water:acetonitrile gradient buffered at pH 10
with 0.15% ammonium hydroxide). Yield: 3.6 mg, 24%. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 12.40 (s, 1H), 8.64 (d, J=5.1 Hz,
1H), 8.60 (d, J=1.6 Hz, 1H), 8.41 (d, J=2.7 Hz, 1H), 8.22-8.17 (m,
1H), 7.80-7.75 (m, 1H), 7.68 (dd, J=5.2, 1.7 Hz, 1H), 3.96 (s, 3H),
2.19 (s, 3H), 2.12 (s, 3H); LCMS (M+H).sup.+: 281.1.
[0588] Examples 77 through 88 were synthesized according to the
procedure of Example 76 and the data are listed in Table 5.
TABLE-US-00005 TABLE 5 ##STR00119## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 77 5-Methoxy-2'-(5- methyl-1H- imidazol-2-yl)-
3,4'-bipyridine ##STR00120## 267.1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.99 (br s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.55
(d, J = 1.8 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 7.91 (s, 1H), 7.62
(dd, J = 5.1, 1.2 Hz, 1H), 7.03 (s, 1H), 4.04 (s, 3H), 2.43 (s, 3H)
78 2-(5-Methoxy- 3,4'-bipyridin-2'- yl)-1,4,5,6- tetrahydrocyclo-
penta[d]imidazole ##STR00121## 293.1 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 12.54 (s, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.61 (s,
1H), 8.43-8.38 (m, 1H), 8.25 (s, 1H), 7.81- 7.75 (m, 1H), 7.73-7.66
(m, 1H), 3.96 (s, 3H), 2.74- 2.65 (m, 2H), 2.64-2.55 (m, 2H),
2.48-2.36 (m, 2H) 79 5-Methoxy-2'-(5- (trifluoromethyl)-
1H-imidazol-2- yl)-3,4'-bipyridine trifluoroacetate salt
##STR00122## 321.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.76
(s, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.15
(s, 1H), 7.70 (d, J = 3.9 Hz, 1H), 7.54 (s, 1H), 4.07 (s, 3H) 80
Ethyl 2-(5- methoxy-3,4'- bipyridin-2'-yl)-5- (trifluoromethyl)-
1H-imidazole-4- carboxylate ##STR00123## 393.0 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.73 (d, J = 5.1 Hz, 1H), 8.59 (s, 1H),
8.52- 8.39 (m, 2H), 7.62 (d, J = 4.4 Hz, 1H), 7.57-7.48 (m, 1H),
4.48 (q, J = 7.0 Hz, 2H), 4.00 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) 81
2-(5-Methoxy- 3,4'-bipyridin-2'- yl)-5- (trifluoromethyl)-
1H-imidazole-4- carboxylic acid trifluoroacetate salt ##STR00124##
365.0 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 13.03 (s, 1H),
11.38 (s, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.63 (d, J = 1.6 Hz, 1H),
8.45 (d, J = 2.7 Hz, 1H), 8.43-8.39 (m, 1H), 7.99 (dd, J = 5.1, 1.6
Hz, 1H), 7.84-7.81 (m, 1H), 3.95 (s, 3H) 82 5-Methoxy-2'-(4-
methyl-5-phenyl- 1H-imidazol-2- yl)-3,4'-bipyridine
trifluoroacetate salt ##STR00125## 343.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 12.85 (br s, 2H), 8.71 (d, J = 5.1 Hz, 1H),
8.65 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.35 (s, 1H), 7.86-7.68 (m,
4H), 7.43 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 3.97 (s,
3H), 2.51 (s, 3H) 83 4- (2-(5-Methoxy- 3,4'-bipyridin-2'-
yl)-1H-imidazol- 5-yl)-N,N- dimethylbenzene- sulfonamide
trifluoroacetate salt ##STR00126## 436.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.80 (d, J = 5.0 Hz, 1H), 8.72 (s, 1H),
8.53- 8.40 (m, 2H), 8.20 (d, J = 8.3 Hz, 2H), 8.12 (s, 1H),
7.96-7.86 (m, 2H), 7.79 (d, J = 8.4 Hz, 2H), 3.99 (s, 3H), 2.64 (s,
6H) 84 2'-(5-Isopropyl- 1H-imidazol-2- yl)-5-methoxy-
3,4'-bipyridine trifluoroacetate salt ##STR00127## 295.1 .sup.1H
NMR (400 MHz, d.sub.6- DMSO) .delta. 8.92 (d, J = 5.1 Hz, 1H),
8.75-8.72 (m, 1H), 8.64 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.12 (d,
J = 4.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.68 (s, 1H), 3.98 (s, 3H),
3.12 (hept, J = 7.5 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H) 85
2'-(5-Ethyl-1H- imidazol-2-yl)-5- methoxy-3,4'- bipyridine
trifluoroacetate salt ##STR00128## 281.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.93-8.91 (m, 1H), 8.68 (d, J = 1.7 Hz, 1H),
8.49 (d, J = 2.7 Hz, 1H), 8.46 (dd, J = 1.5, 0.8 Hz, 1H), 8.00 (dd,
J = 5.1, 1.6 Hz, 1H), 7.96 (dd, J = 2.6, 1.9 Hz, 1H), 7.52- 7.48
(m, 1H), 4.05 (s, 3H), 2.88 (qd, J = 7.6, 0.7 Hz, 2H), 1.42 (t, J =
7.6 Hz, 3H) 86 2'-(5- Cyclopropyl-1H- imidazol-2-yl)-5-
methoxy-3,4'- bipyridine ##STR00129## 293.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.66 (d, J = 5.1 Hz, 1H), 8.61 (br s, 1H),
8.42 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 7.80-7.76 (m, 1H), 7.71
(dd, J = 5.0, 1.5 Hz, 1H), 6.97 (br s, 0.65H), 6.68 (br s, 0.35H),
3.96 (s, 3H), 1.98-1.80 (m, 1H), 0.95-0.76 (m, 2H), 0.76-0.62 (m,
2H) 87 5-Methoxy-2'-(5- (pyridin-2-yl)-1H- imidazol-2-yl)-
3,4'-bipyridine trifluoroacetate salt ##STR00130## 330.1 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.75 (d, J = 5.2 Hz, 1H), 8.72
(s, 1H), 8.65 (d, J = 5.3 Hz, 1H), 8.60 (d, J = 1.2 Hz, 1H), 8.40-
8.30 (m, 3H), 8.22 (t, J = 7.1 Hz, 1H), 7.84 (br m, 1H), 7.67 (dd,
J = 5.1, 1.4 Hz, 1H), 7.58 (t, J = 6.5 Hz, 1H), 4.02 (s, 3H) 88
2'-(5-tert-Butyl- 1H-imidazol-2- yl)-5-methoxy- 3,4'-bipyridine
trifluoroacetate salt ##STR00131## 309.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.92 (d, J = 5.1 Hz, 1H), 8.75 (d, J = 1.4
Hz, 1H), 8.68 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.13 (dd, J = 5.1,
1.2 Hz, 1H), 7.94-7.82 (m, 1H), 7.66 (s, 1H), 3.98 (s, 3H), 1.41
(s, 9H)
Example 94.
2-[4-(5-Methoxypyridin-3-yl)pyrimidin-2-yl]-1H-benzimidazole
trifluoroacetate salt
##STR00132##
[0589] Step 1. 2-Chloro-4-(5-methoxypyridin-3-yl)pyrimidine
##STR00133##
[0591] A mixture of 2,4-dichloropyrimidine (0.30 g, 2.0 mmol,
Aldrich),
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(0.47 g, 2.0 mmol, Aldrich) and CsF (0.95 g, 6.2 mmol) in
1,4-dioxane (10 mL) and water (5 mL) was degassed by a stream of
nitrogen through the solution for 10 minutes.
4-(di-tert-Butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.23 g, 0.32 mmol, Aldrich) was added and the reaction was
heated to 90.degree. C. for 3 hours. Upon cooling to room
temperature, the reaction was diluted with EtOAc and the organic
solution was washed with water. The aqueous layer was extracted
with two further portions of EtOAc, which were combined with the
original organic layer and dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-80% EtOAc in hexanes. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.82 (s, 1H), 8.70 (d, J=5.2 Hz, 1H),
8.47 (s, 1H), 7.97 (s, 1H), 7.70 (d, J=5.2 Hz, 1H), 3.97 (s, 3H);
LCMS (M+H).sup.+: 222.0/224.0.
Step 2. 4-(5-Methoxypyridin-3-yl)pyrimidine-2-carbonitrile
##STR00134##
[0593] To a degassed mixture of
2-chloro-4-(5-methoxypyridin-3-yl)pyrimidine (0.21 g, 0.95 mmol,
from Step 1) and zinc cyanide (1.11 g, 9.47 mmol) in DMF (10 mL)
was added tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.24
mmol, Strem) and the reaction mixture was heated to 165.degree. C.
in a microwave reactor for 10 minutes. Upon cooling, the reaction
mixture was diluted with water and extracted with three portions of
EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-80% EtOAc in hexanes. To remove residual DMF, the purified
product was diluted with EtOAc and washed with three portions of
water, then with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Yield: 80 mg, 40%. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.91 (d, J=5.4 Hz, 1H), 8.87 (s, 1H), 8.50 (s, 1H), 8.01
(s, 1H), 7.98 (d, J=5.4 Hz, 1H), 3.98 (s, 3H). LCMS (M+H).sup.+:
213.1.
Step 3.
2-[4-(5-Methoxypyridin-3-yl)pyrimidin-2-yl]-1H-benzimidazole
trifluoroacetate salt
[0594] To 4-(5-methoxypyridin-3-yl)pyrimidine-2-carbonitrile (0.080
g, 0.38 mmol, from Step 2) in MeOH (2.5 mL) was added sodium
methoxide (25 wt % in MeOH, 0.010 mL, 0.045 mmol) and the reaction
mixture was heated to 40.degree. C. for 1 hour. Upon cooling to
room temperature, 1,2-benzenediamine (0.041 g, 0.38 mmol, Aldrich)
and AcOH (0.041 mL) were added. The reaction was heated in a sealed
vial in an oil bath at 100.degree. C. for 30 minutes. The reaction
vial was removed from the heating bath and after a few minutes,
MeOH (1 mL) and 6.0 N HCl (0.17 mL, 1.0 mmol) were added. The
reaction was not heated further, as the product had formed. The
mixture was diluted with water and the product was purified by
preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). Yield:
89 mg.
[0595] .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 9.48 (d, J=1.2
Hz, 1H), 9.11 (d, J=1.6 Hz, 1H), 8.93 (d, J=1.2 Hz, 1H), 8.53 (d,
J=2.8 Hz, 1H), 8.25 (dd, J=2.6, 2.0 Hz, 1H), 7.73 (dd, J=6.0, 3.2
Hz, 2H), 7.35 (dd, J=6.1, 3.2 Hz, 2H), 4.01 (s, 3H); LCMS
(M+H).sup.+: 304.0.
[0596] Example 95 was synthesized according to the procedure of
Example 94 and the data are listed in Table 7.
TABLE-US-00006 TABLE 7 ##STR00135## Ex. MS No. Name Y (M + H).sup.+
.sup.1H NMR 95 2-[6-(5- N 304.0 .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. Methoxypyridin- 9.38 (s, 1H), 9.27 (d, J = 5.1 Hz,
3-yl)pyrimidin- 1H), 8.63-8.57 (m, 1H), 8.53 (d, 4-yl]-1H- J = 5.3
Hz, 1H), 8.45 (s, 1H), 7.89 benzimidazole (dd, J = 5.7, 2.8 Hz,
2H), 7.62 (dd, trifluoroacetate J = 5.8, 2.8 Hz, 2H), 4.03 (s, 3H)
salt
Example 97.
2'-(5-Methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
##STR00136##
[0597] Step 1. 5-Morpholin-4-yl-3,4'-bipyridine-2-carbonitrile
##STR00137##
[0599] A degassed mixture of 4-bromopyridine-2-carbonitrile (0.51
g, 2.8 mmol, Synthonix),
4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]morpholine
(0.80 g, 2.8 mmol, Aldrich), CsF (1 g, 8 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.20 g, 0.28 mmol, Aldrich) in 1,4-dioxane (7 mL) and
H.sub.2O (2 mL) was heated to 120.degree. C. for 3 hours. Upon
cooling, EtOAc and water were added. The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The product was purified by flash chromatography, eluting with a
gradient from 0-100% EtOAc in hexanes. Yield: 0.40 g, 54%. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.91 (d, J=4.4 Hz, 1H), 8.43-8.35
(m, 2H), 7.98 (s, 1H), 7.76-7.71 (m, 2H), 4.01-3.76 (m, 4H),
3.52-3.42 (m, 4H); LCMS (M+H).sup.+: 267.1.
Step 2. 5-Morpholin-4-yl-3,4'-bipyridine-2-carboximidamide
##STR00138##
[0601] To a suspension of
5-morpholin-4-yl-3,4'-bipyridine-2'-carbonitrile (0.40 g, 1.5 mmol,
from Step 1) in MeOH (6.0 mL) was added sodium methoxide (25 wt %
in MeOH, 0.36 mL, 1.3 mmol, Aldrich). After stirring for 1.5 hours,
ammonium chloride (160 mg, 3.0 mmol) was added, and the reaction
was stirred overnight. Solvent was removed in vacuo and the product
was triturated in water, isolated by filtration, and dried by
azeotropic removal with acetonitrile. Yield: 0.39 g, 92%. .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 9.69 (s, 2H), 9.38 (s, 2H),
8.89 (d, J=5.1 Hz, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.46 (d, J=2.2
Hz, 1H), 8.22 (d, J=4.1 Hz, 1H), 7.83 (s, 1H), 3.97-3.60 (m, 4H),
3.44-3.09 (m, 4H); LCMS (M+H).sup.+: 284.2.
Step 3.
2'-(5-Methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4-bipyridine
[0602] To a mixture of
5-morpholin-4-yl-3,4'-bipyridine-2'-carboximidamide (15 mg, 0.053
mmol, from Step 2) and chloroacetone (5.0 .mu.L, 0.064 mmol,
Aldrich) in EtOH (0.3 mL) was added K.sub.2CO.sub.3 (29 mg, 0.21
mmol). The sealed reaction vial was heated to 100.degree. C. for
1.5 hours. Additional chloroacetone (5.0 .mu.L, 0.064 mmol) was
added and heating at 100.degree. C. was continued overnight. Upon
cooling to room temperature, the reaction was diluted with MeOH and
CH.sub.3CN and the product was purified by preparative HPLC (C-18
column eluting with a water:acetonitrile gradient buffered at pH 2
with 0.1% trifluoroacetic acid), followed by further purification
via preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 10 with 0.15% ammonium hydroxide). .sup.1H
NMR (400 MHz, d.sub.6-DMSO, tautomers) .delta. 12.63 (s, 0.5H),
12.51 (s, 0.5H), 8.64 (d, J=4.9 Hz, 1H), 8.45-8.39 (m, 2H),
8.25-8.21 (m, 1H), 7.71-7.64 (m, 2H), 6.96 (s, 0.5H), 6.79 (s,
0.5H), 3.84-3.74 (m, 4H), 3.36-3.25 (m, 4H), 2.25 (s, 1.5H), 2.20
(s, 1.5H); LCMS(M+H).sup.+: 322.1.
[0603] Examples 98 through 105 were synthesized according to the
procedure of Example 97 and the data are listed in Table 8.
TABLE-US-00007 TABLE 8 ##STR00139## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 98 4-(2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin-5- yl)morpholine trifluoroacetate salt ##STR00140##
336.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.88 (d, J = 5.1
Hz, 1H), 8.56-8.52 (m, 2H), 8.50 (d, J = 2.6 Hz, 1H), 8.07 (dd, J =
5.2, 1.4 Hz, 1H), 7.81- 7.77 (m, 1H), 3.84-3.76 (m, 4H), 3.38-3.29
(m, 4H), 2.32 (s, 6H);\ 99 4-(2'-(5- (Trifluoromethyl)-
1H-imidazol-2- yl)-3,4'-bipyridin- 5-yl)morpholine trifluoroacetate
salt ##STR00141## 376.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 13.59 (br s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.54- 8.51 (m,
1H), 8.46 (d, J = 2.5 Hz, 1H), 8.36-8.30 (m, 1H), 7.94-7.91 (m,
1H), 7.87 (dd, J = 5.2, 1.7 Hz, 1H), 7.86- 7.82 (m, 1H), 3.88-3.70
(m, 4H), 3.45-3.20 (m, 4H) 100 4-(2'-(5-Ethyl- 1H-imidazol-2-
yl)-3,4'-bipyridin- 5-yl)morpholine trifluoroacetate salt
##STR00142## 336.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
8.88 (d, J = 5.1 Hz, 1H), 8.60 (s, 1H), 8.55 (d, J = 1.5 Hz, 1H),
8.49 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 5.2, 1.4 Hz, 1H), 7.81-7.75
(m, 1H), 7.61 (s, 1H), 3.84-3.76 (m, 4H), 3.36-3.31 (m, 4H), 2.75
(q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H) 101 4-(2'-(5-
Isopropyl-1H- imidazol-2-yl)- 3,4'-bipyridin-5- yl)morpholine
trifluoroacetate salt ##STR00143## 350.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.89 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.55
(d, J = 1.6 Hz, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.09 (dd, J = 5.2,
1.4 Hz, 1H), 7.81-7.75 (m, 1H), 7.65 (s, 1H), 3.84-3.77 (m, 4H),
3.38-3.29 (m, 4H), 3.11 (hept, J = 6.8 Hz, 1H), 1.34 (d, J = 6.9
Hz, 6H) 102 4-(2'-(5- Cyclopropyl-1H- imidazol-2-yl)-
3,4'-bipyridin-5- yl)morpholine trifluoroacetate salt ##STR00144##
348.3 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.88 (d, J = 5.1
Hz, 1H), 8.61-8.57 (m, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.50 (d, J =
2.7 Hz, 1H), 8.08 (dd, J = 5.2, 1.5 Hz, 1H), 7.87-7.78 (m, 1H),
7.57 (s, 1H), 3.86- 3.67 (m, 4H), 3.45-3.08 (m, 4H), 2.13-1.92 (m,
1H), 1.12- 0.94 (m, 2H), 0.91-0.78 (m, 2H) 103 4-(2'-(5-
Cyclobutyl-1H- imidazol-2-yl)- 3,4'-bipyridin-5- yl)morpholine
trifluoroacetate salt ##STR00145## 362.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.90 (d, J = 5.1 Hz, 1H), 8.61 (s, 1H), 8.57
(s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 4.7 Hz, 1H), 7.86
(s, 1H), 7.78 (s, 1H), 3.85- 3.76 (m, 4H), 3.67 (p, J = 8.6 Hz,
1H), 3.41-3.27 (m, 4H), 2.44-2.18 (m, 4H), 2.14- 1.98 (m, 1H),
1.98-1.83 (m, 1H) 104 4-(2'-(5- Cyclopropyl-4- methyl-1H-
imidazol-2-yl)- 3,4'-bipyridin-5- yl)morpholine trifluoroacetate
salt ##STR00146## 362.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 8.87 (d, J = 5.0 Hz, 1H), 8.57 (s, 1H), 8.55 (d, J = 1.1 Hz
1H), 8.50 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 5.1, 1.3 Hz 1H),
7.84-7.79 (m, 1H), 3.88-3.68 (m, 4H), 3.44- 3.17 (m, 4H), 2.37 (s,
3H), 2.06-1.93 (m, 1H), 1.10- 1.00 (m, 2H), 0.97-0.85 (m, 2H) 105
4-(2'-(5-Ethyl-4- methyl-1H- imidazol-2-yl)- 3,4'-bipyridin-5-
yl)morpholine ##STR00147## 350.2 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 12.38 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.44- 8.41
(m, 2H), 8.18 (dd, 1H), 7.67-7.65 (m, 1H), 7.64 (dd, J = 5.1, 1.7
Hz, 1H), 3.90- 3.61 (m, 4H), 3.33-3.26 (m, 4H), 2.59 (q, J = 7.5
Hz, 2H), 2.20 (s, 1.5 H), 2.13 (s, 1.5 H), 1.16 (t, J = 7.5 Hz,
3H)
Example 106.
2'-(5-Cyclohexyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine
trifluoroacetate salt
##STR00148##
[0604] Step 1.
5-(Methylsulfonyl)-3,4'-bipyridine-2-carbonitrile
##STR00149##
[0606] A degassed mixture of 4-bromopyridine-2-carbonitrile (1.0 g,
5.5 mmol, Synthonix),
3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
e (1.5 g, 5.4 mmol, PepTech Corp.), CsF (2 g, 20 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.38 g, 0.54 mmol, Aldrich) in 1,4-dioxane (10 mL) and
H.sub.2O (3 mL) was heated to 120.degree. C. for 2 hours. Upon
cooling to room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and H.sub.2O. The layers were shaken and separated
and the organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated to give a mixture of solids and oil.
CH.sub.2Cl.sub.2 was added to this mixture and the solid product
was isolated by filtration. The solid was then triturated with
Et.sub.2O.
[0607] Yield: 0.71 g, 50%. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.29 (d, J=1.7 Hz, 1H), 9.16 (d, J=1.8 Hz, 1H), 8.90 (d,
J=5.1 Hz, 1H), 8.46 (t, J=2.0 Hz, 1H), 8.00-7.89 (m, 1H), 7.78 (dd,
J=5.1, 1.7 Hz, 1H), 3.20 (s, 3H); LCMS (M+H).sup.+: 260.1.
Step 2. 5-(Methylsulfonyl)-3,4'-bipyridine-2-carboximidamide
##STR00150##
[0609] To a suspension of
5-(methylsulfonyl)-3,4'-bipyridine-2'-carbonitrile (0.70 g, 2.7
mmol, from Step 1) in MeOH (11 mL) was added sodium methoxide (25
wt % in MeOH, 0.68 mL, 2.4 mmol, Aldrich). The mixture was stirred
at room temperature overnight. Ammonium chloride (290 mg, 5.4 mmol)
was then added and the reaction mixture was heated to 40.degree. C.
overnight. Solvent was removed via rotary evaporation and the
product was triturated with water, then isolated by filtration and
dried by repeated azeotropic removal of water with acetonitrile.
Yield: 0.71 g, 86%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
9.57 (br s, 3H), 9.50 (s, 1H), 9.24-9.20 (m, 1H), 8.98 (d, J=5.0
Hz, 1H), 8.89 (s, 2H), 8.36 (d, J=4.5 Hz, 1H), 3.45 (s, 3H);
LCMS(M+H).sup.+: 277.1.
Step 3.
2'-(5-Cyclohexyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4-bipyridi-
ne trifluoroacetate salt
[0610] To a mixture of
5-(methylsulfonyl)-3,4'-bipyridine-2'-carboximidamide (16 mg, 0.053
mmol, from Step 2) and 2-bromo-1-cyclohexylethanone (16 mg, 0.079
mmol, Enamine Ltd.) in EtOH (0.3 mL) was added K.sub.2CO.sub.3 (29
mg, 0.21 mmol). The reaction mixture was heated to 100.degree. C.
in a sealed vial for 1.5 hours. Upon cooling to room temperature,
the reaction mixture was diluted with MeOH and CH.sub.3CN,
filtered, and purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield 4.0 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.45 (s, 1H), 9.26 (s, 1H), 8.97 (d, J=5.0
Hz, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.21 (d, J=4.5 Hz, 1H), 7.65
(s, 1H), 3.46 (s, 3H), 2.79 (t, J=10.9 Hz, 1H), 2.11-1.98 (m, 2H),
1.88-1.77 (m, 2H), 1.77-1.67 (m, 1H), 1.57-1.14 (m, 5H); LCMS
(M+H).sup.+: 383.2.
[0611] Examples 107 through 119 were synthesized according to the
procedure of Example 106 and the data are listed in Table 9.
TABLE-US-00008 TABLE 9 ##STR00151## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 107 2'-(5-Methyl-1H- imidazol-2-yl)-5-
(methylsulfonyl)- 3,4'-bipyridine trifluoroacetate salt
##STR00152## 315.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.44 (d, J = 2.1 Hz, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.94 (d, J =
5.2 Hz, 1H), 8.77 (t, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.20- 8.10 (m,
1H), 7.52 (s, 1H), 3.46 (s, 3H), 2.38 (s, 3H) 108 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00153## 329.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.44 (d, J = 2.1 Hz, 1H), 9.26 (d, J = 2.1
Hz, 1H), 8.95 (d, J = 5.1 Hz, 1H), 8.76 (t, J = 2.1 Hz, 1H),
8.61-8.56 (m, 1H), 8.20 (dd, J = 5.1, 1.6 Hz, 1H), 3.45 (s, 3H),
2.33 (s, 6H) 109 5- (Methylsulfonyl)- 2'-(5- (trifluoromethyl)-
1H-imidazol-2- yl)-3,4'- bipyridine trifluoroacetate ##STR00154##
369.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.41 (d, J = 1.9
Hz, 1H), 9.17 (d, J = 1.9 Hz, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.78
(t, J = 1.9 Hz, 1H), 8.49-8.45 (m, 1H), 7.99 (dd, J = 5.2, 1.6 Hz,
1H), 7.95-7.88 (m, 1H), salt 3.45 (s, 3H) 110 2'-(5-Ethyl-1H-
imidazol-2-yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00155## 329.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.47-9.43 (m, 1H), 9.28-9.25 (m, 1H), 8.97
(d, J = 5.1 Hz, 1H), 8.79-8.77 (m, 1H), 8.69 (s, 1H), 8.25-8.19 (m,
1H), 7.68 (s, 1H), 3.46 (s, 3H), 2.77 (q, J = 7.4 Hz, 2H), 1.30 (t,
J = 7.5 Hz, 3H) 111 2'-(5-Isopropyl- 1H-imidazol-2- yl)-5-
(methylsulfonyl)- 3,4'-bipyridine trifluoroacetate salt
##STR00156## 343.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.45 (d, J = 2.1 Hz, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.97 (d, J =
5.1 Hz, 1H), 8.78 (t, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.22 (dd, J =
5.2, 1.5 Hz, 1H), 7.67 (s, 1H), 3.46 (s, 3H), 3.12 (hept, J = 7.2
Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H) 112 2'-(5- Cyclopropyl-1H-
imidazol-2-yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00157## 341.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.44 (d, J = 2.1 Hz, 1H), 9.25 (d, J = 2.0
Hz, 1H), 8.94 (d, J = 5.1 Hz, 1H), 8.77 (t, J = 2.1 Hz, 1H), 8.63
(s, 1H), 8.20- 8.15 (m, 1H), 7.53 (s, 1H), 3.46 (s, 3H), 2.08-1.95
(m, 1H), 1.10-0.96 (m, 2H), 0.92-0.81 (m, 2H) 113 2'-(5-Cyclobutyl-
1H-imidazol-2- yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00158## 355.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.44 (d, J = 1.9 Hz, 1H), 9.25 (d, J = 1.8
Hz, 1H), 8.96 (d, J = 5.1 Hz, 1H), 8.79-8.75 (m, 1H), 8.68 (s, 1H),
8.21 (dd, J = 5.0, 1.0 Hz, 1H), 7.77 (s, 1H), 3.67 (p, J = 8.4 Hz,
1H), 3.45 (s, 3H), 2.43- 2.19 (m, 4H), 2.12-1.97 (m, 1H), 1.97-1.83
(m, 1H) 114 2'-(5- Cyclopentyl-1H- imidazol-2-yl)-5-
(methylsulfonyl)- 3,4'-bipyridine trifluoroacetate salt
##STR00159## 369.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.45 (d, J = 2.1 Hz, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.97 (d, J =
5.2 Hz, 1H), 8.78 (t, J = 2.1 Hz, 1H), 8.68 (s, 1H), 8.22 (dd, J =
5.2, 1.5 Hz, 1H), 7.71 (s, 1H), 3.46 (s, 3H), 3.22 (p, J = 7.5, 7.0
Hz, 1H), 2.18- 2.00 (m, 2H), 1.83-1.58 (m, 6H) 115 2'-(5-Benzyl-1H-
imidazol-2-yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00160## 391.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.31 (d, J = 2.1 Hz, 1H), 9.24 (d, J = 2.0 Hz,
1H), 8.93 (d, J = 5.1 Hz, 1H), 8.76 (t, J = 2.1 Hz, 1H), 8.48 (s,
1H), 8.04 (dd, J = 5.1, 1.5 Hz, 1H), 7,44 (s, 1H), 7.41-7.20 (m,
5H), 4.19 (s, 2H), 3.33 (s, 3H) 116 2'-(5- Cyclopropyl-4-
methyl-1H- imidazol-2-yl)-5- (methylsulfonyl)- 3,4'-bipyridine
trifluoroacetate salt ##STR00161## 355.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.43 (d, J = 2.1 Hz, 1H), 9.25 (d, J = 2.0
Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.76 (t, J = 2.1 Hz, 1H), 8.62
(s, 1H), 8.17 (dd, J = 5.1, 1.3 Hz, 1H), 3.45 (s, 3H), 2.37 (s,
3H), 2.05- 1.95 (m, 1H), 1.07-1.00 (m, 2H), 0.96-0.89 (m, 2H) 117
2'-(5-Ethyl-4- methyl-1H- imidazol-2-yl)-5- (methylsulfonyl)-
3,4'-bipyridine ##STR00162## 343.1 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 12.45 (brs, 1H), 9.40-9.35 (m, 1H), 9.19- 9.14 (m,
1H), 8.75-8.71 (m, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.33 (d, J = 10.1
Hz, 1H), 7.85-7.69 (m, 1H), 3.45 (s, 3H), 2.59 (q, J = 7.4 Hz, 2H),
2.21 (s, 1.5 H), 2.15 (s, 1.5 H), 1.17 (t, J = 7.5 Hz, 3H) 118 5-
(Methylsulfonyl)- 2'-(5-(pyridin-2- yl)-1H-imidazol- 2-yl)-3,4'-
bipyridine ##STR00163## 378.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 13.15 (br s, 1H), 9.43 (d, J = 2.0 Hz, 1H), 9.19 (d, J =
1.9 Hz, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.78 (t, J = 2.0 Hz, 1H),
8.60-8.45 (m, 2H), 8.06 (d, J = 7.7 Hz, 1H), 7.93 (dd, J = 5.1, 1.4
Hz, 1H), 7.86- 7.80 (m, 2H), 7.28-7.21 (m, 1H), 3.46 (s, 3H) 119
5-Methyl-2-(5- (methylsulfonyl)- 3,4'-bipyridin- 2'-yl)-1H-
imidazole-4- carboxylic acid trifluoroacetate salt ##STR00164##
359.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.43 (d, J = 2.1
Hz, 1H), 9.21 (d, J = 2.1 Hz, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.77
(t, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.03 (dd, J = 5.2, 1.6 Hz, 1H),
3.46 (s, 3H), 2.55 (s, 3H)
Example 120.
4-Cyclohexyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazol-5-am-
ine trifluoroacetate salt
##STR00165##
[0612] Step 1.
2-(4-Cyclohexyl-5-nitro-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4-bipyridi-
ne
##STR00166##
[0614] A solution of
2'-(5-cyclohexyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine
trifluoroacetate salt (0.040 g, 0.10 mmol, from Example 106) in
HNO.sub.3 (0.09 mL) and H.sub.2SO.sub.4 (0.2 mL) was stirred at
room temperature for 1 hour. The reaction mixture was added into
saturated NaHCO.sub.3 and stirred for 30 minutes. The aqueous
solution was extracted with three portions of EtOAc. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was used without further purification in
Step 2. LCMS (M+H).sup.+: 428.1.
Step 2.
4-Cyclohexyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2-yl]-1H-imidazo-
l-5-amine
[0615] trifluoroacetate salt
2'-(4-Cyclohexyl-5-nitro-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyri-
dine (0.014 g, 0.033 mmol, from Step 1) in EtOH (6 mL) and H.sub.2O
(2 mL) was treated with iron (0.013 g, 0.23 mmol) and concentrated
HCl (0.019 mL, 0.23 mmol) and heated to 70.degree. C. for 2.5
hours. The reaction mixture was diluted with water and DMF and was
filtered and purified by preparative HPLC (C-18 column eluting with
a water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 2 mg. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.31 (d, J=2.1 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H),
8.84 (d, J=5.0 Hz, 1H), 8.76 (t, J=2.1 Hz, 1H), 8.43-8.39 (m, 1H),
7.92 (dd, J=5.1, 1.7 Hz, 1H), 2.91-2.78 (m, 1H), 1.95-1.83 (m, 4H),
1.83-1.74 (m, 1H), 1.74-1.56 (m, 2H), 1.56-1.24 (m, 3H); LCMS
(M+H).sup.+: 398.1.
Example 121.
2'-[4-(Difluoromethyl)-5-methyl-1H-imidazol-2-yl]-5-(methylsulfonyl)-3,4'-
-bipyridine trifluoroacetate salt
##STR00167##
[0617] Carbon monoxide was introduced into a degassed mixture of
2'-(4-iodo-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl-
)-5-(methyl sulfonyl)-3,4'-bipyridine (0.22 g, 0.38 mmol, Peak 1
from Example 243, Step 3), Na.sub.2CO.sub.3 (82 mg, 0.77 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (31 mg, 0.038 mmol, Aldrich) and
triethylsilane (180 .mu.L, 1.2 mmol, Aldrich) in DMF (5.5 mL) by
bubbling through the reaction mixture subsurface for 3 minutes. The
reaction vessel was sealed and heated to 65.degree. C. for 2.5
hours. Upon cooling to room temperature, water was added and the
mixture was extracted with EtOAc. The organic layer was washed
twice with water and once with saturated NaCl solution, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The aldehyde product
was purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes. Yield: 0.14 g, 77%. LCMS (M+H).sup.+:
473.1.
[0618] To a solution of the aldehyde (10. mg, 0.021 mmol) in DCM
(0.50 mL) was added Deoxofluor.RTM. (7.8 .mu.L, 0.042 mmol)
dropwise, followed by ethanol (0.25 .mu.L, 0.0042 mmol, as a
solution of 0.25 .mu.L of EtOH in 0.10 ml DCM). The mixture was
stirred overnight and then heated to 35.degree. C. for 30 minutes.
Additional Deoxofluor.RTM. (3.9 .mu.L, 0.021 mmol) was added and
the reaction was heated to 40.degree. C. for 30 minutes. Upon
cooling to room temperature, TFA (0.50 mL) was added and the
reaction mixture was stirred for 1.5 hours. TFA was removed in
vacuo and the product was purified by preparative HPLC (C-18 column
eluting with a gradient from 8.6-26.6% acetonitrile in water
containing 0.1% trifluoroacetic acid over 12 minutes). Yield: 2.1
mg. .sup.1H NMR (400 MHz, CD3OD) .delta. 9.33 (d, J=1.4 Hz, 1H),
9.22 (d, J=1.4 Hz, 1H), 8.87 (d, J=5.1 Hz, 1H), 8.80-8.72 (m, 1H),
8.54 (s, 1H), 7.97 (d, J=4.5 Hz, 1H), 7.02 (t, J=53.5 Hz, 1H), 3.30
(s, 3H), 2.50 (s, 3H); LCMS (M+H).sup.+: 365.1.
Example 122.
[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]meth-
anol
##STR00168##
[0619] Step 1.
2'-(5-Methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4-bipyridine
##STR00169##
[0621] To 5-morpholin-4-yl-3,4'-bipyridine-2'-carbonitrile (0.75 g,
2.8 mmol, prepared as in Example 97, Step 1) in MeOH (11 mL) was
added sodium methoxide (25 wt % in MeOH, 0.05 mL, 0.24 mmol) and
the solution was stirred overnight. 1,1-Diethoxypropan-2-amine
(0.41 g, 2.8 mmol, AstaTech) and acetic acid (0.32 mL) were added
dropwise. The reaction was heated in a sealed vial immersed in an
oil bath to 100.degree. C. for 1 hour. The mixture was cooled to
room temperature and concentrated HCl (0.60 mL, 7.2 mmol) was
added. The mixture was then heated in an oil bath at 85.degree. C.
for 5.5 hours. The mixture was cooled and solvent was removed via
rotary evaporation. A solution of K.sub.2CO.sub.3 in water was
added to adjust to pH 10. The precipitated product was isolated by
filtration. Yield: 0.70 g, 70%. LCMS (M+H).sup.+: 322.2.
Step 2.
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4-bipyrid-
ine
##STR00170##
[0623] N-Iodosuccinimide (0.463 g, 2.06 mmol, Aldrich) was added to
a solution of
2'-(5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
(0.70 g, 2.0 mmol, from Step 1) in DMF (6.2 mL). After stirring for
20 minutes, water (50 mL) and saturated NaHCO.sub.3 solution (20
mL) were added. The precipitated product was isolated by filtration
and dried by repeated azeotropic removal of water by evaporation
with acetonitrile.
[0624] Yield: 0.86 g, 98%. LCMS (M+H).sup.+: 448.0.
Step 3.
5-Methyl-2-(5-morpholin-4-yl-3,4-bipyridin-2'-yl)-1H-imidazole-4-c-
arbaldehyde
##STR00171##
[0626] Carbon monoxide was introduced to a degassed mixture of
2'-(4-iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
(0.50 g, 1.1 mmol, from Step 2), Na.sub.2CO.sub.3 (0.24 g, 2.2
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (91 mg, 0.11 mmol, Aldrich) and
triethylsilane (0.54 mL, 3.4 mmol, Aldrich) in DMF (12 mL) by
bubbling the CO through the reaction mixture subsurface for 5
minutes. The reaction vessel was then sealed and heated to
65.degree. C. for 2.5 hours. Upon cooling to room temperature,
water (60 mL) was added and the aqueous mixture was saturated with
NaCl to afford a precipitate that was isolated by filtration. The
aqueous mixture was then extracted with three portions of DCM. The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentrated. This material was combined with the
solid isolated by the initial filtration. The product was purified
by flash chromatography, eluting with a gradient from 0-5% MeOH in
DCM. Yield: 0.14 g, 36%. LCMS (M+H).sup.+: 350.2.
Step 4.
[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4--
yl]methanol
[0627]
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-c-
arbaldehyde (10. mg, 0.029 mmol, from Step 3) in EtOH (0.50 mL) was
treated with NaBH.sub.4 (2.2 mg, 0.057 mmol). After stirring for 1
hour at room temperature, additional NaBH.sub.4 (1.1 mg, 0.029
mmol) was added. The reaction was quenched by the addition of
water. The product was initially purified by preparative HPLC (C-18
column eluting with 7.3% to 27.3% MeCN in water containing 0.1% TFA
over 5 minutes) and the second peak with mass M+H=352 (retention
time: 6.6 min) was collected. The product was further purified by
preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 10 with 0.15% ammonium hydroxide). Yield:
2.1 mg, 21%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (d,
J=5.1 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.43 (s, 1H), 8.41 (d, J=2.6
Hz, 1H), 7.92 (dd, J=5.1, 1.5 Hz, 1H), 7.83-7.79 (m, 1H), 4.69 (s,
2H), 3.93-3.82 (m, 4H), 3.40-3.33 (m, 4H), 2.44 (s, 3H); LCMS
(M+H).sup.+: 352.2.
Example 123.
2-[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]et-
hanol
##STR00172##
[0628] Step 1.
2'-{4-[(E)-2-Methoxyvinyl]-5-methyl-1H-imidazol-2-yl}-5-morpholin-4-yl-3,-
4'-bipyridine and
2-{4-[(Z)-2-methoxyvinyl]-5-methyl-1H-imidazol-2-yl}-5-morpholin-4-yl-3,4-
'-bipyridine (mixture of isomers)
##STR00173##
[0630] To (methoxymethyl)(triphenyl)phosphonium chloride (0.22 g,
0.64 mmol, Aldrich) in THF (6.8 mL) at 0.degree. C. was added 1.0 M
KO.sup.tBu in THF (0.64 mL, 0.64 mmol, Aldrich). After stirring for
30 minutes at 0.degree. C., a slurry of
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carbald-
ehyde (50. mg, 0.14 mmol, from Example 122, Step 3) in THF (3.4 mL)
was added. The reaction mixture was stirred at 0.degree. C. for 1.5
hours, then at room temperature for 30 minutes. Most of the THF was
then removed in vacuo and the mixture was diluted with MeCN and
MeOH and filtered. The product was purified by preparative HPLC
(C-18 column eluting with a water:acetonitrile gradient buffered at
pH 10 with 0.15% ammonium hydroxide). Yield: 33 mg, 61%.
[0631] LCMS (M+H).sup.+: 378.2.
Step 2.
[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4--
yl]acetaldehyde
##STR00174##
[0633] A mixture of
2'-{4-[(E)-2-methoxyvinyl]-5-methyl-1H-imidazol-2-yl}-5-morpholin-4-yl-3,-
4'-bipyridine and
2'-{4-[(Z)-2-methoxyvinyl]-5-methyl-1H-imidazol-2-yl}-5-morpholin-4-yl-3,-
4'-bipyridine (33 mg, 0.087 mmol, from Step 1) in MeCN (1.9 mL) was
treated with NaI (26 mg, 0.17 mmol) and TMSCl (22 .mu.L, 0.17
mmol). The reaction was stirred at room temperature for 3 hours, at
which time additional NaI (13 mg, 0.087 mmol) and TMSCl (11 .mu.L,
0.087 mmol) were added. After stirring for an additional 1.5 hours,
the reaction was quenched by the addition of water (0.20 mL). The
mixture was diluted with MeCN/MeOH (1:1, 20 mL). The mixture was
filtered and solvent was removed from the filtrate in vacuo. The
product was used without further purification in Step 3.
Step 3.
2-[5-Methyl-2-(5-morpholin-4-yl-3,4-bipyridin-2'-yl)-1H-imidazol-4-
-yl]ethanol
[0634]
[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-y-
l]acetaldehyde (9.0 mg, 0.025 mmol) in EtOH (0.50 mL) was treated
with NaBH.sub.4 (2.2 mg, 0.057 mmol). After stirring at room
temperature for one hour, the reaction was quenched by the addition
of 1.0 N HCl. The product was purified by preparative HPLC (C-18
column eluting with a water:acetonitrile gradient buffered at pH 10
with 0.15% ammonium hydroxide). Yield: 2.7 mg, 30%. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.62 (d, J=5.2 Hz, 1H), 8.41 (d,
J=1.7 Hz, 1H), 8.34-8.31 (m, 2H), 7.75-7.70 (m, 1H), 7.61 (dd,
J=5.2, 1.7 Hz, 1H), 3.91-3.83 (m, 4H), 3.78 (t, J=6.9 Hz, 2H),
3.36-3.31 (m, 4H), 2.82 (t, J=5.7 Hz, 2H), 2.27 (s, 3H); LCMS
(M+H).sup.+: 366.2.
Example 124.
1-[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]et-
hanol (racemic mixture)
##STR00175##
[0636]
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-c-
arbaldehyde (10. mg, 0.029 mmol) in THF (0.50 mL) at 0.degree. C.
was treated with 1.0 M methyl magnesium bromide in THF (57 .mu.L,
0.057 mmol, Aldrich). After stirring for 20 minutes at 0.degree.
C., the reaction was quenched with 0.10 mL 1.0 N HCl. The mixture
was diluted with MeOH/MeCN, filtered and purified by preparative
HPLC (C-18 column eluting with a water:acetonitrile gradient
buffered at pH 10 with 0.15% ammonium hydroxide). Yield: 7.2 mg,
69%. .sup.1H NMR (500 MHz, d.sub.6-DMSO, tautomers) .delta. 12.44
(s, 0.7H), 12.22 (s, 0.3H), 8.66-8.59 (m, 1H), 8.46-8.36 (m, 2H),
8.20 (s, 0.3H), 8.16 (s, 0.7H), 7.69-7.61 (m, 2H), 4.96 (br m,
0.3H), 4.86 (br m, 0.3H), 4.75 (br m, 0.7H), 4.69 (br m, 0.7H),
3.81-3.75 (m, 4H), 3.31-3.26 (m, 4H), 2.27 (s, 2H), 2.19 (s, 1H),
1.44-1.35 (m, 3H);
[0637] LCMS (M+H).sup.+: 366.2.
Example 125. Methyl
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxy-
late
##STR00176##
[0639]
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyrid-
ine (0.98 g, 2.2 mmol, from Example 122, Step 2) in MeOH (24 mL)
containing triethylamine (0.76 mL, 5.5 mmol) was degassed by
bubbling nitrogen through the solution, and
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.16
g, 0.22 mmol, Aldrich) was added. The slurry was then saturated
with carbon monoxide by bubbling the CO gas through the reaction
mixture subsurface for 3 minutes. The reaction vessel was sealed
and heated to 60.degree. C. overnight. Additional triethylamine
(0.49 mL, 3.5 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (0.14 g, 0.18 mmol) were added,
and the slurry was again saturated with CO. The sealed reaction
vessel was heated to about 60-65.degree. C. for an additional 24
hours. Upon cooling to room temperature, water (50 mL) was added to
the reaction mixture. The suspension was stirred for 15 minutes,
and the solid product was isolated by filtration. The product was
purified by flash chromatography, eluting with a gradient from
0-10% MeOH in DCM. Theoretical yield obtained. A portion was
subsequently purified via preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 2 with 0.1% TFA).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.77 (d, J=5.1 Hz, 1H),
8.61 (d, J=1.2 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.39-8.34 (m, 1H),
8.05 (s, 1H), 7.87 (dd, J=5.2, 1.7 Hz, 1H), 3.83-3.74 (m, 4H), 3.80
(s, 3H), 3.47-3.33 (m, 4H), 2.54 (s, 3H); LCMS (M+H).sup.+:
380.1.
Example 126. tert-Butyl
[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbamate
##STR00177##
[0640] Step 1. tert-Butyl
(2'-cyano-3,4'-bipyridin-5-yl)carbamate
##STR00178##
[0642] A degassed mixture of 4-bromopyridine-2-carbonitrile (1.0 g,
5.5 mmol, Synthonix), tert-butyl
[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]carbamate
(1.7 g, 5.4 mmol, Small Molecules, Inc.), CsF (2 g, 20 mmol,
Aldrich), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.38 g, 0.54 mmol) in 1,4-dioxane (10 mL) and water (3 mL)
was heated to 120.degree. C. for 70 minutes. Upon cooling to room
temperature, EtOAc and water were added. The layers were shaken and
separated, and the organic layer was washed twice with water, once
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-80% EtOAc in hexanes. Yield: 1.1 g,
68%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.81 (d, J=5.1 Hz,
1H), 8.63-8.59 (m, 2H), 8.53 (s, 1H), 7.94 (s, 1H), 7.76 (dd,
J=5.0, 1.4 Hz, 1H), 7.23 (s, 1H), 1.55 (s, 9H); LCMS (M+H).sup.+:
297.2.
Step 2. tert-Butyl
{2-[amino(imino)methyl]-3,4-bipyridin-5-yl}carbamate
##STR00179##
[0644] To a suspension of tert-butyl
(2'-cyano-3,4'-bipyridin-5-yl)carbamate (1.1 g, 3.7 mmol, from Step
1) in MeOH (15 mL) was added sodium methoxide (25 wt % in MeOH,
0.93 mL, 3.3 mmol). The mixture was stirred at room temperature for
1.5 hours. Ammonium chloride (0.40 g, 7.4 mmol) was then added and
the reaction was stirred overnight. Solvent was removed in vacuo
and the solid was triturated with a mixture of water and ether and
isolated by filtration. The aqueous layer of the filtrate was then
extracted with CHCl.sub.3 (3 times) to wash out a small impurity.
The volume of the aqueous mixture was reduced via rotary
evaporation and solid NaCl was added to precipitate additional
solid product, which was isolated by filtration. Combined yield:
1.0 g, yield 86%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 9.85
(s, 1H), 9.69 (br s, 2H), 9.48 (br s, 2H), 8.91 (d, J=5.1 Hz, 1H),
8.78-8.72 (m, 1H), 8.72-8.62 (m, 2H), 8.42 (s, 1H), 8.13-8.00 (m,
1H), 1.51 (s, 9H); LCMS (M+H).sup.+: 314.2.
Step 3. tert-Butyl
[2-(5-phenyl-1H-imidazol-2-yl)-3,4-bipyridin-5-yl]carbamate
[0645] To a mixture of tert-butyl
{2'-[amino(imino)methyl]-3,4'-bipyridin-5-yl}carbamate (0.30 g,
0.96 mmol, from Step 2) and 2-bromoacetophenone (0.28 g, 1.4 mmol,
Aldrich) in EtOH (5.0 mL) was added K.sub.2CO.sub.3 (0.53 g, 3.8
mmol). The mixture was sealed and heated in a sealed vessel to
80.degree. C. for 1 hour. Additional 2-bromoacetophenone (95 mg,
0.48 mmol) was added and heating was continued for 40 minutes. Upon
cooling to room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient of 0-5%
MeOH in CH.sub.2Cl.sub.2. The product so obtained was further
purified by trituration with Et.sub.2O. Yield: 0.12 g, 29%. .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 13.04 (s, 1H), 9.79 (s, 1H),
8.77 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H),
8.35-8.30 (m, 2H), 7.92 (d, J=7.6 Hz, 2H), 7.80 (d, J=1.9 Hz, 1H),
7.73-7.70 (m, 1H), 7.43-7.35 (m, 2H), 7.27-7.17 (m, 1H), 1.52 (s,
9H); LCMS (M+H).sup.+: 414.2.
Example 127. 2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt
##STR00180##
[0647] A solution of tert-butyl
[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]carbamate (80.
mg, 0.19 mmol, from Example 126) in CH.sub.2Cl.sub.2 (5 mL) was
treated with 4.0 M HCl in dioxane (0.97 mL, 3.9 mmol) overnight.
Volatiles were removed in vacuo and the mixture was neutralized by
the addition of aqueous NH.sub.4OH. The product was purified by
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 56 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.84 (d, J=5.2 Hz, 1H), 8.49 (s, 2H), 8.14
(d, J=2.3 Hz, 1H), 8.00-7.92 (m, 3H), 7.88 (br m, 1H), 7.83 (dd,
J=5.1, 1.4 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 7.33 (t, J=7.4 Hz, 1H);
LCMS(M+H).sup.+: 314.1.
[0648] Examples 128 through 129 were synthesized according to the
procedure of Example 126 and 127, and the data are listed in Table
10.
TABLE-US-00009 TABLE 10 ##STR00181## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 128 tert-Butyl [2'-(4, Boc 365.9 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 5-dimethyl-1H- 10.04 (s, 1H), 8.62
(d, J = imidazol-2-yl)- 1.8 Hz, 1H), 8.54 (d, J = 3,4'-bipyridin-5-
5.1 Hz, 1H), 8.50 (d, J = 2.4 Hz, yl]carbamate 1H), 8.31 (s, 1H),
8.30-8.26 (m, 1H), 7.40 (dd, J = 5.1, 1.6 Hz, 1H), 6.72 (s, 1H),
2.26 (s, 6H), 1.55 (s, 9H) 129 2'-(4,5- H 266.1 .sup.1H NMR (400
MHz, d.sub.6-DMSO, Dimethyl-1H- tautomers) .delta. 12.38 (s, 1H),
8.59 imidazol-2-yl)- (d, J = 5.1 Hz, 1H), 8.18 (d, J =
3,4'-bipyridin-5- 1.9 Hz, 1H), 8.14-8.08 (m, 1H), amine 8.04 (d, J
= 2.5 Hz, 1H), 7.56 (dd, J = 5.2, 1.8 Hz, 1H), 7.36 (t, J = 2.2 Hz,
1H), 2.18 (s, 3H), 2.11 (s, 3H)
Example 130.
N-[2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]ethanesulfonamide
trifluoroacetate salt
##STR00182##
[0650] 2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt (10. mg, 0.015 mmol, from Example 127) in
CH.sub.2Cl.sub.2 (1.0 mL) was treated with
N,N-diisopropylethylamine (16 .mu.L, 0.092 mmol), and
ethanesulfonyl chloride (2.9 .mu.L, 0.030 mmol, Aldrich). After 70
minutes, solvent was removed under reduced pressure and the residue
was treated with aqueous NH.sub.4OH (0.2 mL) in MeOH (1 mL) for 30
minutes. Volatiles were removed in vacuo and the product was
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
10.34 (s, 1H), 8.87 (d, J=5.1 Hz, 1H), 8.84 (s, 1H), 8.60 (s, 1H),
8.54 (s, 1H), 8.11 (s, 1H), 8.05 (br m, 1H), 7.96 (d, J=7.6 Hz,
2H), 7.91 (d, J=4.6 Hz, 1H), 7.50 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.2
Hz, 1H), 3.29 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H); LCMS
(M+H).sup.+: 406.1.
Example 131.
2-Methoxy-N-[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]acetamide
trifluoroacetate salt
##STR00183##
[0652] 2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt (13 mg, 0.020 mmol, from Example 127) in
CH.sub.2Cl.sub.2 (1.3 mL, 20. mmol) was treated with
N,N-diisopropylethylamine (34.5 .mu.L, 0.198 mmol) and
methoxyacetyl chloride (7.2 .mu.L, 0.079 mmol, Aldrich) for 30
minutes. The solvent was removed in vacuo and the residue was
reconstituted in MeOH and treated with NH.sub.4OH (0.10 mL) for 30
minutes. Volatiles were removed in vacuo and the product was
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid).
[0653] Yield: 6.3 mg. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
10.29 (s, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.88 (d, J=5.1 Hz, 1H), 8.85
(d, J=1.9 Hz, 1H), 8.67 (t, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.14 (s,
1H), 7.96 (d, J=7.4 Hz, 2H), 7.93 (dd, J=5.1, 1.2 Hz, 1H), 7.51 (t,
J=7.6 Hz, 2H), 7.40 (t, J=7.3 Hz, 1H), 4.12 (s, 2H), 3.44 (s, 3H);
LCMS (M+H).sup.+: 386.2.
[0654] Examples 132 through 138 were synthesized according to the
procedure of Example 131 and the data are listed in Table 11.
TABLE-US-00010 TABLE 11 ##STR00184## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 132 N-(2'-(5- Phenyl-1H- imidazol-2- yl)-3,4'-
bipyridin-5- yl)benzamide ##STR00185## 418.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 10.72 (s, 1H), 9.11 (d, J = 1.7 Hz, 1H),
8.90-8.84 (m, 2H), 8.81- 8.72 (m, 1H), 8.59 (s, 1H), 8.14-8.00 (m,
3H), 7.98- 7.87 (m, 3H), 7.70-7.64 (m, 1H), 7.64-7.55 (m, 2H), 7.50
(t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H) 133 2-Chloro-N-
(2'-(5-phenyl- 1H-imidazol- 2-yl)-3,4'- bipyridin-5- yl)benzamide
##STR00186## 452.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
11.02 (s, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.91-8.82 (m, 2H), 8.79-
8.67 (m, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 7.99-7.84 (m, 3H),
7.72-7.67 (m, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.61-7.55 (m, 1H),
7.55-7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H) 134 3-Chloro-N-
(2'-(5-phenyl- 1H-imidazol- 2-yl)-3,4'- bipyridin-5- yl)benzamide
##STR00187## 452.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
10.81 (s, 1H), 9.12 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 1.7 Hz, 1H),
8.85 (d, J = 5.1 Hz, 1H), 8.77-8.67 (m, 1H), 8.54 (s, 1H),
8.18-8.07 (m, 1H), 8.04-7.98 (m, 2H), 7.95 (d, J = 7.5 Hz, 2H),
7.90 (d, J = 5.0 Hz, 1H), 7.77-7.68 (m, 1H), 7.64 (t, J = 7.9 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H) 135
4-Chloro-N- (2'-(5-phenyl- 1H-imidazol- 2-yl)-3,4'- bipyridin-5-
yl)benzamide ##STR00188## 452.2 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 10.77 (s, 1H), 9.11 (d, J = 2.1 Hz, 1H), 8.88 (d, J =
1.9 Hz, 1H), 8.84 (d, J = 5.1 Hz, 1H), 8.72 (t, J = 2.1 Hz, 1H),
8.54 (s, 1H), 8.11 -8.02 (m, 2H), 8.00 (s, 1H), 7.98- 7.92 (m, 2H),
7.90 (dd, J = 5.1, 1.2 Hz, 1H), 7.72- 7.66 (m, 2H), 7.47 (t, J =
7.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H) 136 3-Cyano-N- (2'-(5-phenyl-
1H-imidazol- 2-yl)-3,4'- bipyridin-5- yl)benzamide ##STR00189##
443.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 10.88 (s, 1H),
9.10 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.86 (d, J =
5.0 Hz, 1H), 8.73 (t, J = 1.9 Hz, 1H), 8.56 (s, 1H), 8.52-8.44 (m,
1H), 8.39-8.28 (m, 1H), 8.18-8.10 (m, 1H), 8.04 (s, 1H), 7.98-7.94
(m, 2H), 7.94-7.90 (m, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.48 (t, J =
7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H) 137 4-Cyano-N- (2'-(5-phenyl-
1H-imidazol- 2-yl)-3,4'- bipyridin-5- yl)benzamide ##STR00190##
443.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 10.92 (s, 1H),
9.11 (d, J = 1.9 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.84 (d, J =
5.1 Hz, 1H), 8.78-8.67 (m, 1H), 8.52 (s, 1H), 8.20 (d, J = 8.4 Hz,
2H), 8.10 (d, J = 8.3 Hz, 2H), 8.01-7.91 (m, 3H), 7.91-7.86 (m,
1H), 7.46 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H) 138
N-(2'-(5- Phenyl-1H- imidazol-2- yl)-3,4'- bipyridin-5-
yl)cyclopentane- carboxamide ##STR00191## 410.2 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 10.40 (s, 1H), 8.91-8.85 (m, 2H), 8.80
(s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.14 (s, 1H), 7.96 (d, J = 7.8
Hz, 2H), 7.93 (d, J = 4.1 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.41
(t, J = 7.2 Hz, 1H), 2.88 (p, J = 8.1 Hz, 1H), 1.99-1.85 (m, 2H),
1.85-1.45 (m, 6H)
Example 139.
N-Ethyl-N-[2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]urea
trifluoroacetate salt
##STR00192##
[0656] 2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt (15 mg, 0.023 mmol, from Example 127) in
CH.sub.2Cl.sub.2 (1.0 mL) was treated with triethylamine (16 .mu.L,
0.11 mmol) and ethyl isocyanate (3 .mu.L, 0.04 mmol) overnight.
Additional ethyl isocyanate (8 .mu.L, 0.1 mmol) was added and the
reaction was stirred for 72 hours. The product was purified by
preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). Yield:
10. mg. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 9.10 (s, 1H),
8.88 (d, J=5.1 Hz, 1H), 8.72-8.68 (m, 2H), 8.58 (s, 1H), 8.54 (t,
J=2.0 Hz, 1H), 8.14 (s, 1H), 8.00-7.94 (m, 2H), 7.91 (dd, J=5.1,
1.3 Hz, 1H), 7.52 (t, J=7.6 Hz, 2H), 7.41 (t, J=7.4 Hz, 1H), 6.59
(t, J=5.1 Hz, 1H), 3.23-3.09 (m, 2H), 1.10 (t, J=7.2 Hz, 3H); LCMS
(M+H).sup.+: 385.1.
Example 140. Ethyl
2'-(5-phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-ylcarbamate
trifluoroacetate salt
##STR00193##
[0658] 2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt (10.6 mg, 0.016 mmol, from Example 127) in
CH.sub.2Cl.sub.2 (1.0 mL) was treated with pyridine (13 .mu.L, 0.16
mmol) and ethyl chloroformate (3 uL, 0.03 mmol). After 10 minutes,
volatiles were removed in vacuo and the residue was dissolved in
MeOH (1.0 mL) and treated with NH.sub.4OH (0.10 mL) for 15 minutes.
Volatiles were again removed in vacuo and the residue was
reconstituted and the product was purified by preparative HPLC
(C-18 column eluting with a water:acetonitrile gradient buffered at
pH 2 with 0.1% trifluoroacetic acid). Yield: 7.0 mg. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 10.14 (s, 1H), 8.86 (d, J=5.2 Hz,
1H), 8.78-8.72 (m, 2H), 8.55 (s, 1H), 8.45-8.40 (m, 1H), 8.12 (s,
1H), 7.98-7.92 (m, 2H), 7.92-7.85 (m, 1H), 7.50 (t, J=7.6 Hz, 2H),
7.39 (t, J=7.4 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz,
3H); LCMS (M+H).sup.+: 386.1.
Example 141.
2'-(5-Phenyl-1H-imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-3,4'-bi-
pyridin-5-amine trifluoroacetate salt
##STR00194##
[0660] 2'-(5-Phenyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-amine
trifluoroacetate salt (15 mg, 0.023 mmol, from Example 127) and
tetrahydro-2H-pyran-4-carbaldehyde (13 mg, 0.11 mmol, PharmaCore)
were combined in 1,2-dichloroethane (1.0 mL), and
N,N-diisopropylethylamine (20. .mu.L, 0.11 mmol) was added. After
stirring for 1 hour, AcOH (0.50 mL) and Na(OAc).sub.3BH (39 mg,
0.18 mmol) were added. After 1 hour, the solvent was removed via
rotary evaporation and the product was purified by preparative HPLC
(C-18 column eluting with a water: acetonitrile gradient buffered
at pH 2 with 0.1% trifluoroacetic acid). Yield: 7.2 mg. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.87 (d, J=5.0 Hz, 1H), 8.54 (s,
1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=7.5 Hz,
2H), 7.93-7.86 (m, 2H), 7.48 (t, J=7.6 Hz, 2H), 7.35 (t, J=7.3 Hz,
1H), 3.97-3.77 (m, 2H), 3.33 (t, J=11.3 Hz, 2H), 3.21-3.03 (m, 2H),
1.94-1.79 (m, 1H), 1.72 (d, J=12.9 Hz, 2H), 1.31 (ddt, J=16.0,
12.5, 5.0 Hz, 2H); LCMS (M+H).sup.+: 412.3.
[0661] Examples 142 through 144 were synthesized according to the
procedure of Example 141 and the data are listed in Table 12.
TABLE-US-00011 TABLE 12 ##STR00195## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 142 2'-(5-Phenyl- 1H-imidazol-2- yl)-N-
(tetrahydro-2H- pyran-4-yl)- 3,4'-bipyridin-5- ##STR00196## 398.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.86 (d, J = 5.1 Hz,
1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.01 (s,
1H), 7.98-7.93 (m, 2H), 7.91-7.82 (m, 2H), 7.47 (t, amine J = 7.6
Hz, 2H), 7.35 (t, J = trifluoroacetate 7.3 Hz, 1H), 3.92 (dt, J =
11.7, salt 3.0 Hz, 2H), 3.78 (tt, J = 9.9, 4.1 Hz, 1H), 3,48 (td, J
= 11.4, 1.6 Hz, 2H), 2.03-1.91 (m, 2H), 1.53-1.34 (m, 2H) 143 N-(1-
Methylpiperidin- 4-yl)-2'-(5- phenyl-1H- imidazol-2-yl)-
3,4'-bipyridin-5- ##STR00197## 411.2 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 9.48 (br s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.45 (s,
1H), 8.40 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.98-7.88 (m, 3H),
7.83-7.74 (m, 1H), 7.63 amine (s, 1H), 7.45 (t, J = 7.6 Hz,
trifluoroacetate 2H), 7.31 (t, J = 7.3 Hz, 1H), salt 3.79-3.63 (m,
1H), 3.59-3.45 (m, 2H), 3.17-3.00 (m, 2H), 2.82 (d, J = 4.4 Hz,
3H), 2.27- 2.16 (m, 2H), 1.69-1.53 (m, 2H) 144 N-((1-
Methylpiperidin- 4-yl)methyl)- 2'-(5-phenyl- 1H-imidazol-2-
##STR00198## 425.3 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.37 (br s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.49 (s, 1H), 8.44 (s,
1H), 8.21 (d, J = 2.4 Hz, 1H), 7.99-7.90 (m, yl)-3,4'- 3H), 7.86
(dd, J = 5.1, 1.5 Hz, bipyridin-5- 1H), 7.76 (s, 1H), 7.46 (t, J =
amine 7.7 Hz, 2H), 7.33 (t, J = trifluoroacetate 7.4 Hz, 1H),
3.52-3.41 (m, 2H), salt 3.22-3.13 (m, 2H), 3.01-2.87 (m, 2H), 2.77
(d, J = 4.6 Hz, 3H), 2.07-1.96 (m, 2H), 1.94- 1.76 (m, 1H),
1.50-1.32 (m, 2H)
[0662] Examples 145-145C was synthesized according to the procedure
of Example 141 and the data are listed in Table 13. Example 145C
was prepared with the modification that the imine was formed first
with heating at 190-200.degree. C. prior to reduction with sodium
cyanoborohydride.
TABLE-US-00012 TABLE 13 ##STR00199## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 145 2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
N-(tetrahydro- 2H-pyran-4- ylmethyl)-3,4'- bipyridin-5-
##STR00200## 364.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
12.38 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.16 (s, 1H), 8.13 (s,
1H), 8.08 (d, J = 2.1 Hz, 1H), 7.62-7.53 (m, 1H), 7.36-7.23 (m,
1H), 6.14 (t, J = 5.5 Hz, 1H), 3.88 (dd, amine J = 11.0, 2.8 Hz,
2H), 3.32- 3.25 (m, 2H), 3.05 (t, J = 6.0 Hz, 2H), 2.18 (s, 3H),
2.11 (s, 3H), 1.92-1.77 (m, 1H), 1.72 (d, J = 13.0 Hz, 2H), 1.27
(qd, J = 12.4, 4.0 Hz, 2H) 145B 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N- (tetrahydrofuran- ##STR00201## 350.1 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 10.22 (br s, 1H), 8.55 (d, J = 5.1
Hz, 1H), 8.30 (s, 2H), 8.10 (d, J = 2.6 Hz, 1H), 7.40 (dd, J = 5.1,
1.5 Hz, 1H), 7.19 3-ylmethyl)- (s, 1H), 4.06-3.88 (m, 3H),
3,4'-bipyridin- 3.86-3.77 (m, 1H), 3.72- 5-amine 3.66 (m, 1H),
3.30-3.20 (m, (racemic 2H), 2.71-2.55 (m, 1H), 2.28 mixture (s,
6H), 2.23-2.09 (m, 1H), prepared) 1.80-1.70 (m, 1H) 145C 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- phenylethyl)- 3,4'-bipyridin- 5-amine
##STR00202## 370.1 .sup.1H NMR (400 MHz, DMSO) .delta. 8.85 (d, J =
5.1 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.08 (d, J =
2.5 Hz, 1H), 7.80 (dd, J = 5.1, 1.4 Hz, 1H), 7.49-7.41 (m, 2H),
7.41- trifluoroacetate 7.28 (m, 3H), 7.28-7.15 salt (racemic (m,
1H), 7.01 (br s, 1H), 4.79- mixture 4.64 (m, 1H), 2.31 (s, 6H),
prepared) 1.50 (d, J = 6.7 Hz, 3H)
Example 146.
(S)-(2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl)(3-hydroxypyr-
rolidin-1-yl)methanone
##STR00203##
[0663] Step 1. Ethyl 2'-cyano-3,4'-bipyridine-5-carboxylate
##STR00204##
[0665] A degassed mixture of 4-bromopyridine-2-carbonitrile (1.0 g,
5.5 mmol, Synthonix), ethyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.5 g,
5.4 mmol, Frontier Scientific), CsF (2 g, 20 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.38 g, 0.54 mmol, Aldrich) in 1,4-dioxane (10 mL) and water
(3 mL) was heated to 120.degree. C. for 2 hours. Upon cooling to
room temperature, EtOAc and H.sub.2O were added. The biphasic
mixture was filtered. The organic layer was washed with H.sub.2O,
followed by brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-100% EtOAc/hexanes. The eluent was
evaporated and the solid was dried at 40.degree. C. overnight.
Yield: 0.9 g, 66%. LCMS (M+H).sup.+: 254.1.
[0666] Step 2. Methyl
2-[amino(imino)methyl]-3,4-bipyridine-5-carboxylate
##STR00205##
[0667] A solution of ethyl 2'-cyano-3,4'-bipyridine-5-carboxylate
(0.40 g, 1.6 mmol, from Step 1) in THF (4 mL) and methanol (4 mL)
was treated with NaOMe in methanol (25 wt % in MeOH, 0.030 mL, 0.13
mmol). After heating to reflux for 2.5 hours, the reaction mixture
was cooled to room temperature and NH.sub.4Cl (0.125 g, 2.34 mmol)
was added. After stirring for 4 days, the solid product was
isolated by filtration. The product was triturated with EtOAc and
isolated by filtration. The solid was washed with EtOAc and dried
under vacuum at 40.degree. C. overnight. Yield: 0.18 g, 44%. LCMS
(M+H).sup.+: 257.0.
Step 3. Methyl
2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carboxylate
##STR00206##
[0669] To a suspension of methyl
2'-[amino(imino)methyl]-3,4'-bipyridine-5-carboxylate (0.25 g, 0.78
mmol, from Step 2) in DMF (3 mL) was added K.sub.2CO.sub.3 (0.16 g,
1.2 mmol), followed by 3-bromo-2-butanone (0.088 mL, 1.2 mmol, Alfa
Aesar). The reaction mixture was stirred for 4 days. Water (10 mL)
and EtOAc (10 mL) were added and the mixture was stirred for 30
minutes. The precipitated solid was isolated by filtration and
washed with both water and EtOAc. The solid was dried under vacuum
at 40.degree. C. for 1.5 hours. The filtrate contained some product
and the mixture was washed with water, followed by saturated NaCl.
The organic layer was dried over sodium sulfate, filtered, and
concentrated. The residue was triturated with DCM (2 mL) and
additional solid product was isolated by filtration. Yield: 0.18 g,
75%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 12.44 (br s, 1H),
9.30 (d, J=2.2 Hz, 1H), 9.19 (d, J=1.9 Hz, 1H), 8.67 (d, J=5.1 Hz,
1H), 8.62 (t, J=2.1 Hz, 1H), 8.29-8.15 (m, 1H), 7.76 (dd, J=5.2,
1.7 Hz, 1H), 3.96 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H); LCMS
(M+H).sup.+: 309.0.
Step 4.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4-bipyridine-5-carboxylic acid
HCl salt
##STR00207##
[0671] To a suspension of methyl
2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carboxylate
(0.18 g, 0.58 mmol, from Step 3) in THF (6 mL) and MeOH (6 mL) was
added 1.0 N NaOH (1.2 mL, 1.2 mmol). The reaction mixture was
stirred for 5 hours. 1.0 N HCl (1.0 mL, 1.0 mmol) was then added.
After stirring for 3 hours, the volume of solution was reduced to
about 3 mL via rotary evaporation. THF (1 mL) and MeOH (1 mL) were
added. The solid product was isolated by filtration and dried under
vacuum at 40.degree. C. overnight. Yield: 142 mg, 83%. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 13.75 (br s, 1H), 9.30 (d, J=2.3
Hz, 1H), 9.18 (d, J=1.9 Hz, 1H), 8.75 (d, J=5.2 Hz, 1H), 8.65 (t,
J=2.1 Hz, 1H), 8.43 (s, 1H), 7.90 (dd, J=5.0, 1.1 Hz, 1H), 2.21 (s,
6H); LCMS (M+H).sup.+: 295.1.
Step 5.
(3S)-1-{[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4-bipyridin-5-yl]car-
bonyl}pyrrolidin-3-ol trifluoroacetate salt
[0672] To a suspension of
2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridine-5-carboxylic
acid (7.0 mg, 0.024 mmol, from Step 4) and HATU (0.014 g, 0.036
mmol) in DMF (1 mL, 10 mmol) was added N,N-diisopropylethylamine
(0.015 mL, 0.086 mmol). After 1 hour, (3S)-pyrrolidin-3-ol (13.0
mg, 0.149 mmol) was added. The product was purified by preparative
HPLC (C-18 column eluting with a water:acetonitrile gradient
buffered at pH 2 with 0.1% trifluoroacetic acid). Yield: 5.6 mg.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.11 (d, J=2.2 Hz, 1H),
8.91-8.85 (m, 2H), 8.43-8.38 (m, 1H), 8.38-8.34 (m, 1H), 7.95 (dd,
J=5.1, 1.5 Hz, 1H), 4.58-4.53 (m, 0.5H, rotamers), 4.48-4.43 (m,
0.5H, rotamers), 3.95-3.34 (m, 4H), 2.38 (s, 6H), 2.24-1.89 (m,
2H); LCMS (M+H).sup.+: 364.2.
[0673] Examples 147 through 212B were synthesized according to the
procedure of Example 146 and the data are listed in Table 14.
TABLE-US-00013 TABLE 14 ##STR00208## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 147 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5-yl)(4- methylpiperazin- ##STR00209## 377.1
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 12.40 (br s, 1H), 9.10
(s, 1H), 8.70 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.28 (s, 1H), 8.24
(s, 1H), 7.72 (d, J = 3.9 Hz, 1H), 1-yl)methanone 3.68 (br m, 2H),
3.39 (br m, 2H), 2.36 (br m, J = 40.0 Hz, 4H), 2.22 (s, 3H), 2.18
(s, 3H), 2.13 (s, 3H) 148 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5- yl)(morpholino) ##STR00210## 364.1 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 12.40 (br s, 1H), 9.11 (d, J = 2.1
Hz, 1H), 8.73 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.31
(t, J = 2.0 Hz, 1H), 8.24 methanone (s, 1H), 7.72 (dd, J = 5.2, 1.7
Hz, 1H), 3,69 (br m, 4H), 3.60 (br m, 2H), 3.41 (br m, 2H), 2.19
(s, 3H), 2.13 (s, 3H) 149 2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
N-(3- (dimethylamino) propyl)-3,4'- bipyridine-5- ##STR00211##
379.2 .sup.1H NMR (400 MHz, DMSO) .delta. 12.40 (br s, 1H), 9.16
(d, J = 1.9 Hz, 1H), 9.08 (d, J = 1.7 Hz, 1H), 8.93 (t, J = 4.9 Hz,
1H), 8.67 (d, J = 5.2 Hz, 1H), 8.63-8.58 (m, 1H), 8.30 (s, 1H),
7.74 (dd, J = carboxamide 5.1, 1.6 Hz, 1H), 3.35 (q, J = 6.2 Hz,
2H), 2.29 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H), 2.15 (s, 6H), 2.13 (s,
3H), 1.71 (p, J = 7.1 Hz, 2H) 150 4-(2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridine- 5- carbonyl) piperazine-1-
carboxamide ##STR00212## 406.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 12.37 (br s, 1H), 9.16-9.07 (m, 1H), 8.73 (s, 1H), 8.66 (d,
J = 5.1 Hz, 1H), 8.34-8.28 (m, 1H), 8.25 (s, 1H), 7.75-7.69 (m,
1H), 6.08 (s, 2H), 3.64 (br m, 2H), 3.43 (br m, 2H), 3.35 (br m,
4H), 2.19 (s, 3H), 2.12 (s, 3H) 151 (2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridin- 5- yl)(pyrrolidin- ##STR00213##
348.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 12.41 (br s,
1H), 9.10 (d, J = 2.2 Hz, 1H), 8.81 (d, J = 1.9 Hz, 1H), 8.65 (d, J
= 5.2 Hz, 1H), 8.35 (t, J = 2.1 Hz, 1H), 8.24- 1- 8.22 (m, 1H),
7.72 (dd, J = yl)methanone 5.2, 1.8 Hz, 1H), 3.53 (t, J = 6.7 Hz,
2H), 3.48 (t, J = 6.4 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H),
1.96-1.81 (m, 4H) 152 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5-yl)(3- hydroxyazetidin- ##STR00214## 350.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.25 (d, J = 2.2 Hz,
1H), 8.96 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.58 (s,
1H), 8.48 (t, J = 2.0 Hz, 1H), 8.15 (dd, J = 1- 5.2, 1.4 Hz, 1H),
4.62-4.43 yl)methanone (m, 2H), 4.39-4.23 (m, trifluoroacetate 1H),
4.23-4.04 (m, 1H), salt 3.97-3.76 (m, 1H), 2.33 (s, 6H) 153
1-(2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridine- 5-
carbonyl) ##STR00215## 359.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 9.26 (d, J = 2.2 Hz, 1H), 8.96 (d, J = 1.8 Hz, 1H), 8.92
(d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 8.48 (t, J = 2.0 Hz, 1H), 8.14
(dd, J = azetidine-3- 5.2, 1.4 Hz, 1H), 4.77-4.67 carbonitrile (m,
1H), 4.67-4.57 (m, trifluoroacetate 1H), 4.47-4.36 (m, 1H), salt
4.33-4.20 (m, 1H), 3.91 (tt, J = 9.1, 6.4 Hz, 1H), 2.33 (s, 6H) 154
(2'-4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin- 5-yl)(3-
hydroxypiperidin- 1- yl)methanone ##STR00216## 378.2 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.09 (s, 1H), 8.88 (d, J = 5.1 Hz,
1H), 8.78 (d, J = 12.1 Hz, 1H), 8.42-8.28 (m, 2H), 7.94 (dd, J =
5.1, 1.6 Hz, 1H), 4.18-3.31 (m, 5H), 2.38 (s, 6H), 2.09- 1.41 (m,
4H) (racemic mixture prepared) 155 (R)-(2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridin- 5-yl)(3- fluoropyrrolidin-
##STR00217## 366.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.24 (d, J = 2.1 Hz, 1H), 8.97-8.85 (m, 2H), 8.60 (s, 1H), 8.50-
8.43 (m, 1H), 8.21-8,12 (m, 1H), 5.40 (dd, J = 52.7, 1- 35.8 Hz,
1H), 4.00-3.52 yl)methanone (m, 4H), 2.33 (s, 6H), 2.30-
trifluoroacetate 2.00 (m, 2H) salt 156 (2'-4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridin- 5-yl)(3-oxa-9- azaspiro[5.5]
undecan-9- yl)methanone ##STR00218## 432.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.19 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 5.2
Hz, 1H), 8.77 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 8.33 (t, J = 2.1
Hz, 1H), 8.13 (dd, J = 5.2, 1.5 Hz, 1H), 3.73-3.62 (m, 2H), 3.56
(q, J = 5.5 Hz, trifluoroacetate 4H), 3.41-3.22 (m, 2H), salt 2.32
(s, 6H), 1.62-1.54 (m, 2H), 1.54-1.41 (m, 6H) 157 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- N-isopropyl- ##STR00219## 336.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.24 (d, J = 2.2 Hz,
1H), 9.16 (d, J = 1.9 Hz, 1H), 8.93 (d, J = 5.1 Hz,
3,4'-bipyridine- 1H), 8.66 (t, J = 2.1 Hz, 1H), 5-carboxamide 8.63
(d, J = 7.6 Hz, 1H), trifluoroacetate 8.60 (s, 1H), 8.14 (dd, J =
salt 5.1, 1.4 Hz, 1H), 4.24-4.07 (m, 1H), 2.33 (s, 6H), 1.23 (d, J
= 6.6 Hz, 6H) 158 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5-yl)(4-(1- methylpiperidin- 4- yl)piperazin-1-
yl)methanone ##STR00220## 460.3 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.07 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.66
(d, J = 5.2 Hz, 1H), 8.33-8.29 (m, 1H), 8.28 (t, J = 2.0 Hz, 1H),
7.64 (dd, J = 5.2, 1.7 Hz, 1H), 4.70 (br d, J = 11.3 Hz, 1H), 3.79
(br d, J = 13.1 Hz, 1H), 2.95 (br t, J = 13.0 Hz, 1H), 2.81-2.35
(m, 9H), 2.27 (s, 3H), 2.23 (s, 6H), 2.10- 1.99 (m, 1H), 1.96-1.84
(m, 1H), 1.66-1.40 (m, 2H) 159 1-(4-(2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridine- 5- carbonyl) piperazin-1-
yl)ethanone ##STR00221## 405.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO,
tautomers) .delta. 12.40 (br s, 1H), 9.12-9.06 (m, 1H), 8.72-8.68
(m, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.32-8.26 (m, 1H), 8.24 (s, 1H),
7.75-7.67 (m, 1H), 3.79-3.59 (br m, 2H), 3.44- trifluoroacetate
3.35 (br m, 2H), 2.45- salt 2.37 (br m, 2H), 2.37-2.26 (br m, 2H),
2.22 (s, 3H), 2.18 (br s, 3H), 2.13 (br s, 3H) 160 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- N-(tetrahydro- 2H-pyran-4-
##STR00222## 378.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.23 (d, J = 2.2 Hz, 1H), 9.15 (d, J = 1.9 Hz, 1H), 8.91 (d, J =
5.2 Hz, 1H), 8.70 (d, J = 7.6 Hz, yl)-3,4'- 1H), 8.65 (t, J = 2.1
Hz, 1H), bipyridine-5- 8.57 (s, 1H), 8.20-7.97 (m, carboxamide 1H),
4.15-3.99 (m, 1H), trifluoroacetate 3.99-3.83 (m, 2H), 3.67- salt
3.06 (m, 2H), 2.31 (s, 6H), 1.89-1.74 (m, 2H), 1.61 (qd, J = 12.1,
4.4 Hz, 2H) 161 (R)-(2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5-yl)(3- (dimethylamino) ##STR00223## 391.2 .sup.1H
NMR (400 MHz, CD.sub.3OD, rotamers) .delta. 9.13 (d, J = 2.0 Hz,
1H), 8.90-8.84 (m, 2H), 8.43 (t, J = 2.1 Hz, 1H), 8.40 (s, 1H),
7.94 (d, J = 4.0 Hz, 1H), 4.20-3.67 pyrrolidin-1- (m, 5H), 3.00 (s,
3.8H), 2.91 yl)methanone (s, 2.2H), 2.62-2.41 (m, trifluoroacetate
1H), 2.38 (s, 6H), 2.33- salt 2.16 (m, 1H) 162 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- N-((tetrahydro- 2H-pyran-4-
yl)methyl)- ##STR00224## 392.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 9.25 (d, J = 2.2 Hz, 1H), 9.16 (d, J = 1.9 Hz, 1H), 8.93
(d, J = 5.2 Hz, 1H), 8.88 (t, J = 5.6 Hz, 1H), 8.68 (t, J = 2.0 Hz,
1H), 8.60 3,4'-bipyridine- (s, 1H), 8.13 (dd, J = 5.1,
5-carboxamide 1.3 Hz, 1H), 3.93-3.80 (m, trifluoroacetate 2H),
3.33-3.22 (m, 4H), salt 2.33 (s, 6H), 1.92-1.76 (m, 1H), 1.71-1.57
(m, 2H), 1.25 (qd, J = 12.4, 4.3 Hz, 2H) 163 (R)-(2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin- 5-yl)(3-
hydroxypyrrolidin- ##STR00225## 364.1 .sup.1H NMR (400 MHz,
CD.sub.3OD, rotamers) .delta. 9.11 (d, J = 2.2 Hz, 1H), 8.90-8.85
(m, 2H), 8.43-8.39 (m, 1H), 8.39-8.35 (m, 1H), 7.95 (dd, J = 5.1,
1.5 Hz, 1- 1H), 4.55-4.50 (m, 0.5H), yl)methanone 4.45-4.39 (m,
0.5H), 3.90- trifluoroacetate 3.36 (m, 4H), 2.38 (s, 6H), salt
2.24-1.87 (m, 2H) 164 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- N-(2-
(tetrahydro- 2H-pyran-4- ##STR00226## 406.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.25 (d, J = 2.2 Hz, 1H), 9.15 (d, J = 1.8
Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.84 (t, J = 5.5 Hz, 1H), 8.67
(t, J = 2.0 Hz, 1H), 8.60 yl)ethyl)-3,4'- (s, 1H), 8.14 (dd, J =
5.1, bipyridine-5- 1.4 Hz, 1H), 3.85 (dd, J = 11.1, carboxamide 3.5
Hz, 2H), 3.39 (q, J = trifluoroacetate 6.7 Hz, 2H), 3.28 (td, J =
11.8, salt 1.4 Hz, 2H), 2.33 (s, 6H), 1.70-1.43 (m, 5H), 1.28- 1.11
(m, 2H) 165 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin-
5-yl)(2-oxa-7- azaspiro[3.5] nonan-7- ##STR00227## 404.1 .sup.1H
NMR (400 MHz, d.sub.6- DMSO) .delta. 9.21 (d, J = 2.2 Hz, 1H), 8.91
(d, J = 5.2 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.33
(t, J = 2.0 Hz, 1H), 8.13 (dd, J= 5.2, 1.5 Hz, 1H), 4.36 (br m,
yl)methanone 4H), 3.61 (br m, 2H), 3.32 trifluoroacetate (br m,
2H), 2.33 (s, 6H), salt 1.86 (br m, 4H) 166 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N-(2- ##STR00228## 352.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.25 (d, J = 2.1 Hz, 1H), 9.17 (d, J = 1.9
Hz, 1H), 8.99-8.94 (m, 1H), methoxyethyl)- 8.93 (d, J = 5.2 Hz,
1H), 3,4'-bipyridine- 8.69 (t, J = 2.0 Hz, 1H), 8.60 5-carboxamide
(s, 1H), 8.14 (dd, J = 5.1, trifluoroacetate 1.4 Hz, 1H), 3.55-3.48
(m, salt 4H), 3.30 (s, 3H), 2.33 (s, 6H) 167 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N- ((tetrahydrofuran- 2- ##STR00229## 378.2 .sup.1H
NMR (400 MHz, d.sub.6- DMSO) .delta. 9.25 (d, J = 2.2 Hz, 1H), 9.17
(d, J= 1.9 Hz, 1H), 8.98 (t, J = 5.7 Hz, 1H), 8.93 (d, J = 5.1 Hz,
1H), 8.70 (t, J = 2.1 Hz, 1H), 8.61 yl)methyl)- (s, 1H), 8.14 (dd,
J = 5.2, 3,4'-bipyridine- 1.5 Hz, 1H), 4.03 (p, J = 6.3 Hz,
5-carboxamide 1H), 3.81 (q, J = 7.0 Hz, trifluoroacetate 1H), 3.66
(q, J = 7.5 Hz, salt (racemic 1H), 3.41 (t, J = 5.8 Hz, 2H),
mixture 2.33 (s, 6H), 2.02-1.72 (m, prepared) 3H), 1.69-1.52 (m,
1H) 168 1-(2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridine-
5-carbonyl) pyrrolidin-3-one ##STR00230## 362.1 trifluoroacetate
salt 169 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin-
5-yl)(3-(2- hydroxyethyl) pyrrolidin-1- yl)methanone ##STR00231##
392.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.24-
9.18 (m, 1H), 8.94-8.86 (m, 2H), 8.62-8.57 (m, 1H), 8.44-8.38 (m,
1H), 8.17-8.06 (m, 1H), 3.77 (dd, J = 12.0, 7.4 Hz, 0.5H), 3.71
-3.24 (m, 4.5H), 3.20 (racemic (t, J = 9.6 Hz, 0.5H), 3.12 mixture
(dd, J = 11.9, 9.0 Hz, 0.5H), prepared) 2.33 (s, 6H), 2.28-1.94 (m,
2H), 1.69-1.39 (m, 3H) 170 (2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
3,4'-bipyridin- 5-yl)(3- (pyridin-2- ##STR00232## 425.2 .sup.1H NMR
(400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.26- 9.17 (m, 1H),
8.98-8.86 (m, 2H), 8.63-8.58 (m, 1.5H), 8.54-8.50 (m, 0.5H),
8.49-8.42 (m, 1H), 8.19- yl)pyrrolidin- 8.10 (m, 1H), 7.89 (td, J =
1- 8.0, 1.6 Hz, 0.5H), 7.81 (td, yl)methanone J = 7.7, 1.5 Hz,
0.5H), 7.52 trifluoroacetate (d, J = 7.9 Hz, 0.5H), 7.44- salt
(racemic 7.36 (m, 1H), 7.32(dd, J = mixture 7.1, 5.4 Hz, 0.5H),
4.05 (dd, prepared) J = 11.1, 7.2 Hz, 0.5H), 3,89 1 (dd, J = 9.8,
7.8 Hz, 0.5H),
3.84-3.53 (m, 4H), 2.45- 2.07 (m, 2H), 2.335 (s, 3H), 2.330 (s, 3H)
171 2-(2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridine-
5-carbonyl)-6- methyl-2,6- diazaspiro[3.4] ##STR00233## 417.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.25 (d, J= 2.2 Hz,
1H), 8.98 (d, J = 1.9 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.59 (s,
1H), 8.49 (t, J = 2.1 Hz, 1H), 8.15 (dd, J = 5.2, 1.5 Hz, 1H), 4.41
(s, octan-5-one 2H), 4.21 (d, J = 9.9 Hz, trifluoroacetate 1H),
4.03 (d, J = 10.0 Hz, salt 1H), 3.33-3.24 (m, 2H), 2.76 (s, 3H),
2.36 (t, J = 6.9 Hz, 2H), 2.33 (s, 6H) 172 ((3R,4R)-1- {[2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin- 5- yl]carbonyl}- 4-
##STR00234## 392.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 9.24- 9.18 (m, 1H), 8.94-8.86 (m, 2H), 8.60 (s, 1H), 8.44-
8.36 (m, 1H), 8.15 (d, J = 5.1 Hz, 1H), 3.83 (dd, J = 12.0, 7.8 Hz,
0.5H), 3.73 (dd, J = 12.4, 7.8 Hz, 0.5H), 3.68- methylpyrrolidin-
3.55 (m, 1.5H), 3.55-3.27 3-yl)methanol (m, 2.5H), 3.20 (t, J = 9.6
Hz, trifluoroacetate 0.5H), 3.10 (dd, J = salt 12.0, 9.0 Hz, 0.5H),
2.33 (s, 6H), 2.12-1.84 (m, 2H), 1.08 (d, J = 6.5 Hz, 1.5H), 0.97
(d, J = 6.4 Hz, 1.5H) 173 5-[(3,3- Difluoropyrrolidin- 1-
yl)carbonyl]- 2'-(4,5- dimethyl-1H- ##STR00235## 384.1 .sup.1H NMR
(400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.24 (s, 1H), 8.94-8.92
(m, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.63-8.56 (m, 1H), 8.49- 8.39
(m, 1H), 8.14 (dd, J = imidazol-2-yl)- 5.2, 1.4 Hz, 1H), 4.05 (t, J
= 3,4'-bipyridine 12.5 Hz, 0.9H), 3.98 (t, J = trifluoroacetate
13.3 Hz, 1.1H), 3.80 (t, J = salt 7.4 Hz, 2H), 2.58-2.41 (m, 2H),
2.33 (s, 6H) 174 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-[(3-
methoxypyrrolidin- 1- ##STR00236## 378.2 .sup.1H NMR (400 MHz,
CD.sub.3OD, rotamers) .delta. 9.16- 9.12 (m, 1H), 8.93-8.89 (m,
2H), 8.45-8.42 (m, 1H), 8.42-8.39 (m, 1H), 8.00-7.95 (m, 1H), 4.19-
yl)carbonyl]- 4.11 (m, 0.5H), 4.11-3.98 3,4'-bipyridine (m, 0.5H),
3.88-3.66 (m, trifluoroacetate 3H), 3.66-3.57 (m, 0.5H), salt
(racemic 3.57-3.50 (m, 0.5H), 3.41 mixture (s, 1.5H), 3.31 (s,
1.5H), prepared) 2.41 (s, 6H), 2.29-1.99 (m, 2H) 175 Methyl 1-{[2'-
(4,5-dimethyl- 1H-imidazol-2- yl)-3,4'- bipyridin-5- yl]carbonyl}
##STR00237## 406.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 9.26- 9.18 (m, 1H), 8.95-8.86 (m, 2H), 8.60 (s, 1H), 8.46-
8.35 (m, 1H), 8.17-8.10 (m, 1H),3.69 (s, 1.5H), 3.88-
pyrrolidine-3- 3.46 (m, 4H), 3.61 (s, carboxylate 1.5H), 3.34-3.15
(m, 1H), trifluoroacetate 2.33 (s, 6H), 2.29-1.93 (m, salt (racemic
2H) mixture prepared) 176 2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
N-[(3R)- tetrahydrofuran- ##STR00238## 364.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.25 (d, J = 2.2 Hz, 1H), 9.17 (d, J = 1.9
Hz, 1H), 8.98-8.89 (m, 2H), 8.68 (t, J = 2.1 Hz, 1H), 8.60
3-yl]-3,4'- (s, 1H), 8.14 (dd, J = 5.2, bipyridine-5- 1.5 Hz, 1H),
4.60-4.45 (m, carboxamide 1H), 3.97-3.82 (m, 2H), trifluoroacetate
3.75 (td, J = 8.1, 5.9 Hz, salt 1H), 3.67 (dd, J = 9.0, 4.0 Hz,
1H), 2.33 (s, 6H), 2.23 (dq, J = 13.0, 7.9 Hz, 1H), 2.03-1.86 (m,
1H) 177 1-{[2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin-
5- yl]carbonyl} piperidin-4-ol ##STR00239## 378.1 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 9.20 (d, J = 2.2 Hz, 1H), 8.91 (d, J =
5.1 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 8.33 (t, J =
2.0 Hz, 1H), 8.13 (dd, J = 5.2, 1.4 Hz, 1H), 4.12-3.89 (m, 1H),
3.79 (tt, J = 7.7, 3.4 Hz, 1H), 3.63-3.43 (m, 1H), 3.43-3.28 (m,
1H), 3.28-3.13 (m, 1H), 2.33 (s, 6H), 1.92-1.78 (m, 1H), 1.79-1.63
(m, 1H), 1.55- 1.31 (m, 2H) 178 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-{[3- (trifluoromethyl) pyrrolidin-1- ##STR00240##
416.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.26-9.21 (m,
1H), 8.96-8.85 (m, 2H), 8.60 (s, 1H), 8.48-8.35 (m, 1H), 8.15 (dd,
J = 5.2, 1.4 Hz, 1H), 3.92-3.78 (m, yl]carbonyl}- 1H), 3.78-3.52
(m, 3H), 3,4'-bipyridine 3.47-3.15 (m, 1H), 2.33 (s,
trifluoroacetate 6H), 2.29-2.13 (m, 1H), salt (racemic 2.13-1.85
(m, 1H) mixture prepared) 179 5-(7- Azabicyclo [2.2.1]hept-7-
ylcarbonyl)-2'- (4,5-dimethyl- 1H-imidazol-2- yl)-3,4'-
##STR00241## 374.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.25 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8 89 (d, J =
1.8 Hz, 1H), 8.60 (s, 1H), 8.41 (t, J = 2.1 Hz, 1H), 8.16 (dd, J =
5.2, 1.5 Hz, 1H), 4.62 (s, bipyridine 1H), 4.13 (s, 1H), 2.33 (s,
trifluoroacetate 6H), 1.93-1.68 (m, 4H), salt 1.68-1.37 (m, 4H) 180
1-{[2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin- 5-
yl]carbonyl}- ##STR00242## 378.2 .sup.1H NMR (400 MHz, d.sub.6-
DMSO, rotamers) .delta. 9.24- 9.20 (m, 1H), 8.94-8.84 (m, 2H), 8.60
(s, 1H), 8.44- 8.38 (m, 1H), 8.15 (dd, J = 5.2, 1.2 Hz, 1H),
3.78-3.57 3- (m, 1.5H), 3.57-3.44 (m, methylpyrrolidin- 1.5H), 3.37
(d, J = 12.4 Hz, 3-ol 0.5H), 3.26 (d, J = 10.4 Hz, trifluoroacetate
0.5H), 2.33 (s, 6H), 1.96- salt (racemic 1.69 (m, 2H), 1.37 (s,
1.5H), mixture 1.26 (s, 1.5H) prepared) 181 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-[(3- phenylpyrrolidin- 1- ##STR00243## 424.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.24 (d, J =
2.1 Hz, 0.4H), 9.21 (d, J = 2.1 Hz, 0.6H), 8.98-8.84 (m, 2H), 8.62
(s, 0.4H), 8.60 (s, 0.6H), 8.49-8.43 (m, yl)carbonyl]- 1H), 8.16
(dd, J = 5.1, 1.2 Hz, 3,4'-bipyridine 0.4H), 8.13 (dd, J = 5.1,
trifluoroacetate 1.2 Hz, 0.6H), 7.41-7.19 salt (racemic (m, 5H),
4.12-3.31 (m, mixture 5H), 2.42-2.24 (m, 1H), prepared) 2.335 (s,
2.4H), 2.330 (s, 3.6H), 2.16-1.95 (m, 1H) 182 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-[(3-pyridin- 4-ylpyrrolidin- 1-yl)carbonyl]-
##STR00244## 425.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 9.13 (d, J = 2.1 Hz, 0.5H), 9.11 (d, J = 2.1 Hz, 0.5H),
8.86-8.84 (m, 1H), 8.68-8.62 (m, 1H), 8.56-8.52 (m, 1H),
3,4'-bipyridine 8.49-8.46 (m, 1H), 8.39 (t, (racemic J = 2.0 Hz,
0.5H), 8.38 (t, mixture J = 2.0 Hz, 0.5H), 8.25 (s, prepared)
0.5H), 8.23 (s, 0.5H), 7.74 (dd, J = 5.2, 1.6 Hz, 0.5H), 7.71 (dd,
J = 5.2, 1.6 Hz, 0.5H), 7.40 (d, J = 5.9 Hz, 1H), 7.32 (d, J = 5.9
Hz, 1H), 4.14-3.41 (m, 5H), 2.43-2.26 (m, 1H), 2.19 (s, 3H), 2.12
(s, 3H), 2.10- 1.95 (m, 1H) 183 1-{[2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridin- 5- yl]carbonyl} ##STR00245## 373.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.18(d, J = 2.1 Hz, 1H),
8.99-8.96 (m, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.50 (t, J = 2.1 Hz,
1H), 8.44-8.35 (m, 1H), 8.00 pyrrolidine-3- (dd, J = 5.1, 1.6 Hz,
1H), carbonitrile 4.99 (dd, J = 7.5, 5.0 Hz, trifluoroacetate 1H),
3.87-3.75 (m, 1H), salt (racemic 3.75-3.61 (m, 1H), 2.41 (s,
mixture 6H), 2.57-2.30 (m, 2H), prepared) 2.30-2.00 (m, 2H) 184
2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-{[2- (trifluoromethyl)
##STR00246## 402.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.27 (d, J = 2.2 Hz, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.91 (d, J =
5.1 Hz, 1H), 8.58 (s, 1H), 8.50 (t, J = azetidin-1- 2.0 Hz, 1H),
8.14 (dd, J = yl]carbonyl}- 5.2, 1.4 Hz, 1H), 4.68 (t, J =
3,4'-bipyridine 9.1 Hz, 1H), 4.53 (dd, J = trifluoroacetate 8.6,
5.2 Hz, 1H), 4.38 (t, J = salt (racemic 9.9 Hz, 1H), 4.13 (dd, J =
mixture 10.5, 5.3 Hz, 1H), 3.82- prepared) 3.67 (m, 1H), 2.33 (s,
6H) 185 5-[(3,3- Dimethylazetidin- 1- yl)carbonyl]- 2'-(4,5-
dimethyl-1H- imidazol-2-yl)- ##STR00247## 362.2 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 9.23 (d, J = 2.2 Hz, 1H), 8.97 (d, J =
1.9 Hz, 1H), 8.91 (d, J = 5.1 Hz, 1H),8.59 (s, 1H),8.48 (t, J = 2.1
Hz, 1H), 8.13 (dd, J = 5.2, 1.5 Hz, 1H), 4.10 (s, 3,4'-bipyridine
2H), 3.81 (s, 2H), 2.33 (s, trifluoroacetate 6H), 1.28 (s, 6H) salt
186 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-[(4- phenylpiperidin-
1- yl)carbonyl]- 3,4'-bipyridine trifluoroacetate ##STR00248##
438.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.22 (d, J = 2.2
Hz, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.61
(s, 1H), 8.39 (t, J = 2.0 Hz, 1H), 8.14 (dd, J = 5.2, 1.5 Hz, 1H),
7,36-7.18 (m, 5H), 4.78-4.64 (br m, 1H), 3.76-3.62 (br m, 1H), salt
3.39-3.17 (br m, 1H), 3.06- 2.80 (br m, 2H), 2.33 (s, 6H),
1.99-1.85 (br m, 1H), 1.82- 1.57 (br m, 3H) 187 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- 5-[(4aR,8aS)- octahydro-
isoquinolin-2(1H)- ylcarbonyl]- 3,4'-bipyridine ##STR00249## 416.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.21 (d, J = 1.3 Hz,
1H), 8.91 (d, J = 5.1 Hz, 1H),8.77 (d, J = 1.8 Hz, 1H), 8.59 (s,
1H), 8.34- 8.26 (m, 1H), 8.14 (dd, J = 5.2, 1.4 Hz, 1H), 4,72-2.38
(m, 4H), 2.33 (s, 6H), 1.83- trifluoroacetate 0.75 (m, 12H) salt
188 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-[(3- phenylpiperidin-
1- ##STR00250## 438.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO,
rotamers) .delta. 9.26- 9.13 (m, 1H), 8.96-8.87 (m, 1H), 8.83 (s,
1H), 8.65- 8.53 (m, 1H), 8.42-8.31 (m, 1H), 8.19-8.05 (m,
yl)carbonyl]- 1H), 7.48-6.99 (m, 5H), 3,4'-bipyridine 4.71-2.73 (m,
5H), 2.33 (s, trifluoroacetate 6H), 2.05-1.56 (m, 4H) salt (racemic
mixture prepared) 189 5-[(4- Benzylpiperidin- 1- yl)carbonyl]-
2'-(4,5- dimethyl-1H- ##STR00251## 452.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.20 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 5.2
Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.32 (t, J = 2.0
Hz, 1H), 8.13 (dd, J = imidazol-2-yl)- 5.2, 1.4 Hz, 1H), 7.32-7.24
3,4'-bipyridine (m, 2H), 7.23-7.14 (m, trifluoroacetate 3H),
4.60-2.72 (m, 4H), salt 2.56 (d, J = 7.0 Hz, 2H), 2.33 (s, 6H),
1.92-1.47 (m, 3H), 1.32-1.12 (m, 2H) 190 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-[(2- methylpiperidin- 1- yl)carbonyl]-
##STR00252## 376.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.20 (d, J = 2.1 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.75 (d, J =
1.4 Hz, 1H), 8.60 (s, 1H), 8.34- 8.27 (m, 1H), 8.14 (dd, J = 5.2,
1.5 Hz, 1H), 5.00-2.69 3,4'-bipyridine (m, 3H), 2.33 (s, 6H), 1.84-
trifluoroacetate 1.33 (m, 6H), 1.25 (d, J = salt (racemic 6.9 Hz,
3H) mixture prepared) 191 5-(Azetidin-1- ylcarbonyl)-2'-
(4,5-dimethyl- 1H-imidazol-2- yl)-3,4'- ##STR00253## 334.1 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.15 (d, J = 2.2 Hz, 1H), 8.97
(d, J = 1.9 Hz, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.51 (t, J = 2.1 Hz,
1H), bipyridine 8.42-8.38 (m, 1H), 7.98 trifluoroacetate (dd, J =
5.1, 1.6 Hz, 1H), salt 4.52 (t, J = 7.7 Hz, 2H), 4.30 (t, J = 7.8
Hz, 2H), 2.46 (pent, J = 15.8, 7.9 Hz, 2H), 2.41 (s, 6H) 192
N-Benzyl-2'- (4,5-dimethyl- 1H-imidazol-2- yl)-3,4'- bipyridine-5-
carboxamide ##STR00254## 384.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 9.44 (t, J = 5.9 Hz, 1H), 9.27 (d, J = 2.2 Hz, 1H), 9.22
(d, J = 2.0 Hz, 1H), 8.93 (d, J = 5.1 Hz, 1H), 8.74 (t, J = 2.1 Hz,
1H), trifluoroacetate 8.61 (s, 1H), 8.15 (dd, J = salt 5.2, 1.6 Hz,
1H), 7.43-7.23 (m, 5H), 4.58 (d, J = 5.9 Hz,
2H), 2.33 (s, 6H) 193 N-Benzyl-2'- (4,5-dimethyl- 1H-imidazol-2-
yl)-N-methyl- 3,4'-bipyridine- 5-carboxamide ##STR00255## 398.1
.sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.24- 9.16
(m, 1H), 8.96-8.74 (m, 2H), 8.62-8.53 (m, 1H), 8.47-8.34 (m, 1H),
8.21-8.10 (m, 0.6H), 8.09- trifluoroacetate 7.97 (m, 0.4H),
7.48-7.14 salt (m, 5H), 4.75 (s, 1.2H), 4.56 (s, 0.8H), 3.01 (s,
1.2H), 2.95 (s, 1.8H), 2.33 (s, 6H) 194 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N-methyl-N- phenyl-3,4'- bipyridine-5- ##STR00256##
384.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.99 (d, J = 1.9
Hz, 1H), 8.88 (d, J = 5.1 Hz, 1H), 8.52 (s, 1H), 8.46 (br, 1H),
8.31-8.26 (m, 1H), 7.95-7.90 (m, carboxamide 1H), 7.35-7.26 (m,
4H), trifluoroacetate 7.25-7.17 (m, 1H), 3.46 salt (s, 3H), 2.33
(s, 6H) 195 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- phenylethyl]-
3,4'-bipyridine- 5-carboxamide trifluoroacetate ##STR00257## 398.1
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.26 (d, J = 2.3 Hz,
1H), 9.23-9.18 (m, 2H), 8.93 (d, J = 5.3 Hz, 1H), 8.69 (t, J = 2.1
Hz, 1H), 8.62-8.53 (m, 1H), 8.15 (dd, J = 5.2, 1.7 Hz, 1H), salt
7.48-7.41 (m, 2H), 7.41- 7.32 (m, 2H), 7.30-7.21 (m, 1H), 5.24 (p,
J = 7.2 Hz, 1H), 2.33 (s, 6H), 1.54 (d, J = 7.1 Hz, 3H) 196
4-Benzyl-1- {[2'-(4,5- dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridin-
5- yl]carbonyl} piperidin-4-ol ##STR00258## 468.2 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 9.20 (d, J = 2.3 Hz, 1H), 8.91 (d, J =
5.2 Hz, 1H), 8.76 (d, J = 1.9 Hz, 1H), 8.59-8.55 (m, 1H), 8.32 (t,
J = 2.1 Hz, 1H), 8.13 (dd, J = 5.2, 1.6 Hz, 1H), 7.30-7.15 (m, 5H),
4.36- trifluoroacetate 4.17 (br m, 1H), 3.48-3.32 salt (br m, 2H),
3.23-3.04 (br m, 1H), 2.73 (s, 2H), 2.33 (s, 6H), 1.60-1.22 (m, 4H)
197 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-[(3-pyrazin-
2-ylpyrrolidin- 1-yl)carbonyl]- ##STR00259## 426.2 .sup.1H NMR (400
MHz, d.sub.6- DMSO, rotamers) .delta. 9.25- 9.21 (m, 1H), 8.96-8.86
(m, 2H), 8.76-8.50 (m, 4H), 8.48-8.44 (m, 1H), 8,18-8.11 (m, 1H),
4.12- 3,4'-bipyridine 3.61 (m, 5H), 2.33 (s, 3H), trifluoroacetate
2.33 (s, 3H), 2.47-2.10 (m, salt 2H) 198 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N-ethyl-N- methyl-3,4'- ##STR00260## 336.1 .sup.1H
NMR (400 MHz, d.sub.6- DMSO, rotamers) .delta. 9.21 (br s, 1H),
8.91 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 9.1 Hz, 1H), 8.59 (s, 1H),
8.37- bipyridine-5- 8.29 (m, 1H), 8.15 (dd, J = carboxamide 5.2,
1.6 Hz, 1H), 3.54 (q, J = trifluoroacetate 6.5 Hz, 1H), 3.28 (q, J
= salt 6.5 Hz, 1H), 3.03 (s, 1.5H), 2.97 (s, 1.5H), 2.33 (s, 6H),
1.20 (t, J = 7.1 Hz, 1.5H), 1.11 (t, J = 6.9 Hz, 1.5H) 199 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- 5-[(3- methoxyazetidin- 1-
##STR00261## 364.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
12.43 (br s, 1H), 9.15 (d, J = 2.2 Hz, 1H), 8.90(d, J = 1.9 Hz,
1H), 8.66 (d, J = 5.1 Hz, 1H), 8.38 (t, J = 2.1 Hz, 1H), 8.29-
yl)carbonyl]- 8.14 (m, 1H), 7.73 (dd, J = 3,4'-bipyridine 5.2, 1.8
Hz, 1H), 4.60-4.41 (m, 1H), 4.36-4.21 (m, 3H), 3.99-3.84 (m, 1H),
3.24 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H) 200 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-[(4-methyl- 1,4-diazepan-1- yl)carbonyl]-
3,4'-bipyridine ##STR00262## 391.2 .sup.1H NMR (400 MHz, d.sub.6-
DMSO, rotamers) .delta. 12.42 (s, 1H), 9.09 (d, J = 2.2 Hz, 1H),
8.71-8.68 (m, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.31-8.25 (m, 1H),
8.24 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 3.73-3.62 (m, 2H),
3.51-3.39 (m, 2H), 2.72- 2.63 (m, 1H), 2.63-2.49 (m, 3H), 2.30 (s,
1.5H), 2.26 (s, 1.5H,), 2.19 (s, 3H), 2.12 (s, 3H), 1.94-1.83 (m,
1H), 1.83-1.70 (m, 1H) 201 2'-(4,5- Dimethyl-1H- imidazol-2-yl)-
N-(2- hydroxyethyl)- ##STR00263## 352.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO, rotamers) .delta. 9.21- 9.16 (m, 1H), 8.91 (d, J =
5.1 Hz, 1H), 8.83-8.79 (m, 1H), 8.59 (s, 1H), 8.38- N-methyl-3,4'-
8.32 (m, 1H), 8.16-8.05 bipyridine-5- (m, 1H), 3.71-3.64 (m,
carboxamide 0.8H), 3.61-3.56 (m, 0.8H), trifluoroacetate 3.56-3.49
(m, 1.2H), 3.38- salt 3.29 (m, 1.2H), 3.06 (s, 1.8H), 3.04 (s,
1.2H), 2.33 (s, 6H) 202 N- (Cyclopropyl- methyl)-2'-(4,5-
dimethyl-1H- imidazol-2-yl)- ##STR00264## 348.2 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 9.25 (d, J = 2.2 Hz, 1H), 9.17 (d, J =
1.9 Hz, 1H), 8.99 (t, J = 5.5 Hz, 1H), 8.93 (d, J = 5.1 Hz, 1H),
3,4'-bipyridine- 8.69 (t, J = 2.1 Hz, 1H), 8.61 5-carboxamide (s,
1H), 8.14 (dd, J = 5.2, trifluoroacetate 1.5 Hz, 1H), 3.23 (t, J =
6.2 Hz, salt 2H), 2.33 (s, 6H), 1.13- 0.99 (m, 1H), 0.53-0.43 (m,
2H), 0.33-0.20 (m, 2H) 203 N- (Cyanomethyl)- 2'-(4,5- dimethyl-1H-
imidazol-2-yl)- ##STR00265## 347.1 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 12.42 (s, 1H), 9.16 (d, J = 2.2 Hz, 1H), 8.78 (s,
1H), 8.66 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.29- N-methyl-3,4'-
8.17 (m, 1H), 7.74 (dd, J = bipyridine-5- 5.2, 1.6 Hz, 1H), 4.62
(s, carboxamide 2H), 3.10 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H) 204
2'-(4,5- Dimethyl-1H- imidazol-2-yl)- N-(2- methoxyethyl)-
##STR00266## 366.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 9.20 (s, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.82-8.72 (m, 1H),
8.59 (s, 1H), 8.37-8.29 (m, N-methyl-3,4'- 1H), 8.19-8.04 (m, 1H),
bipyridine-5- 3.72-3.66 (m, 1H), 3.66- carboxamide 3.58 (m, 1H),
3.46 (br s, trifluoroacetate 2H), 3.33 (s, 1.4H), 3.20 (s, salt
1.6H), 3.06 (s, 1.6H), 3.03 (s, 1.4H), 2.33 (s, 6H) 205 2'-(4,5-
Dimethyl-1H- imidazol-2-yl)- N-{[1- (hydroxymethyl) ##STR00267##
392.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.22-9.06 (m,
1H), 8.94-8.84 (m, 1H), 8.82-8.73 (m, 1H), 8.58 (s, 1H), 8.35 (s,
1H), 8.16- cyclopropyl] 8.08 (m, 1H), 3.57 (s, 1H), methyl}-N- 3.38
(s, 1H), 3.28 (s, 1H), methyl-3,4'- 3.16 (s, 1H), 3.07 (s, 1.6H),
bipyridine-5- 3.03 (s, 1.4H), 2.33 (s, 6H), carboxamide 0.56-0.30
(m, 4H) trifluoroacetate salt 206 N- (Cyclobutyl- methyl)-2'-(4,5-
dimethyl-1H- imidazol-2-yl)- ##STR00268## 362.1 .sup.1H NMR (400
MHz, d.sub.6- DMSO) .delta. 9.24 (d, J = 2.2 Hz, 1H), 9.15 (d, J =
1.9 Hz, 1H), 8.93 (d, J = 5.1 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H),
3,4'-bipyridine- 8.67 (t, J = 2.1 Hz, 1H), 8.61 5-carboxamide (s,
1H), 8.14 (dd, J = 5.2, trifluoroacetate 1.5 Hz, 1H), 3.44-3.33 (m,
salt 2H), 2.63-2.53 (m, 1H), 2.33 (s, 6H), 2.11-1.95 (m, 2H),
1.94-1.81 (m, 2H), 1.81-1.68 (m, 2H) 207 N- (Cyclopentyl-
methyl)-2'-(4,5- dimethyl-1H- imidazol-2-yl)- 3,4'-bipyridine-
##STR00269## 376.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.24 (d, J = 2.2 Hz, 1H), 9.15 (d, J = 1.9 Hz, 1H), 8.93 (d, J =
5.1 Hz, 1H), 8.88 (t, J = 5.6 Hz, 1H), 8.67 5-carboxamide (t, J =
2.1 Hz, 1H), 8.61 trifluoroacetate (s, 1H), 8.14 (dd, J = 5.2, salt
1.5 Hz, 1H), 3.32-3.22 (m, 2H), 2.33 (s, 6H), 2.19 (hept, J = 7.4
Hz, 1H), 1.79-1.43 (m, 6H), 1.37-1.17 (m, 2H) 208 N-(tert-Butyl)-
2'-(4,5- dimethyl-1H- imidazol-2-yl)- ##STR00270## 350.2 .sup.1H
NMR (400 MHz, d.sub.6- DMSO) .delta. 9.22 (d, J = 2.2 Hz, 1H), 9.11
(d, J = 1.9 Hz, 1H), 8.92 (d, J = 5.2 Hz, 3,4'-bipyridine- 1H),
8.64-8.57 (m, 2H), 5-carboxamide 8.23 (s, 1H), 8.15 (dd, J =
trifluoroacetate 5.1, 1.4 Hz, 1H), 2.33 (s, salt 6H), 1.44 (s, 9H)
209 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- N-(3- hydroxypropyl)-
##STR00271## 366.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 12.43 (s, 1H), 9.09 (d, J= 2.2 Hz, 1H),8.70 (d, J = 4.3 Hz,
1H), 8.65 (d, J =5.2 Hz, N-methyl- 1H), 8.33-8.15 (m, 2H),
3,4'-bipyridine- 7.73 (d, J = 4.8 Hz, 1H), 5-carboxamide 4.68 (s,
0.5H), 4.53 (s, 0.5H), 3.61-3.43 (m, 2H), 3.39-3.22 (m, 2H), 3.02
(s, 1.5H), 2.97 (s, 1.5H), 2.19 (s, 3H), 2.12 (s, 3H), 1.84- 1.68
(m, 2H) 210 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- N-methyl-N-
propyl-3,4'- ##STR00272## 350.1 .sup.1H NMR (400 MHz, CD.sub.3OD,
rotamers) .delta. 9.10 (s, 1H), 8.75-8.65 (m, 2H), 8.35 (s, 1H),
8.33-8.24 (m, 1H), 7.72-7.62 (m, 1H), bipyridine-5- 3.60 (t, J =
7.4 Hz, 1H), 3.37 carboxamide (t, J = 7.4 Hz, 1H), 3.16 (s, 1.5H),
3.10 (s, 1.5H), 2.26 (s, 6H), 1.79 (h, J = 7.2 Hz, 1H), 1.68 (h, J
= 7.0 Hz, 1H), 1.05 (t, J = 7.3 Hz, 1.5H), 0.83 (t, J = 7.4 Hz,
1.5H) 211 2'-(4,5- Dimethyl-1H- imidazol-2-yl)- 5-[(3-
ethylpyrrolidin- 1- ##STR00273## 376.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO, rotamers) .delta. 9.23- 9.18 (m, 1H), 8.93-8.86 (m,
2H), 8.60 (s, 1H), 8.43- 8.39 (m, 1H), 8.17-8.10 (m, 1H), 3.80-3.40
(m, yl)carbonyl]- 3H), 3.23-3.04 (m, 1H), 3,4'-bipyridine 2.33 (s,
6H), 2.18-1.95 (m, trifluoroacetate 2H), 1.63-1.17 (m, 3H), salt
0.95 (t, J = 7.4 Hz, 1.5H), 0.85 (t, J = 7.4 Hz, 1.5H) 212 5-(5-
Azaspiro[2.4] hept-5- ylcarbonyl)-2'- (4,5-dimethyl- 1H-imidazol-2-
##STR00274## 374.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, rotamers)
.delta. 9.25- 9.18 (m, 1H), 8.96-8.87 (m, 2H), 8.62-8.55 (m, 1H),
8.46 (t, J = 2.0 Hz, 0.5H), 8.43 (t, J = 2.0 Hz, yl)-3,4'- 0.5H),
8.19-8.10 (m, 1H), bipyridine 3.74-3.63 (m, 2H), 3.47 (s,
trifluoroacetate 1H), 3.43 (s, 1H), 2.33 (s, salt 6H), 1.88 (t, J =
7.0 Hz, 1H), 1.83 (t, J = 6.7 Hz, 1H), 0.72- 0.67 (m, 1H),
0.67-0.61 (m, 1H), 0.57 (s, 2H) 212B 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 5-{[(3S)-3- methoxypyrrolidin- 1- yl]carbonyl}-
3,4'-bipyridine ##STR00275## 378.1 .sup.1H NMR (400 MHz, d.sub.6-
DMSO, rotamers) .delta. 9.24- 9.19 (m, 1H), 8.93-8.85 (m, 2H),
8.62-8.56 (m, 1H), 8.45-8.39 (m, 1H), 8.17-8.12 (m, 1H), 4.10- 4.03
(m, 0.5H), 4.02-3.95 (m, 0.5H), 3.79-3.38 (m, trifluoroacetate 4H),
3.30 (s, 1.5H), 3.19 (s, salt 1.5H), 2.33 (s, 6H), 2.13- 1.89 (m,
2H)
Example 214.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1,2,5,6-tetrahydro--
3,4'-bipyridine trifluoroacetate salt
##STR00276##
[0675] To
2'-(4,5-dimethyl-1H-imidazol-2-yl)-1,2,5,6-tetrahydro-3,4'-bipyr-
idine (0.015 g, 0.059 mmol, from Step 3) in DCM (0.3 mL) was added
Et.sub.3N (0.025 mL, 0.18 mmol), followed by benzenesulfonyl
chloride (0.007 mL, 0.05 mmol). After stirring overnight, the
reaction mixture was diluted with MeOH and water. The product was
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 8 mg. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.69 (d, J=5.0 Hz, 1H), 8.01-7.98 (m, 1H),
7.92-7.87 (m, 2H), 7.72-7.66 (m, 1H), 7.66-7.59 (m, 2H), 7.55 (dd,
J=5.2, 1.6 Hz, 1H), 6.68-6.61 (m, 1H), 4.18-3.92 (m, 2H), 3.34-3.31
(m, 2H), 2.51-2.42 (m, 2H), 2.36 (s, 6H); LCMS (M+H).sup.+:
395.1.
Example 215.
2-(4,5-Dimethyl-1H-imidazol-2-yl)-4-[1-(phenylsulfonyl)piperidin-3-yl]pyr-
idine trifluoroacetate salt, racemic mixture prepared
##STR00277##
[0677] A mixture of
2'-(4,5-dimethyl-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1,2,5,6-tetrahydro--
3,4'-bipyridine trifluoroacetate salt (0.049 g, 0.079 mmol, from
Step 4), Na.sub.2CO.sub.3 (0.025 g, 0.24 mmol), and palladium (10%
on carbon, 0.025 g, 0.024 mmol) in MeOH (10 mL) was degassed and
shaken under 40 psi H.sub.2 for 2 hours. The reaction mixture was
filtered and the MeOH was removed in vacuo. The product was
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 4 mg. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.67 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.82-7.74
(m, 2H), 7.71-7.64 (m, 1H), 7.64-7.54 (m, 2H), 7.48 (dd, J=5.1, 1.4
Hz, 1H), 3.91-3.82 (m, 1H), 3.81-3.69 (m, 1H), 3.08-2.96 (m, 1H),
2.57-2.40 (m, 2H), 2.34 (s, 6H), 2.05-1.95 (m, 1H), 1.95-1.85 (m,
1H), 1.85-1.66 (m, 1H), 1.59 (qd, J=12.0, 3.6 Hz, 1H); LCMS
(M+H).sup.+: 397.2.
[0678] Examples 217 and 219 through 230 were synthesized by the
methods of Examples 213-215 and the data are listed in Table 15.
Examples 217, 219, 222 and 226 were prepared via the procedure of
Example 214, using acyl chlorides instead of sulfonyl chlorides, as
outlined in Scheme 15. Examples 223-225 and 228-230 were prepared
by reductive aminations as described in Scheme 15.
TABLE-US-00014 TABLE 15 ##STR00278## Ex. MS No. Name R= (M +
H).sup.+ .sup.1H NMR 217 1-(4-(2-(4,5- Dimethyl-1H- imidazol-2-
yl)pyridin-4-yl)- 5,6- dihydropyridin- 1(2H)- yl)ethanone
trifluoroacetate salt ##STR00279## 297.2 .sup.1H NMR (400 MHz,
CD.sub.3OD, rotamers) .delta. 8.73 (d, J = 5.2 Hz, 1H), 8.11-8.09
(m, 0.6H), 8.09-8.06 (m, 0.4H), 7.68- 7.64 (m, 0.4H), 7.64-7.61 (m,
0.6H), 6.65-6.58 (m, 1H), 4.37-4.25 (m, 2H), 3.87 (t, J = 5.7 Hz,
0.8H), 3.82 (t, J = 5.7 Hz, 1.2H), 2.76-2.68 (m, 1.2H), 2.68-2.60
(m, 0.8H), 2.38 (s, 6H), 2.22 (s, 1.8H), 2.18 (s, 1.2H) 219
1-(3-(2-(4,5- Dimethyl-1H- imidazol-2- yl)pyridin-4-yl)- 5,6-
dihydropyridin- 1(2H)- yl)ethanone trifluoroacetate salt
##STR00280## 297.1 .sup.1H NMR (400 MHz, CD.sub.3OD, rotamers)
.delta. 8.72-8.67 (m, 2H, major and minor rotamers), 8.10-8.06 (m,
1H, minor rotamer), 8.06-8.00 (m, 1H, major rotamer), 7.65-7.57 (m,
2H, major and minor rotamer), 6.83-6.80 (m, 1H, minor rotamer),
6.80-6.75 (m, 1H, major rotamer), 4.52-4.49 (m, 2H, major rotamer),
4.49-4.45 (m, 2H, minor rotamer), 3.75 (t, J = 5.9 Hz, 2H, minor
rotamer), 3.71 (t, J = 5.8 Hz, 2H, major rotamer), 2.56-2.46 (m,
2H, major rotamer), 2.45- 2.38 (m, 2H, minor rotamer), 2.36 (s, 6H,
minor rotamer), 2.35 (s, 6H, major rotamer), 2.22 (s, 3H, minor
rotamer), 2.20 (s, 3H, major rotamer) 220 2-(4,5-Dimethyl-
1H-imidazol-2- yl)-4-(1- (methylsulfonyl)- 1,2,5,6-
tetrahydropyridin- 3-yl)pyridine trifluoroacetate salt ##STR00281##
333.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71 (d, J = 5.2
Hz, 1H), 8.09- 7.97 (m, 1H), 7.62 (dd, J = 5.2, 1.6 Hz, 1H),
6.82-6.74 (m, 1H), 4.31-4.13 (m, 2H), 3.46 (t, J = 5.8 Hz, 2H),
2.97 (s, 3H), 2.69-2.46 (m, 2H), 2.36 (s, 6H) 221 4-(1-(4-
Chlorophenylsulfonyl)- 1,2,5,6- tetrahydropyridin- 3-yl)-2-(4,5-
dimethyl-1H- imidazol-2- yl)pyridine trifluoroacetate salt
##STR00282## 429.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.69
(d, J = 5.2 Hz, 1H), 8.01- 7.97 (m, 1H), 7.88 (d, J = 8.6 Hz, 2H),
7.64 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 5.2, 1.6 Hz, 1H), 6.68-6.63
(m, 1H), 4.13- 4.02 (m, 2H), 3.33 (t, J = 5.8 Hz, 2H), 2.52-2.41
(m, 2H), 2.37 (s, 6H) 222 (3-(2-(4,5- Dimethyl-1H- imidazol-2-
yl)pyridin-4-yl)- 5,6- dihydropyridin- 1(2H)- yl)(phenyl) methanone
trifluoroacetate salt ##STR00283## 359.1 223 4-(1-Benzyl- 1,2,5,6-
tetrahydropyridin- 3-yl)-2-(4,5- dimethyl-1H- imidazol-2-
yl)pyridine trifluoroacetate salt ##STR00284## 345.2 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.74 (d, J = 5.2 Hz, 1H), 8.14 (s,
1H), 7.64-7.56 (m, 2H), 7.56-7.46 (m, 4H), 6.84- 6.73 (m, 1H), 4.55
(s, 2H), 4.27 (s, 2H), 3.65-3.38 (m, 2H), 2.81-2.53 (m, 2H), 2.37
(s, 6H) 224 4-(1-(4- Chlorobenzyl)- 1,2,5,6- tetrahydropyridin-
3-yl)-2-(4,5- dimethyl-1H- imidazol-2- yl)pyridine trifluoroacetate
salt ##STR00285## 379.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.74 (d, J = 5.2 Hz, 1H), 8.16- 8.08 (m, 1H), 7.60 (d, J = 8.5 Hz,
2H), 7.56-7.49 (m, 3H), 6.95-6.68 (m, 1H), 4.54 (s, 2H), 4.27 (s,
2H), 3.67-3.35 (m, 2H), 2.83-2.53 (m, 2H), 2.37 (s, 6H) 225
2-(4,5-Dimethyl- 1H-imidazol-2- yl)-4-(1- ((tetrahydro-2H- pyran-4-
yl)methyl)- 1,2,5,6- tetrahydropyridin- 3-yl)pyridine
trifluoroacetate salt ##STR00286## 353.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.76 (d, J = 5.2 Hz, 1H), 8.21- 8.09 (m, 1H),
7.60 (dd, J = 5.2, 1.6 Hz, 1H), 6.91-6.68 (m, 1H), 4.05-3.93 (m,
2H), 3.50 (td, J = 11.8, 1.8 Hz, 2H), 3.26 (d, J = 7.1 Hz, 2H),
2.37 (s, 6H), 2.34-2.21 (m, 1H), 1.83- 1.71 (m, 2H), 1.43 (qd, J =
12.2, 4.5 Hz, 2H) 226 1-(3-(2-(4,5- Dimethyl-1H- imidazol-2-
yl)pyridin-4-yl)- 2,5-dihydro-1H- pyrrol-1- yl)ethanone
trifluoroacetate salt ##STR00287## 283.1 .sup.1H NMR (400 MHz,
CD.sub.3OD, rotamers) .delta. 8.77-8.72 (m, 1H), 8.11 (s, 0.4H),
8.05 (s, 0.6H), 7.68 (dd, J = 5.1, 1.4 Hz, 0.6H), 7.63 (d, J = 3.8
Hz, 0.4H), 6.83-6.75 (m, 1H), 4.83-4.75 (m, 1H), 4.67- 4.56 (m,
2H), 4.48-4.41 (m, 1H), 2.37 (s, 6H), 2.20 (s, 1.2H), 2.15 (s,
1.8H) 227 2-(4,5-Dimethyl- 1H-imidazol-2- yl)-4-(1-
(methylsulfonyl)- 2,5-dihydro-1H- pyrrol-3- yl)pyridine
trifluoroacetate salt ##STR00288## 319.0 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.74 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.63
(dd, J = 5.2, 1.4 Hz, 1H), 6.77-6.72 (m, 1H), 4.72-4.54 (m, 2H),
4.50- 4.26 (m, 2H), 2.98 (s, 3H), 2.37 (s, 6H) 228 4-(1-Benzyl-2,5-
dihydro-1H- pyrrol-3-yl)-2- (4,5-dimethyl- 1H-imidazol-2-
yl)pyridine trifluoroacetate salt ##STR00289## 331.1 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.78 (d, J = 5.1 Hz, 1H), 8.09 (s,
1H), 7.64-7.56 (m, 3H), 7.56-7.49 (m, 3H), 6.89- 6.16 (m, 1H), 4.65
(s, 2H), 4.63- 4.59 (m, 2H), 4.49-4.42 (m, 2H), 2.36 (s, 6H) 229
4-(1-(4- Chlorobenzyl)- 2,5-dihydro-1H- pyrrol-3-yl)-2-
(4,5-dimethyl- 1H-imidazol-2- yl)pyridine trifluoroacetate salt
##STR00290## 365.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.77
(d, J = 5.1 Hz, 1H), 8.10 (s, 1H), 7.64-7.57 (m, 3H), 7.57-7.51 (m,
2H), 6.96- 6.68 (m, 1H), 4.64 (s, 2H), 4.63- 4.57 (m, 2H),
4.49-4.40 (m, 2H), 2.36 (s, 6H) 230 2-(4,5-Dimethyl- 1H-imidazol-2-
yl)-4-(1- ((tetrahydro-2H- pyran-4- yl)methyl)-2,5- dihydro-1H-
pyrrol-3- yl)pyridine trifluoroacetate salt ##STR00291## 339.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.80 (d, J = 5.1 Hz, 1H),
8.18 (s, 1H), 7.63 (dd, J = 5.1, 1.4 Hz, 1H), 6.83-6.78 (m, 1H),
4.06-3.92 (m, 2H), 3.50 (td, J = 11.8, 1.7 Hz, 2H), 3.40 (d, J =
7.1 Hz, 2H), 2.37 (s, 6H), 2.25-2.09 (m, 1H), 1.83- 1.72 (m, 2H),
1.44 (qd, J = 12.3, 4.6 Hz, 2H)
Example 231.
(3R)-1-[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]pyrrolidin-
-3-ol
##STR00292##
[0679] Step 1.
4-Bromo-2-(4,5-dimethyl-1H-imidazol-2-yl)pyridine
##STR00293##
[0681] 4-Bromopyridine-2-carbonitrile (1.0 g, 5.5 mmol, Synthonix)
in MeOH (10 mL) was treated with sodium methoxide (25 wt % in MeOH,
0.095 mL, 0.47 mmol) and the reaction was stirred for 1 hour.
Ammonium chloride (0.37 g, 6.9 mmol) was added and the reaction was
stirred for 4 days. Solvent was then removed in vacuo. Water (4 mL)
and EtOAc (6 mL) were added, the mixture was saturated with solid
NaCl, and the mixture was stirred overnight. The solid product was
isolated by filtration and dried at 40.degree. C. under vacuum
overnight. The product was used below without further
purification.
[0682] To 4-bromopyridine-2-carboximidamide (0.50 g, 2.5 mmol) in
DMF (5 mL) was added K.sub.2CO.sub.3 (0.52 g, 3.7 mmol) and
3-bromo-2-butanone (0.24 mL, 3.2 mmol). The reaction was stirred
for 4 days. The reaction mixture was partitioned between EtOAc and
H.sub.2O. The aqueous layer was extracted with two further portions
of EtOAc. The combined organic extracts were washed sequentially
with water and saturated NaCl solution. The organic solution was
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was triturated with methyl tert-butyl ether (MTBE, 2 mL)
and the solid product was isolated by filtration and dried under
vacuum at 40.degree. C. for 3 hours. Yield: 372 mg, 59%. LCMS
(M+H).sup.+: 252.0/254.0.
Step 2.
4-Bromo-2-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-im-
idazol-2-yl)pyridine
##STR00294##
[0684] To a solution of
4-bromo-2-(4,5-dimethyl-1H-imidazol-2-yl)pyridine (0.31 g, 1.2
mmol, from Step 1) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (0.60
g, 1.8 mmol) and [3-(trimethylsilyl)ethoxy]methyl chloride (0.33
mL, 1.8 mmol, Aldrich). The reaction mixture was stirred overnight.
Water was then added. After the mixture was stirred for 15 minutes,
it was extracted with EtOAc. The organic layer was washed with
water, followed by saturated NaCl, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The product was purified by flash
chromatography, eluting with a gradient from 0-100% EtOAc in
hexanes. Yield: 0.35 g, 76%. LCMS (M+H).sup.+: 382.1/384.1.
Step 3.
5-Chloro-2'-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H--
imidazol-2-yl)-3,4-bipyridine
##STR00295##
[0686] A degassed mixture of (5-chloropyridin-3-yl)boronic acid
(0.15 g, 0.96 mmol, Aldrich), CsF (0.42 g, 2.7 mmol),
4-bromo-2-(4,5-dimethyl-1-{[2-(trimethyl
silyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine (0.35 g, 0.92 mmol,
from Step 2) and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (65 mg, 0.092 mmol, Aldrich) in 1,4-dioxane (4 mL) and
H.sub.2O (1 mL) was heated to 90.degree. C. for 2.5 hours. Upon
cooling, the reaction mixture was filtered. The filtrate was
diluted with water and extracted with EtOAc. The organic extract
was washed with water, followed by brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was used
without further purification in coupling reactions as in Step 4.
LCMS (M+H).sup.+: 415.1.
Step 4.
(3R)-1-[2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]pyr-
rolidin-3-ol
[0687] A degassed mixture of
5-chloro-2'-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo-
l-2-yl)-3,4'-bipyridine (0.020 g, 0.048 mmol, from Step 3),
(3R)-pyrrolidin-3-ol (12.0 .mu.L, 0.144 mmol, Aldrich),
Cs.sub.2CO.sub.3 (47 mg, 0.14 mmol) and tBuBrettPhos Pd G3 (4.1 mg,
0.0048 mmol, Aldrich) in toluene (0.3 mL) and 1,4-dioxane (30
.mu.L) was heated to 100.degree. C. overnight. Upon cooling, the
reaction mixture was diluted with water and EtOAc and filtered. The
organic layer of the filtrate was removed via rotary evaporation.
The product was purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 10 with 0.15%
ammonium hydroxide).
(3R)-1-[2'-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-
-2-yl)-3,4'-bipyridin-5-yl]pyrrolidin-3-ol (3.2 mg, 0.0069 mmol)
was stirred in TFA (2.0 mL) for 5 hours. The TFA was removed via
rotary evaporation and the residue was reconstituted in DCM and
MeOH and again removed via rotary evaporation. The residue was
reconstituted in a mixture of THF, MeOH, and DMF for purification
by preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 10 with 0.15% ammonium hydroxide). Yield:
1.2 mg, 52%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.61 (d,
J=5.1 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.96 (d, J=2.0 Hz, 1H),
7.62-7.52 (m, 1H), 7.36-7.29 (m, 1H), 4.64-4.53 (m, 1H), 3.64-3.54
(m, 2H), 3.50 (td, J=8.8, 3.1 Hz, 1H), 3.35 (d, J=10.4 Hz, 1H),
2.30-2.00 (m, 2H), 2.23 (s, 6H);
[0688] LCMS (M+H).sup.+: 336.1.
[0689] Examples 232 through 234 were synthesized according to the
procedure of Example 231 and the data are listed in Table 16.
TABLE-US-00015 TABLE 16 ##STR00296## Ex. MS No. Name R= (M +
H).sup.+ .sup.1H NMR 232 (3S)-1-[2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- 3,4'-bipyridin-5- yl]pyrrolidin-3- ol ##STR00297##
336.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.63 (d, J = 5.1
Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.6
Hz, 1H), 7.68 (dd, J = 5.1, 1.5 Hz, 1H), 7.19-7.13 (m, 1H), 5.02
(d, J = 3.4 Hz, 1H), 4.52- 4.39 (m, 1H), 3.53 (dd, J = 10.3, 4.8
Hz, 1H), 3.48-3.40 (m, 2H), 3.23 (d, J = 10.9 Hz, 1H), 2.17 (s,
6H), 2.12-1.99 (m, 1H), 1.99-1.87 (m, 1H) 233 2'-(4,5- Dimethyl-1H-
imidazol-2-yl)- N-phenyl-3,4'- bipyridin-5- amine ##STR00298##
342.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.62 (d, J = 5.1
Hz, 1H), 8.35 (s, 2H), 8.22 (s, 1H), 7.82 (t, J = 2.1 Hz, 1H), 7.53
(dd, J = 5.1, 1.4 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.21 (d, J =
7.6 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 2.22 (s, 6H) 234
5-Chloro-2'-(4,5- Cl 285.0 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. dimethyl-1H- 8.85 (d, J = 1.9 Hz, 1H), 8.64 imidazol-2-yl)-
(d, J = 5.2 Hz, 1H), 8.62 (d, J = 3,4'-bipyridine 2.2 Hz, 1H),
8.32-8.25 (m, 1H), 8.19 (t, J = 2.1 Hz, 1H), 7.52 (dd, J = 5.2, 1.7
Hz, 1H), 2.25 (s, 6H)
Example 235. tert-Butyl
3-[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]-2,5-dihydro-1H-
-pyrrole-1-carboxylate
##STR00299##
[0690] Step 1. 5-Chloro-3,4'-bipyridine-2-carbonitrile
##STR00300##
[0692] A degassed mixture of 4-bromopyridine-2-carbonitrile (0.99
g, 5.4 mmol, Synthonix), (5-chloropyridin-3-yl)boronic acid (0.847
g, 5.38 mmol, Aldrich), CsF (2.4 g, 16 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.38 g, 0.54 mmol, Aldrich) in 1,4-dioxane (10 mL) and water
(3 mL) was heated to 90-105.degree. C. for 2.5 hours. The reaction
mixture was filtered and the volume was reduced via rotary
evaporation. The mixture was diluted with water and extracted with
EtOAc. The combined organic extracts were washed sequentially with
water and brine, dried over sodium sulfate, filtered, and
concentrated. The resulting solid was triturated with MTBE (5 mL).
The solid product was isolated by filtration and air dried. Yield:
0.95 g, 82%. LCMS (M+H).sup.+: 216.0/218.0.
Step 2. tert-Butyl
3-(2-cyano-3,4'-bipyridin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate
##STR00301##
[0694] A degassed mixture of
5-chloro-3,4'-bipyridine-2'-carbonitrile (0.65 g, 3.0 mmol, from
Step 1), tert-butyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1--
carboxylate (0.83 g, 3.1 mmol, Synthonix), K.sub.3PO.sub.4 (1.9 g,
9.2 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.21
g, 0.31 mmol, Aldrich) in 1,4-dioxane (7 mL) and water (2 mL) was
refluxed at 120.degree. C. for 2 hours. Upon cooling, the reaction
mixture was filtered and the filtrate was partitioned between water
and EtOAc. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes. Yield: 0.39 g, 45%. LCMS (M+H).sup.+:
349.1.
Step 3. tert-Butyl
3-{2-[amino(imino)methyl]-3,4-bipyridin-5-yl}-2,5-dihydro-1H-pyrrole-1-ca-
rboxylate
##STR00302##
[0696] A mixture of tert-butyl
3-(2'-cyano-3,4'-bipyridin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate
(0.45 g, 1.3 mmol, from Step 2) in MeOH (6 mL) and THF (3 mL) was
treated with sodium methoxide (25 wt %, 24 .mu.L, 0.11 mmol,
Aldrich). After 24 hours, NH.sub.4Cl (95.0 mg, 1.78 mmol) was added
and the reaction was stirred overnight. The reaction was cooled in
an ice bath and the precipitate formed was isolated by filtration
and washed with THF and MeOH. The product was dried under vacuum at
50.degree. C. for 2 hours. Yield: 0.33 g, 70%. LCMS (M+H).sup.+:
366.1.
Step 4. tert-Butyl
3-[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]-2,5-dihydro-1H-
-pyrrole-1-carboxylate
[0697] A suspension of tert-butyl
3-{2'-[amino(imino)methyl]-3,4'-bipyridin-5-yl}-2,5-dihydro-1H-pyrrole-1--
carboxylate (0.33 g, 0.90 mmol, from Step 3) in DMF (4 mL) was
treated with 3-bromo-2-butanone (0.10 mL, 1.4 mmol) and
K.sub.2CO.sub.3 (0.25 g, 1.8 mmol). The reaction was stirred over
three nights. The reaction was diluted with EtOAc (13 mL) and water
(13 mL) and a precipitate was formed, which was isolated by
filtration and then dried under vacuum at 40.degree. C. overnight.
Yield: 0.26 g, 69%. .sup.1H NMR (400 MHz, d.sub.6-DMSO, rotamers)
.delta. 12.39 (s, 1H), 8.95-8.89 (m, 1H), 8.84-8.78 (m, 1H), 8.64
(d, J=5.1 Hz, 1H), 8.30-8.26 (m, 1H), 8.24 (d, J=7.3 Hz, 1H),
7.76-7.67 (m, 1H), 6.78-6.68 (m, 1H), 4.64-4.45 (m, 2H), 4.35-4.08
(m, 2H), 2.18 (s, 3H), 2.11 (s, 3H), 1.47 (s, 4H), 1.46 (s, 5H);
LCMS (M+H).sup.+: 418.2.
Example 236.
5-(2,5-Dihydro-1H-pyrrol-3-yl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bi-
pyridine
##STR00303##
[0699] tert-Butyl
3-[2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]-2,5-dihydro-1H-
-pyrrole-1-carboxylate (0.10 g, 0.24 mmol, from Example 235) was
stirred in TFA (2.0 mL) for 1 hour and 45 minutes. The TFA was
removed in vacuo and the residue was redissolved in MeOH and rotary
evaporated to remove TFA. Acetonitrile (1 mL) and 1.0 N NaOH (1.5
mL, 1.5 mmol) were added. After the mixture was stirred for 2
hours, the fine powder that formed was isolated by filtration,
washed with MeCN and water. The solid was dried at 50.degree. C.
under vacuum for 1 hour. Yield: 59 mg, 77%. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 12.41 (br s, 1H), 8.90 (d, J=2.0 Hz, 1H),
8.78 (d, J=1.9 Hz, 1H), 8.65 (d, J=5.1 Hz, 1H), 8.24 (t, J=2.0 Hz,
1H), 8.23-8.21 (m, 1H), 7.70 (dd, J=5.2, 1.8 Hz, 1H), 6.89-6.42 (m,
1H), 4.19-4.12 (m, 2H), 3.94-3.87 (m, 2H), 2.14 (br, 9H);
[0700] LCMS (M+H).sup.+: 318.1.
Example 237.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[1-(methylsulfonyl)-2,5-dihydro-1H-p-
yrrol-3-yl]-3,4'-bipyridine
##STR00304##
[0702] To a suspension of
5-(2,5-dihydro-1H-pyrrol-3-yl)-2'-(4,5-dimethyl-1H-imidazol-2-yl)-3,4'-bi-
pyridine (7.0 mg, 0.022 mmol, from Example 235) in DMF (1 mL) was
added N,N-diisopropylethylamine (15 .mu.L, 0.088 mmol) and
methanesulfonyl chloride (MsCl, 2.6 .mu.L, 0.033 mmol). After
stirring overnight, additional MsCl was added in sufficient
quantity to drive the reaction to completion as determined by LCMS.
The product was purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 10 with 0.15%
ammonium hydroxide). Yield: 3.8 mg, 43%. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 12.41 (s, 1H), 8.95 (d, J=1.4 Hz, 1H), 8.87
(d, J=1.4 Hz, 1H), 8.65 (d, J=5.0 Hz, 1H), 8.31-8.28 (m, 1H), 8.26
(s, 1H), 7.79-7.61 (m, 1H), 6.79-6.67 (m, 1H), 4.80-4.56 (m, 2H),
4.49-4.20 (m, 2H), 3.01 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H); LCMS
(M+H).sup.+: 396.1.
[0703] Examples 238 through 239 were synthesized according to the
procedure of Example 237, using acetyl chloride and methyl
chloroformate, respectively, in place of methane sulfonyl chloride.
The data are listed in Table 17.
TABLE-US-00016 TABLE 17 ##STR00305## Ex. MS No. Name R= (M +
H).sup.+ .sup.1H NMR 238 1-(3-(2'-(4,5- COMe 360.2 .sup.1H NMR (400
MHz, Dimethyl-1H- CD.sub.3OD) .delta. 8.90 (d, J = imidazol-2-yl)-
2.0 Hz, 1H), 8.77 (t, J = 3,4'-bipyridin- 1.7 Hz, 1H), 8.66 (d,
5-yl)-2,5-dihydro- J = 5.2 Hz, 1H), 8.34- 1H-pyrrol-1- 8.32 (m,
1H), 8.30 (q, yl)ethanone J = 1.8 Hz, 1H), 7.67 (dd, J = 5.2, 1.7
Hz, 1H), 6.70-6.63 (m, 1H), 4.71- 4.63 (m, 1H), 4.60-4.52 (m, 1H),
4.46-4.36 (m, 1H), 2.24 (s, 6H), 2.21 (s, 1.5H, rotamers), 2.14 (s,
1.5H, rotamers) 239 Methyl 3-(2'-(4,5- CO.sub.2Me 376.1 .sup.1H NMR
(400 MHz, d.sub.6- dimethyl-1H- DMSO, rotamers) .delta. 9.04-
imidazol-2-yl)- 9.01 (m, 1H), 8.97-8.89 3,4'-bipyridin-5- (m, 2H),
8.57 (s, 1H), yl)-2,5-dihydro- 8.37-8.34 (m, 1H), 8.17-
1H-pyrrole-1- 8.13 (m, 1H), 6.81-6.72 carboxylate (m, 1H),
4.66-4.60 (m, 2H), 4.41-4.29 (m, 2H), 3.69 (s, 1.5H), 3.68 (s,
1.5H), 2.33 (s, 6H)
Example 240.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-5-[1-(methylsulfonyl)pyrrolidin-3-yl]--
3,4'-bipyridine racemic mixture prepared
##STR00306##
[0705] To a solution of
2'-(4,5-dimethyl-1H-imidazol-2-yl)-5-[1-(methylsulfonyl)-2,5-dihydro-1H-p-
yrrol-3-yl]-3,4'-bipyridine (5.5 mg, 0.014 mmol, prepared as in
Example 237) in MeOH (1 mL) and THF (1 mL) was added palladium (10%
on carbon, 4.1 mg, 0.0038 mmol). The mixture was degassed and
stirred under 1 atm H.sub.2 overnight. The reaction mixture was
filtered and the product was purified by preparative HPLC (C-18
column eluting with 14.6-32.6% acetonitrile in water containing
0.15% ammonium hydroxide over 12 minutes). Yield: 2.9 mg, 53%.
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 12.40 (s, 1H), 8.91 (d,
J=2.1 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.64 (d, J=5.2 Hz, 1H),
8.26-8.16 (m, 2H), 7.69 (dd, J=5.2, 1.7 Hz, 1H), 3.82 (dd, J=9.4,
7.7 Hz, 1H), 3.63-3.49 (m, 2H), 3.40 (td, J=9.9, 6.9 Hz, 1H),
3.36-3.29 (m, 1H), 3.01 (s, 3H), 2.44-2.30 (m, 1H), 2.24-2.13 (m,
1H), 2.19 (s, 3H), 2.12 (s, 3H); LCMS (M+H).sup.+: 398.1.
Example 241. Ethyl
5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-4-carbo-
xylate
##STR00307##
[0706] Step 1. Methyl
5-(methylsulfonyl)-3,4'-bipyridine-2-carboxylate
##STR00308##
[0708] A degassed mixture of methyl 4-bromopyridine-2-carboxylate
(1.5 g, 6.9 mmol, Combi-Blocks),
3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
e (2.2 g, 7.6 mmol, Aldrich), CsF (3 g, 20 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.49 g, 0.69 mmol, Aldrich) in 1,4-dioxane (20 mL) and
H.sub.2O (5 mL) was heated to 105.degree. C. for 1.5 hours. Upon
cooling to room temperature, the reaction mixture was diluted with
EtOAc and washed with water. The water layer was extracted with two
portions of EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes. Yield: 1.84 g, 77%. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.41 (d, J=1.8 Hz, 1H), 9.18 (d, J=1.8 Hz,
1H), 8.89 (d, J=5.0 Hz, 1H), 8.78-8.75 (m, 1H), 8.54-8.49 (m, 1H),
8.23-8.13 (m, 1H), 3.95 (s, 3H), 3.44 (s, 3H); LCMS (M+H).sup.+:
293.0.
Step 2. Lithium
5-(methylsulfonyl)-3,4'-bipyridine-2'-carboxylate
##STR00309##
[0710] A solution of methyl
5-(methylsulfonyl)-3,4'-bipyridine-2'-carboxylate (1.84 g, 6.3
mmol, from Step 1) in THF (50 mL) and H.sub.2O (12 mL) was treated
with LiOH--H.sub.2O (1.1 g, 26 mmol) for 2 hours. The reaction
mixture was filtered to afford a white solid, 1.7 g (95%). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 9.34 (d, J=1.7 Hz, 1H), 9.14
(d, J=1.7 Hz, 1H), 8.71-8.65 (m, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.35
(s, 1H), 7.91-7.85 (m, 1H), 3.44 (s, 3H); LCMS calculated for
C.sub.12H.sub.11N.sub.2O.sub.4S (M+H).sup.+: m/z=279.0; found
279.1.
Step 3. Ethyl
5-methyl-2-[5-(methylsulfonyl)-3,4-bipyridin-2'-yl]-1H-imidazole-4-carbox-
ylate
[0711] Lithium 5-(methylsulfonyl)-3,4'-bipyridine-2'-carboxylate
(0.22 g, 0.76 mmol, from Step 2) in DMF (5.4 mL) was treated with
HATU (0.32 g, 0.84 mmol) for 35 minutes, at which time a solution
of ethyl 2-amino-3-oxobutanoate hydrochloride (0.14 g, 0.80 mmol,
AstaTech) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in DMF
(1.1 mL, 14 mmol) was added. After stirring overnight, additional
HATU (0.29 g, 0.76 mmol) was added. Fifteen minutes later,
additional ethyl 2-amino-3-oxobutanoate hydrochloride (0.16 g, 0.91
mmol) and N,N-diisopropylethylamine (0.16 mL, 0.91 mmol) in DMF
(2.0 mL) were added. After a reaction time of 5 minutes, the
solution was diluted with EtOAc and washed sequentially with water,
saturated NaHCO.sub.3 solution, water, and brine. The organic
solution was then dried over Na.sub.2SO.sub.4, filtered and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-90% EtOAc in hexanes to afford 89 mg
of product. LCMS (M+H).sup.+: 406.1.
[0712] The product was then dissolved in acetic acid (1.0 mL).
Ammonium acetate (85 mg, 1.1 mmol) was added, and the reaction was
heated to about 120-130.degree. C. in a sealed vial overnight. Upon
cooling to room temperature, AcOH was removed in vacuo and the
product was purified by preparative HPLC (C-18 column eluting with
a water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). Yield: 19 mg, 6.5%. .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 13.34 (s, 1H), 9.42 (s, 1H), 9.18 (s, 1H), 8.83-8.74 (m,
2H), 8.43 (s, 1H), 7.97-7.89 (m, 1H), 4.27 (q, J=7.7, 6.4 Hz, 2H),
3.46 (s, 3H), 2.54 (s, 3H), 1.31 (t, J=6.5 Hz, 3H); LCMS
(M+H).sup.+: 387.1.
Example 242.
5-Methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-4-carbo-
xylic acid trifluoroacetate salt
##STR00310##
[0714] Ethyl
5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imidazole-4-carbo-
xylate (16 mg, 0.041 mmol, from Example 241) was treated with
LiOH--H.sub.2O (7.0 mg, 0.16 mmol) in THF (2 mL) and H.sub.2O (0.2
mL) for 35 minutes. 1.0 M aq. NaOH (0.50 mL, 0.50 mmol) was added
and the reaction mixture was stirred overnight. 1.0 M aq. KOH (0.20
mL, 0.20 mmol) was added and the mixture was heated to 60.degree.
C. for 24 hours and then to 70.degree. C. for 4 hours. Upon cooling
to room temperature, TFA was added and the solvent was removed in
vacuo. The product was dissolved in CH.sub.3CN and MeOH and
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 13 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.43 (d, J=2.1 Hz, 1H), 9.21 (d, J=2.1 Hz,
1H), 8.85 (d, J=5.2 Hz, 1H), 8.77 (t, J=2.1 Hz, 1H), 8.57 (s, 1H),
8.03 (dd, J=5.2, 1.6 Hz, 1H), 3.46 (s, 3H), 2.55 (s, 3H); LCMS
(M+H).sup.+: 359.1.
Example 243.
N-Cyclopentyl-5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-1H-imi-
dazole-4-carboxamide
##STR00311##
[0715] Step 1.
2'-(5-Methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4-bipyridine
##STR00312##
[0717] To 5-(methylsulfonyl)-3,4'-bipyridine-2'-carbonitrile (1.15
g, 4.44 mmol, from Example 106, Step 1) in MeOH (17 mL) was added
sodium methoxide (25 wt % in MeOH, 0.08 mL, 0.35 mmol, Aldrich) and
the reaction mixture was heated to 45.degree. C. for 3 hours.
Additional sodium methoxide (25 wt % in MeOH, 0.48 mL, 2.0 mmol)
was added and the mixture was heated for 30 minutes.
1,1-Diethoxypropan-2-amine (0.65 g, 4.4 mmol, AstaTech) and AcOH
(0.76 mL) were added dropwise. The reaction was heated in a sealed
vial immersed in an oil bath at 100.degree. C. for 1 hour. The
reaction was cooled to room temperature and 6.0 N HCl (3.6 mL, 21
mmol) was added and the reaction vial was then heated in an oil
bath held at 75.degree. C. for one hour and 85.degree. C. for three
hours. The solvent was then removed via rotary evaporation. An
aqueous solution of K.sub.2CO.sub.3 was added to adjust to pH 10.
The isolated solid was triturated with water, filtered, and air
dried to afford a yellow solid. Yield: 1.12 g, 80%. LCMS
(M+H).sup.+: 315.1.
Step 2.
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4-bipyr-
idine
##STR00313##
[0719] N-Iodosuccinimide (0.800 g, 3.55 mmol) was added to a
solution of
2'-(5-methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine
(1.12 g, 3.38 mmol, from Step 1) in DMF (11 mL). The reaction was
stirred at room temperature for 20 minutes. Water (60 mL) was
added, followed by saturated NaHCO.sub.3 solution (30 mL). The
solid product was isolated by filtration, washed with water and air
dried. Yield: 1.27 g 85%.
[0720] LCMS (M+H).sup.+: 441.0.
Step 3.
2'-(4-Iodo-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidaz-
ol-2-yl)-5-(methylsulfonyl)-3,4'-bipyridine (Peak 1) and
2-(5-Iodo-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-
-5-(methylsulfonyl)-3,4-bipyridine (Peak 2) (isomers separated)
##STR00314##
[0722]
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-(methylsulfonyl)-3,4'-bipyr-
idine (1.27 g, 2.88 mmol, from Step 2) and NaH (60% in mineral oil,
0.23 g, 5.8 mmol, Aldrich) were combined under nitrogen and the
flask was immersed in a dry-ice acetone bath. DMF (28 mL) was
introduced, and the cooling bath was removed and the mixture was
warmed to room temperature and stirred for 15 minutes. The reaction
mixture was then cooled to 0.degree. C. and
[.beta.-(trimethylsilyl)ethoxy]methyl chloride (0.76 mL, 4.3 mmol,
Aldrich) was added. The reaction was allowed to proceed at
0.degree. C. for 20 minutes. The reaction was then quenched by the
addition of water, followed by saturated NaHCO.sub.3, and the
mixture was extracted with EtOAc. The combined organic extracts
were washed sequentially with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-80% EtOAc in hexanes and the first isomer to elute (Peak 1) was
the major product and the second isomer to elute (Peak 2) was the
minor product. The major product (Peak 1),
2'-(4-iodo-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl-
)-5-(methylsulfonyl)-3,4'-bipyridine) was used in Step 4. Yield
(Peak 1): 0.70 g, 43%. Yield (Peak 2): 0.47 g, 29%. Peak 1
LCMS(M+H).sup.+: 571.1. Peak 2 LCMS(M+H).sup.+: 571.1.
Step 4.
N-Cyclopentyl-5-methyl-2-[5-(methylsulfonyl)-3,4'-bipyridin-2'-yl]-
-1H-imidazole-4-carboxamide
[0723] To a degassed mixture of
2'-(4-iodo-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl-
)-5-(methyl sulfonyl)-3,4'-bipyridine (0.36 g, 0.63 mmol, Peak 1
from Step 3) in MeOH (5 mL) and triethylamine (0.22 mL, 1.6 mmol)
was added [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II), complex with dichloromethane (1:1)] (52 mg,
0.063 mmol, Aldrich) and the solution was saturated with CO by
bubbling the gas through the reaction subsurface for 3 minutes. The
reaction vessel was sealed and heated to 60.degree. C. for 2 hours.
Upon cooling to room temperature, the reaction mixture was diluted
with water and the precipitated product was isolated by filtration
and air dried. The methyl ester intermediate was further purified
by flash chromatography, eluting with a gradient from 0-100% EtOAc
in hexanes. Yield: 0.30 g, 94%. LCMS (M+H).sup.+: 503.1.
[0724] The ester was hydrolyzed to the acid intermediate by
treating a solution of the ester in THF (10 mL) and MeOH (1 mL)
with 2 N NaOH (2.8 mL, 5.7 mmol). The reaction mixture was stirred
overnight with gentle warming (33.degree. C.). Upon cooling, the pH
of the reaction mixture was adjusted to pH 5 by the addition of 1.0
N HCl. The aqueous mixture was saturated with NaCl and was
extracted with three portions of EtOAc. The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford the crude carboxylic acid. Yield: 0.26 g,
89%. LCMS (M+H).sup.+: 489.1.
[0725] To a portion of the carboxylic acid (15 mg, 0.031 mmol) in
DCM (0.5 mL) was added N,N-diisopropylethylamine (16 .mu.L, 0.092
mmol), HATU (15 mg, 0.040 mmol), and cyclopentylamine (6.0 uL,
0.061 mmol) and the reaction mixture was stirred for 1 hour.
Trifluoroacetic acid (0.50 mL) was added and the reaction mixture
was stirred at 35.degree. C. for 1 hour. Solvent and TFA were then
removed in vacuo and the residue was reconstituted in MeCN and
MeOH. The product was purified by preparative HPLC (C-18 column
eluting with a water:acetonitrile gradient buffered at pH 2 with
0.1% trifluoroacetic acid). Yield: 14. mg, 71%. .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 9.41 (d, J=1.9 Hz, 1H), 9.20 (d, J=1.9
Hz, 1H), 8.81 (d, J=5.1 Hz, 1H), 8.76 (t, J=1.8 Hz, 1H), 8.55 (s,
1H), 7.98 (dd, J=5.1, 1.4 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 4.21 (h,
J=6.8, 6.3 Hz, 1H), 3.45 (s, 3H), 2.54 (s, 3H), 1.97-1.81 (m, 2H),
1.78-1.64 (m, 2H), 1.64-1.37 (m, 4H). LCMS(M+H).sup.+: 426.1.
[0726] Examples 244 through 256 were synthesized according to the
procedure of Example 243 and the data are listed in Table 18.
TABLE-US-00017 TABLE 18 ##STR00315## Ex. MS No. Name R= (M +
H).sup.+ .sup.1H NMR 244 2'-[5-Methyl-4- (morpholin-4-
ylcarbonyl)-1H- imidazol-2-yl]-5- (methylsulfonyl)-3,4'- bipyridine
##STR00316## 428.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
13.16 (s, 1H), 9.39 (d, J = 2.2 Hz, 1H), 9.18 (d, J = 2.1 Hz, 1H),
8.78 (d, J = 5.1 Hz, 1H), 8.72 (t, J = 2.1 Hz, 1H), 8.37-8.30 (m,
1H), 7.89 (dd, J = 5.2, 1.9 Hz, 1H), 3.45 (s, 3H), 3.41-3.27 (m,
4H), 3.65-3.60 (m, 4H), 2.43 (s, 3H) 245 (3R)-1-({5-Methyl-2-
[5-(methylsulfonyl)-3, 4'-bipyridin-2'-yl]-1H- imidazol-4-
yl}carbonyl)pyrrolidin- 3-ol ##STR00317## 428.1 .sup.1H NMR (400
MHz, d.sub.6- DMSO, rotamers) .delta. 13.09 (br s, 0.5H), 9.41-9.34
(m, 1H), 9.22-9.14 (m, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.74-8.65 (m,
1H), 8.40-8.37 (m, 0.5H), 8.37-8.35 (m, 0.5H), 7.87 (dd, J = 5.2,
1.7 Hz, 2H), 4.93 (d, J = 3.0 Hz, 0.5H), 4.88 (d, J = 3.0 Hz,
0.5H), 4.35-4.19 (m, 1H), 4.15-4.07 (m, 0.5H), 4.07-3.97 (m, 1H),
3.91-3.85 (m, 0.5H), 3.58-3.41 (m, 2H), 3.44 (s, 3H), 2.47 (s,
1.5H, tautomers), 2.47 (s, 1.5H, tautomers), 2.02- 1.50 (m, 2H) 246
(3S)-1-({5-Methyl-2- [5-(methylsulfonyl)-3, 4'-bipyridin-2'-yl]-1H-
imidazol-4- yl}carbonyl)pyrrolidin- 3-ol ##STR00318## 428.2 .sup.1H
NMR (400 MHz, d.sub.6- DMSO, rotamers) .delta. 13.11 (br s, 0.5H),
9.41-9.34 (m, 1H), 9.20-9.16 (m, 1H), 8.77 (d, J = 5.1 Hz, 1H),
8.73-8.67 (m, 1H), 8.40-8.37 (m, 0.5H), 8.37-8.33 (m, 0.5H), 7.88
(dd, J = 5.2, 1.8 Hz, 1H 4.92 (d, J = 3.3 Hz, 0.5H), 4.87 (d, J =
3.4 Hz, 0.5H), 4.36-4.24 (m, 1H), 4.18-3.97 (m, 1.5H), 3.91-3.84
(m, 0.5H), 3.58-3.39 (m, 2H), 3.44 (s, 3H), 2.47 (s, 1.5H,
tautomers), 2.47 (s, 1.5H, tautomers), 2.04- 1.66 (m, 2H) 247
1-({5-Methyl-2-[5- (methylsulfonyl)-3,4'- bipyridin-2'-yl]-1H-
imidazol-4- yl}carbonyl)azetidin-3- ol ##STR00319## 414.1 .sup.1H
NMR (400 MHz, d.sub.6- DMSO) .delta. 13.10 (s, 1H), 9.38 (d, J =
2.1 Hz, 1H), 9.19 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 5.2 Hz, 1H),
8.71 (t, J = 2.1 Hz, 1H), 8.39-8.33 (m, 1H), 7.88 (dd, J = 5.2, 1.8
Hz, 1H), 5.64 (d, J = 6.3 Hz, 1H), 4.85 (dd, J = 10.0, 7.0 Hz, 1H),
4.54-4.44 (m, 1H), 4.32 (dd, J = 10.6, 3.6 Hz, 1H), 4.17 (dd, J =
9.5, 7.1 Hz, 1H), 3.72 (dd, J = 9.7, 3.6 Hz, 1H), 3.45 (s, 3H),
2.50 (s, 3H) 248 1-({5-Methyl-2-[5- (methylsulfonyl)-3,4'-
bipyridin-2'-yl]-1H- imidazol-4- yl}carbonyl)azetidine-
3-carbonitrile ##STR00320## 423.1 .sup.1H NMR (400 MHz, d.sub.6-
DMSO) .delta. 9.40 (d, J = 2.1 Hz, 1H), 9.19 (d, J = 2.1 Hz, 1H),
8.78 (d, J = 5.2 Hz, 1H), 8.72 (t, J = 2.1 Hz, 1H), 8.43-8.37 (m,
1H), 7.89 (dd, J = 5.2, 1.8 Hz, 1H), 4.99-4.88 (m, 1H), 4.88-4.76
(m, 1H), 4.34-4.23 (m, 1H), 4.19- 4.02 (m, 1H), 3.83 (tt, J = 8.9,
5.9 Hz, 1H), 3.45 (s, 3H), 2.51 (s, 3H) 249 5-Methyl-2-[5-
(methylsulfonyl)-3,4'- bipyridin-2'-yl]-1H- imidazole-4-
carboxamide trifluoroacetate salt ##STR00321## 358.1 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 9.41 (d, J = 2.1 Hz, 1H), 9.20 (d,
J = 2.1 Hz, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.75 (t, J = 2.1 Hz,
1H), 8.55-8.48 (m, 1H), 7.95 (dd, J = 5.1, 1.6 Hz, 1H), 7.41 (br s,
1H), 7.14 (br s, 1H), 3.45 (s, 3H), 2.53 (s, 3H) 250
N,5-Dimethyl-2-[5- (methylsulfonyl)-3,4'- bipyridin-2'-yl]-1H-
imidazole-4- carboxamide trifluoroacetate salt ##STR00322## 372.1
.sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 9.40 (d, J = 2.1 Hz,
1H), 9.21 (d, J = 2.1 Hz, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.74 (t, J
= 2.1 Hz, 1H), 8.54-8.46 (m, 1H), 7.97 (dd, J = 5.2, 1.7 Hz, 1H),
7.95 (s, 1H), 3.46 (s, 3H), 2.79 (d, J = 4.4 Hz, 3H), 2.54 (s, 3H)
251 N,N,5-Trimethyl-2-[5- (methylsulfonyl)-3,4'-
bipyridin-2'-yl]-1H- imidazole-4- carboxamide trifluoroacetate salt
##STR00323## 386.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.41 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.86 (d, J =
5.2 Hz, 1H), 8.75 (t, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.03 (dd, J =
5.1, 1.5 Hz, 1H), 3.45 (s, 3H), 3.25 (s, 3H), 3.00 (s, 3H), 2.40
(s, 3H) 252 N-Ethyl-5-methyl-2- [5-(methylsulfonyl)-3,
4'-bipyridin-2'-yl]-1H- imidazole-4- carboxamide trifluoroacetate
salt ##STR00324## 386.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 9.41 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 2.1 Hz, 1H), 8.81
(d, J = 5.2 Hz, 1H), 8.75 (t, J = 2.1 Hz, 1H), 8.57-8.44 (m, 1H),
8.00 (t, J = 6.1 Hz, 1H), 7.97 (dd, J = 5.2, 1.7 Hz, 1H), 3.46 (s,
3H), 3.30 (p, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.13 (t, J = 7.2 Hz,
3H) 253 N-Isopropyl-5-methyl- 2-[5-(methylsulfonyl)-
3,4'-bipyridin-2'-yl]- 1H-imidazole-4- carboxamide trifluoroacetate
salt ##STR00325## 400.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 9.42 (d, J = 2.1 Hz, 1H), 9.20 (d, J = 2.1 Hz, 1H), 8.81
(d, J = 5.2 Hz, 1H), 8.76 (t, J = 2.1 Hz, 1H), 8.57-8.50 (m, 1H),
7.96 (dd, J = 5.2, 1.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 4.14-4.04
(m, 1H), 3.46 (s, 3H), 2.54 (s, 3H), 1.19 (d, J = 6.6 Hz, 6H) 254
5-Methyl-2-[5- (methylsulfony1)-3,4'- bipyridin-2'-yl]-N-
(tetrahydro-2H-pyran- 4-yl)-1H-imidazole-4- carboxamide
trifluoroacetate salt ##STR00326## 442.1 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 9.42 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 2.1
Hz, 1H), 8.81 (d, J = 5.2 Hz, 1H), 8.76 (t, J = 2.1 Hz, 1H),
8.55-8.49 (m, 1H), 7.96 (dd, J = 5.2, 1.7 Hz, 1H), 7.82 (d, J = 8.2
Hz, 1H), 4.05-3.93 (m, 1H), 3.92-3.85 (m, 2H), 3.46 (s, 3H), 3.40
(td, J = 11.7, 1.9 Hz, 2H), 2.54 (s, 3H), 1.80-1.70 (m, 2H), 1.64
(qd, J = 12.1, 4.5 Hz, 2H) 255 5-Methyl-2-[5-
(methylsulfonyl)-3,4'- bipyridin-2'-yl]-N- [(3S)-tetrahydrofuran-
3-yl]-1H-imidazole-4- carboxamide trifluoroacetate salt
##STR00327## 428.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.42 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.82 (d, J =
5.2 Hz, 1H), 8.77 (t, J = 2.1 Hz, 1H), 8.57-8.49 (m, 1H), 8.01-7.95
(m, 2H), 4.52-4.41 (m, 1H), 3.89 (q, J = 8.0 Hz, 1H), 3.84 (dd, J =
8.9, 6.3 Hz, 1H), 3.73 (td, J = 8.1, 6.2 Hz, 1H), 3.61 (dd, J =
8.8, 4.4 Hz, 1H), 3.46 (s, 3H), 2.54 (s, 3H), 2.19 (dq, J = 14.4,
7.8 Hz, 1H), 1.94 (dq, J = 12.5, 5.9 Hz, 1H) 256 5-Methyl-2-[5-
(methylsulfonyl)-3,4'- bipyridin-2'-yl]-N- [(3R)-tetrahydrofuran-
3-yl]-1H-imidazole-4- carboxamide trifluoroacetate salt
##STR00328## 428.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta.
9.42 (d, J = 2.1 Hz, 1H), 9.20 (d, J = 2.0 Hz, 1H), 8.80 (d, J =
5.1 Hz, 1H), 8.77 (t, J = 2.1 Hz, 1H), 8.57-8.42 (m, 1H), 7.95 (dd,
J = 5.0, 1.5 Hz, 1H), 7.95-7.93 (br, 1H), 4.52-4.39 (m, 1H), 3.89
(q, J = 8.0 Hz, 1H), 3.84 (dd, J = 8.8, 6.3 Hz, 1H), 3.73 (td, J =
8.1, 6.2 Hz, 1H), 3.60 (dd, J = 8.8, 4.5 Hz, 1H), 3.46 (s, 3H),
2.54 (s, 3H), 2.26-2.11 (m, 1H), 1.95 (dq, J = 12.7, 5.9 Hz,
1H)
Example 257.
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxy-
lic acid trifluoroacetate salt
##STR00329##
[0727] Step 1.
2-(5-Methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4-bipyridine
##STR00330##
[0729] 5-Morpholin-4-yl-3,4'-bipyridine-2'-carbonitrile (0.75 g,
2.8 mmol, from Example 97, Step 1) in MeOH (11 mL) was treated with
sodium methoxide (25 wt % in MeOH, check calculation, 0.05 mL, 0.3
mmol) overnight. 1,1-Diethoxypropan-2-amine (0.41 g, 2.8 mmol) and
AcOH (0.32 mL) were added and the reaction mixture was heated in a
sealed vial in an oil bath held at 100.degree. C. for 1 hour. The
reaction mixture was cooled and concentrated HCl (0.60 mL, 7.2
mmol) was added and the mixture was heated in the sealed vial in an
oil bath held at 85.degree. C. for 5.5 hours. The solvent was then
removed via rotary evaporation. A solution of K.sub.2CO.sub.3 was
added to adjust to pH 10 and the solid product was isolated by
filtration. Yield: 0.70 g, 70%. LCMS (M+H).sup.+: 322.2.
[0730] Step 2.
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4-bipyridine
##STR00331##
[0731] N-Iodosuccinimide (0.463 g, 2.06 mmol, Aldrich) was added to
a solution of
2'-(5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
(0.70 g, 2.0 mmol, from Step 1) in DMF (6.2 mL). After stirring for
20 minutes, water (50 mL) and sat'd NaHCO.sub.3 solution (20 mL)
were added. The solid product was isolated by filtration, washed
with water and dried by azeotropic removal of water with
acetonitrile in vacuo. Yield: 0.86 g, 98%. LCMS (M+H).sup.+:
448.0.
Step 3. Methyl
5-methyl-2-(5-morpholin-4-yl-3,4-bipyridin-2'-yl)-1H-imidazole-4-carboxyl-
ate
##STR00332##
[0733] A mixture of
2'-(4-iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
(1.0 g, 2.2 mmol, prepared as in Step 2), MeOH (25 mL) and
triethylamine (0.78 mL, 5.6 mmol) was degassed with a stream of
nitrogen and [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II), complex with dichloromethane (1:1) (180 mg,
0.22 mmol) was added. The slurry was saturated with CO by bubbling
the gas through the reaction subsurface for 3 minutes. The vessel
was sealed and was heated to 60.degree. C. overnight. Upon cooling,
the reaction mixture was diluted with water (50 mL) and stirred for
15 minutes. The solid product was isolated by filtration. Yield:
0.85 g, 99%. LCMS (M+H).sup.+: 380.2.
Step 4.
5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4--
carboxylic acid trifluoroacetate salt
[0734] Methyl
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carboxy-
late (0.85 g, 2.2 mmol, from Step 3) in THF (17 mL) and water (4.2
mL) was treated with lithium hydroxide hydrate (0.38 g, 9.0 mmol).
2.0 N NaOH (11 mL, 22 mmol) and MeOH (2.0 mL) were subsequently
added and the mixture was heated in a sealed vial to 60.degree. C.
overnight. The organic solvents were then evaporated. The basic
aqueous mixture was washed once with DCM and filtered. The aqueous
filtrate was acidified to pH 5 by the addition of concentrated HCl
and the solution was then saturated with NaCl. The resulting solid
product was isolated by filtration and was then mixed with a
mixture of CH.sub.3CN (20 mL) and CHCl.sub.3 containing 20%
.sup.iPrOH (300 mL) and filtered to remove salts. The filtrate was
concentrated to give the desired acid, which was used without
further purification in Example 258. A small portion was purified
by preparative HPLC (C-18 column eluting with a water:acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.80 (d, J=5.2 Hz, 1H), 8.60
(d, J=1.4 Hz, 1H), 8.52-8.43 (m, 2H), 8.03-7.96 (m, 1H), 7.93 (dd,
J=5.2, 1.6 Hz, 1H), 3.84-3.73 (m, 4H), 3.46-3.36 (m, 4H), 2.54 (s,
3H); LCMS (M+H).sup.+: 366.1.
Example 258.
N-Cyclopentyl-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imida-
zole-4-carboxamide
##STR00333##
[0736] To
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole--
4-carboxylic acid (15 mg, 0.033 mmol, from Example 257) in DMF
(0.50 mL) was added N,N-diisopropylethylamine (17 .mu.L, 0.098
mmol) and HATU (16 mg, 0.043 mmol), followed by cyclopentanamine
(6.5 .mu.L, 0.066 mmol, Aldrich). After stirring for 30 minutes,
the product was purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 10 with 0.15%
ammonium hydroxide). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.72
(d, J=5.1 Hz, 1H), 8.43 (s, 1H), 8.40-8.30 (m, 2H), 7.78-7.72 (m,
1H), 7.70 (dd, J=5.1, 1.6 Hz, 1H), 4.33 (p, J=6.5 Hz, 1H),
3.99-3.81 (m, 4H), 3.38-3.35 (m, 4H), 2.63 (s, 3H), 2.12-1.99 (m,
2H), 1.88-1.75 (m, 2H), 1.75-1.54 (m, 4H);
[0737] LCMS (M+H).sup.+: 433.2.
[0738] Examples 259 through 282 were synthesized according to the
procedure of Example 258 and the data are listed in Table 19.
TABLE-US-00018 TABLE 19 ##STR00334## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 259 N-Isopropyl-N,5- dimethyl-2-(5-
morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4- carboxamide
##STR00335## 421.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71
(d, J = 5.3 Hz, 1H), 8.47- 8.30 (m, 3H), 7.76 (br m, 1H), 7.73-7.65
(m, 1H), 4.52 (br m, 1H), 3.96-3.85 (m, 4H), 3.38-3.34 (m, 4H),
3.04 (br s, 3H), 2.43 (s, 3H), 1.29 (d, J = 6.7 Hz, 6H) 260
N-Ethyl-N,5- dimethyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)-
1H-imidazole-4- carboxamide ##STR00336## 407.2 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.71 (d, J = 4.9 Hz, 1H), 8.46- 8.32 (m,
3H), 7.78- 7.73 (m, 1H), 7.72- 7.66 (m, 1H), 3.96- 3.85 (m, 4H),
3.80- 3.05 (br m, 2H), 3.39- 3.34 (m, 4H), 2.97 (s, 3H), 2.44 (s,
3H), 1.33- 1.22 (m, 3H) 261 N,5-Dimethyl-2- (5-morpholin-4-yl-
3,4'-bipyridin-2'- yl)-N- (tetrahydrofuran-3- yl)-1H-imidazole-
4-carboxamide (racemic mixture prepared) ##STR00337## 449.2 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.71 (d, J = 5.2 Hz, 1H), 8.46-
8.31 (m, 3H), 7.78- 7.73 (m, 1H), 7.70 (dd, J = 5.0, 1.4 Hz, 1H),
5.29 (br, 1H), 4.10 (td, J = 8.6, 4.7 Hz, 1H), 3.97 (dd, J = 9.8,
3.8 Hz, 1H), 3.94-3.84 (m, 1H), 3.93-3.89 (m, 4H), 3.81-3.63 (m,
1H), 3.39-3.34 (m, 4H), 3.13 (br s, 3H), 2.45 (s, 3H), 2.40- 2.26
(m, 1H), 2.18- 2.08 (m, 1H) 262 2'-(5-Methyl-4- {[3-
(trifluoromethyl) azetidin-1- yl]carbonyl}-1H- imidazol-2-yl)-5-
morpholin-4-yl- 3,4'-bipyridine ##STR00338## 473.2 263 2'-{4-[(3-
Methoxyazetidin- 1-yl)carbonyl]-5- methyl-1H- imidazol-2-yl}-5-
morpholin-4-yl- 3,4'-bipyridine ##STR00339## 435.2 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.70 (d, J = 5.2 Hz, 1H), 8.43- 8.34 (m,
2H), 8.32 (s, 1H), 7.75-7.70 (m, 1H), 7.70-7.62 (m, 1H), 4.58-4.46
(m, 1H), 4.38-4.29 (m, 2H), 4.98-4.79 (m, 1H), 4.04-3.94 (m, 1H),
3.94-3.85 (m, 4H), 3.38-3.34 (m, 7H), 2.59 (s, 3H) 264 tert-Butyl
(1-{[5- methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)-
1H-imidazol-4- yl]carbonyl}azetidin- 3-yl)carbamate ##STR00340##
520.2 265 N-Cyclohexyl-5- methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)- 1H-imidazole-4- carboxamide ##STR00341## 447.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.72 (d, J = 5.1 Hz, 1H),
8.43 (s, 1H), 8.41-8.35 (m, 2H), 7.78-7.72 (m, 1H), 7.72-7.64 (m,
1H), 3.94-3.89 (m, 5H), 3.40-3.35 (m, 4H), 2.62 (s, 3H), 2.04- 1.20
(m, 10H) 266 N-(tert-Butyl)-5- methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)- 1H-imidazole-4- carboxamide ##STR00342## 421.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.72 (d, J = 5.0 Hz, 1H),
8.43 (s, 1H), 8.38 (s, 0H), 8.35 (s, 1H), 7.78-7.73 (m, 1H), 7.70
(dd, J = 5.0, 1.4 Hz, 1H), 3.95- 3.87 (m, 4H), 3.40- 3.34 (m, 4H),
2.61 (s, 3H), 1.51 (s, 9H) 267 2'-{4-[(3,3- Dimethylazetidin-
1-yl)carbonyl]-5- methyl-1H- imidazol-2-yl}-5- morpholin-4-yl-
3,4'-bipyridine ##STR00343## 433.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.70 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H),
8.39-8.34 (m, 1H), 8.33-8.28 (m, 1H), 7.76-7.69 (m, 1H), 7.66 (dd,
J = 5.1, 1.5 Hz, 1H), 3.93- 3.87 (m, 4H), 3.38- 3.35 (m, 4H), 2.97
(s, 4H), 2.59 (s, 3H), 1.36 (s, 6H) 268 N-Isopropyl-5- methyl-2-(5-
morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4- carboxamide
trifluoroacetate salt ##STR00344## 407.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.79 (d, J = 5.2 Hz, 1H), 8.65 (s, 1H), 8.53
(d, J = 2.5 Hz, 1H), 8.47 (s, 1H), 8.19-8.12 (m, 1H), 7.89 (dd, J =
5.2, 1.6 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 4.14- 4.04 (m, 1H),
3.86- 3.76 (m, 4H), 3.50- 3.39 (m, 4H), 2.54 (s, 3H), 1.19 (d, J =
6.6 Hz, 6H) 269 5-Methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)- N-(tetrahydro-2H- pyran-4-yl)-1H- imidazole-4-
carboxamide trifluoroacetate salt ##STR00345## 449.2 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 8.80 (d, J = 5.2 Hz, 1H), 8.68-
8.64 (m, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.50- 8.46 (m, 1H), 8.23-
8.14 (m, 1H), 7.90 (dd, J = 5.2, 1.7 Hz, 1H), 7.75 (d, J = 8.3 Hz,
1H), 3.99 (tdt, J = 12.3, 8.6, 4.5 Hz, 1H), 3.93- 3.85 (m, 2H),
3.84- 3.77 (m, 4H), 3.50- 3.43 (m, 4H), 3.44- 3.33 (m, 2H), 2.54
(s, 3H), 1.84-1.70 (m, 2H), 1.61 (qd, J = 12.1, 4.4 Hz, 2H) 270
5-Methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)- N-[(3R)-
tetrahydrofuran-3- yl]-1H-imidazole- 4-carboxamide trifluoroacetate
salt ##STR00346## 435.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 8.78 (d, J = 5.2 Hz, 1H), 8.67- 8.62 (m, 1H), 8.52 (d, J =
2.6 Hz, 1H), 8.50- 8.46 (m, 1H), 8.16 (s, 1H), 7.92-7.84 (m, 2H),
4.53-4.41 (m, 1H), 3.89 (q, J = 7.9 Hz, 1H), 3.84 (dd, J = 8.9, 6.2
Hz, 1H), 3.82- 3.79 (m, 4H), 3.73 (td, J = 8.2, 6.2 Hz, 1H), 3.60
(dd, J = 8.9, 4.3 Hz, 1H), 3.48-3.42 (m, 4H), 2.54 (s, 3H),
2.25-2.13 (m, 1H), 1.97-1.87 (m, 1H) 271 5-Methyl-2-(5-
morpholin-4-yl-3,4'- bipyridin-2'-yl)- N-[(3S)- tetrahydrofuran-3-
yl]-1H-imidazole- 4-carboxamide trifluoroacetate salt ##STR00347##
435.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.77 (d, J = 5.1
Hz, 1H), 8.63 (d, J = 1.2 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.49-
8.46 (m, 1H), 8.12- 8.06 (m, 1H), 7.92- 7.82 (m, 2H), 4.51- 4.40
(m, 1H), 3.89 (q, J = 8.0 Hz, 1H), 3.84 (dd, J = 8.9, 6.3 Hz, 1H),
3.82-3.79 (m, 4H), 3.73 (td, J = 8.1, 6.1 Hz, 1H), 3.60 (dd, J =
8.8, 4.3 Hz, 1H), 3.46- 3.42 (m, 4H), 2.53 (s, 3H), 2.24-2.12 (m,
1H), 2.00-1.86 (m, 1H) 272 N-Benzyl-5- methyl-2-(5-
morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4- carboxamide
trifluoroacetate salt ##STR00348## 455.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.77 (d, J = 5.1 Hz, 1H), 8.63- 8.54 (m,
1H), 8.50 (d, J = 2.5 Hz, 1H), 8.46- 8.39 (m, 2H), 8.10- 8.04 (m,
1H), 7.86 (dd, J = 5.2, 1.7 Hz, 1H), 7.42-7.20 (m, 5H), 4.47 (d, J
= 6.3 Hz, 2H), 3.83-3.73 (m, 4H), 3.47-3.37 (m, 4H), 2.55 (s, 3H)
273 5-Methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)-
N-[(1S)-1- phenylethyl]-1H- imidazole-4- carboxamide
trifluoroacetate salt ##STR00349## 469.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.78 (d, J = 5.2 Hz, 1H), 8.66- 8.60 (m,
1H), 8.52 (d, J = 2.5 Hz, 1H), 8.50- 8.42 (m, 1H), 8.15- 8.08 (m,
2H), 7.88 (dd, J = 5.2, 1.6 Hz, 1H), 7.42 (d, J = 7.5 Hz, 2H), 7.34
(t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 5.17 (p, J = 7.0 Hz,
1H), 3.85-3.72 (m, 4H), 3.48-3.39 (m, 4H), 2.52 (s, 3H), 1.52 (d, J
= 7.0 Hz, 3H) 274 5-Methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)- N-[(1R)-1- phenylethyl]-1H- imidazole-4-
carboxamide trifluoroacetate salt ##STR00350## 469.1 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 8.77 (d, J = 5.2 Hz, 1H), 8.67-
8.58 (m, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.49- 8.44 (m, 1H), 8.12
(d, J = 8.5 Hz, 1H), 8.10- 8.05 (m, 1H), 7.87 (dd, J = 5.2, 1.7 Hz,
1H), 7.42 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.24 (t, J
= 7.3 Hz, 1H), 5.17 (p, J = 6.9 Hz, 1H), 3.84-3.75 (m, 4H),
3.47-3.39 (m, 4H), 2.52 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H) 275
N-[(1R)-2- Methoxy-1- phenylethyl]-5- methyl-2-(5-
morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4- carboxamide
trifluoroacetate salt ##STR00351## 499.2 .sup.1H NMR (400 MHz,
d.sub.6- DMSO) .delta. 8.77 (d, J = 5.1 Hz, 1H), 8.65- 8.57 (m,
1H), 8.51 (d, J = 2.6 Hz, 1H), 8.47- 8.43 (m, 1H), 8.18 (d, J = 8.6
Hz, 1H), 8.12- 8.01 (m, 1H), 7.86 (dd, J = 5.2, 1.7 Hz, 1H), 7.43
(d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz,
1H), 5.31-5.17 (m, 1H), 3.82-3.79 (m, 4H), 3.77 (dd, J = 10.0, 7.2
Hz, 1H), 3.65 (dd, J = 10.0, 5.2 Hz, 1H), 3.46-3.37 (m, 4H), 3.31
(s, 3H), 2.52 (s, 3H) 276 N-[(1S)-2- Methoxy-1- phenylethyl]-5-
methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4-
carboxamide trifluoroacetate salt ##STR00352## 499.2 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 8.78 (d, J = 5.1 Hz, 1H), 8.65-
8.56 (m, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.49- 8.41 (m, 1H), 8.18
(d, J = 8.6 Hz, 1H), 8.14- 8.05 (m, 1H), 7.87 (dd, J = 5.2, 1.7 Hz,
1H), 7.43 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.26 (t, J
= 7.2 Hz, 1H), 5.30-5.19 (m, 1H), 3.83-3.78 (m, 4H), 3.77 (dd, J =
10.0, 7.2 Hz, 1H), 3.65 (dd, J = 10.0, 5.1 Hz, 1H), 3.47-3.40 (m,
4H), 3.30 (s, 3H), 2.52 (s, 3H) 277 N-[1-(3- Fluorophenyl)ethyl]-
5-methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)-
1H-imidazole-4- carboxamide trifluoroacetate salt (racemic mixture
prepared) ##STR00353## 487.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO)
.delta. 8.77 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 1.3 Hz, 1H), 8.51
(d, J = 2.6 Hz, 1H), 8.49- 8.44 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H),
8.09- 7.97 (m, 1H), 7.86 (dd, J = 5.2, 1.7 Hz, 1H), 7.42-6.97 (m,
4H), 5.17 (p, J = 7.2 Hz, 1H), 3.84-3.73 (m, 4H), 3.48-3.33 (m,
4H), 2.51 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H) 278 N-2-Adamantyl-5-
methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4-
carboxamide trifluoroacetate salt ##STR00354## 499.3 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 8.76 (d, J = 5.2 Hz, 1H), 8.63 (s,
1H), 8.51-8.47 (m, 1H), 8.46 (s, 1H), 8.08- 7.96 (m, 1H), 7.87 (dd,
J = 5.2, 1.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 4.05 (d, J = 7.8
Hz, 1H), 3.83- 3.74 (m, 4H), 3.46- 3.30 (m, 4H), 2.54 (s, 3H),
2.02-1.56 (m, 14H) 279 N-[(3S)-1- Benzylpyrrolidin-
3-yl]-5-methyl-2- (5-morpholin-4-yl- 3,4'-bipyridin-2'-
yl)-1H-imidazole- 4-carboxamide trifluoroacetate salt ##STR00355##
524.3 .sup.1H NMR (400 MHz, d.sub.6- DMSO, interconverting cis and
trans salts) .delta. 10.59-10.32 (2 br s, together 1H), 8.76- 8.68
(m, 2H), 8.50 (br, 1H), 8.47 (br, 1H), 8.43 (s, 1H), 8.37-8.31 (m,
1H), 7.86-7.79 (m, 2H), 7.63-7.53 (m, 2H), 7.52-7.42 (m, 3H),
4.80-4.52 (m, 1H), 4.47-4.35 (m, 2H), 3.84-3.72 (m, 4H), 3.72-3.53
(m, 1H), 3.53-3.29 (m, 6H), 3.27-3.12 (m, 1H), 2.64-1.94 (m, 5H)
280 N-[(3R)-1- Benzylpyrrolidin- 3-yl]-5-methyl-2-
(5-morpholin-4-yl- 3,4'-bipyridin-2'- yl)-1H-imidazole-
4-carboxamide trifluoroacetate salt ##STR00356## 524.3 .sup.1H NMR
(600 MHz, d.sub.6- DMSO, interconverting cis and trans salts)
.delta. 10.02 (s, 1H), 8.78- 8.72 (m, 1H), 8.57- 8.48 (m, 2H), 8.42
(s, 0.4H), 8.36 (s, 0.6H), 8.33 (d, J = 7.4 Hz, 0.4H), 8.17 (d, J =
7.4 Hz, 0.6H), 7.92 (d, J = 14.1 Hz, 1H), 7.87- 7.82 (m, 1H), 7.59-
7.52 (m, 2H), 7.51- 7.41 (m, 3H), 4.73- 4.66 (m, 0.6H), 4.61- 4.53
(m, 0.4H), 4.47- 4.35 (m, 2H), 3.82- 3.76 (m, 4H), 3.71- 3.59 (m,
1H), 3.54- 3.44 (m, 1H), 3.44- 3.30 (m, 5H), 3.28- 3.17 (m, 1H),
2.56- 2.53 (m, 0.4H), 2.52 (2 singlets, together 3H), 2.33-2.13 (m,
1H), 2.06-1.96 (m, 0.6H) 281 5-Methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)- N-(tetrahydro-2H- thiopyran-4-yl)-
1H-imidazole-4- carboxamide trifluoroacetate salt ##STR00357##
465.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO) .delta. 8.77 (d, J = 5.2
Hz, 1H), 8.64- 8.59 (m, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.48- 8.43
(m, 1H), 8.11- 8.04 (m, 1H), 7.87 (dd, J = 5.2, 1.7 Hz, 1H), 7.78
(d, J = 8.4 Hz, 1H), 3.86-3.74 (m, 5H), 3.53-3.31 (m, 4H),
2.79-2.60 (m, 4H), 2.53 (s, 3H), 2.15- 2.01 (m, 2H), 1.71 (qd, J =
11.7, 3.3 Hz, 2H) 282 N-(2,3-Dihydro- 1H-inden-2-yl)-5-
methyl-2-(5- morpholin-4-yl-3,4'- bipyridin-2'-yl)- 1H-imidazole-4-
carboxamide trifluoroacetate salt ##STR00358## 481.2 .sup.1H NMR
(400 MHz, d.sub.6- DMSO) .delta. 8.75 (d, J = 5.1 Hz, 1H), 8.59 (d,
J = 1.3 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.44- 8.38 (m, 1H),
8.07- 8.02 (m, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 5.2,
1.7 Hz, 1H), 7.28-7.22 (m, 2H), 7.20-7.14 (m, 2H), 4.71 (h, J = 7.2
Hz, 1H), 3.85-3.75 (m, 4H), 3.46-3.34 (m, 4H), 3.23 (dd, J = 15.9,
7.7 Hz, 2H), 2.99 (dd, J = 15.8, 6.7 Hz, 2H), 2.55 (s, 3H)
Example 283.
N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-4-yl]
methyl}tetrahydro-2H-pyran-4-amine
##STR00359##
[0739] Step 1.
5-Methyl-2-(5-morpholin-4-yl-3,4-bipyridin-2'-yl)-1H-imidazole-4-carbalde-
hyde
##STR00360##
[0741]
2'-(4-Iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyrid-
ine (0.70 g, 1.6 mmol, prepared as in Example 257, Step 2) was
dissolved in DMF (17 mL), and Na.sub.2CO.sub.3 (0.33 g, 3.1 mmol),
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (110
mg, 0.16 mmol, Aldrich) and triethylsilane (0.75 mL, 4.7 mmol,
Aldrich) were added. The mixture was degassed with a stream of
nitrogen first, and then the solution was saturated with carbon
monoxide by bubbling CO gas through the reaction subsurface for 5
minutes. The reaction vessel was then sealed and heated to
60.degree. C. for 3 hours. Upon cooling to room temperature, the
reaction mixture was diluted with DCM, filtered, and concentrated.
The product was purified by flash chromatography, eluting with a
gradient from 0-10% MeOH in DCM containing 1% ammonium hydroxide.
Yield: 0.22 g, 40%.
[0742] LCMS(M+H).sup.+: 350.2.
Step 2.
N-{[5-Methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazol-
-4-yl]methyl}tetrahydro-2H-pyran-4-amine
[0743] To a mixture of
5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-imidazole-4-carbald-
ehyde (10. mg, 0.029 mmol, from Step 1) and
tetrahydro-2H-pyran-4-amine (4.4 .mu.L, 0.043 mmol, Combi-Blocks)
in 1,2-dichloroethane (0.20 mL) was added a drop of acetic acid and
the mixture was stirred for 15 minutes. Sodium
triacetoxyborohydride (12 mg, 0.057 mmol) was then added and the
reaction was stirred overnight. The reaction was quenched by the
addition of a small amount of water, and the product was purified
by preparative HPLC (C-18 column eluting with 21.6-39.6%
acetonitrile in water containing 0.15% ammonium hydroxide over 12
minutes). Yield: 3.6 mg, 29%. .sup.1H NMR (400 MHz, d.sub.6-DMSO,
tautomers) .delta. 8.63 (d, J=5.2 Hz, 1H), 8.46-8.40 (m, 2H), 8.20
(s, 1H), 7.71-7.62 (m, 2H), 3.88-3.75 (m, 6H), 3.70 (br s, 1H),
3.63 (br s, 1H), 3.40-3.20 (m, 3H), 2.23 (br s, 1.5H), 2.17 (br s,
1.5H), 1.86-1.67 (m, 2H), 1.35-1.18 (m, 2H); LCMS (M+H).sup.+:
435.3.
[0744] Examples 284 through 292 were synthesized according to the
procedure of Example 283 and the data are listed in Table 20.
TABLE-US-00019 TABLE 20 ##STR00361## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 284 N-{[5-Methyl- 2-(5- morpholin-4- yl-3,4'-
bipyridin-2'- yl)-1H- imidazol-4- yl]methyl}cyclo- pentanamine
##STR00362## 419.2 .sup.1H NMR (400 MHz, d.sub.6- DMSO, tautomers)
.delta. 12.47 (br s, 0.5H), 12.34 (br s, 0.5H), 8.65-8.61 (m, 1H),
8.45-8.39 (m, 2H), 8.22- 8.17 (m, 1H), 7.70-7.64 (m, 2H), 3.82-3.73
(m, 4H), 3.64 (s, 1H), 3.56 (s, 1H), 3.37-3.28 (m, 4H), 3.06 (p, J
= 6.4 Hz, 0.5H), 2.93 (p, J = 5.9 Hz, 0.5H), 2.24 (s, 1.5H), 2.16
(s, 1.5H), 1.79- 1.54 (m, 4H), 1.54-1.41 (m, 2H), 1.41-1.26 (m, 2H)
285 N-{[5-Methyl- 2-(5- morpholin-4- yl-3,4'- bipyridin-2'- yl)-1H-
imidazol-4- yl]methyl} propan-2-amine ##STR00363## 393.2 .sup.1H
NMR (400 MHz, d.sub.6- DMSO, tautomers) .delta. 12.47 (s, 0.5H),
12.35 (s, 0.5H), 8.66-8.59 (m, 1H), 8.45- 8.38 (m, 2H), 8.23-8.17
(m, 1H), 7.71-7.63 (m, 2H), 3.84-3.73 (m, 4H), 3.66 (s, 1H), 3.58
(s, 1H), 3.34- 3.29 (m, 4H), 2.77 (p, J = 6.2 Hz, 0.5H), 2.63 (p, J
= 6.3 Hz, 0.5H), 2.24 (s, 1.5H), 2.16 (s, 1.5H), 1.02 (d, J = 6.2
Hz, 3H), 0.97 (d, J = 6.2 Hz, 3H) 286 (3S)-N-{[5- Methyl-2-(5-
morpholin-4- yl-3,4'- bipyridin-2'- yl)-1H- imidazol-4-
yl]methyl}tetra- hydrofuran-3- amine ##STR00364## 421.2 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.68 (d, J = 5.1 Hz, 1H), 8.44 (d, J
= 1.5 Hz, 1H), 8.37 (d, J = 2.6 Hz, 1H), 8.35 (s, 1H), 7.79- 7.73
(m, 1H), 7.66 (dd, J = 5.1, 1.6 Hz, 1H), 3.99-3.93 (m, 1H),
3.93-3.89 (m, 4H), 3.86 (dd, J = 8.8, 6.2 Hz, 1H), 3.82-3.71 (m,
3H), 3.63 (dd, J = 8.9, 4.3 Hz, 1H), 3.51-3.42 (m, 1H), 3.39-3.35
(m, 4H), 2.34 (s, 3H), 2.23-2.09 (m, 1H), 1.89-1.78 (m, 1H) 287
(3R)-N-{[5- Methyl-2-(5- morpholin-4- yl-3,4'- bipyridin-2'-
yl)-1H- imidazol-4- yl]methyl}tetra- hydrofuran-3- amine
##STR00365## 421.1 .sup.1H NMR (400 MHz, d.sub.6- DMSO, tautomers)
.delta. 12.49 (br s, 0.5H), 12.38 (br s, 0.5H), 8.67-8.56 (m, 1H),
8.46-8.37 (m, 2H), 8.23- 8.13 (m, 1H), 7.70-7.62 (m, 2H), 3.82-3.76
(m, 4H), 3.76-3.52 (m, 5H), 3.47- 3.38 (m, 1H), 3.36-3.28 (m, 4H),
3.25-3.17 (m, 0.5H), 2.24 (s, 1.5H), 2.17 (s, 1.5H), 2.02-1.59 (m,
2H) 288 N-Methyl-1-[5- methyl-2-(5- morpholin-4- yl-3,4'-
bipyridin-2'- yl)-1H- imidazol-4- yl]methanamine ##STR00366## 365.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO, tautomers) .delta. 8.63 (d, J
= 5.2 Hz, 1H), 8.48-8.37 (m, 2H), 8.20 (d, J = 4.6 Hz, 1H),
7.75-7.61 (m, 2H), 3.84-3.75 (m, 4H), 3.62 (s, 1H), 3.54 (s, 1H),
3.34- 3.29 (m, 4H), 2.30 (s, 1.5H), 2.24 (s, 1.5H), 2.21 (s, 1.5H),
2.17 (s, 1.5H) 289 N,N-Dimethyl- 1-[5-methyl-2- (5-morpholin-
4-yl-3,4'- bipyridin-2'- yl)-1H- imidazol-4- yl]methanamine
##STR00367## 379.3 .sup.1H NMR (400 MHz, d.sub.6- DMSO, tautomers)
.delta. 12.52 (s, 0.6H), 12.43 (s, 0.4H), 8.67-8.57 (m, 1H), 8.46-
8.35 (m, 2H), 8.24-8.21 (m, 0.4H), 8.21-8.13 (m, 0.6H), 7.71-7.61
(m, 2H), 3.83- 3.72 (m, 4H), 3.43 (s, 0.8H), 3.35-3.30 (m, 4H),
3.29 (s, 1.2H), 2.24 (s, 1.8H), 2.17 (s, 1.2H), 2.14 (s, 6H) 290
2-Methoxy-N- {[5-methyl-2- (5-morpholin- 4-yl-3,4'- bipyridin-2'-
yl)-1H- imidazol-4- yl]methyl} ethanamine ##STR00368## 409.2
.sup.1H NMR (400 MHz, d.sub.6- DMSO, tautomers) .delta. 12.48 (s,
0.5H), 12.39 (s, 0.5H), 8.66-8.58 (m, 1H), 8.46- 8.38 (m, 2H),
8.22-8.18 (m, 1H), 7.70-7.65 (m, 2H), 3.84-3.73 (m, 4H), 3.68 (s,
1H), 3.59 (s, 1H), 3.44- 3.35 (m, 2H), 3.35-3.28 (m, 4H), 3.24 (s,
1.5H), 3.22 (s, 1.5H), 2.69 (t, J = 5.6 Hz, 1H), 2.59 (t, J = 5.6
Hz, 1H), 2.24 (s, 1.5H), 2.16 (s, 1.5H) 291 3-Methoxy-N-
{[5-methyl-2- (5-morpholin- 4-yl-3,4'- bipyridin-2'- yl)-1H-
imidazol-4- yl]methyl}propan- 1-amine ##STR00369## 423.3 .sup.1H
NMR (400 MHz, d.sub.6- DMSO, tautomers) .delta. 12.47 (s, 0.5H),
12.34 (s, 0.5H), 8.66-8.58 (m, 1H), 8.47- 8.36 (m, 2H), 8.23-8.15
(m, 1H), 7.71-7.63 (m, 2H), 3.83-3.75 (m, 4H), 3.65 (s, 1H), 3.57
(s, 1H), 3.37 (q, J = 6.2 Hz, 2H), 3.33-3.28 (m, 4H), 3.21 (s,
1.5H), 3.20 (s, 1.5H), 2.57 (t, J = 6.9 Hz, 1H), 2.47 (t, J = 7.0
Hz, 1H), 2.24 (s, 1.5H), 2.16 (s, 1.5H), 1.70-1.57 (m, 2H) 292
2'-[5-Methyl- 4-(morpholin- 4-ylmethyl)- 1H-imidazol-2- yl]-5-
morpholin-4- yl-3,4'- bipyridine ##STR00370## 421.2 .sup.1H NMR
(400 MHz, d.sub.6- DMSO, tautomers) .delta. 8.64 (d, J = 5.1 Hz,
1H), 8.48-8.38 (m, 2H), 8.24-8.15 (m, 1H), 7.72-7.62 (m, 2H),
3.83-3.71 (m, 4H), 3.59- 3.53 (m, 4H), 3.53-3.25 (m, 6H), 2.44-2.30
(m, 4H), 2.25 (s, 2H), 2.19 (s, 1H)
Example 293.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4'-bipyridin-5-yl]
methanol
##STR00371##
[0745] Step 1.
4-Bromo-2-(4,5-dimethyl-1H-imidazol-2-yl)pyridine
##STR00372##
[0747] 4-Bromopyridine-2-carbonitrile (1.37 g, 7.51 mmol)
(Synthonix) was treated according to the procedure of Example 75,
Step 1, using 3,3-dimethoxybutan-2-amine (prepared as in J. Med.
Chem. 2005, 48(14), 4618-4627). When complete, the reaction was
evaporated to dryness. 1.0 N NaOH was added and the solid product
was isolated by filtration and washed with water. The solid was
dried by azeotropic removal of water by repeated evaporation from
toluene via rotary evaporation. Yield: 1.32 g, 70%. LCMS
(M+H).sup.+: 251.9, 254.0.
Step 2.
4-Bromo-2-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-im-
idazol-2-yl)pyridine
##STR00373##
[0749] To 4-bromo-2-(4,5-dimethyl-1H-imidazol-2-yl)pyridine (1.32
g, 5.24 mmol, from Step 1) in DMF (30 mL) at 0.degree. C. was added
NaH (60% in mineral oil, 0.42 g, 10. mmol) and the reaction mixture
was stirred for 20 minutes. [.beta.-(Trimethylsilyl)ethoxy]methyl
chloride (1.1 mL, 6.3 mmol, Aldrich) was then added. The reaction
was continued for 45 minutes. Water was then added and the reaction
mixture was extracted with EtOAc. The combined organic extracts
were washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The product was purified by flash
chromatography, eluting with a gradient from 0-50% EtOAc in
hexanes. Yield: 1.46 g, 76%. LCMS (M+H)+: 382.0
Step 3. Ethyl
2'-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-3-
,4-bipyridine-5-carboxylate
##STR00374##
[0751] To a degassed mixture of ethyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.72 g,
2.6 mmol) (Fronteir Scientific),
4-bromo-2-(4,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol--
2-yl)pyridine (1.00 g, 2.62 mmol, from Step 2), and CsF (1 g, 8
mmol) in 1,4-dioxane (7 mL) and water (1 mL) was added
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.18 g, 0.26 mmol, Aldrich), and the mixture was heated to
60.degree. C. for 2 hours. Additional ethyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.35 g,
1.3 mmol) was added and heating was resumed for 4 hours at
60.degree. C. Water was then added to the reaction mixture and the
aqueous mixture was extracted with EtOAc three times. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-50% EtOAc in hexanes. Yield: 0.92 g,
78%. LCMS (M+H).sup.+: 453.2.
Step 4.
(2'-(4,5-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-
-2-yl)-3,4'-bipyridin-5-yl)methanol
##STR00375##
[0753] To a -75.degree. C. solution of ethyl
2'-(4,5-dimethyl-1-{[2-(trimethyl
silyl)ethoxy]methyl}-1H-imidazol-2-yl)-3,4'-bipyridine-5-carboxylate
(0.40 g, 0.88 mmol, from Step 3) in toluene (4 mL) was added 1.0 M
diisobutylaluminum hydride in toluene (1.1 mL, 1.1 mmol). The
reaction was slowly warmed to 0.degree. C. over 2 hours. The
mixture was re-cooled to -75.degree. C. and additional 1.0 M
diisobutylaluminum hydride in toluene (0.77 mL, 0.77 mmol) was
added. After gradually warming to -55.degree. C. over 30 minutes,
the reaction was quenched by the addition of Rochelle's salt
solution. Ethyl acetate was added and the reaction mixture was
allowed to stir overnight, and the mixture was then filtered. The
organic layer of the filtrate was washed with saturated NaCl, dried
over sodium sulfate, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
50-100% EtOAc containing 10% .sup.iPrOH in hexanes, followed by a
gradient from 5-10% MeOH in DCM containing 0.5-1% NH.sub.4OH.
[0754] Yield: 0.083 g, 23%. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.74 (d, J=2.1 Hz, 1H), 8.59 (d, J=5.1 Hz, 1H), 8.53 (d,
J=1.6 Hz, 1H), 8.31-8.26 (m, 1H), 8.05 (t, J=1.9 Hz, 1H), 7.37 (dd,
J=5.1, 1.7 Hz, 1H), 6.03 (s, 2H), 4.75 (s, 2H), 3.60-3.24 (m, 2H),
2.28 (s, 3H), 2.24 (s, 3H), 0.90-0.64 (m, 2H), -0.13 (s, 9H); LCMS
(M+H).sup.+: 411.1.
Step 5.
2'-(4,5-Dimethyl-1H-imidazol-2-yl)-3,4-bipyridin-5-yl]methanol
[0755]
(2'-(4,5-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol--
2-yl)-3,4'-bipyridin-5-yl)methanol from Step 4 was stirred in TFA
solution for 1 hour. The solvent was then removed in vacuo. The
product was purified by preparative HPLC (C-18 column eluting with
a water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 12.42 (br
s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.67-8.54 (m, 2H), 8.23-8.20 (m,
1H), 8.20-8.13 (m, 1H), 7.68 (dd, J=5.2, 1.7 Hz, 1H), 5.46 (t,
J=5.8 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H);
LCMS (M+H).sup.+: 281.1.
Example 294.
4-(1-(4-Chlorobenzyl)-1H-pyrazol-4-yl)-2-(4,5-dimethyl-1H-imidazol-2-yl)p-
yridine trifluoroacetate salt
##STR00376##
[0756] Step 1.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carbonitrile
##STR00377##
[0758] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.60 g, 3.1 mmol, Aldrich) in DMF (16 mL) was treated with
1-(bromomethyl)-4-chlorobenzene (0.70 g, 3.4 mmol, Aldrich) and
K.sub.2CO.sub.3 (1.3 g, 9.3 mmol). After stirring for 2 hours, the
mixture was partitioned between water and EtOAc. The organic layer
was washed with water, followed by brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product
(0.90 g, 2.8 mmol) was combined with 4-bromopyridine-2-carbonitrile
(0.45 g, 2.4 mmol, Synthonix), CsF (1 g, 6 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (0.15 g, 0.22 mmol, Aldrich) in 1,4-dioxane (6 mL, 70 mmol)
and water (1 mL, 70 mmol). The mixture was degassed and heated to
100.degree. C. for 10 minutes. Upon cooling to room temperature,
the mixture was partitioned between water and EtOAc. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-70% EtOAc in hexanes. Yield: 0.38 g,
44%.
[0759] LCMS (M+H).sup.+: 295.0.
Step 2.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboximidamide
##STR00378##
[0761] A suspension of
4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carbonitrile (0.38
g, 1.1 mmol, from Step 1) in MeOH (12 mL) was treated with sodium
methoxide (25 wt % in MeOH in MeOH, 0.089 mL, 0.39 mmol) and heated
to 40.degree. C. for 35 minutes. Ammonium chloride (0.32 g, 6.0
mmol) was added and the temperature was raised to 65.degree. C. for
30 minutes. Solvent was removed in vacuo and the product was
triturated with water to give an off-white solid, which was
isolated by filtration. The product was further purified by
triturating with DCM/CH.sub.3CN. Yield: 0.34 g, 90%.
[0762] LCMS (M+H).sup.+: 312.1.
Step 3.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4,5-dimethyl-1H-imidazol-
-2-yl)pyridine trifluoroacetate salt
[0763]
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboximidamide
(100. mg, 0.289 mmol) in DMF (2.0 mL) was treated with
3-bromo-2-butanone (24 .mu.L, 0.32 mmol) and K.sub.2CO.sub.3 (60.
mg, 0.43 mmol) at 80.degree. C. for 1.5 hours. After cooling to
room temperature, the mixture was diluted with CH.sub.3CN/MeOH,
filtered, and purified by preparative HPLC (C-18 column eluting
with a water:acetonitrile gradient buffered at pH 2 with 0.1%
trifluoroacetic acid). Yield: 100 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.71 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 8.31
(s, 1H), 8.14 (s, 1H), 7.81 (dd, J=5.2, 1.3 Hz, 1H), 7.49-7.42 (m,
2H), 7.37-7.28 (m, 2H), 5.46 (s, 2H), 2.31 (s, 6H);
LCMS(M+H).sup.+: 364.1.
Example 295.
(2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-N-[(3S)--
tetrahydrofuran-3-yl]-1H-imidazole-4-carboxamide
##STR00379##
[0764] Step 1. 4-(1H-Pyrazol-4-yl)pyridine-2-carbonitrile
##STR00380##
[0766] A degassed mixture of 4-bromopyridine-2-carbonitrile (3.3 g,
18 mmol, Synthonix), 1H-pyrazol-4-ylboronic acid (2.00 g, 17.9
mmol, Aldrich), CsF (8 g, 50 mmol), and
4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium
(2:1) (1.3 g, 1.8 mmol, Aldrich) in 1,4-dioxane (50 mL) and water
(10 mL) was heated to 120.degree. C. for 2 h 40 minutes, then
cooled to room temperature. The organic layer was separated, and
the aqueous layer was extracted with two further portions of EtOAc.
The combined organic extracts were washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
product was purified by flash chromatography, eluting with a
gradient from 0-10% MeOH/DCM. Yield: 1.16 g, 38%. LCMS (M+H).sup.+:
171.0.
Step 2. 4-(1-Benzyl-1H-pyrazol-4-yl)pyridine-2-carbonitrile
##STR00381##
[0768] 4-(1H-Pyrazol-4-yl)pyridine-2-carbonitrile (0.635 g, 3.73
mmol, from Step 1) in DMF (10 mL, 200 mmol) was treated with benzyl
bromide (BnBr, 0.38 mL, 3.2 mmol) and K.sub.2CO.sub.3 (1.55 g, 11.2
mmol). After stirring for 1 hour, water was added and the reaction
mixture was extracted with three portions of EtOAc. The combined
organic extracts were washed with water twice, then dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
purified by flash chromatography, eluting with a gradient from
0-40% EtOAc in hexanes. Yield: 496 mg, 51%. LCMS (M+H).sup.+:
261.0.
Step 3.
4-(1-Benzyl-1H-pyrazol-4-yl)-2-(5-methyl-1H-imidazol-2-yl)pyridine
##STR00382##
[0770] 4-(1-Benzyl-1H-pyrazol-4-yl)pyridine-2-carbonitrile (0.495
g, 1.90 mmol, from Step 2) in MeOH (10 mL) was treated with sodium
methoxide (25 wt % in MeOH, 0.03 mL, 0.16 mmol) and the reaction
mixture was heated to 45.degree. C. for 2 hours. Upon cooling to
room temperature, 1,1-diethoxypropan-2-amine (0.31 g, 2.1 mmol,
AstaTech) and acetic acid (0.21 mL) were added and the reaction was
heated in a sealed vial to 100.degree. C. for 30 minutes. The
mixture was cooled to room temperature and 6.0 N HCl (0.870 mL,
5.22 mmol) was added and the sealed reaction vessel was then heated
in an oil bath held at 70.degree. C. overnight, then at 90.degree.
C. for 2 hours. The solvent was then removed in vacuo and the
resulting residue was treated with 1.0 N NaOH. The solid product
was isolated by filtration, washed with a small amount of water,
transferred to a round bottom flask and azeotroped twice with
toluene. The filtrate was extracted with EtOAc three times. The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, concentrated, and combined with the original isolated
solid. Yield: 0.46 g, 77%. LCMS (M+H).sup.+: 316.1.
Step 4.
4-(1-Benzyl-1H-pyrazol-4-yl)-2-(5-methyl-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1H-imidazol-2-yl)pyridine and
4-(1-Benzyl-1H-pyrazol-4-yl)-2-(4-methyl-1-{[2-(trimethylsilyl)ethoxy]met-
hyl}-1H-imidazol-2-yl)pyridine (a mixture of isomers prepared)
##STR00383##
[0772]
4-(1-Benzyl-1H-pyrazol-4-yl)-2-(5-methyl-1H-imidazol-2-yl)pyridine
(0.50 g, 1.6 mmol, from Step 3) in DMF (9 mL) at 0.degree. C. was
treated with NaH (60% in mineral oil, 0.13 g, 3.2 mmol) for 20
minutes. [.beta.-(Trimethylsilyl)ethoxy]methyl chloride (0.34 mL,
1.9 mmol, Aldrich) was added and the reaction was continued for 2
hours. Water was added and the reaction mixture was extracted with
EtOAc. The combined organic extracts were washed with water and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
product was purified by flash chromatography, eluting with a
gradient from 0-25% EtOAc/hexanes. Yield: 0.50 g, 70%. LCMS
(M+H).sup.+: 446.3.
Step 5.
2-(5-Methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-
-4-(1H-pyrazol-4-yl)pyridine and
2-(4-Methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-(1H--
pyrazol-4-yl)pyridine (a mixture of isomers as the trifluoroacetate
salts prepared)
##STR00384##
[0774] To a solution of
4-(1-benzyl-1H-pyrazol-4-yl)-2-(5-methyl-1-{[2-(trimethyl
silyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine and
4-(1-benzyl-1H-pyrazol-4-yl)-2-(4-methyl-1-{[2-(trimethylsilyl)ethoxy]met-
hyl}-1H-imidazol-2-yl)pyridine (0.400 g, 0.898 mmol, from Step 3)
in DMSO (0.955 mL) was added 1.0 M KO.sup.tBu in THF (9.42 mL, 9.42
mmol) dropwise. Oxygen gas was introduced by bubbling the O.sub.2
through the solution for 10 minutes. The reaction flask was then
sealed and stirred for 30 minutes. Water and EtOAc were added to
the reaction mixture. The pH was adjusted to neutral by the
addition of 1.0 N HCl. The layers were shaken, separated, and the
aqueous layer was extracted with two additional portions of EtOAc.
The combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The product was purified by preparative
HPLC (C-18 column eluting with a water:acetonitrile gradient
buffered at pH 2 with 0.1% trifluoroacetic acid). Yield: 106 mg,
33%. LCMS (M+H).sup.+: 356.2.
Step 6.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-methyl-1H-imidazol-2-y-
l)pyridine
##STR00385##
[0776] A mixture of
2-(5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-(1H--
pyrazol-4-yl)pyridine and
2-(4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-(1H--
pyrazol-4-yl)pyridine (0.132 g, 0.371 mmol, from Step 5) in DMF (2
mL) was treated with K.sub.2CO.sub.3 (0.154 g, 1.11 mmol) and
1-(bromomethyl)-4-chlorobenzene (0.0763 g, 0.371 mmol, Aldrich)
overnight. Water was added and the reaction mixture was extracted
with three portions of EtOAc. The combined organic extracts were
washed with water twice, then dried over Na.sub.2SO.sub.4, filtered
and concentrated. The product was used without further
purification. LCMS (M+H).sup.+: 480.3.
[0777] The alkylated mixture of products generated above (0.178 g,
0.371 mmol) was stirred in 1:1 TFA:DCM (4 mL) for 3 hours. Solvent
was removed in vacuo. The residue was partitioned between saturated
NaHCO.sub.3 and EtOAc. The aqueous was extracted a total of three
times with EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The product was used
without further purification. LCMS (M+H).sup.+: 350.2/352.1.
Step 7.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1H-imida-
zol-2-yl)pyridine
##STR00386##
[0779]
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-methyl-1H-imidazol-2-yl-
)pyridine (0.130 g, 0.372 mmol, from Step 6) in DMF (3 mL) was
treated with N-Iodosuccinimide (0.0836 g, 0.372 mmol) for 1 hour.
Water was added and the aqueous mixture was extracted with three
portions of EtOAc. The combined organic extracts were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-40% EtOAc in hexanes. Yield: 50 mg,
28%. LCMS (M+H).sup.+: 475.9/477.9.
Step 8.
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-1H-
-imidazole-4-carboxylic acid trifluoroacetate salt
##STR00387##
[0781]
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1H-imidaz-
ol-2-yl)pyridine (0.050 g, 0.10 mmol, from Step 7) in DMF (0.8 mL)
and water (0.09 mL) containing triethylamine (0.029 mL, 0.21 mmol)
was degassed with a stream of nitrogen and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (0.0086 g, 0.010 mmol, Aldrich)
was added. The solution was saturated with carbon monoxide by
bubbling the CO gas through the reaction subsurface for 3 minutes.
The vessel was sealed and was heated to 60.degree. C. for 5 hours.
Additional CO was introduced, and water (0.3 mL, 20 mmol) and
Na.sub.2CO.sub.3 (0.033 g, 0.32 mmol) were added and heating was
continued for 8 hours. Upon cooling, the reaction mixture was
diluted with MeOH and filtered. The product was partially purified
by preparative HPLC (C-18 column eluting with a water: acetonitrile
gradient buffered at pH 2 with 0.1% trifluoroacetic acid). The
impure product was then used in Step 9. LCMS (M+H).sup.+:
394.1/396.1.
Step 9.
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-N--
[(3S)-tetrahydrofuran-3-yl]-1H-imidazole-4-carboxamide
[0782] A mixture containing
2-{4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-1H-imidaz-
ole-4-carboxylic acid trifluoroacetate salt (12 mg) in DMF (0.5 mL)
was treated with N,N-diisopropylethylamine (0.010 mL, 0.058 mmol),
(3S)-tetrahydrofuran-3-amine (0.003 g, 0.03 mmol, Advanced Chem
Blocks) and HATU (0.009 g, 0.02 mmol). After 2.5 hours, additional
N,N-diisopropylethylamine (0.010 mL, 0.057 mmol), HATU (0.009 g,
0.02 mmol), and (3S)-tetrahydrofuran-3-amine (0.003 g, 0.03 mmol)
were added and the reaction was stirred overnight. The product was
purified by preparative HPLC (C-18 column eluting with a
water:acetonitrile gradient buffered at pH 10 with 0.15% ammonium
hydroxide). Yield: 4 mg, 40% over 2 steps. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.52 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 8.27-8.17
(m, 1H), 8.10 (s, 1H), 7.53 (dd, J=5.2, 1.6 Hz, 1H), 7.43-7.33 (m,
2H), 7.33-7.17 (m, 2H), 5.40 (s, 2H), 4.61-4.50 (m, 1H), 4.02 (q,
J=7.7 Hz, 1H), 3.96 (dd, J=9.1, 5.9 Hz, 1H), 3.86 (td, J=8.4, 5.9
Hz, 1H), 3.75 (dd, J=9.2, 3.8 Hz, 1H), 2.58 (s, 3H), 2.38-2.26 (m,
1H), 2.05-1.95 (m, 1H). LCMS (M+H).sup.+: 463.1.
[0783] Example 296 was synthesized according to the procedure of
Example 295 and the data are listed in Table 21.
TABLE-US-00020 TABLE 21 ##STR00388## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 296 2-{4-[1-(4- CH.sub.3 407.1 .sup.1H NMR
(400 MHz, Chlorobenzyl)-1H- CD.sub.3OD) .delta. 8.52 (d, J =
pyrazol-4-yl]pyridin- 5.3 Hz, 1H), 8.28 (s, 2-yl}-N,5-dimethyl-
1H), 8.23 (s, 1H), 8.08 1H-imidazole-4- (s, 1H), 7.80 (s, 1H),
carboxamide (free 7.51 (dd, J = 5.2, 1.6 base) Hz, 1H), 7.42-7.34
(m, 2H), 7.33-7.24 (m, 2H), 5.41 (s, 2H), 2.95 (s, 3H), 2.61 (s,
3H)
Example 297.
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-1H-imidaz-
ole-4-carbonitrile trifluoroacetate salt
##STR00389##
[0785] Step 1.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine and
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-iodo-4-methyl-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine
##STR00390##
[0786] To
4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1H-imi-
dazol-2-yl)pyridine (50.0 mg, 0.10 mmol, from Example 295, Step 7)
in DMF (1 mL) at 0.degree. C. was added NaH (60% in mineral oil,
8.4 mg, 0.21 mmol) and the reaction was stirred for 20 minutes.
[.beta.-(Trimethylsilyl)ethoxy]methyl chloride (28 .mu.L, 0.16
mmol) was then added and the reaction was continued for 30 minutes.
The reaction was quenched by the addition of water, and the
reaction mixture was extracted with EtOAc (3.times.). The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was purified by flash chromatography,
eluting with a gradient of 0-30% EtOAc in hexanes. Two isomers were
isolated: Peak 1 (first to elute,
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine): 0.030 g, 47%.
LCMS(M+H).sup.+: 606.1; Peak 2 (second to elute,
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(5-iodo-4-methyl-1-{[2-(trimethy-
l silyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine): 0.019 g,
30%.
[0787] LCMS(M+H).sup.+: 606.1.
Step 2.
2-{4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-5-methyl-1H-
-imidazole-4-carbonitrile trifluoroacetate salt
[0788] A degassed mixture of
4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-iodo-5-methyl-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyridine (0.015 g, 0.025
mmol, Peak 1 from Step 1), zinc cyanide (29 mg, 0.25 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.7
mg, 0.0037 mmol) in DMF (0.5 mL) was heated to 150.degree. C. for
35 minutes in a microwave reactor. Upon cooling, the reaction
mixture was diluted with DCM, filtered, and concentrated. TFA (1
mL) was added, and the mixture was stirred overnight. Volatiles
were then removed in vacuo and the product was purified by
preparative HPLC/MS (pH 2). Yield: 11 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.72 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.21
(s, 1H), 8.20 (s, 1H), 7.66 (d, J=4.6 Hz, 1H), 7.44 (d, J=8.3 Hz,
2H), 7.34 (d, J=8.2 Hz, 2H), 5.38 (s, 2H), 2.40 (s, 3H). LCMS
(M+H).sup.+: 375.1.
Example 298.
N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-2'-(4-methyl-1H-imidazol-2-yl)-[-
3,4'-bipyridine]-5-sulfonamide trifluoroacetate salt
##STR00391##
[0789] Step 1.
5-Bromo-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyridine-3-sulfonamide
##STR00392##
[0791] To a mixture of (1r,4r)-4-amino-1-methylcyclohexan-1-ol
(0.081 g, 0.62 mmol, PharmaBlock) and triethylamine (0.087 mL, 0.62
mmol) in DCM (3 mL) was added 5-bromopyridine-3-sulfonyl chloride
(0.08 g, 0.3 mmol, Enamine Ltd) as a suspension in DCM (1 mL). The
reaction was stirred for 16 hours and quenched by the addition of
saturated NaHCO.sub.3 (aq.) solution. The layers were separated and
the aqueous layer was extracted with EtOAc. The combined organic
extracts were dried over MgSO.sub.4, filtered, and concentrated.
The product was used without further purification. Yield: 0.08 g,
70%.
[0792] LCMS(M+H).sup.+: 349.1.
Step 2.
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-(4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide
##STR00393##
[0794] A degassed mixture of
5-bromo-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyridine-3-sulfonamide
(0.050 g, 0.14 mmol), bis(pinacolato)diboron (0.036 g, 0.14 mmol),
dichlorobis(triphenylphosphine)-palladium(II) (4.0 mg, 5.7 .mu.mol)
and potassium acetate (0.046 g, 0.47 mol) in THF (1.2 mL) was
heated to 140.degree. C. in a microwave reactor for 20 minutes.
Upon cooling to room temperature, water and EtOAc were added and
after filtration through Celite.RTM., the layers were separated and
the organic layer was washed with brine, dried over MgSO.sub.4,
filtered, and concentrated to afford
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)pyridine-3-sulfonamide, which was used without
further purification. Yield: 57 mg.
[0795] LCMS (M+H).sup.+: 397.1.
Step 3.
N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-2-(4-methyl-1H-imidazol-2-
-yl)-[3,4'-bipyridine]-5-sulfonamide trifluoroacetate salt
[0796] A mixture of
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)pyridine-3-sulfonamide (0.022 g, 0.071 mmol) and
4-bromo-2-(4-methyl-1-((2-(trimethyl
silyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (0.020 g, 0.054
mmol, prepared by treating the product of Example 75, Step 1
according to the method of Example 1, Step 2) in THF (1.0 mL) and
1.0 M K.sub.2CO.sub.3 (0.136 mL, 0.136 mmol) was degassed and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichlorometha-
ne adduct (6.6 mg, 8.1 .mu.mol) was added. The mixture was again
degassed and heated to 80.degree. C. for 3 hours. Upon cooling to
room temperature, the reaction mixture was diluted with water and
extracted with EtOAc. The organic layer was washed with brine,
dried over MgSO.sub.4, filtered, and concentrated. The crude
product was dissolved in DCM (1 mL) and TFA (2 mL) was added. The
mixture was stirred for 1 hour and volatiles were removed in vacuo.
The product was purified by preparative HPLC/MS (pH 2). Yield: 4.0
mg, 14%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 9.34 (d, J=1.9
Hz, 1H), 9.14 (d, J=1.9 Hz, 1H), 8.92 (d, J=5.1 Hz, 1H), 8.64 (dd,
J=1.9 Hz, 1.9 Hz, 1H), 8.58 (s, 1H), 8.10 (d, J=4.4 Hz, 1H), 8.00
(d, J=7.0 Hz, 1H), 7.50 (s, 1H), 3.29-3.18 (m, 1H), 2.37 (s, 3H),
1.72-1.56 (m, 2H), 1.54-1.38 (m, 2H), 1.37-1.17 (m, 4H), 1.07 (s,
3H).
[0797] LCMS (M+H).sup.+: 428.1.
[0798] Example 299 was synthesized according to the procedure of
Example 298 using (1r,4r)-4-aminocyclohexan-1-ol (Combi-Blocks) and
the data are listed in Table 22.
TABLE-US-00021 TABLE 22 ##STR00394## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 299 N-((1r,4r)-4- Hydroxycyclohexyl)-
2'-(4-methyl-1H- imidazol-2-yl)-[3,4'- bipyridine]-5- sulfonamide
trifluoroacetate salt ##STR00395## 414.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.35 (d, J = 1.9 Hz, 1H), 9.13 (d, J = 1.8
Hz, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.64 (dd, J = 1.9 Hz, 1.8 Hz,
1H), 8.58 (s, 1H), 8.13-8.08 (m, 1H), 8.03 (d, J = 7.3 Hz, 1H),
7.49 (s, 1H), 3.35-3.26 (m, 1H), 3.14-3.01 (m, 1H), 2.37 (s, 3H),
1.77- 1.67 (m, 2H), 1.67- 1.53 (m, 2H), 1.30- 1.03 (m, 4H)
Example 300.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-{4-[1-(methylsulfonyl)pyrrolidin-
-3-yl]-1H-imidazol-2-yl}pyridine trifluoroacetate salt (single
enantiomer prepared)
##STR00396##
[0799] Step 1. tert-Butyl
3-[2-(4-bromopyridin-2-yl)-1H-imidazol-4-yl]pyrrolidine-1-carboxylate
(racemic mixture prepared)
##STR00397##
[0801] The title compound was prepared according to the procedure
of Example 231, Step 1, using tert-butyl
3-(bromoacetyl)pyrrolidine-1-carboxylate (1.07 g, 3.66 mmol,
prepared as described in WO2010/051245). The product was purified
by flash chromatography, eluting with a gradient from 0-100%
EtOAc/hexanes. Yield: 0.169 g, 12%. LCMS(M+H).sup.+: 393.0.
Step 2.
1-(4-Chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-1H-pyrazole
##STR00398##
[0803] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.300 g, 1.55 mmol, Aldrich) in DMF (8 mL) was treated with
K.sub.2CO.sub.3 (0.64 g, 4.6 mmol) and
1-(bromomethyl)-4-chlorobenzene (0.35 g, 1.7 mmol, Aldrich). After
stirring for 16 hours, the reaction mixture was diluted with water
and extracted with EtOAc. The combined organic extracts were washed
with water, followed by brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The product was used without further
purification in Step 3. LCMS (M+H).sup.+: 319.1.
Step 3. tert-Butyl
3-(2-{4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-4-yl)pyrrolidine-1-carboxylate
(single enantiomers isolated)
##STR00399##
[0805] Using tert-butyl
3-[2-(4-bromopyridin-2-yl)-1H-imidazol-4-yl]pyrrolidine-1-carboxylate
(0.149 g, 0.379 mmol, racemic mixture from Step 1) and
1-(4-chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyr-
azole (0.14 g, 0.45 mmol, from Step 2), the methods of Example 231,
Steps 2 and 3 were followed to afford the title compound. Yield:
0.100 g, 42%. LCMS(M+H).sup.+: 635.3. The enantiomers were
separated by chiral preparative HPLC (CHIRALCEL AD-H, 5 .mu.m,
20.times.250 mm, 20% EtOH in hexane @ 18 mL/min, loading 18 mg in
900 .mu.L). Peak 1 (first to elute): 7.1 min; Peak 2 (second to
elute): 9.5 min.
Step 4.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-pyrrolidin-3-yl-1H-imi-
dazol-2-yl)pyridine (single enantiomer prepared)
##STR00400##
[0807] tert-Butyl
3-(2-{4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1-{[2-(trimethy-
lsilyl)ethoxy]methyl}-1H-imidazol-4-yl)pyrrolidine-1-carboxylate
(Peak 2 from Step 3, 0.040 g, 0.063 mmol) was stirred with TFA (1
mL) in DCM (1 mL) for 1 hour. Volatiles were removed in vacuo and
the product was used without further purification in Step 5.
LCMS(M+H).sup.+: 405.1.
Step 5.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-{4-[1-(methylsulfonyl)pyr-
rolidin-3-yl]-1H-imidazol-2-yl}pyridine trifluoroacetate salt
(single enantiomer prepared)
[0808] To
4-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-pyrrolidin-3-yl-1H-i-
midazol-2-yl)pyridine trifluoroacetate salt (from Step 4, 0.01 g,
0.02 mmol) in DCM (0.5 mL) was added N,N-diisopropylethylamine
(0.017 mL, 0.099 mmol) followed by methanesulfonyl chloride (0.002
mL, 0.02 mmol, as an aliquot of a stock solution). A small quantity
of water was added and DCM was then evaporated under a stream of
nitrogen. The reaction mixture was diluted with MeOH and the
product was purified by preparative HPLC/MS (pH 2). Yield: 7 mg,
50%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71 (d, J=5.0 Hz,
1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J=5.1, 1.5
Hz, 1H), 7.62 (s, 1H), 7.43-7.37 (m, 2H), 7.37-7.19 (m, 2H), 5.44
(s, 2H), 3.86 (dd, J=9.7, 7.3 Hz, 1H), 3.73 (p, J=7.0 Hz, 1H),
3.67-3.57 (m, 1H), 3.57-3.44 (m, 2H), 2.98 (s, 3H), 2.60-2.45 (m,
1H), 2.34-2.22 (m, 1H). LCMS(M+H).sup.+: 483.0.
[0809] Examples 301-302 were synthesized according to the procedure
of Example 300 using Peak 2 from Step 3 and alternative acyl
chlorides or sulfonyl chlorides in Step 5, and the data are listed
in Table 23.
TABLE-US-00022 TABLE 23 ##STR00401## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 301 2-[4-(1- Acetylpyrrolidin-3-
yl)-1H-imidazol-2- yl]-4-[1-(4- chlorobenzyl)-1H-
pyrazol-4-yl]pyridine trifluoroacetate salt ##STR00402## 447.1
.sup.1H NMR (400 MHz, CD.sub.3OD, rotamers) .delta. 8.72 (d, J =
5.1 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.79 (d, J =
5.2 Hz, 1H), 7.62 (s, 0.5H), 7.60 (s, 0.5H), 7.40 (d, J = 8.5 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 5.44 (s, 2H), 4.11- 3.96 (m, 1H),
3.85- 3.61 (m, 3H), 3.61- 3.47 (m, 1H), 2.61- 2.39 (m, 1H), 2.36-
2.15 (m, 1H), 2.13 (s, 1.5H), 2.12 (s, 1.5H) 302 4-[1-(4-
Chlorobenzyl)-1H- pyrazol-4-yl]-2-{4-[1- (phenylsulfonyl)pyrrol-
idin-3-yl]-1H- imidazol-2- yl}pyridine trifluoroacetate salt
##STR00403## 545.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71
(d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H),
7.93-7.82 (m, 2H), 7.78 (dd, J = 5.2, 1.4 Hz, 1H), 7.72- 7.62 (m,
1H), 7.62- 7.55 (m, 2H), 7.43- 7.30 (m, 5H), 5.45 (s, 2H),
3.84-3.71 (m, 1H), 3.64-3.39 (m, 4H), 2.44-2.27 (m, 1H), 2.22-2.06
(m, 1H)
[0810] Examples 303-305 were synthesized according to the procedure
of Example 300 using Peak 1 from Step 3 and alternative acyl
chlorides or sulfonyl chlorides in Step 5, and the data are listed
in Table 24.
TABLE-US-00023 TABLE 24 ##STR00404## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 303 2-[4-(1- Acetylpyrrolidin-3-
yl)-1H-imidazol-2- yl]-4-[1-(4- chlorobenzyl)-1H-
pyrazol-4-yl]pyridine trifluoroacetate salt ##STR00405## 447.1
.sup.1H NMR (400 MHz, CD.sub.3OD, rotamers) .delta. 8.71 (d, J =
5.4 Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J
= 5.3, 1.3 Hz, 1H), 7.61 (s, 0.5H), 7.59 (s, 0.5H), 7.41 (d, J =
8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 5.45 (s, 2H), 4.11-3.94 (m,
1H), 3.84-3.60 (m, 3H), 3.60-3.46 (m, 1H), 2.60-2.38 (m, 1H),
2.37-2.16 (m, 1H), 2.13 (s, 1.5H), 2.12 (s, 1.5H) 304 4-[1-(4-
Chlorobenzyl)-1H- pyrazol-4-yl]-2-{4-[1- (methylsulfonyl)pyrrol-
idin-3-yl]-1H- imidazol-2- yl}pyridine trifluoroacetate salt
##STR00406## 483.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71
(d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.78
(dd, J = 5.0, 1.2 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 5.44 (s, 2H), 3.86 (dd, J = 9.6, 7.4 Hz,
1H), 3.73 (p, J = 7.5 Hz, 1H), 3.66- 3.57 (m, 1H), 3.57- 3.45 (m,
2H), 2.98 (s, 3H), 2.59-2.42 (m, 1H), 2.34-2.20 (m, 1H) 305
4-[1-(4- Chlorobenzyl)-1H- pyrazol-4-yl]-2-{4-[1-
(phenylsulfonyl)pyrrol- idin-3-yl]-1H- imidazol-2- yl}pyridine
trifluoroacetate salt ##STR00407## 545.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.71 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.25
(s, 1H), 8.13 (s, 1H), 7.90-7.84 (m, 2H), 7.78 (dd, J = 5.2, 1.4
Hz, 1H), 7.69- 7.62 (m, 1H), 7.62- 7.55 (m, 2H), 7.43- 7.29 (m,
5H), 5.44 (s, 2H), 3.84-3.72 (m, 1H), 3.64-3.38 (m, 4H), 2.44-2.28
(m, 1H), 2.24-2.06 (m, 1H)
Example 306.
4-[1-(4-Chlorobenzyl)-1H-pyrazol-4-yl]-2-(4-pyrrolidin-3-yl-1H-imidazol-2-
-yl)pyridine trifluoroacetate salt (racemic mixture prepared)
##STR00408##
[0812] The racemic product prepared in Example 300, Step 3 (before
chiral separation), was deprotected as described in Example 300,
Step 4, and the product was purified by preparative HPLC/MS (pH 2).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.67 (d, J=5.3 Hz, 1H),
8.39 (s, 1H), 8.36-8.31 (m, 1H), 8.14 (s, 1H), 7.76 (dd, J=5.3, 1.5
Hz, 1H), 7.56 (s, 1H), 7.46-7.36 (m, 2H), 7.36-7.28 (m, 2H), 5.44
(s, 2H), 3.88-3.70 (m, 2H), 3.66-3.54 (m, 1H), 3.54-3.40 (m, 2H),
2.67-2.51 (m, 1H), 2.40-2.18 (m, 1H).
[0813] LCMS(M+H).sup.+: 405.1.
Example 307.
N-(2-Methoxyphenyl)-5-methyl-2-(5-morpholin-4-yl-3,4'-bipyridin-2'-yl)-1H-
-imidazol-4-amine trifluoroacetate salt
##STR00409##
[0815] To a degassed mixture of
2'-(4-iodo-5-methyl-1H-imidazol-2-yl)-5-morpholin-4-yl-3,4'-bipyridine
(30 mg, 0.067 mmol, from Example 257, Step 2),
di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine
(2.0 mg, 0.0040 mmol), .sup.tBuBrettPhos Pd G3 (3.4 mg, 0.0040
mmol), and 2-methoxyaniline (9.7 .mu.L, 0.080 mmol) in THF (0.25
mL) was added 1.0 M LHMDS (lithium bis(trimethylsilyl)amide) in THF
(150 .mu.L, 0.15 mmol). The mixture was sealed and heated at
70.degree. C. for 2 hours. Upon cooling to room temperature, the
reaction mixture was quenched by the addition of 1N HCl (1 mL). The
mixture was diluted with ACN/MeOH, filtered, and purified via
preparative HPLC/MS (pH 2). Yield: 8.5 mg. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.88 (d, J=5.2 Hz, 1H), 8.58-8.52 (m, 2H),
8.50 (d, J=2.2 Hz, 1H), 8.10-8.02 (m, 1H), 7.87-7.78 (m, 1H), 7.45
(br s, 1H), 7.05-6.95 (m, 1H), 6.86-6.73 (m, 2H), 6.64-6.53 (m,
1H), 3.89 (s, 3H), 3.85-3.72 (m, 4H), 3.43-3.27 (m, 4H), 2.21 (s,
3H). LCMS(M+H).sup.+: 443.1.
[0816] Example 308 was synthesized according to the procedure of
Example 307 using alternative anilines, and the data are listed in
Table 25.
TABLE-US-00024 TABLE 25 ##STR00410## Ex. MS No. Name R = (M +
H).sup.+ .sup.1H NMR 308 N-[5-Methyl-2-(5- morpholin-4-yl-3,4'-
bipyridin-2'-yl)-1H- imidazol-4- yl]pyridazin-4-amine
trifluoroacetate salt ##STR00411## 415.2 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 13.21 (br s, 0.7H), 10.99 (s, 1H), 8.86 (d, J
= 7.3 Hz, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.60- 8.53 (m, 1H), 8.49
(d, J = 2.6 Hz, 1H), 8.29 (s, 1H), 8.12 (br s, 0.5H), 7.90 (s, 1H),
7.81 (dd, J = 5.2, 1.7 Hz, 1H), 3.93-3.65 (m, 4H), 3.51-3.13 (m,
4H), 2.32 (s, 3H)
Example A. THP-1 RPS6 ELISA Assay
[0817] To measure the Phosphorylated Ribosomal Protein S6 (RPS6) in
cell lysates, THP-1 cells (Human Acute Monocytic Leukemia) are
purchased from ATCC (Manassas, Va.) and maintained in RPMI with 10%
FBS (Gibco/Life Technologies, Carlsbad, Calif.). For the assay,
THP-1 cells are serum starved overnight in RPMI, then plated in
RPMI (2.times.10.sup.5 cells/well in 90 .mu.L) into 96-well
flat-bottom tissue culture treated plates (Corning, Corning, N.Y.),
in the presence or absence of a concentration range of test
compounds. Covered plates are incubated for 2 hours at 37.degree.
C., 5% CO.sub.2 then treated with or without 10 nM MCP-1
(MYBioSource, San Diego, Calif.) for 15 minutes at 37.degree. C.,
5% CO.sub.2. Plates are centrifuged at 1600 RPM and supernatants
are removed. Cells are lysed in Lysis Buffer (Cell Signaling,
Danvers, Mass.) with Protease Inhibitor (Calbiochem/EMD, Germany),
PMSF (Sigma, St Louis Mo.), HALTS (Thermo Fisher, Rockford, Ill.)
for 30 min on wet ice. Cell lysates are frozen at -80 OC before
testing. The lysates are tested in the Human/Mouse/Rat Phospho-RPS6
ELISA (R&D Systems, Inc. Minn, Minn.). The plate is measured
using a microplate reader (SpectraMax M5-Molecular Devices, LLC
Sunnyvale, Calif.) set to 450 nm with a wavelength correction of
540. IC.sub.50 determination is performed by fitting the curve of
inhibitor percent inhibition versus the log of the inhibitor
concentration using the GraphPad Prism 5.0 software.
[0818] Data for the Examples, obtained using the methods described
in Example A, are provided in Table A.
TABLE-US-00025 TABLE A Example # THP p-RPS6 ELISA IC50 (nM) 1
.dagger..dagger..dagger..dagger. 5 .dagger..dagger..dagger. 6
.dagger..dagger..dagger..dagger. 7 .dagger..dagger..dagger..dagger.
8 N/A 9 .dagger..dagger..dagger. 10 .dagger..dagger..dagger. 11 N/A
12 N/A 13 N/A 14 N/A 16 N/A 17 .dagger..dagger. 18 .dagger..dagger.
19 .dagger..dagger..dagger. 20 N/A 21 N/A 25 N/A 26 N/A 30 N/A 31
N/A 32 N/A 33 N/A 34 N/A 35 N/A 37 N/A 40 .dagger. 41 N/A 43
.dagger..dagger..dagger..dagger. 44 N/A 45 N/A 46
.dagger..dagger..dagger..dagger. 47 N/A 48 N/A 49 N/A 50 N/A 51 N/A
52 N/A 53 N/A 54 .dagger..dagger..dagger..dagger. 55 N/A 56
.dagger. 57 N/A 58 N/A 59 N/A 60 N/A 61 N/A 62
.dagger..dagger..dagger..dagger. 63
.dagger..dagger..dagger..dagger. 64 N/A 65
.dagger..dagger..dagger..dagger. 66
.dagger..dagger..dagger..dagger. 67
.dagger..dagger..dagger..dagger. 68
.dagger..dagger..dagger..dagger. 70
.dagger..dagger..dagger..dagger. 71
.dagger..dagger..dagger..dagger. 72 N/A 73 N/A 74
.dagger..dagger..dagger..dagger. 75 N/A 76 .dagger..dagger. 77
.dagger..dagger. 78 N/A 79 .dagger..dagger..dagger..dagger. 80 N/A
81 N/A 82 .dagger..dagger..dagger..dagger. 83
.dagger..dagger..dagger..dagger. 84 .dagger..dagger..dagger. 85
.dagger..dagger..dagger..dagger. 86 .dagger..dagger. 87
.dagger..dagger..dagger..dagger. 88
.dagger..dagger..dagger..dagger. 94 .dagger..dagger..dagger. 95 N/A
97 .dagger..dagger. 98 .dagger. 99 .dagger..dagger..dagger..dagger.
100 N/A 101 N/A 102 .dagger..dagger. 103 .dagger..dagger..dagger.
104 .dagger. 105 .dagger. 106 .dagger. 107 .dagger. 108 .dagger.
109 .dagger..dagger. 110 .dagger..dagger. 111 .dagger..dagger. 112
.dagger..dagger. 113 .dagger. 114 .dagger. 115 .dagger. 116
.dagger. 117 .dagger. 118 .dagger..dagger. 119
.dagger..dagger..dagger..dagger. 120
.dagger..dagger..dagger..dagger. 121 .dagger. 122
.dagger..dagger..dagger. 123 .dagger. 124 N/A 125 .dagger..dagger.
126 N/A 127 .dagger..dagger..dagger. 128 N/A 129 N/A 130
.dagger..dagger. 131 .dagger..dagger..dagger..dagger. 132 N/A 133
N/A 134 N/A 135 N/A 136 N/A 137 N/A 138
.dagger..dagger..dagger..dagger. 139 N/A 140 N/A 141
.dagger..dagger..dagger..dagger. 142
.dagger..dagger..dagger..dagger. 143 N/A 144 N/A 145 N/A .sup. 145B
.dagger. .sup. 145C .dagger. 146 .dagger. 147 N/A 148 N/A 149 N/A
150 N/A 151 .dagger. 152 .dagger..dagger. 153 .dagger. 154
.dagger..dagger. 155 .dagger. 156 .dagger..dagger..dagger. 157
.dagger..dagger..dagger. 158 .dagger..dagger..dagger. 159
.dagger..dagger..dagger. 160 .dagger..dagger..dagger. 161 .dagger.
162 N/A 163 .dagger. 164 N/A 165 .dagger. 166 N/A 167 N/A 168
.dagger. 169 .dagger..dagger..dagger. 170 N/A 171 N/A 172
.dagger..dagger. 173 .dagger. 174 .dagger. 175 .dagger. 176 N/A 177
N/A 178 .dagger. 179 .dagger. 180 .dagger..dagger..dagger. 181 N/A
182 N/A 183 .dagger..dagger. 184 .dagger..dagger. 185 .dagger. 186
.dagger. 187 .dagger..dagger. 188 N/A 189 N/A 190 .dagger..dagger.
191 .dagger. 192 .dagger..dagger..dagger. 193 .dagger. 194 .dagger.
195 N/A 196 N/A 197 .dagger..dagger. 198 .dagger..dagger. 199
.dagger. 200 N/A 201 .dagger..dagger. 202 .dagger..dagger. 203
.dagger..dagger. 204 N/A 205 .dagger..dagger. 206
.dagger..dagger..dagger. 207 .dagger..dagger..dagger. 208
.dagger..dagger..dagger. 209 N/A 210 N/A 211 .dagger. 212 .dagger.
.sup. 212B .dagger..dagger. 214 .dagger..dagger..dagger..dagger.
215 N/A 217 N/A 219 N/A 220 N/A 221
.dagger..dagger..dagger..dagger. 222 N/A 223 N/A 224 N/A 225 N/A
226 N/A 227 N/A 228 N/A 229 N/A 230 N/A 231 .dagger..dagger. 232
.dagger..dagger. 233 .dagger..dagger..dagger. 234 N/A 235 N/A 236
N/A 237 .dagger. 238 N/A 239 N/A 240 .dagger..dagger..dagger. 241
.dagger..dagger. 242 .dagger..dagger..dagger..dagger. 243 .dagger.
244 .dagger..dagger..dagger..dagger. 245
.dagger..dagger..dagger..dagger. 246 N/A 247
.dagger..dagger..dagger..dagger. 248 .dagger..dagger..dagger. 249
.dagger..dagger..dagger. 250 .dagger..dagger. 251 N/A 252 .dagger.
253 .dagger. 254 .dagger. 255 .dagger..dagger. 256
.dagger..dagger..dagger. 257 N/A 258 .dagger. 259 N/A 260 N/A 261
N/A 262 .dagger..dagger. 263 N/A 264 .dagger..dagger..dagger. 265
.dagger..dagger. 266 .dagger. 267 .dagger..dagger..dagger.
268 .dagger..dagger. 269 .dagger..dagger. 270 .dagger..dagger. 271
.dagger..dagger. 272 .dagger. 273 .dagger. 274
.dagger..dagger..dagger. 275 .dagger. 276 .dagger. 277 .dagger. 278
.dagger..dagger. 279 .dagger. 280 N/A 281 .dagger. 282
.dagger..dagger. 283 N/A 284 N/A 285 N/A 286 N/A 287 N/A 288 N/A
289 N/A 290 N/A 291 N/A 292 N/A 293 N/A 294
.dagger..dagger..dagger..dagger. 295 .dagger..dagger..dagger. 296
.dagger..dagger..dagger..dagger. 297
.dagger..dagger..dagger..dagger. 298 .dagger. 299 .dagger. 300
.dagger..dagger. 301 N/A 302 N/A 303 N/A 304 N/A 305 N/A 306 N/A
307 N/A 308 N/A .dagger. refers to IC.sub.50 of .ltoreq.300 nM
.dagger..dagger. refers to IC.sub.50 of .ltoreq.1000 nM
.dagger..dagger..dagger. refers to an IC.sub.50 of .ltoreq.5000 nM
.dagger..dagger..dagger..dagger. refers to an IC.sub.50 of >5000
nM N/A refers to not available
Example B. PI3K-.gamma. Scintillation Proximity Assay
[0819] Materials
[0820] [.gamma.-.sup.33P]ATP (10 mCi/mL) and Wheat Germ Agglutinin
(WGA) YSi SPA Scintillation Beads was purchased from Perkin-Elmer
(Waltham, Mass.). Lipid kinase substrate,
D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D
(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS
204858-53-7, was purchased from Echelon Biosciences (Salt Lake
City, Utah). PI3K.gamma. (p110.gamma.) Recombinant Human Protein
was purchased from Life technology (Grand Island, N.Y.). ATP,
MgCl.sub.2, DTT, EDTA, MOPS and CHAPS were purchased from
Sigma-Aldrich (St. Louis, Mo.).
[0821] The kinase reaction was conducted in polystyrene 384-well
Greiner Bio-one white plate from Thermo Fisher Scientific in a
final volume of 25 .mu.L. Inhibitors were first diluted serially in
DMSO and added to the plate wells before the addition of other
reaction components. The final concentration of DMSO in the assay
was 2%. The PI3K.gamma. assay was carried out at room temperature
in 20 mM MOPS, pH 6.7, 10 mM MgCl.sub.2, 5 mM DTT and CHAPS 0.03%.
Reactions were initiated by the addition of ATP, the final reaction
mixture consisted of 20 .mu.M PIP2, 2 .mu.M ATP, 0.5 .mu.Ci
[.gamma.-.sup.33P] ATP, 13 nM PI3K.gamma.. Reactions were incubated
for 120 min and terminated by the addition of 40 .mu.L SPA beads
suspended in quench buffer: 163 mM potassium phosphate pH 7.8, 20%
glycerol, 25 mM EDTA. The final concentration of SPA beads is 1.0
mg/mL. After the plate sealing, plates were shaken overnight at
room temperature and centrifuged at 1500 rpm for 10 min, the
radioactivity of the product was determined by scintillation
counting on Topcount (Perkin-Elmer). IC.sub.50 determination was
performed by fitting the curve of percent of the solvent control
activity versus the log of the inhibitor concentration using the
GraphPad Prism 6.0 software. Data for the Examples, obtained using
the methods described in Example B, are provided in Table B.
Example C. PI3K.delta. Scintillation Proximity Assay
[0822] Materials
[0823] [.gamma.-.sup.33P]ATP (10 mCi/mL) and Wheat Germ Agglutinin
(WGA) YSi SPA Scintillation Beads was purchased from Perkin-Elmer
(Waltham, Mass.). Lipid kinase substrate,
D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D
(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS
204858-53-7, was purchased from Echelon Biosciences (Salt Lake
City, Utah). PI3K.delta. (p110.delta./p85.alpha.) Recombinant Human
Protein was purchased from Eurofins (St Charles, Mo.). ATP,
MgCl.sub.2, DTT, EDTA, MOPS and CHAPS were purchased from
Sigma-Aldrich (St. Louis, Mo.).
[0824] The kinase reaction was conducted in polystyrene 384-well
Greiner Bio-one white plate from Thermo Fisher Scientific in a
final volume of 25 .mu.L. Inhibitors were first diluted serially in
DMSO and added to the plate wells before the addition of other
reaction components. The final concentration of DMSO in the assay
was 2%. The PI3K.delta. assay was carried out at room temperature
in 20 mM MOPS, pH 6.7, 10 mM MgCl.sub.2, 5 mM DTT and CHAPS 0.03%.
Reactions were initiated by the addition of ATP, the final reaction
mixture consisted of 20 .mu.M PIP2, 2 .mu.M ATP, 0.5 .mu.Ci
[.gamma.-.sup.33P] ATP, 3.4 nM PI3K.delta.. Reactions were
incubated for 120 min and terminated by the addition of 40 .mu.L
SPA beads suspended in quench buffer: 163 mM potassium phosphate pH
7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads
is 1.0 mg/mL. After the plate sealing, plates were shaken overnight
at room temperature and centrifuged at 1500 rpm for 10 min, the
radioactivity of the product was determined by scintillation
counting on Topcount (Perkin-Elmer). IC.sub.50 determination was
performed by fitting the curve of percent of the solvent control
activity versus the log of the inhibitor concentration using the
GraphPad Prism 6.0 software.
[0825] Data for the Examples, obtained using the methods described
in Example C, are provided in Table B.
TABLE-US-00026 TABLE B Example # PI3K-gamma SPA IC50 (nM)
PI3K-delta SPA IC50 (nM) 1 .dagger.
.dagger..dagger..dagger..dagger. 5 .dagger..dagger. .dagger. 6
.dagger..dagger. .dagger..dagger..dagger. 7 .dagger..dagger.
.dagger..dagger..dagger. 8 .dagger..dagger..dagger.
.dagger..dagger..dagger. 9 .dagger..dagger.
.dagger..dagger..dagger. 10 .dagger..dagger..dagger.
.dagger..dagger..dagger. 11 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 12 .dagger..dagger..dagger.
.dagger..dagger..dagger. 13 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 14
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
16 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 17 .dagger. .dagger. 18 .dagger.
.dagger. 19 .dagger. .dagger. 20 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 21 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 25
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
26 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 30
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
31 .dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 32
.dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 33
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 34
.dagger..dagger..dagger. .dagger..dagger..dagger. 35
.dagger..dagger..dagger. .dagger..dagger..dagger. 37
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
40 .dagger. .dagger. 41 .dagger..dagger..dagger..dagger. .dagger.
43 .dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 44
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 45
.dagger..dagger..dagger. .dagger..dagger..dagger. 46
.dagger..dagger. .dagger..dagger..dagger. 47
.dagger..dagger..dagger. .dagger. 48
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
49 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 50
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
51 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 52
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 53
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
54 .dagger..dagger. .dagger..dagger. 55 .dagger..dagger..dagger.
.dagger..dagger..dagger. 56 .dagger..dagger. .dagger..dagger. 57
.dagger..dagger..dagger. .dagger..dagger. 58
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
59 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 60 .dagger..dagger..dagger.
.dagger..dagger..dagger. 61 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 62 .dagger..dagger.
.dagger..dagger..dagger..dagger. 63 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 64 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 65 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 66 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 67 .dagger..dagger..dagger.
.dagger..dagger..dagger. 68 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 70 .dagger..dagger..dagger.
.dagger..dagger..dagger. 71 .dagger..dagger..dagger.
.dagger..dagger..dagger. 72 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 73
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
74 .dagger. .dagger. 75 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 76 .dagger. .dagger..dagger. 77
.dagger. .dagger..dagger..dagger. 78 .dagger..dagger..dagger.
.dagger..dagger..dagger. 79 .dagger. .dagger..dagger..dagger. 80
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
81 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 82 .dagger. .dagger. 83 .dagger.
.dagger. 84 .dagger..dagger. .dagger..dagger..dagger. 85
.dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 86
.dagger. .dagger..dagger..dagger. 87 .dagger..dagger. .dagger. 88
.dagger..dagger..dagger. .dagger. 94 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 95
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
97 .dagger. .dagger..dagger..dagger. 98 .dagger..dagger.
.dagger..dagger. 99 .dagger. .dagger..dagger..dagger. 100
.dagger..dagger..dagger. .dagger..dagger..dagger. 101
.dagger..dagger..dagger. .dagger..dagger..dagger. 102
.dagger..dagger. .dagger. 103 .dagger..dagger. .dagger. 104
.dagger. .dagger. 105 .dagger..dagger. .dagger..dagger. 106
.dagger. .dagger. 107 .dagger..dagger. .dagger..dagger. 108
.dagger. .dagger. 109 .dagger. .dagger. 110 .dagger. .dagger. 111
.dagger. .dagger. 112 .dagger. .dagger. 113 .dagger. .dagger. 114
.dagger. .dagger. 115 .dagger. .dagger. 116 .dagger. .dagger. 117
.dagger. .dagger. 118 .dagger. .dagger. 119 .dagger.
.dagger..dagger..dagger..dagger. 120 .dagger..dagger. .dagger. 121
.dagger. .dagger. 122 .dagger..dagger..dagger.
.dagger..dagger..dagger. 123 .dagger. .dagger. 124
.dagger..dagger..dagger. .dagger..dagger..dagger. 125
.dagger..dagger. .dagger. 126 .dagger..dagger..dagger.
.dagger..dagger..dagger. 127 .dagger. .dagger. 128
.dagger..dagger..dagger. .dagger..dagger..dagger. 129
.dagger..dagger. .dagger..dagger..dagger. 130 .dagger. .dagger. 131
.dagger. .dagger. 132 .dagger..dagger..dagger.
.dagger..dagger..dagger. 133 .dagger..dagger..dagger.
.dagger..dagger. 134 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 135
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 136
.dagger..dagger..dagger. .dagger..dagger..dagger. 137
.dagger..dagger..dagger. .dagger..dagger..dagger. 138
.dagger..dagger..dagger. .dagger..dagger. 139
.dagger..dagger..dagger. .dagger..dagger. 140 .dagger..dagger.
.dagger. 141 .dagger. .dagger. 142 .dagger. .dagger. 143
.dagger..dagger. .dagger..dagger. 144 .dagger..dagger.
.dagger..dagger. 145 .dagger. .dagger..dagger..dagger. .sup. 145B
.dagger. .dagger. .sup. 145C .dagger. .dagger. 146 .dagger.
.dagger. 147 .dagger..dagger..dagger. .dagger..dagger..dagger. 148
.dagger..dagger. .dagger..dagger..dagger. 149 .dagger..dagger.
.dagger..dagger..dagger..dagger. 150 .dagger..dagger..dagger.
.dagger..dagger. 151 .dagger. .dagger. 152 .dagger. .dagger. 153
.dagger. .dagger. 154 .dagger. .dagger..dagger. 155 .dagger.
.dagger. 156 .dagger. .dagger. 157 .dagger..dagger.
.dagger..dagger..dagger. 158 .dagger. .dagger..dagger. 159 .dagger.
.dagger..dagger. 160 .dagger. .dagger..dagger..dagger. 161 .dagger.
.dagger..dagger. 162 .dagger..dagger..dagger.
.dagger..dagger..dagger. 163 .dagger. .dagger. 164
.dagger..dagger..dagger. .dagger. 165 .dagger. .dagger..dagger. 166
.dagger..dagger. .dagger. 167 .dagger..dagger.
.dagger..dagger..dagger. 168 .dagger. .dagger. 169 .dagger..dagger.
.dagger. 170 .dagger..dagger. .dagger. 171 .dagger..dagger.
.dagger..dagger. 172 .dagger. .dagger. 173 .dagger. .dagger. 174
.dagger. .dagger. 175 .dagger. .dagger. 176 .dagger..dagger.
.dagger..dagger..dagger. 177 .dagger..dagger. .dagger..dagger. 178
.dagger. .dagger. 179 .dagger. .dagger..dagger. 180 .dagger.
.dagger. 181 .dagger..dagger. .dagger. 182 .dagger..dagger..dagger.
.dagger..dagger..dagger. 183 .dagger. .dagger. 184 .dagger.
.dagger. 185 .dagger. .dagger..dagger. 186 .dagger. .dagger. 187
.dagger. .dagger..dagger. 188 .dagger..dagger..dagger.
.dagger..dagger..dagger. 189 .dagger..dagger. .dagger. 190 .dagger.
.dagger..dagger. 191 .dagger. .dagger. 192 .dagger..dagger.
.dagger..dagger. 193 .dagger. .dagger. 194 .dagger. .dagger. 195
.dagger..dagger..dagger. .dagger..dagger..dagger. 196
.dagger..dagger..dagger. .dagger. 197 .dagger..dagger. .dagger. 198
.dagger. .dagger. 199 .dagger. .dagger. 200
.dagger..dagger..dagger. .dagger..dagger..dagger. 201 .dagger.
.dagger..dagger..dagger. 202 .dagger..dagger. .dagger..dagger. 203
.dagger. .dagger..dagger. 204 .dagger..dagger. .dagger. 205
.dagger. .dagger..dagger. 206 .dagger..dagger. .dagger..dagger. 207
.dagger. .dagger..dagger..dagger. 208 .dagger. .dagger..dagger. 209
.dagger..dagger. .dagger..dagger. 210 .dagger..dagger.
.dagger..dagger..dagger. 211 .dagger. .dagger. 212 .dagger.
.dagger. .sup. 212B .dagger. .dagger..dagger. 214 .dagger.
.dagger..dagger..dagger. 215 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 217
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
219 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 220 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 221 .dagger..dagger.
.dagger..dagger..dagger. 222 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 223
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
224 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 225
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
226 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 227
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
228 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 229
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
230 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 231 .dagger. .dagger..dagger. 232
.dagger..dagger. .dagger..dagger..dagger. 233 .dagger.
.dagger..dagger..dagger. 234 .dagger..dagger. .dagger..dagger. 235
.dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 236
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
237 .dagger. .dagger. 238 .dagger..dagger..dagger..dagger.
.dagger..dagger..dagger. 239 .dagger..dagger..dagger.
.dagger..dagger..dagger. 240 .dagger..dagger.
.dagger..dagger..dagger. 241 .dagger..dagger. .dagger. 242 .dagger.
.dagger..dagger..dagger..dagger. 243 .dagger. .dagger. 244
.dagger..dagger. .dagger. 245 .dagger. .dagger. 246
.dagger..dagger..dagger. .dagger..dagger..dagger. 247 .dagger.
.dagger. 248 .dagger. .dagger. 249 .dagger. .dagger. 250 .dagger.
.dagger. 251 .dagger..dagger..dagger. .dagger..dagger. 252 .dagger.
.dagger. 253 .dagger. .dagger. 254 .dagger. .dagger. 255 .dagger.
.dagger. 256 .dagger. .dagger. 257 .dagger..dagger..dagger.
.dagger..dagger..dagger..dagger. 258 .dagger. .dagger. 259
.dagger..dagger..dagger. .dagger..dagger..dagger. 260
.dagger..dagger..dagger. .dagger..dagger..dagger. 261
.dagger..dagger..dagger. .dagger..dagger..dagger. 262 .dagger.
.dagger. 263 .dagger..dagger. .dagger. 264 .dagger..dagger.
.dagger. 265 .dagger. .dagger. 266 .dagger. .dagger. 267 .dagger.
.dagger.
268 .dagger. .dagger. 269 .dagger. .dagger. 270 .dagger. .dagger.
271 .dagger. .dagger. 272 .dagger. .dagger. 273 .dagger. .dagger.
274 .dagger. .dagger. 275 .dagger. .dagger. 276 .dagger..dagger.
.dagger. 277 .dagger. .dagger. 278 .dagger. .dagger. 279
.dagger..dagger. .dagger. 280 .dagger..dagger..dagger. .dagger. 281
.dagger. .dagger. 282 .dagger. .dagger. 283
.dagger..dagger..dagger..dagger. .dagger..dagger. 284
.dagger..dagger..dagger..dagger. .dagger..dagger. 285
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 286
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 287
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 288
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger. 289
.dagger..dagger..dagger..dagger. .dagger. 290
.dagger..dagger..dagger..dagger. .dagger..dagger. 291
.dagger..dagger..dagger..dagger. .dagger. 292
.dagger..dagger..dagger. .dagger..dagger. 293 N/A N/A 294 .dagger.
.dagger..dagger..dagger..dagger. 295 .dagger.
.dagger..dagger..dagger. 296 .dagger.
.dagger..dagger..dagger..dagger. 297 .dagger.
.dagger..dagger..dagger..dagger. 298 .dagger. .dagger. 299 .dagger.
.dagger. 300 .dagger. .dagger..dagger..dagger. 301
.dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 302
.dagger..dagger..dagger. .dagger..dagger..dagger. 303
.dagger..dagger..dagger. .dagger..dagger..dagger..dagger. 304
.dagger..dagger. .dagger..dagger..dagger. 305
.dagger..dagger..dagger. .dagger..dagger..dagger. 306
.dagger..dagger..dagger..dagger. .dagger..dagger..dagger..dagger.
307 .dagger..dagger..dagger. .dagger. 308 .dagger..dagger..dagger.
.dagger. .dagger. refers to IC.sub.50 of .ltoreq.50 nM
.dagger..dagger. refers to IC.sub.50 of .ltoreq.100 nM
.dagger..dagger..dagger. refers to an IC.sub.50 of .ltoreq.500 nM
.dagger..dagger..dagger..dagger. refers to an IC.sub.50 of >500
nM N/A refers to not available
[0826] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference,
including all patent, patent applications, and publications, cited
in the present application is incorporated herein by reference in
its entirety.
* * * * *