U.S. patent application number 15/906655 was filed with the patent office on 2019-03-07 for heterocyclic compounds as immunomodulators.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Zhenwu Li, Liangxing Wu, Wenqing Yao.
Application Number | 20190071439 15/906655 |
Document ID | / |
Family ID | 58709629 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190071439 |
Kind Code |
A1 |
Li; Zhenwu ; et al. |
March 7, 2019 |
HETEROCYCLIC COMPOUNDS AS IMMUNOMODULATORS
Abstract
Disclosed are compounds of Formula (I), methods of using the
compounds as immunomodulators, and pharmaceutical compositions
comprising such compounds. The compounds are useful in treating,
preventing or ameliorating diseases or disorders such as cancer or
infections. ##STR00001##
Inventors: |
Li; Zhenwu; (Wilmington,
DE) ; Wu; Liangxing; (Wilmington, DE) ; Yao;
Wenqing; (Chadds Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
58709629 |
Appl. No.: |
15/906655 |
Filed: |
February 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15587466 |
May 5, 2017 |
|
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15906655 |
|
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62332655 |
May 6, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 31/12 20180101; C07D 513/04 20130101; A61P 35/00 20180101;
C07D 471/04 20130101; C07D 487/04 20130101; C07D 498/04
20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 513/04 20060101 C07D513/04; C07D 487/04 20060101
C07D487/04; C07D 498/04 20060101 C07D498/04 |
Claims
1. A compound of Formula (I): ##STR00112## or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein: X.sup.1 is O,
S, N, NR.sup.1 or CR.sup.1; X.sup.2 is N or C; X.sup.3 is O, S, N,
NR.sup.3 or CR.sup.3; X.sup.4 is N or CR.sup.4; X.sup.5 is N or
CR.sup.5; X.sup.6 is N or CR.sup.6; Y is C or N; at least one of
X.sup.1, X.sup.2, X.sup.3 and Y is a heteroatom selected from N, O
and S, wherein N is optionally substituted by R.sup.1 or R.sup.3;
Cy is C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5- to 14-membered
heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is
optionally substituted with 1 to 5 independently selected R.sup.7
substituents; R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
each independently selected from H, C.sub.1-4 alkyl, C.sub.3-4
cycloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, CN, OH,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
NH.sub.2, --NH--C.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2,
NHOR.sup.10, C(O)R.sup.10, C(O)NR.sup.10R.sup.10, C(O)OR.sup.10,
OC(O)R.sup.10, OC(O)NR.sup.10R.sup.10, NR.sup.10C(O)R.sup.10,
NR.sup.10C(O)OR.sup.10, NR.sup.10C(O)NR.sup.10R.sup.10,
C(.dbd.NR.sup.10)R.sup.10, C(.dbd.NR.sup.10)NR.sup.10R.sup.10,
NR.sup.10C(.dbd.NR.sup.10)NR.sup.10R.sup.10, NR.sup.10S(O)R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NR.sup.10S(O).sub.2NR.sup.10R.sup.10,
S(O)R.sup.10, S(O)NR.sup.10R.sup.10, S(O).sub.2R.sup.10, and
S(O).sub.2NR.sup.10R.sup.10, wherein each R.sup.10 is independently
selected from H and C.sub.1-4 alkyl optionally substituted with 1
or 2 groups independently selected from halo, OH, CN and C.sub.1-4
alkoxy; and wherein the C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of
R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN and C.sub.1-4 alkoxy; R.sup.9 is C.sub.1-4 alkyl,
halo, CN, OH, cyclopropyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
NH.sub.2, --NH--C.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2,
NHOR.sup.11, C(O)R.sup.11, C(O)NR.sup.11R.sup.11, C(O)OR.sup.11,
OC(O)R.sup.11, OC(O)NR.sup.11R.sup.11, NR.sup.11C(O)R.sup.11,
NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.11,
C(.dbd.NR.sup.11)R.sup.11, C(.dbd.NR.sup.11)NR.sup.11R.sup.11,
NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.11, NR.sup.11S(O)R.sup.11,
NR.sup.11S(O).sub.2R.sup.11, NR.sup.11S(O).sub.2NR.sup.11R.sup.11,
S(O)R.sup.11, S(O)NR.sup.11R.sup.11, S(O).sub.2R.sup.11, and
S(O).sub.2NR.sup.11R.sup.11, wherein C.sub.1-4 alkyl, cyclopropyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of
R.sup.9 are each optionally substituted with 1 or 2 substituents
selected from halo, OH, CN and OCH.sub.3 and each R.sup.11 is
independently selected from H and C.sub.1-4 alkyl optionally
substituted with 1 or 2 halo, OH, CN or OCH.sub.3 substituents;
R.sup.7, R.sup.13 and R.sup.14 are each independently selected from
H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN,
NO.sub.2, OR.sup.a, SR.sup.a, NHOR.sup.a, C(O)R.sup.a,
C(O)NR.sup.aR.sup.a, C(O)OR.sup.a, OC(O)R.sup.a,
OC(O)NR.sup.aR.sup.a, NHR.sup.a, NR.sup.aR.sup.a,
NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a,
NR.sup.aC(O)NR.sup.aR.sup.a, C(.dbd.NR.sup.a)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
NR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a, NR.sup.aS(O)R.sup.a,
NR.sup.aS(O).sub.2R.sup.a, NR.sup.aS(O).sub.2NR.sup.aR.sup.a,
S(O)R.sup.a, S(O)NR.sup.aR.sup.a, S(O).sub.2R.sup.a, and
S(O).sub.2NR.sup.aR.sup.a, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.7, R.sup.13
and R.sup.14 are each optionally substituted with 1, 2, 3, or 4
R.sup.b substituents; or two adjacent R.sup.7 substituents on the
Cy ring, taken together with the atoms to which they are attached,
form a fused phenyl ring, a fused 5-, 6- or 7-membered
heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or
a fused C.sub.3-6 cycloalkyl ring, wherein the fused 5-, 6- or
7-membered heterocycloalkyl ring and fused 5- or 6-membered
heteroaryl ring each have 1-4 heteroatoms as ring members selected
from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or
7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl
ring and fused C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2 or 3 independently selected R.sup.b
substituents; or two R.sup.13 substituents attached to the same
carbon atom, taken together with the carbon atom to which they are
attached, form a C.sub.3-6 cycloalkyl ring or 4-, 5-, 6- or
7-membered heterocycloalkyl ring, wherein the C.sub.3-6 cycloalkyl
ring and 4-, 5-, 6- or 7-membered heterocycloalkyl ring are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents; each R.sup.a is independently selected from
H, CN, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents; each R.sup.d is independently selected from
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, halo, C.sub.3-10 cycloalkyl,
4-10 membered heterocycloalkyl, CN, NH.sub.2, NHOR.sup.e, OR.sup.e,
SR.sup.e, C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e,
OC(O)R.sup.e, OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-4 alkyl, C.sub.3-10 cycloalkyl and 4-10
membered heterocycloalkyl of R.sup.d are each further optionally
substituted with 1-3 independently selected R.sup.q substituents;
each R.sup.b substituent is independently selected from halo,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NRCS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-(5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.b are each further optionally substituted with 1-3
independently selected R.sup.d substituents; each R.sup.c is
independently selected from H, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.c are each optionally
substituted with 1, 2, 3, 4, or 5 R.sup.f substituents
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, halo,
CN, NHOR.sup.g, OR.sup.g, SR.sup.g, C(O)R.sup.g,
C(O)NR.sup.gR.sup.g, C(O)OR.sup.g, OC(O)R.sup.g,
OC(O)NR.sup.gR.sup.g, NHR.sup.g, NR.sup.gR.sup.g,
NR.sup.gC(O)R.sup.g, NR.sup.gC(O)NR.sup.gR.sup.g,
NR.sup.gC(O)OR.sup.g, C(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NR.sup.g)NR.sup.gR.sup.g, S(O)R.sup.g,
S(O)NR.sup.gR.sup.g, S(O).sub.2R.sup.g NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, and S(O).sub.2NR.sup.gR.sup.g;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.f are each
optionally substituted with 1, 2, 3, 4, or 5 R.sup.n substituents
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
halo, CN, NHOR.sup.o, OR.sup.o, SR.sup.o, C(O)R.sup.o,
C(O)NR.sup.oR.sup.o, C(O)OR.sup.o, OC(O)R.sup.o,
OC(O)NR.sup.oR.sup.o, NHR.sup.o, NR.sup.oR.sup.o,
NR.sup.oC(O)R.sup.o, NR.sup.oC(O)NR.sup.oR.sup.o,
NR.sup.oC(O)OR.sup.o, C(.dbd.NR)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR)NR.sup.oR.sup.o, S(O)R.sup.o,
S(O)NR.sup.oR.sup.o, S(O).sub.2R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and S(O).sub.2NR.sup.oR.sup.o;
each R.sup.g is independently selected from H, C.sub.1-6 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.g are each optionally substituted with 1-3 independently
selected R.sup.p substituents; or any two R.sup.a substituents
together with the nitrogen atom to which they are attached form a
4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group
optionally substituted with 1, 2 or 3 R.sup.h substituents
independently selected from C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl,
4-7 membered heterocycloalkyl, C.sub.6-10 aryl, 5-6 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, SR.sup.i,
NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i, C(O)OR.sup.i,
OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i, NR.sup.iR.sup.i, NR
C(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i, NR C(O)OR.sup.i,
C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-7 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-6 membered heteroaryl,
C.sub.3-10cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents
independently selected from C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
5 or 6-membered heteroaryl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN, NHOR.sup.k,
OR.sup.k, SR.sup.k, C(O)R.sup.k, C(O)NR.sup.kR.sup.k, C(O)OR.sup.k,
OC(O)R.sup.k, OC(O)NR.sup.kR.sup.k, NHR.sup.k, NR.sup.kR.sup.k,
NR.sup.kC(O)R.sup.k, NR.sup.kC(O)NR.sup.kR.sup.k,
NR.sup.kC(O)OR.sup.k, C(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NR.sup.k)NR.sup.kR.sup.k, S(O)R.sup.k,
S(O)NR.sup.kR.sup.k, S(O).sub.2R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, and S(O).sub.2NR.sup.kR.sup.k;
or two R.sup.h groups attached to the same carbon atom of the 4- to
10-membered heterocycloalkyl taken together with the carbon atom to
which they are attached form a C.sub.3-6 cycloalkyl or 4- to
6-membered heterocycloalkyl having 1-2 heteroatoms as ring members
selected from O, N or S; or any two R.sup.c substituents together
with the nitrogen 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.h substituents; or any
two R.sup.e substituents together with the nitrogen 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.h substituents; or any two R.sup.g substituents together with
the nitrogen 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.h substituents; or any two
R.sup.i substituents together with the nitrogen 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.h substituents; or any two R.sup.k substituents together with
the nitrogen 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.h substituents; or any two R.sup.o substituents together with
the nitrogen 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.h substituents; and each R.sup.e,
R.sup.i, R.sup.k, R.sup.o or R.sup.p is independently selected from
H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or
6-membered heteroaryl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, and
C.sub.2-4 alkynyl, wherein the C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered heteroaryl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl of R.sup.e, R.sup.i, R.sup.k,
R.sup.o or R.sup.p are each optionally substituted with 1, 2 or 3
R.sup.q substituents; each R.sup.q is independently selected from
OH, CN, --COOH, NH.sub.2, halo, C.sub.1-6haloalkyl, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylthio,
phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,
C.sub.3-6 cycloalkyl, NHR.sup.12, NR.sup.12R.sup.12, and C.sub.1-4
haloalkoxy, wherein the C.sub.1-6 alkyl, phenyl, C.sub.3-6
cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered
heteroaryl of R.sup.q are each optionally substituted with halo,
OH, CN, --COOH, NH.sub.2, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl and 4-6
membered heterocycloalkyl and each R.sup.12 is independently
C.sub.1-6 alkyl; is a single bond or a double bond to maintain ring
A being aromatic; the subscript n is an integer of 1, 2, 3, 4, 5 or
6; and when R.sup.9 is OH, Cy is other than
6-carbamimidoyl-1H-benzo[d]imidazol-2-yl.
2. The compound of claim 1, having Formula (II): ##STR00113## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
3. The compound of claim 2, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.4, R.sup.5 and R.sup.6 are
each H.
4. The compound of claim 1, having Formula (III): ##STR00114## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
5. The compound of claim 1, having Formula (IV): ##STR00115## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
6. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein Cy is phenyl, 5- or 6-membered
heteroaryl, C.sub.3-6 cycloalkyl or 5- or 6-membered
heterocycloalkyl, each of which is optionally substituted with 1 to
5 independently selected R.sup.7 substituents.
7. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein Cy is phenyl, 2-thiophenyl,
3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C.sub.3-6 cycloalkyl
or 3,6-dihydro-2H-pyran-4-yl, each of which is optionally
substituted with 1 to 5 R.sup.7 substituents.
8. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein Cy is phenyl optionally
substituted with 1 to 5 R.sup.7 substituents.
9. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein Cy is unsubstituted phenyl.
10. The compound of claim 1, having Formula (V): ##STR00116## or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
the subscript m is an integer of 1, 2, 3, 4 or 5.
11. The compound of claim 1, having Formula (VI): ##STR00117## or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
m is an integer of 1, 2, 3 or 4.
12. The compound of claim 1, having Formula (VII): ##STR00118## or
a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein m is an integer of 1, 2 or 3.
13. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.9 is CH.sub.3, CN or
halo.
14. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the moiety: ##STR00119## is
selected from: ##STR00120## ##STR00121##
15. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is S, and Y is C.
16. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is S, X.sup.2 is C,
X.sup.3 is N, and Y is C.
17. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is CR.sup.3, and Y is N.
18. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is NR.sup.3, and Y is C.
19. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is S, X.sup.6 is N, and Y is C.
20. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is N,
X.sup.3 is CR.sup.3, and Y is C.
21. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is CR.sup.1, X.sup.2 is
N, X.sup.3 is N, and Y is C.
22. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is CR.sup.1, X.sup.2 is
C, X.sup.3 is N, and Y is N.
23. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is NR.sup.1, X.sup.2 is
C, X.sup.3 is N, and Y is C.
24. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is O, and Y is C.
25. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is O, X.sup.2 is C,
X.sup.3 is N, and Y is C.
26. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is N, and Y is N.
27. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X.sup.1 is N, X.sup.2 is C,
X.sup.3 is S, X.sup.4 is N, and Y is C.
28. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 when present are each H.
29. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.14 is 2-hydroxyethyl,
2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl,
tetrahydro-2H-pyran-4-yl, 4-carboxycyclohexyl, 3-carboxypropyl,
2-carboxycyclopropylmethyl, 1H-pyrazol-4-ylmethyl or
4-cyanomethylcyclohexyl.
30. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.13 is H or C.sub.1-6
alkyl.
31. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the compound is selected from
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine;
5-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-
pyridine;
2-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyri-
din-5(4H)-yl]ethanol;
(2S)-1-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin--
5 (4H)-yl]propan-2-ol;
2-(2-methylbiphenyl-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-
[1,3]thiazolo[5,4-c]pyridine;
4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-
-yl]cyclohexanecarboxylic acid;
4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-
-yl]butanoic acid;
trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridi-
n-5(4H)-yl]methyl}cyclopropanecarboxylic acid;
2-(2-methylbiphenyl-3-yl)-5-(1H-pyrazol-4-ylmethyl)-4,5,6,7-tetrahydro[1,-
3]thiazolo[5,4-c]pyridine;
{4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5
(4H)-yl]cyclohexyl}acetonitrile;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine;
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,5,6,7-tetrahydro[1,3]thiazolo[5-
,4-c]pyridin-2-yl)benzonitrile;
2-(3-methyl-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]p-
yridine;
2-[4-(3-methoxyphenyl)-3-methylpyridin-2-yl]-4,5,6,7-tetrahydro[1-
,3]thiazolo[5,4-c]pyridine;
2-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-2-yl]-4,5,6,7-tet-
rahydro[1,3]thiazolo[5,4-c]pyridine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;
7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,-
4-c]pyridine;
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine;
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine;
5-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]p-
yridine;
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a-
]pyrazine;
2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-4-
,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine;
2-[2-methyl-3-(3-thienyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]py-
ridine;
2-(3'-methoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazo-
lo[5,4-c]pyridine;
2-[3-(3,6-dihydro-2H-pyran-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]t-
hiazolo[5,4-c]pyridine;
2-[3-(2-methoxypyridin-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiaz-
olo[5,4-c]pyridine;
2-[3-(5-fluoropyridin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazo-
lo[5,4-c]pyridine;
2-(3-cyclohex-1-en-1-yl-2-methylphenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5-
,4-c]pyridine;
2-(3'-ethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c-
]pyridine;
2-(3',5'-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,-
3]thiazolo[5,4-c]pyridine;
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4,5,6,7-tetrahydro[1,3]thiazolo[5-
,4-c]pyridin-2-yl)nicotinonitrile;
2-{[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biph-
enyl-3-yl]oxy}ethanol;
2-(2',6'-difluoro-3',5'-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahyd-
ro[1,3]thiazolo[5,4-c]pyridine;
2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-
-3-carboxamide;
2-[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphe-
nyl-3-yl]acetamide; and
2-[2-methyl-3-(1-methyl-1H-indazol-4-yl)phenyl]-4,5,6,7-tetrahydro[1,3]th-
iazolo[5,4-c]pyridine.
32. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or a stereoisomer thereof,
and at least one pharmaceutically acceptable carrier or
excipient.
33. A method of inhibiting PD-1/PD-L1 interaction, said method
comprising administering to an individual a compound of claim 1, or
a pharmaceutically acceptable salt or a stereoisomer thereof.
34. A method of treating a disease or disorder associated with
inhibition of PD-1/PD-L1 interaction, said method comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt or a stereoisomer thereof.
35. The method of claim 34, wherein the disease or disorder is a
viral infection or cancer.
36. A method of enhancing, stimulating and/or increasing the immune
response in a patient, said method comprising administering to the
patient in need thereof a therapeutically effective amount of a
compound of claim 1, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
Description
FIELD OF THE INVENTION
[0001] The present application is concerned with pharmaceutically
active compounds. The disclosure provides compounds as well as
their compositions and methods of use. The compounds modulate
PD-1/PD-L1 protein/protein interaction and are useful in the
treatment of various diseases including infectious diseases and
cancer.
BACKGROUND OF THE INVENTION
[0002] The immune system plays an important role in controlling and
eradicating diseases such as cancer. However, cancer cells often
develop strategies to evade or to suppress the immune system in
order to favor their growth. One such mechanism is altering the
expression of co-stimulatory and co-inhibitory molecules expressed
on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9).
Blocking the signaling of an inhibitory immune checkpoint, such as
PD-1, has proven to be a promising and effective treatment
modality.
[0003] Programmed cell death-1 (PD-1), also known as CD279, is a
cell surface receptor expressed on activated T cells, natural
killer T cells, B cells, and macrophages (Greenwald et al, Annu.
Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol
2006, (4): 195-201). It functions as an intrinsic negative feedback
system to prevent the activation of T-cells, which in turn reduces
autoimmunity and promotes self-tolerance. In addition, PD-1 is also
known to play a critical role in the suppression of
antigen-specific T cell response in diseases like cancer and viral
infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al,
J. Clinical Oncol 2015, 1-9).
[0004] The structure of PD-1 consists of an extracellular
immunoglobulin variable-like domain followed by a transmembrane
region and an intracellular domain (Parry et al, Mol Cell Biol
2005, 9543-9553). The intracellular domain contains two
phosphorylation sites located in an immunoreceptor tyrosine-based
inhibitory motif and an immunoreceptor tyrosine-based switch motif,
which suggests that PD-1 negatively regulates T cell
receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2
(Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat
Immunol 2001, 2, 261-268), and they differ in their expression
patterns. PD-L1 protein is upregulated on macrophages and dendritic
cells in response to lipopolysaccharide and GM-CSF treatment, and
on T cells and B cells upon T cell receptor and B cell receptor
signaling. PD-L1 is also highly expressed on almost all tumor
cells, and the expression is further increased after IFN-.gamma.
treatment (Iwai et al, PNAS 2002, 99(19):12293-7; Blank et al,
Cancer Res 2004, 64(3):1140-5). In fact, tumor PD-L1 expression
status has been shown to be prognostic in multiple tumor types
(Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015;
Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2
expression, in contrast, is more restricted and is expressed mainly
by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73).
Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells
delivers a signal that inhibits IL-2 and IFN-.gamma. production, as
well as cell proliferation induced upon T cell receptor activation
(Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J
Exp Med 2000, 192(7): 1027-34). The mechanism involves recruitment
of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling
such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol
2007, 8, 239-245). Activation of the PD-1 signaling axis also
attenuates PKC-.theta. activation loop phosphorylation, which is
necessary for the activation of NF-.kappa.B and API pathways, and
for cytokine production such as IL-2, IFN-.gamma. and TNF (Sharpe
et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol
2002, 32(3):634-43; Freeman et al, J Exp Med 2000,
192(7):1027-34).
[0005] Several lines of evidence from preclinical animal studies
indicate that PD-1 and its ligands negatively regulate immune
responses. PD-1-deficient mice have been shown to develop
lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura
et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001,
291:319-322). Using an LCMV model of chronic infection, it has been
shown that PD-1/PD-L1 interaction inhibits activation, expansion
and acquisition of effector functions of virus-specific CD8 T cells
(Barber et al, Nature 2006, 439, 682-7). Together, these data
support the development of a therapeutic approach to block the
PD-1-mediated inhibitory signaling cascade in order to augment or
"rescue" T cell response. Accordingly, there is a need for new
compounds that block PD-1/PD-L1 protein/protein interaction.
SUMMARY
[0006] The present disclosure provides, inter alia, a compound of
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein constituent variables are defined herein.
[0007] The present disclosure further provides a pharmaceutical
composition comprising a compound of the disclosure, or a
pharmaceutically acceptable salt or a stereoisomer thereof, and at
least one pharmaceutically acceptable carrier or excipient.
[0008] The present disclosure further provides methods of
modulating or inhibiting PD-1/PD-L1 protein/protein interaction,
which comprises administering to an individual a compound of the
disclosure, or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0009] The present disclosure further provides methods of treating
a disease or disorder in a patient comprising administering to the
patient a therapeutically effective amount of a compound of the
disclosure, or a pharmaceutically acceptable salt or a stereoisomer
thereof.
DETAILED DESCRIPTION
I. Compounds
[0010] The present disclosure provides a compound of Formula
(I):
##STR00003##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0011] X.sup.1 is O, S, N, NR.sup.1 or CR.sup.1;
[0012] X.sup.2 is N or C;
[0013] X.sup.3 is O, S, N, NR.sup.3 or CR.sup.3;
[0014] X.sup.4 is N or CR.sup.4;
[0015] X.sup.5 is N or CR.sup.5;
[0016] X.sup.6 is N or CR.sup.6;
[0017] Y is C or N;
[0018] at least one of X.sup.1, X.sup.2, X.sup.3 and Y is a
heteroatom selected from N, O and S;
[0019] Cy is C.sub.6-10 aryl, C.sub.3-10cycloalkyl, 5- to
14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each
of which is optionally substituted with 1 to 5 independently
selected R.sup.7 substituents;
[0020] R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each
independently selected from H, C.sub.1-4 alkyl, C.sub.3-4
cycloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, CN, OH,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
NH.sub.2, --NH--C.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2,
NHOR.sup.10, C(O)R.sup.10, C(O)NR.sup.10R.sup.10, C(O)OR.sup.10,
OC(O)R.sup.10, OC(O)NR.sup.10R.sup.10, NR.sup.10C(O)R.sup.10,
NR.sup.10C(O)OR.sup.10, NR.sup.10C(O)NR.sup.10R.sup.10,
C(.dbd.NR.sup.10)R.sup.10, C(.dbd.NR.sup.10)NR.sup.10R.sup.10,
NR.sup.10C(.dbd.NR.sup.10)NR.sup.10R.sup.10, NR.sup.10S(O)R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NR.sup.10S(O).sub.2NR.sup.10R.sup.10,
S(O)R.sup.10, S(O)NR.sup.10R.sup.10, S(O).sub.2R.sup.10, and
S(O).sub.2NR.sup.10R.sup.10, wherein each R.sup.10 is independently
selected from H and C.sub.1-4 alkyl optionally substituted with 1
or 2 groups independently selected from halo, OH, CN and C.sub.1-4
alkoxy; and wherein the C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of
R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN and C.sub.1-4 alkoxy;
[0021] R.sup.9 is C.sub.1-4 alkyl, halo, CN, OH, cyclopropyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, NH.sub.2, --NH--C.sub.1-4 alkyl,
--N(C.sub.1-4 alkyl).sub.2, NHOR.sup.11, C(O)R.sup.11,
C(O)NR.sup.11R.sup.11, C(O)OR.sup.11, OC(O)R.sup.11,
OC(O)NR.sup.11R.sup.11, NR.sup.11C(O)R.sup.11,
NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.11,
C(.dbd.NR.sup.11)R.sup.11, C(.dbd.NR.sup.11)NR.sup.11R.sup.11,
NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.11, NR.sup.11S(O)R.sup.11,
NR.sup.11S(O).sub.2R.sup.11, NR.sup.11S(O).sub.2NR.sup.11R.sup.11,
S(O)R.sup.11, S(O)NR.sup.11R.sup.11, S(O).sub.2R.sup.11, and
S(O).sub.2NR.sup.11R.sup.11, wherein C.sub.1-4 alkyl, cyclopropyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of
R.sup.9 are each optionally substituted with 1 or 2 substituents
selected from halo, OH, CN and OCH.sub.3 and each R.sup.11 is
independently selected from H and C.sub.1-4 alkyl optionally
substituted with 1 or 2 halo, OH, CN or OCH.sub.3 substituents;
[0022] R.sup.7, R.sup.13 and R.sup.14 are each independently
selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-14 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-(5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.a,
SR.sup.a, NHOR.sup.a, C(O)R.sup.a, C(O)NR.sup.aR.sup.a,
C(O)OR.sup.a, OC(O)R.sup.a, OC(O)NR.sup.aR.sup.a, NHR.sup.a,
NR.sup.aR.sup.a, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a,
NR.sup.aC(O)NR.sup.aR.sup.a, C(.dbd.NR.sup.a)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
NR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a, NR.sup.aS(O)R.sup.a,
NR.sup.aS(O).sub.2R.sup.a, NR.sup.aS(O).sub.2NR.sup.aR.sup.a,
S(O)R.sup.a, S(O)NR.sup.aR.sup.a, S(O).sub.2R.sup.a, and
S(O).sub.2NR.sup.aR.sup.a, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-100 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.7, R.sup.13
and R.sup.14 are each optionally substituted with 1, 2, 3, or 4
R.sup.b substituents;
[0023] or two adjacent R.sup.7 substituents on the Cy ring, taken
together with the atoms to which they are attached, form a fused
phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a
fused 5- or 6-membered heteroaryl ring or a fused C.sub.3-6
cycloalkyl ring, wherein the fused 5-, 6- or 7-membered
heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S
and wherein the fused phenyl ring, fused 5-, 6- or 7-membered
heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and
fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2 or 3 independently selected R.sup.b substituents;
[0024] or two R.sup.13 substituents attached to the same carbon
atom, taken together with the carbon atom to which they are
attached, form a C.sub.3-6 cycloalkyl ring or 4-, 5-, 6- or
7-membered heterocycloalkyl ring, wherein the C.sub.3-6 cycloalkyl
ring and 4-, 5-, 6- or 7-membered heterocycloalkyl ring are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents;
[0025] each R.sup.a is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents;
[0026] each R.sup.d is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, halo, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, CN, NH.sub.2, NHOR.sup.e, OR.sup.e, SR.sup.e,
C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e, OC(O)R.sup.e,
OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-4 alkyl, C.sub.3-10 cycloalkyl and 4-10
membered heterocycloalkyl of R.sup.d are each further optionally
substituted with 1-3 independently selected R.sup.q
substituents;
[0027] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.b are each further optionally substituted with 1-3
independently selected R.sup.d substituents;
[0028] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.c are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.f substituents independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-100 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, halo, CN, NHOR.sup.g, OR.sup.g,
SR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.g, C(O)OR.sup.g,
OC(O)R.sup.g, OC(O)NR.sup.gR.sup.g, NHR.sup.g, NR.sup.gR.sup.g,
NR.sup.gC(O)R.sup.g, NR.sup.gC(O)NR.sup.gR.sup.g,
NR.sup.gC(O)OR.sup.g, C(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NR.sup.g)NR.sup.gR.sup.g, S(O)R.sup.g,
S(O)NR.sup.gR.sup.g, S(O).sub.2R.sup.g, NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, and S(O).sub.2NR.sup.gR.sup.g;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.f are each
optionally substituted with 1, 2, 3, 4, or 5 R.sup.n substituents
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
halo, CN, NHOR.sup.o, OR.sup.o, SR.sup.o, C(O)R.sup.o,
C(O)NR.sup.oR.sup.o, C(O)OR.sup.o, OC(O)R.sup.o,
OC(O)NR.sup.oR.sup.o, NHR.sup.o, NR.sup.oR.sup.o,
NR.sup.oC(O)R.sup.o, NROC(O)NR.sup.oR.sup.o, NR.sup.oC(O)OR.sup.o,
C(.dbd.NR)NR.sup.oR.sup.o, NR.sup.oC(.dbd.NR)NR.sup.oR.sup.o,
S(O)R.sup.o, S(O)NR.sup.oR.sup.o, S(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2R.sup.o, NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and
S(O).sub.2NR.sup.oR.sup.o;
[0029] each R.sup.g is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.g are each optionally substituted with 1-3 independently
selected R.sup.p substituents;
[0030] or any two R.sup.a substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 R.sup.h substituents independently selected from C.sub.1-6
alkyl, C.sub.3-10cycloalkyl, 4-7 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-6 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered heteroaryl)-C.sub.1-4
alkyl-, (4-7 membered heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-7 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-6 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.J substituents
independently selected from C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
5 or 6-membered heteroaryl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN, NHOR.sup.k,
OR.sup.k, SR.sup.k, C(O)R.sup.k, C(O)NR.sup.kR.sup.k, C(O)OR.sup.k,
OC(O)R.sup.k, OC(O)NR.sup.kR.sup.k, NHR.sup.k, NR.sup.kR.sup.k,
NR.sup.kC(O)R.sup.k, NR.sup.kC(O)NR.sup.kR.sup.k,
NR.sup.kC(O)OR.sup.k, C(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NR.sup.k)NR.sup.kR.sup.k, S(O)R.sup.k,
S(O)NR.sup.kR.sup.k, S(O).sub.2R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, and
S(O).sub.2NR.sup.kR.sup.k;
[0031] or two R.sup.h groups attached to the same carbon atom of
the 4- to 10-membered heterocycloalkyl taken together with the
carbon atom to which they are attached form a C.sub.3-6 cycloalkyl
or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring
members selected from O, N or S;
[0032] or any two R.sup.c substituents together with the nitrogen
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.h substituents;
[0033] or any two R.sup.e substituents together with the nitrogen
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.h substituents;
[0034] or any two R.sup.g substituents together with the nitrogen
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.h substituents;
[0035] or any two R.sup.i substituents together with the nitrogen
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.h substituents;
[0036] or any two R.sup.k substituents together with the nitrogen
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.h substituents;
[0037] or any two R.sup.o substituents together with the nitrogen
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.h substituents; and each R.sup.e,
R.sup.i, R.sup.k, R.sup.o or R.sup.p is independently selected from
H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or
6-membered heteroaryl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, and
C.sub.2-4 alkynyl, wherein the C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered heteroaryl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl of R.sup.e, R.sup.i, R.sup.k,
R.sup.o or R.sup.p are each optionally substituted with 1, 2 or 3
R.sup.q substituents; each R.sup.q is independently selected from
OH, CN, --COOH, NH.sub.2, halo, C.sub.1-6haloalkyl, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylthio,
phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,
C.sub.3-6 cycloalkyl, NHR.sup.12, NR.sup.12R.sup.12, and C.sub.1-4
haloalkoxy, wherein the C.sub.1-6 alkyl, phenyl, C.sub.3-6
cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered
heteroaryl of R.sup.q are each optionally substituted with halo,
OH, CN, --COOH, NH.sub.2, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl and 4-6
membered heterocycloalkyl and each R.sup.12 is independently
C.sub.1-6 alkyl;
[0038] is a single bond or a double bond to maintain ring A being
aromatic;
[0039] the subscript n is an integer of 1, 2, 3, 4, 5 or 6; and
[0040] when R.sup.9 is OH, Cy is other than
6-carbamimidoyl-1H-benzo[d]imidazol-2-yl.
[0041] The compounds, or pharmaceutically acceptable salts or
stereoisomers thereof, as described herein are useful as inhibitors
of the PD-1/PD-L1 protein/protein interaction. For example,
compounds or pharmaceutically acceptable salts or stereoisomers
thereof as described herein can disrupt the PD-1/PD-L1
protein/protein interaction in the PD-1 pathway.
[0042] In some embodiments of compounds of Formula (I), when
R.sup.9 is OH, Cy is other than 1H-benzo[d]imidazol-2-yl optionally
substituted with a R.sup.7 substituent.
[0043] In some embodiments of compounds of Formula (I), R.sup.7,
R.sup.13 and R.sup.14 are each independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN,
NO.sub.2, OR.sup.a, SR.sup.a, NHOR.sup.a, C(O)R.sup.a,
C(O)NR.sup.aR.sup.a, C(O)OR.sup.a, OC(O)R.sup.a,
OC(O)NR.sup.aR.sup.a, NHR.sup.a, NR.sup.aR.sup.a,
NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a,
NR.sup.aC(O)NR.sup.aR.sup.a, C(.dbd.NR.sup.a)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
NR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a, NR.sup.aS(O)R.sup.a,
NR.sup.aS(O).sub.2R.sup.a, NR.sup.aS(O).sub.2NR.sup.aR.sup.a,
S(O)R.sup.a, S(O)NR.sup.aR.sup.a, S(O).sub.2R.sup.a, and
S(O).sub.2NR.sup.aR.sup.a, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.7, R.sup.13
and R.sup.14 are each optionally substituted with 1, 2, 3, or 4
R.sup.q substituents.
[0044] In some embodiments of compounds of Formula (I), two
adjacent R.sup.7 substituents on the Cy ring, taken together with
the atoms to which they are attached, form a fused phenyl ring, a
fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or
6-membered heteroaryl ring or a fused C.sub.3-6 cycloalkyl ring,
wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and
fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as
ring members selected from N, O and S and wherein the fused phenyl
ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-6 cycloalkyl ring are
each optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents.
[0045] In some embodiments of compounds of Formula (I), Cy is
C.sub.6-10 aryl, optionally substituted with 1 to 5 independently
selected R.sup.7 substituents. In certain embodiments, Cy is phenyl
or naphthyl, each of which is optionally substituted with 1 to 4
independently selected R.sup.7 substituents. In certain
embodiments, Cy is phenyl optionally substituted with 1 to 5
independently selected R.sup.7 substituents. In certain
embodiments, Cy is unsubstituted phenyl. In certain embodiments, Cy
is 2,3-dihydro-1,4-benzodioxin-6-yl, optionally substituted with 1
to 5 independently selected R.sup.7 substituents.
[0046] In some embodiments of compounds of Formula (I), Cy is
C.sub.3-10 cycloalkyl, optionally substituted with 1 to 5
independently selected R.sup.7 substituents. In certain
embodiments, Cy is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, each of which
is optionally substituted with 1 to 5 independently selected
R.sup.7 substituents.
[0047] In some embodiments of compounds of Formula (I), Cy is 5- to
14-membered heteroaryl, optionally substituted with 1 to 5
independently selected R.sup.7 substituents. In certain
embodiments, Cy is pyridy, primidinyl, pyrazinyl, pyridazinyl,
triazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl,
imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl,
naphthyridinyl, indolyl, benzothiophenyl, benzofuranyl,
benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, 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, each of which is optionally substituted with 1
to 5 independently selected R.sup.7 substituents. In certain
embodiments, Cy is thiophenyl or pyridyl, each of which is
optionally substituted with 1 to 5 independently selected R.sup.7
substituents. In some embodiments, Cy is 2-thiophenyl,
3-thiophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is
optionally substituted with 1 to 5 independently selected R.sup.7
substituents.
[0048] In some embodiments of compounds of Formula (I), Cy is 4- to
10-membered heterocycloalkyl, optionally substituted with 1 to 5
independently selected R.sup.7 substituents. In certain
embodiments, Cy is azetidinyl, azepanyl, dihydrobenzofuranyl,
dihydrofuranyl, dihydropyranyl, morpholino,
3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,
piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,
1,2,3,4-tetrahydroquinolinyl, tropanyl,
2,3-dihydro-1,4-benzodioxin-6-yl, and thiomorpholino, each of which
is optionally substituted with 1 to 4 independently selected
R.sup.7 substituents. In some embodiments, Cy is
3,6-dihydro-2H-pyran-4-yl, optionally substituted with 1 to 5
independently selected R.sup.7 substituents.
[0049] In some embodiments of compounds of Formula (I), Cy is
phenyl, 5- or 6-membered heteroaryl, C.sub.3-6 cycloalkyl or 5- or
6-membered heterocycloalkyl, each of which is optionally
substituted with 1 to 5 independently selected R.sup.7
substituents. In certain instances, Cy is phenyl, 2-thiophenyl,
3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C.sub.3-6 cycloalkyl
or 3,6-dihydro-2H-pyran-4-yl, each of which is optionally
substituted with 1 to 5 R.sup.7 substituents.
[0050] In some embodiments of compounds of Formula (I), X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6. In certain
instances, R.sup.4, R.sup.5 and R.sup.6 are each H.
[0051] In some embodiments of compounds of Formula (I), X.sup.4 is
CR.sup.4, X.sup.5 is N and X.sup.6 is N. In certain instances,
R.sup.4 is H.
[0052] In some embodiments of compounds of Formula (I), X.sup.4 is
CR.sup.4, X.sup.5 is N and X.sup.6 is CR.sup.6. In certain
instances, R.sup.4 and R.sup.6 are each H.
[0053] In some embodiments of compounds of Formula (I), X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is N. In certain
instances, R.sup.4 and R.sup.5 are each H.
[0054] In some embodiments of compounds of Formula (I), X.sup.4 is
N, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6. In certain
instances, R.sup.5 and R.sup.6 are each H.
[0055] In some embodiments of compounds of Formula (I), X.sup.4 is
N, X.sup.5 is N and X.sup.6 is CR.sup.6. In certain instances,
R.sup.6 is H.
[0056] In some embodiments of compounds of Formula (I), X.sup.4 is
N, X.sup.5 is CR.sup.5 and X.sup.6 is N. In certain instances,
R.sup.5 is H.
[0057] In some embodiments, the present disclosure provides
compounds having Formula (II):
##STR00004##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (II) are as defined in Formula (I)
or any embodiment of compounds of Formula (I) as described herein.
In one embodiment of compounds of Formula (II), R.sup.9 is halo, CN
or C.sub.1-4 alkyl optionally substituted with 1 or 2 R.sup.q
groups. In another embodiment, R.sup.9 is Cl, CH.sub.3 or CN.
[0058] In some embodiments, the present disclosure provides
compounds having Formula (IIa):
##STR00005##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (IIa) are as defined in Formula
(I) or any embodiment of compounds of Formula (I) as described
herein. In one embodiment, Cy is phenyl optionally substituted with
1 to 5 R.sup.7 groups. In one embodiment, R.sup.9 is halo, CN or
C.sub.1-4 alkyl optionally substituted with 1 or 2 R.sup.q groups.
In another embodiment, R.sup.9 is Cl, CH.sub.3 or CN.
[0059] In some embodiments, the present disclosure provides
compounds having Formula (III):
##STR00006##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (III) are as defined in Formula
(I) or any embodiment of compounds of Formula (I) as described
herein. In one embodiment, Cy is phenyl optionally substituted with
1 to 5 R.sup.7 groups. In one embodiment, R.sup.5 and R.sup.6 are
H. In one embodiment, R.sup.9 is halo, CN or C.sub.1-4 alkyl
optionally substituted with 1 or 2 R.sup.q groups. In another
embodiment, R.sup.9 is Cl, CH.sub.3 or CN.
[0060] In some embodiments, the present disclosure provides
compounds having Formula (IV):
##STR00007##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (IV) are as defined in Formula (I)
or any embodiment of compounds of Formula (I) as described herein.
In one embodiment, Cy is phenyl optionally substituted with 1 to 5
R.sup.7 groups. In one embodiment, R.sup.4 and R.sup.5 are H. In
one embodiment, R.sup.9 is halo, CN or C.sub.1-4 alkyl optionally
substituted with 1 or 2 R.sup.q groups. In another embodiment,
R.sup.9 is Cl, CH.sub.3 or CN.
[0061] In some embodiments, the present disclosure provides
compounds having Formula (V):
##STR00008##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (V) are as defined in Formula (I)
or any embodiment of compounds of Formula (I) as described herein.
In one embodiment, R.sup.9 is halo, CN or C.sub.1-4 alkyl
optionally substituted with 1 or 2 R.sup.q groups. In another
embodiment, R.sup.9 is Cl, CH.sub.3 or CN.
[0062] In some embodiments, the present disclosure provides
compounds having Formula (VI):
##STR00009##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript m is an integer of 1, 2, 3 or 4 and the
variables of Formula (VI) are as defined in Formula (I) or any
embodiment of compounds of Formula (I) as described herein. The
moiety
##STR00010##
in Formula (VI) is
##STR00011##
[0064] In certain embodiments, the present disclosure provides
compounds having Formula (VIa):
##STR00012##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript m is an integer of 1, 2, 3 or 4 and the
variables of Formula (VIa) are as defined in Formula (I) or any
embodiment of compounds of Formula (I) as described herein.
[0065] In certain embodiments, the present disclosure provides
compounds having Formula (VIb):
##STR00013##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript m is an integer of 1, 2, 3 or 4 and the
variables of Formula (VIb) are as defined in Formula (I) or any
embodiment of compounds of Formula (I) as described herein.
[0066] In certain embodiments, the present disclosure provides
compounds having Formula (VIc):
##STR00014##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript m is an integer of 1, 2, 3 or 4 and the
variables of Formula (VIc) are as defined in Formula (I) or any
embodiment of compounds of Formula (I) as described herein.
[0067] In some embodiments, the present disclosure provides
compounds having Formula (VII):
##STR00015##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein m is an integer of 1, 2 or 3 and the variables of Formula
(VII) are as defined in Formula (I) or any embodiment of compounds
of Formula (I) as described herein. The moiety
##STR00016##
in Formula (VII) is
##STR00017##
[0069] In some embodiments, the present disclosure provides
compounds having Formula (VIIa):
##STR00018##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein m is an integer of 1, 2 or 3 and the variables of Formula
(VIIa) are as defined in Formula (I) or any embodiment of compounds
of Formula (I) as described herein.
[0070] In some embodiments, the present disclosure provides
compounds having Formula (VIIb):
##STR00019##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein m is an integer of 1, 2 or 3 and the variables of Formula
(VIIb) are as defined in Formula (I) or any embodiment of compounds
of Formula (I) as described herein.
[0071] In some embodiments of compounds of any of the Formulas as
disclosed herein or a pharmaceutically acceptable salt or a
stereoisomer thereof, the moiety:
##STR00020##
is selected from:
##STR00021## ##STR00022##
wherein the substituents R.sup.1, R.sup.3, R.sup.13, R.sup.14 and
the subscript n are as defined in Formula (I) or any embodiment of
compounds of Formula (I) as described herein. In certain
embodiments, at each occurrence, R.sup.1 and R.sup.3 are each H. In
other embodiments, R.sup.13 is H or C.sub.1-6 alkyl. In one
embodiment, the subscript n is 2.
[0072] In some embodiments of compounds of any of the Formula as
disclosed herein or a pharmaceutically acceptable salt or a
stereoisomer thereof, the moiety:
##STR00023##
is selected from:
##STR00024##
[0073] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is S and Y is
C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are each CH.
[0074] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is S, X.sup.2 is C, X.sup.3 is N, and Y
is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are each
CH.
[0075] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is CR.sup.3,
and Y is N. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0076] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is NR.sup.3,
and Y is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0077] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is S, X.sup.6
is N, and Y is C. In some instances, X.sup.4 and X.sup.5 are each
CH.
[0078] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is N, X.sup.3 is CR.sup.3,
and Y is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0079] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is CR.sup.1, X.sup.2 is N, X.sup.3 is N,
and Y is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0080] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is CR.sup.1, X.sup.2 is C, X.sup.3 is N,
and Y is N. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0081] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is NR.sup.1, X.sup.2 is C, X.sup.3 is N,
and Y is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are
each CH.
[0082] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is O, and Y
is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are each
CH.
[0083] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is O, X.sup.2 is C, X.sup.3 is N, and Y
is C. In some instances, X.sup.4, X.sup.5 and X.sup.6 are each
CH.
[0084] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is N, and Y
is N. In some instances, X.sup.4, X.sup.5 and X.sup.6 are each
CH.
[0085] In some embodiments of compounds of any of the Formulas as
disclosed herein, X.sup.1 is N, X.sup.2 is C, X.sup.3 is S, X.sup.4
is N, and Y is C. In some instances, X.sup.5 and X.sup.6 are each
CH.
[0086] In some embodiments, R.sup.1, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are each H.
[0087] In some embodiments, R.sup.9 is halo, C.sub.1-4 alkyl or
CN.
[0088] In some embodiments, R.sup.9 is CH.sub.3 or CN. In certain
embodiments, R.sup.9 is Cl, CH.sub.3 or CN. In one embodiment,
R.sup.9 is CH.sub.3. In another embodiment, R.sup.9 is CN. In
another embodiment, R.sup.9 is F, Cl or Br.
[0089] In some embodiments, R.sup.7 is H.
[0090] In some embodiments, R.sup.4, R.sup.5 and R.sup.6 are each
H.
[0091] In some embodiments of compounds of any of the Formulas as
disclosed herein, R.sup.13 is H or C.sub.1-6 alkyl.
[0092] In some embodiments of compounds of any of the Formulas as
disclosed herein, two R.sup.13 substituents attached to the same
carbon atom, taken together with the carbon atom to which they are
attached, form a C.sub.3-6 cycloalkyl ring or 4-, 5-, 6- or
7-membered heterocycloalkyl ring, wherein the C.sub.3-6 cycloalkyl
ring and 4-, 5-, 6- or 7-membered heterocycloalkyl ring are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents. Exemplary spiro C.sub.3-6 cycloalkyl ring
formed by two R.sup.13 substituents include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0093] In some embodiments of compounds of any of the Formulas as
disclosed herein, R.sup.14 is H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-14 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.a,
SR.sup.a, NHOR.sup.a, C(O)R.sup.a, C(O)NR.sup.aR.sup.a,
C(O)OR.sup.a, OC(O)R.sup.a, OC(O)NR.sup.aR.sup.a, NHR.sup.a,
NR.sup.aR.sup.a, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a,
NR.sup.aC(O)NR.sup.aR.sup.a, C(.dbd.NR.sup.a)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
NR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a, NR.sup.aS(O)R.sup.a,
NR.sup.aS(O).sub.2R.sup.a, NR.sup.aS(O).sub.2NR.sup.aR.sup.a,
S(O)R.sup.a, S(O)NR.sup.aR.sup.a, S(O).sub.2R.sup.a, and
S(O).sub.2NR.sup.aR.sup.a, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.14 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents or
1, 2, 3 or 4 R.sup.q substituents.
[0094] In some embodiments of compounds of any of the Formulas as
disclosed herein, R.sup.14 is H, C.sub.1-6 alkyl, phenyl,
phenyl-C.sub.1-4 alkyl-, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, 5- or 6-membered heteroaryl, 4- to
6-membered heterocycloalkyl, (5- or 6-membered
heteroaryl)-C.sub.1-4 alkyl- or (4- to 6-membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
phenyl, phenyl-C.sub.1-4 alkyl-, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, 5- or 6-membered heteroaryl, 4- to
6-membered heterocycloalkyl, (5- or 6-membered
heteroaryl)-C.sub.1-4 alkyl- or (4- to 6-membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.14 is optionally
substituted with 1, 2, 3 or 4 R.sup.q substituents.
[0095] In some embodiments of compounds of any of the Formulas as
disclosed herein, R.sup.14 is 2-hydroxyethyl, 2-hydroxypropyl,
(R)-2-hydroxypropyl, (S)-2-hydroxypropyl, tetrahydro-2H-pyran-4-yl,
4-carboxycyclohexyl, 3-carboxypropyl, 2-carboxycyclopropylmethyl,
1H-pyrazol-4-ylmethyl or 4-cyanomethylcyclohexyl.
[0096] 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 (while the embodiments are intended to be
combined as if written in multiply dependent form). 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. Thus, it is
contemplated as features described as embodiments of the compounds
of Formula (I) can be combined in any suitable combination.
[0097] At various places in the present specification, certain
features of the compounds are disclosed in groups or in ranges. It
is specifically intended that such a disclosure include each and
every individual subcombination of the members of such groups and
ranges. For example, the term "C.sub.1-6 alkyl" is specifically
intended to individually disclose (without limitation) methyl,
ethyl, C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5 alkyl and C.sub.6
alkyl.
[0098] 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.
[0099] At various places in the present specification, variables
defining divalent linking groups may be described. It is
specifically intended that each linking substituent include both
the forward and backward forms of the linking substituent. For
example, --NR(CR'R'').sub.n-includes both --NR(CR'R'').sub.n- and
--(CR'R'').sub.nNR-- and is intended to disclose each of the forms
individually. Where the structure requires a linking group, the
Markush variables listed for that group are understood to be
linking groups. For example, if the structure requires a linking
group and the Markush group definition for that variable lists
"alkyl" or "aryl" then it is understood that the "alkyl" or "aryl"
represents a linking alkylene group or arylene group,
respectively.
[0100] The term "substituted" means that an atom or group of atoms
formally replaces hydrogen as a "substituent" attached to another
group. The term "substituted", unless otherwise indicated, refers
to any level of substitution, e.g., mono-, di-, tri-, tetra- or
penta-substitution, where such substitution is permitted. The
substituents are independently selected, and substitution may be at
any chemically accessible position. It is to be understood that
substitution at a given atom is limited by valency. It is to be
understood that substitution at a given atom results in a
chemically stable molecule. The phrase "optionally substituted"
means unsubstituted or substituted. 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.
[0101] 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.
[0102] The term "alkyl" employed alone or in combination with other
terms, refers to a saturated hydrocarbon group that may be
straight-chained or branched. The term "C.sub.n-m alkyl", refers to
an alkyl group having n to m carbon atoms. An alkyl group formally
corresponds to an alkane with one C--H bond replaced by the point
of attachment of the alkyl group to the remainder of the compound.
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. 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.
[0103] The term "alkenyl" employed alone or in combination with
other terms, refers to a straight-chain or branched hydrocarbon
group corresponding to an alkyl group having one or more double
carbon-carbon bonds. An alkenyl group formally corresponds to an
alkene with one C--H bond replaced by the point of attachment of
the alkenyl group to the remainder of the compound. The term
"C.sub.n-m alkenyl" refers to an alkenyl group having n to m
carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2
to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but
are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,
sec-butenyl and the like.
[0104] The term "alkynyl" employed alone or in combination with
other terms, refers to a straight-chain or branched hydrocarbon
group corresponding to an alkyl group having one or more triple
carbon-carbon bonds. An alkynyl group formally corresponds to an
alkyne with one C--H bond replaced by the point of attachment of
the alkyl group to the remainder of the compound. The term
"C.sub.n-m alkynyl" refers to an alkynyl group 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.
[0105] The term "alkylene", employed alone or in combination with
other terms, refers to a divalent alkyl linking group. An alkylene
group formally corresponds to an alkane with two C--H bond replaced
by points of attachment of the alkylene group to the remainder of
the compound. The term "C.sub.n-m alkylene" refers to an alkylene
group having n to m carbon atoms. Examples of alkylene groups
include, but are not limited to, ethan-1,2-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.
[0106] The term "alkoxy", employed alone or in combination with
other terms, refers to a group of formula --O-alkyl, wherein the
alkyl group is as defined above. The term "C.sub.n-m alkoxy" refers
to an alkoxy group, the alkyl group of which has n to m carbons.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy and the like. In some
embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0107] The term "amino" refers to a group of formula
--NH.sub.2.
[0108] The term "carbonyl", employed alone or in combination with
other terms, refers to a --C(.dbd.O)-- group, which also may be
written as C(O).
[0109] The term "cyano" or "nitrile" refers to a group of formula
--C.ident.N, which also may be written as --CN.
[0110] The terms "halo" or "halogen", used alone or in combination
with other terms, refers to fluoro, chloro, bromo and iodo. In some
embodiments, "halo" refers to a halogen atom selected from F, Cl,
or Br. In some embodiments, halo groups are F.
[0111] The term "haloalkyl" as used herein refers to an alkyl group
in which one or more of the hydrogen atoms has been replaced by a
halogen atom. The term "C.sub.n-mhaloalkyl" refers to a C-m alkyl
group having n to m carbon atoms and from at least one up to {2(n
to m)+1}halogen atoms, which may either be the same or different.
In some embodiments, the halogen atoms are fluoro atoms. In some
embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
Example haloalkyl groups include CF.sub.3, C.sub.2F.sub.5,
CHF.sub.2, CCl.sub.3, CHCl.sub.2, C.sub.2Cl.sub.5 and the like. In
some embodiments, the haloalkyl group is a fluoroalkyl group.
[0112] The term "haloalkoxy", employed alone or in combination with
other terms, refers to a group of formula --O-haloalkyl, wherein
the haloalkyl group is as defined above. The term "C.sub.n-m
haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of
which has n to m carbons. Example haloalkoxy groups include
trifluoromethoxy and the like. In some embodiments, the haloalkoxy
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0113] The term "oxo" refers to an oxygen atom as a divalent
substituent, forming a carbonyl group when attached to carbon, or
attached to a heteroatom forming a sulfoxide or sulfone group, or
an N-oxide group. In some embodiments, heterocyclic groups may be
optionally substituted by 1 or 2 oxo (.dbd.O) substituents.
[0114] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0115] The term "aromatic" refers to a carbocycle or heterocycle
having one or more polyunsaturated rings having aromatic character
(i.e., having (4n+2) delocalized 71 (pi) electrons where n is an
integer).
[0116] 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 fused rings). The term
"C.sub.n-m aryl" refers to an aryl group having from n to m ring
carbon atoms.
[0117] Aryl groups include, e.g., phenyl, naphthyl, indanyl,
indenyl and the like. In some embodiments, aryl groups have from 6
to about 10 carbon atoms. In some embodiments aryl groups have 6
carbon atoms. In some embodiments aryl groups have 10 carbon atoms.
In some embodiments, the aryl group is phenyl. In some embodiments,
the aryl group is naphthyl.
[0118] The term "heteroaryl" or "heteroaromatic," employed alone or
in combination with other terms, 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 has 5-14 ring atoms
including carbon atoms and 1, 2, 3 or 4 heteroatom ring members
independently selected from nitrogen, sulfur and oxygen. In some
embodiments, the heteroaryl has 5-10 ring atoms including carbon
atoms and 1, 2, 3 or 4 heteroatom ring members independently
selected from nitrogen, sulfur and oxygen. In some embodiments, the
heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members
independently selected from nitrogen, sulfur and oxygen. In some
embodiments, the heteroaryl is a five-membered or six-membered
heteroaryl ring. In other embodiments, the heteroaryl is an
eight-membered, nine-membered or ten-membered fused bicyclic
heteroaryl ring. Example heteroaryl groups include, but are not
limited to, pyridintl (pyridyl), pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl,
imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl,
naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-,
2,3- and 2,6-naphthyridine), indolyl, benzothiophenyl,
benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and
the like.
[0119] A five-membered heteroaryl ring is a heteroaryl group 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 include 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.
[0120] A six-membered heteroaryl ring is a heteroaryl group 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.
[0121] The term "cycloalkyl," employed alone or in combination with
other terms, refers to a non-aromatic hydrocarbon ring system
(monocyclic, bicyclic or polycyclic), including cyclized alkyl and
alkenyl groups. The term "C.sub.n-m cycloalkyl" refers to a
cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl
groups can include mono- or polycyclic (e.g., having 2, 3 or 4
fused rings) groups and spirocycles. Cycloalkyl groups can have 3,
4, 5, 6 or 7 ring-forming carbons (C.sub.3-7). In some embodiments,
the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members,
or 3 to 4 ring members. In some embodiments, the cycloalkyl group
is monocyclic. In some embodiments, the cycloalkyl group is
monocyclic or bicyclic.
[0122] In some embodiments, the cycloalkyl group is a C.sub.3-6
monocyclic cycloalkyl group. Ring-forming carbon atoms of a
cycloalkyl group can be optionally oxidized to form an oxo or
sulfido group. Cycloalkyl groups also include cycloalkylidenes. In
some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. 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, e.g.,
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. Examples of cycloalkyl groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptatrienyl, norbomyl, norpinyl, norcarnyl,
bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In
some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl.
[0123] The term "heterocycloalkyl," employed alone or in
combination with other terms, refers to a non-aromatic ring or ring
system, which may optionally contain one or more alkenylene groups
as part of the ring structure, which has at least one heteroatom
ring member independently selected from nitrogen, sulfur oxygen and
phosphorus, and which has 4-10 ring members, 4-7 ring members, or
4-6 ring members. Included within the term "heterocycloalkyl" are
monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups.
[0124] Heterocycloalkyl groups can include mono- or bicyclic (e.g.,
having two fused or bridged rings) ring systems. In some
embodiments, the heterocycloalkyl group is a monocyclic group
having 1, 2 or 3 heteroatoms independently selected from nitrogen,
sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a
heterocycloalkyl group can be optionally oxidized to form an oxo or
sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or
S(O).sub.2, N-oxide etc.) or a nitrogen atom can be quaternized.
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 heterocycloalkyl ring, e.g., 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. Examples of heterocycloalkyl
groups include azetidinyl, azepanyl, dihydrobenzofuranyl,
dihydrofuranyl, dihydropyranyl, morpholino,
3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,
piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,
1,2,3,4-tetrahydroquinolinyl, tropanyl, and thiomorpholino.
[0125] 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 an azetidin-3-yl ring is attached at the
3-position.
[0126] 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 invention 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 invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms.
[0127] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. One 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,
e.g., 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 .beta.-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.
[0128] 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.
[0129] In some embodiments, the compounds of the invention have the
(R)-configuration. In other embodiments, the compounds have the
(S)-configuration. In compounds with more than one chiral centers,
each of the chiral centers in the compound may be independently (R)
or (S), unless otherwise indicated.
[0130] Compounds of the invention 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, e.g., 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.
[0131] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
[0132] The term, "compound," as used herein is meant to include all
stereoisomers, geometric isomers, tautomers and isotopes of the
structures depicted. The term is also meant to refer to compounds
of the inventions, regardless of how they are prepared, e.g.,
synthetically, through biological process (e.g., metabolism or
enzyme conversion), or a combination thereof.
[0133] 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. When
in the solid state, the compounds described herein and salts
thereof may occur in various forms and may, e.g., take the form of
solvates, including hydrates. The compounds may be in any solid
state form, such as a polymorph or solvate, so unless clearly
indicated otherwise, reference in the specification to compounds
and salts thereof should be understood as encompassing any solid
state form of the compound.
[0134] In some embodiments, the compounds of the invention, 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, e.g., a composition
enriched in the compounds of the invention. 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 of the invention, or salt thereof.
[0135] 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.
[0136] The expressions, "ambient temperature" and "room
temperature," 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, e.g., a temperature from about 20.degree. C. to about
30.degree. C.
[0137] The present invention also includes pharmaceutically
acceptable salts of the compounds described herein. The term
"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 invention include the non-toxic salts of the
parent compound formed, e.g., from non-toxic inorganic or organic
acids. The pharmaceutically acceptable salts of the present
invention 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 (MeCN) are preferred. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17.sup.th
Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et
al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al.,
Handbook of Pharmaceutical Salts: Properties, Selection, and Use,
(Wiley, 2002). In some embodiments, the compounds described herein
include the N-oxide forms.
II. Synthesis
[0138] Compounds of the invention, including salts thereof, can be
prepared using known organic synthesis techniques and can be
synthesized according to any of numerous possible synthetic routes,
such as those in the Schemes below.
[0139] The reactions for preparing compounds of the invention 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.
[0140] Preparation of compounds of the invention 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 is described, e.g., in
Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting
Group Chemistry, (Oxford University Press, 2000); Smith et al.,
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 6.sup.th Ed. (Wiley, 2007); Peturssion et al.,
"Protecting Groups in Carbohydrate Chemistry," J Chem. Educ., 1997,
74(11), 1297; and Wuts et al., Protective Groups in Organic
Synthesis, 4th Ed., (Wiley, 2006).
[0141] 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) or thin layer chromatography (TLC).
[0142] The Schemes below provide general guidance in connection
with preparing the compounds of the invention. One skilled in the
art would understand that the preparations shown in the Schemes can
be modified or optimized using general knowledge of organic
chemistry to prepare various compounds of the invention.
[0143] Compounds of Formula (I) can be prepared, e.g., using a
process as illustrated in Schemes 1-7.
[0144] Compounds of formula 1-7 can be synthesized as shown in
Scheme 1. A selective coupling of the iodide 1-1 with compounds of
formula 1-2 [M is B(OR).sub.2, Sn(Alkyl).sub.3, or Zn-Hal] under
suitable Suzuki coupling conditions, Stille coupling conditions, or
Negishi coupling conditions can give derivatives of formula 1-3.
The resulting chloride 1-3 can be converted to its boronic esters
or stannanes of formula 1-4 in the presence of a suitable palladium
catalyst. Another palladium catalyzed coupling of the resulting
compounds of formula 1-4 with a commercially available bromide or
iodide building block 1-5 (e.g. Hal is Br or I) under suitable
Suzuki or Stille coupling conditions can give compounds of formula
1-6. After removal of Boc on the piperidine under acidic condition
(trifluoroacetic acid or hydrochloric acid), the substitution of
R.sup.14 can be introduced to the resulting secondary amine by a
reductive amination with the corresponding aldehydes or ketones or
an alkylation with the corresponding alkyl halides to provide the
desired compounds of formula 1-7.
##STR00025##
[0145] Similarly, compounds of formula 2-4, with C--N bonding
between the five- and six-membered aromatic rings, can be
synthesized as shown in Scheme 2. Compounds of formula 2-1 (e.g.,
Hal is Cl or Br) can be prepared using similar conditions as
described in Scheme 1. The C--N bond can be formed under suitable
Buchwald-Hartwig amination conditions with a commercial amine
moiety of formula 2-2 to give compounds of formula 2-3. After
removal of Boc on the piperidine under acidic condition, the
substitution of R.sup.14 can be introduced to the resulting
secondary amine by a reductive amination with the corresponding
aldehydes or ketones to provide the desired compounds of formula
2-4.
##STR00026##
[0146] Alternatively, compounds of formula 3-7 can be synthesized
as shown in Scheme 3. Selective conversion of the L group in
compound 3-1 (L is Br, I or OTf) to boronic ester can be achieved
in the presence of a suitable palladium catalyst and
bis(pinacolato)diboron to give boronic ester of formula 3-2.
Selective Suzuki coupling of heteroaryl bromide 3-3 with boronic
ester 3-2 can give biaryl chloride 3-4. Installation of Cy ring can
be achieved using similar conditions as described in Scheme 1 by
coupling biaryl chloride 3-4 with compound 3-5 to give compounds of
formula 3-6. Removal of Boc protecting group followed by reductive
amination with the corresponding aldehydes or ketones can provide
the desired compounds of formula 3-7.
##STR00027##
[0147] Thioazole compounds of formula 4-7, with substitutions on
the piperidine ring, can be synthesized as shown in Scheme 4. The
Boc protected oxo-piperidine of formula 4-1 can be brominated at
the ketone a position either by treatment with bromine, or by a
sequence of TMS enol ether formation and NBS bromination. The
resulting bromide 4-2 can be converted to the aminothioazole 4-3
via reacting with thiourea in alcoholic solvents at elevated
temperature. The amine group in 4-3 can be converted to halide
under Sandermeyer conditions (e.g., in the presence of .sup.tBuONO
and CuBr.sub.2) to give bromothiazole 4-4. Compound of formula 4-5
[M' is B(OR).sub.2 or SnBu.sub.3] can be prepared using similar
conditions as described in Scheme 1. Coupling of bromothiazole 4-4
with compound 4-5 can be achieved under suitable Suzuki coupling
conditions or Stille coupling conditions to give compounds of
formula 4-6. After removal of Boc on the coupling product 4-6 under
acidic condition (trifluoroacetic acid or hydrochloric acid), the
substitution of R.sup.14 can be introduced to the resulting
secondary amine by a reductive amination with the corresponding
aldehydes or ketones to provide the desired compounds of formula
4-7.
##STR00028##
[0148] Alternatively, oxazole derivatives of formula 5-7 can be
synthesized according to the synthetic route as outlined in Scheme
5. Condensation of carboxylic acid 5-1 with amino,
hydroxyl-disubstituted pyridine 5-2 in the presence of a
condensation reagent (such as cyanuric chloride) can produce
compounds of formula 5-3. Alkylation of the pyridine in 5-3 with
benzyl bromide can give the quaternary salt 5-4 and subsequent
reduction of 5-4 with NaBH.sub.4 can lead to compound 5-5. Removal
of the benzyl group using Pd/C under hydrogenation conditions can
give compound 5-6. The R.sup.14 group can be introduced under
standard alkylation conditions or reductive amination conditions to
give the final product 5-7.
##STR00029##
[0149] Compounds of formula 6-5 can also be synthesized using
conditions as shown in Scheme 6. Cyclization of .alpha.-bromo
ketone derivatives of formula 6-1 with amino pyrazine 6-2 can give
the heteroaryl compounds 6-3. Selective reduction of the pyrazine
ring in compound 6-3 can be achieved by treating with LiBH.sub.4 or
using a similar reaction sequence as described in Scheme 5 to give
compound 6-4. Similarly, the R.sup.14 group can be introduced under
alkylation conditions or reductive amination conditions to give the
desired product 6-5.
##STR00030##
[0150] Alternatively, compounds of formula 7-5 can be synthesized
as shown in Scheme 7. Coupling of compound 7-1 [M' is B(OR).sub.2
or SnBu.sub.3] with heteroaryl halide 7-2 (Hal is Cl, Br or I) can
be achieved under suitable Suzuki coupling conditions or Stille
coupling conditions to give compounds of formula 7-3. Selective
reduction of the heteroaryl ring in 7-3 using similar conditions as
described in Scheme 5 or Scheme 6 can give compound 7-4.
Installation of R.sup.14 group can be achieved similarly under
alkylation conditions or reductive amination conditions to give
compound 7-5.
##STR00031##
III. Uses of the Compounds
[0151] Compounds of the present disclosure can inhibit the activity
of PD-1/PD-L1 protein/protein interaction and, thus, are useful in
treating diseases and disorders associated with activity of PD-1
and the diseases and disorders associated with PD-L1 including its
interaction with other proteins such as PD-1 and B7-1 (CD80). In
certain embodiments, the compounds of the present disclosure, or
pharmaceutically acceptable salts or stereoisomers thereof, are
useful for therapeutic administration to enhance, stimulate and/or
increase immunity in cancer or chronic infection, including
enhancement of response to vaccination. In some embodiments, the
present disclosure provides a method for inhibiting or blocking the
PD-1/PD-L1 protein/protein interaction. The method includes
administering to an individual or a patient a compound of Formula
(I) or any of the formulas as described herein or of a compound as
recited in any of the claims and described herein, or a
pharmaceutically acceptable salt or a stereoisomer thereof. The
compounds of the present disclosure can be used alone, in
combination with other agents or therapies or as an adjuvant or
neoadjuvant for the treatment of diseases or disorders, including
cancer or infection diseases. For the uses described herein, any of
the compounds of the disclosure, including any of the embodiments
thereof, may be used.
[0152] The compounds of the present disclosure inhibit the
PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway
blockade. The blockade of PD-1 can enhance the immune response to
cancerous cells and infectious diseases in mammals, including
humans. In some embodiments, the present disclosure provides
treatment of an individual or a patient in vivo using a compound of
Formula (I) or a salt or stereoisomer thereof such that growth of
cancerous tumors is inhibited. A compound of Formula (I) or of any
of the formulas as described herein, or a compound as recited in
any of the claims and described herein, or a salt or stereoisomer
thereof, can be used to inhibit the growth of cancerous tumors.
Alternatively, a compound of Formula (I) or of any of the formulas
as described herein, or a compound as recited in any of the claims
and described herein, or a salt or stereoisomer thereof, can be
used in conjunction with other agents or standard cancer
treatments, as described below. In one embodiment, the present
disclosure provides a method for inhibiting growth of tumor cells
in vitro. The method includes contacting the tumor cells in vitro
with a compound of Formula (I) or of any of the formulas as
described herein, or of a compound as recited in any of the claims
and described herein, or of a salt or stereoisomer thereof. In
another embodiment, the present disclosure provides a method for
inhibiting growth of tumor cells in an individual or a patient. The
method includes administering to the individual or patient in need
thereof a therapeutically effective amount of a compound of Formula
(I) or of any of the formulas as described herein, or of a compound
as recited in any of the claims and described herein, or a salt or
a stereoisomer thereof.
[0153] In some embodiments, provided herein is a method for
treating cancer. The method includes administering to a patient in
need thereof, a therapeutically effective amount of a compound of
Formula (I) or any of the formulas as described herein, a compound
as recited in any of the claims and described herein, or a salt
thereof. Examples of cancers include those whose growth may be
inhibited using compounds of the disclosure and cancers typically
responsive to immunotherapy.
[0154] In some embodiments, the present disclosure provides a
method of enhancing, stimulating and/or increasing the immune
response in a patient. The method includes administering to the
patient in need thereof a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein,
a compound as recited in any of the claims and described herein, or
a salt thereof.
[0155] Examples of cancers that are treatable using the compounds
of the present disclosure include, but are not limited to, bone
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular malignant melanoma, uterine cancer,
ovarian cancer, rectal cancer, cancer of the anal region, stomach
cancer, testicular cancer, uterine cancer, carcinoma of the
fallopian tubes, carcinoma of the endometrium, endometrial cancer,
carcinoma of the cervix, carcinoma of the vagina, carcinoma of the
vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the
esophagus, cancer of the small intestine, cancer of the endocrine
system, cancer of the thyroid gland, cancer of the parathyroid
gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer
of the urethra, cancer of the penis, chronic or acute leukemias
including acute myeloid leukemia, chronic myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors
of childhood, lymphocytic lymphoma, cancer of the bladder, cancer
of the kidney or urethra, carcinoma of the renal pelvis, neoplasm
of the central nervous system (CNS), primary CNS lymphoma, tumor
angiogenesis, spinal axis tumor, brain stem glioma, pituitary
adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,
T-cell lymphoma, environmentally induced cancers including those
induced by asbestos, and combinations of said cancers. The
compounds of the present disclosure are also useful for the
treatment of metastatic cancers, especially metastatic cancers that
express PD-L1.
[0156] In some embodiments, cancers treatable with compounds of the
present disclosure include melanoma (e.g., metastatic malignant
melanoma), renal cancer (e.g. clear cell carcinoma), prostate
cancer (e.g. hormone refractory prostate adenocarcinoma), breast
cancer, colon cancer and lung cancer (e.g. non-small cell lung
cancer). Additionally, the disclosure includes refractory or
recurrent malignancies whose growth may be inhibited using the
compounds of the disclosure.
[0157] In some embodiments, cancers that are treatable using the
compounds of the present disclosure include, but are not limited
to, solid tumors (e.g., prostate cancer, colon cancer, esophageal
cancer, endometrial cancer, ovarian cancer, uterine cancer, renal
cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast
cancer, lung cancer, cancers of the head and neck, thyroid cancer,
glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers
(e.g., lymphoma, leukemia such as acute lymphoblastic leukemia
(ALL), acute myelogenous leukemia (AML), chronic lymphocytic
leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle
cell lymphoma, Non-Hodgkin lymphoma (including relapsed or
refractory NHL and recurrent follicular), Hodgkin lymphoma or
multiple myeloma) and combinations of said cancers.
[0158] PD-1 pathway blockade with compounds of the present
disclosure can also be used for treating infections such as viral,
bacteria fungus and parasite infections. The present disclosure
provides a method for treating infections such as viral infections.
The method includes administering to a patient in need thereof, a
therapeutically effective amount of a compound of Formula (I) or
any of the formulas as described herein, a compound as recited in
any of the claims and described herein, a salt thereof. Examples of
viruses causing infections treatable by methods of the present
disclosure include, but are not limit to, human immunodeficiency
virus, human papillomavirus, influenza, hepatitis A, B, C or D
viruses, adenovirus, poxvirus, herpes simplex viruses, human
cytomegalovirus, severe acute respiratory syndrome virus, ebola
virus, and measles virus. In some embodiments, viruses causing
infections treatable by methods of the present disclosure include,
but are not limit to, hepatitis (A, B, or C), herpes virus (e.g.,
VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus),
adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,
coxsackie virus, comovirus, respiratory syncytial virus,
mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus,
vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum
virus, poliovirus, rabies virus, JC virus and arboviral
encephalitis virus.
[0159] The present disclosure provides a method for treating
bacterial infections. The method includes administering to a
patient in need thereof, a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein,
a compound as recited in any of the claims and described herein, or
a salt thereof. Non-limiting examples of pathogenic bacteria
causing infections treatable by methods of the disclosure include
chlamydia, rickettsial bacteria, mycobacteria, staphylococci,
streptococci, pneumonococci, meningococci and conococci,
klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,
salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,
leptospirosis, and Lyme's disease bacteria.
[0160] The present disclosure provides a method for treating fungus
infections. The method includes administering to a patient in need
thereof, a therapeutically effective amount of a compound of
Formula (I) or any of the formulas as described herein, a compound
as recited in any of the claims and described herein, or a salt
thereof. Non-limiting examples of pathogenic fungi causing
infections treatable by methods of the disclosure include Candida
(albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus
neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales
(mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces
dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis
and Histoplasma capsulatum.
[0161] The present disclosure provides a method for treating
parasite infections. The method includes administering to a patient
in need thereof, a therapeutically effective amount of a compound
of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or a
salt thereof. Non-limiting examples of pathogenic parasites causing
infections treatable by methods of the disclosure include Entamoeba
histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0162] The terms "individual" or "patient," used interchangeably,
refer to any animal, including mammals, preferably mice, rats,
other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,
or primates, and most preferably humans.
[0163] The phrase "therapeutically effective amount" refers to the
amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal,
individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician.
[0164] As used herein, the term "treating" or "treatment" refers to
one or more of (1) inhibiting the disease; e.g., 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;
e.g., 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.
[0165] In some embodiments, the compounds of the invention are
useful in preventing or reducing the risk of developing any of the
diseases referred to herein; e.g., preventing or reducing the risk
of developing a disease, condition or disorder in an individual who
may be predisposed to the disease, condition or disorder but does
not yet experience or display the pathology or symptomatology of
the disease.
Combination Therapies
[0166] Cancer cell growth and survival can be impacted by multiple
signaling pathways. Thus, it is useful to combine different
enzyme/protein/receptor inhibitors, exhibiting different
preferences in the targets which they modulate the activities of,
to treat such conditions. Targeting more than one signaling pathway
(or more than one biological molecule involved in a given signaling
pathway) may reduce the likelihood of drug-resistance arising in a
cell population, and/or reduce the toxicity of treatment.
[0167] The compounds of the present disclosure can be used in
combination with one or more other enzyme/protein/receptor
inhibitors for the treatment of diseases, such as cancer or
infections. Examples of cancers include solid tumors and liquid
tumors, such as blood cancers. Examples of infections include viral
infections, bacterial infections, fungus infections or parasite
infections. For example, the compounds of the present disclosure
can be combined with one or more inhibitors of the following
kinases for the treatment of cancer: 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, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1,
FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,
VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src,
Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. 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 or infections. Non-limiting examples of
inhibitors that can be combined with the compounds of the present
disclosure for treatment of cancer and infections 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, a PI3K-gamma
inhibitor such as PI3K-gamma selective inhibitor (e.g., INCB50797),
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.
[0168] Compounds of the present disclosure 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.
[0169] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0170] 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. In some
embodiments, the anti PD-1 antibody is SHR-1210.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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).
[0177] The compounds of the present disclosure can further be used
in combination with other methods of treating cancers, for example
by chemotherapy, irradiation therapy, tumor-targeted therapy,
adjuvant therapy, immunotherapy or surgery. Examples of
immunotherapy include cytokine treatment (e.g., interferons,
GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine,
monoclonal antibody, adoptive T cell transfer, oncolytic
virotherapy and immunomodulating small molecules, including
thalidomide or JAK1/2 inhibitor and the like. The compounds can be
administered in combination with one or more anti-cancer drugs,
such as a chemotherapeutics. Example chemotherapeutics include any
of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,
altretamine, anastrozole, arsenic trioxide, asparaginase,
azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin,
bortezombi, bortezomib, busulfan intravenous, busulfan oral,
calusterone, capecitabine, carboplatin, carmustine, cetuximab,
chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,
cytarabine, dacarbazine, dactinomycin, dalteparin sodium,
dasatinib, daunorubicin, decitabine, denileukin, denileukin
diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone
propionate, eculizumab, epirubicin, erlotinib, estramustine,
etoposide phosphate, etoposide, exemestane, fentanyl citrate,
filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant,
gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate,
histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide,
imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib
ditosylate, lenalidomide, letrozole, leucovorin, leuprolide
acetate, levamisole, lomustine, meclorethamine, megestrol acetate,
melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C,
mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,
nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,
pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,
pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,
rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib,
sunitinib maleate, tamoxifen, temozolomide, teniposide,
testolactone, thalidomide, thioguanine, thiotepa, topotecan,
toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,
valrubicin, vinblastine, vincristine, vinorelbine, vorinostat and
zoledronate.
[0178] Other anti-cancer agent(s) include antibody therapeutics
such as trastuzumab (Herceptin), antibodies to costimulatory
molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to
PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-.beta.,
etc.). Examples of antibodies to PD-1 and/or PD-L1 that can be
combined with compounds of the present disclosure for the treatment
of cancer or infections such as viral, bacteria, fungus and
parasite infections include, but are not limited to, nivolumab,
pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
[0179] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0180] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be combined with another
immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate
molecules), cells, and cells transfected with genes encoding immune
stimulating cytokines. Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0181] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
a vaccination protocol for the treatment of cancer. In some
embodiments, the tumor cells are transduced to express GM-CSF. In
some embodiments, tumor vaccines include the proteins from viruses
implicated in human cancers such as Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present
disclosure can be used in combination with tumor specific antigen
such as heat shock proteins isolated from tumor tissue itself. In
some embodiments, the compounds of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or salts thereof can be combined with
dendritic cells immunization to activate potent anti-tumor
responses.
[0182] The compounds of the present disclosure can be used in
combination with bispecific macrocyclic peptides that target Fe
alpha or Fe gamma receptor-expressing effectors cells to tumor
cells. The compounds of the present disclosure can also be combined
with macrocyclic peptides that activate host immune
responsiveness.
[0183] The compounds of the present disclosure can be used in
combination with bone marrow transplant for the treatment of a
variety of tumors of hematopoietic origin.
[0184] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
vaccines, to stimulate the immune response to pathogens, toxins,
and self antigens. Examples of pathogens for which this therapeutic
approach may be particularly useful, include pathogens for which
there is currently no effective vaccine, or pathogens for which
conventional vaccines are less than completely effective. These
include, but are not limited to, HIV, Hepatitis (A, B, & C),
Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus
aureus, Pseudomonas Aeruginosa.
[0185] Viruses causing infections treatable by methods of the
present disclosure include, but are not limit to human
papillomavirus, influenza, hepatitis A, B, C or D viruses,
adenovirus, poxvirus, herpes simplex viruses, human
cytomegalovirus, severe acute respiratory syndrome virus, ebola
virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6,
HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus,
rhinovirus, coxsackie virus, comovirus, respiratory syncytial
virus, mumpsvirus, rotavirus, measles virus, rubella virus,
parvovirus, vaccinia virus, HTLV virus, dengue virus,
papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus
and arboviral encephalitis virus.
[0186] Pathogenic bacteria causing infections treatable by methods
of the disclosure include, but are not limited to, chlamydia,
rickettsial bacteria, mycobacteria, staphylococci, streptococci,
pneumonococci, meningococci and conococci, klebsiella, proteus,
serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli,
cholera, tetanus, botulism, anthrax, plague, leptospirosis, and
Lyme's disease bacteria.
[0187] Pathogenic fungi causing infections treatable by methods of
the disclosure include, but are not limited to, Candida (albicans,
krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans,
Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor,
absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis,
Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma
capsulatum.
[0188] Pathogenic parasites causing infections treatable by methods
of the disclosure include, but are not limited to, Entamoeba
histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0189] When more than one pharmaceutical agent is administered to a
patient, they can be administered simultaneously, separately,
sequentially, or in combination (e.g., for more than two
agents).
IV. Formulation, Dosage Forms and Administration
[0190] When employed as pharmaceuticals, the compounds of the
present disclosure can be administered in the form of
pharmaceutical compositions. Thus the present disclosure provides a
composition comprising a compound of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or a pharmaceutically acceptable salt
thereof, or any of the embodiments thereof, and at least one
pharmaceutically acceptable carrier or excipient. 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 indicated 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, e.g., 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.
[0191] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, the compound of the
present disclosure or a pharmaceutically acceptable salt thereof,
in combination with one or more pharmaceutically acceptable
carriers or excipients. In some embodiments, the composition is
suitable for topical administration. In making the compositions of
the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, e.g., 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,
e.g., up to 10% by weight of the active compound, soft and hard
gelatin capsules, suppositories, sterile injectable solutions and
sterile packaged powders.
[0192] 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.
[0193] The compounds of the invention 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 invention can be prepared by processes known in the art see,
e.g., WO 2002/000196.
[0194] 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 of the invention 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.
[0195] In some embodiments, the pharmaceutical composition
comprises silicified microcrystalline cellulose (SMCC) and at least
one compound described herein, or a pharmaceutically acceptable
salt thereof. In some embodiments, the silicified microcrystalline
cellulose comprises about 98% microcrystalline cellulose and about
2% silicon dioxide w/w.
[0196] In some embodiments, the composition is a sustained release
composition comprising at least one compound described herein, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier or excipient. In some
embodiments, the composition comprises at least one compound
described herein, or a pharmaceutically acceptable salt thereof,
and at least one component selected from microcrystalline
cellulose, lactose monohydrate, hydroxypropyl methylcellulose and
polyethylene oxide. In some embodiments, the composition comprises
at least one compound described herein, or a pharmaceutically
acceptable salt thereof, and microcrystalline cellulose, lactose
monohydrate and hydroxypropyl methylcellulose. In some embodiments,
the composition comprises at least one compound described herein,
or a pharmaceutically acceptable salt thereof, and microcrystalline
cellulose, lactose monohydrate and polyethylene oxide. In some
embodiments, the composition further comprises magnesium stearate
or silicon dioxide. In some embodiments, the microcrystalline
cellulose is Avicel PH102.TM.. In some embodiments, the lactose
monohydrate is Fast-flo 316.TM.. In some embodiments, the
hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208
K4M (e.g., Methocel K4 M Premier.TM.) and/or hydroxypropyl
methylcellulose 2208 K100LV (e.g., Methocel KOOLV.TM.). In some
embodiments, the polyethylene oxide is polyethylene oxide WSR 1105
(e.g., Polyox WSR 1105.TM.).
[0197] In some embodiments, a wet granulation process is used to
produce the composition. In some embodiments, a dry granulation
process is used to produce the composition.
[0198] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1,000 mg (1 g), more
usually about 100 mg to about 500 mg, of the active ingredient. In
some embodiments, each dosage contains about 10 mg of the active
ingredient. In some embodiments, each dosage contains about 50 mg
of the active ingredient. In some embodiments, each dosage contains
about 25 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.
[0199] The components used to formulate the pharmaceutical
compositions are of high purity and are substantially free of
potentially harmful contaminants (e.g., at least National Food
grade, generally at least analytical grade, and more typically at
least pharmaceutical grade). Particularly for human consumption,
the composition is preferably manufactured or formulated under Good
Manufacturing Practice standards as defined in the applicable
regulations of the U.S. Food and Drug Administration. For example,
suitable formulations may be sterile and/or substantially isotonic
and/or in full compliance with all Good Manufacturing Practice
regulations of the U.S. Food and Drug Administration.
[0200] The active compound may be effective over a wide dosage
range and is generally administered in a therapeutically 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.
[0201] The therapeutic dosage of a compound of the present
invention can vary according to, e.g., 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 of the invention 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 .mu.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.
[0202] 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 invention. 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, e.g.,
about 0.1 to about 1000 mg of the active ingredient of the present
invention.
[0203] The tablets or pills of the present invention 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.
[0204] The liquid forms in which the compounds and compositions of
the present invention 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.
[0205] 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.
[0206] Topical formulations can contain one or more conventional
carriers. In some embodiments, ointments can contain water and one
or more hydrophobic carriers selected from, e.g., 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, e.g.,
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,
e.g., 100 g which are optionally associated with instructions for
the treatment of the select indication, e.g., psoriasis or other
skin condition.
[0207] 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. 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.
[0208] 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.
[0209] The therapeutic dosage of a compound of the present
invention can vary according to, e.g., 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 of the invention 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 pig/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.
V. Labeled Compounds and Assay Methods
[0210] The compounds of the present disclosure can further be
useful in investigations of biological processes in normal and
abnormal tissues. Thus, another aspect of the present invention
relates to labeled compounds of the invention (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 PD-1 or PD-L1 protein in tissue
samples, including human, and for identifying PD-L1 ligands by
inhibition binding of a labeled compound.
[0211] Accordingly, the present invention includes PD-1/PD-L1
binding assays that contain such labeled compounds.
[0212] The present invention further includes isotopically-labeled
compounds of the 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 invention
include but are not limited to 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 PD-L1 protein 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.
[0213] It is to be 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. In some embodiments, the compound incorporates 1, 2, 3,
4, 5, 6, 7 or 8 deuterium atoms. Synthetic methods for
incorporating radio-isotopes into organic compounds are known in
the art.
[0214] Specifically, a labeled compound of the invention can be
used in a screening assay to identify and/or 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 PD-L1 protein by monitoring its concentration variation when
contacting with the PD-L1 protein, 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 PD-L1 protein (i.e., standard compound).
Accordingly, the ability of a test compound to compete with the
standard compound for binding to the PD-L1 protein directly
correlates to its binding affinity.
[0215] 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.
VI. Kits
[0216] The present disclosure also includes pharmaceutical kits
useful, e.g., in the treatment or prevention of diseases or
disorders associated with the activity of PD-L1 including its
interaction with other proteins such as PD-1 and B7-1 (CD80), such
as cancer or infections, which include one or more containers
containing a pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula (I), or
any of the embodiments thereof. Such kits can further include one
or more of various conventional pharmaceutical kit components, such
as, e.g., 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.
[0217] 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 inhibit the activity of PD-1/PD-L1
protein/protein interaction according to at least one assay
described herein.
EXAMPLES
[0218] Experimental procedures for compounds of the invention are
provided below. Open Access Preparative LCMS Purification of some
of the compounds prepared was 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 literature. See, e.g., Blom, "Two-Pump At
Column Dilution Configuration for Preparative LC-MS", K. Blom, J.
Combi. Chem., 2002, 4, 295-301; Blom et al., "Optimizing
Preparative LC-MS Configurations and Methods for Parallel Synthesis
Purification", J. Combi. Chem., 2003, 5, 670-83; and Blom et al.,
"Preparative LC-MS Purification: Improved Compound Specific Method
Optimization", J. Combi. Chem., 2004, 6, 874-883.
Example 1
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine
##STR00032##
[0219] Step 1:
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
##STR00033##
[0221] A mixture of 3-chloro-2-methylbiphenyl (1.44 mL, 8.08 mmol)
(Aldrich, cat#361623),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(6.15 g, 24.2 mmol), palladium acetate (72.5 mg, 0.323 mmol),
K.sub.3PO.sub.4 (5.14 g, 24.2 mmol) and
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (332 mg,
0.808 mmol) in 1,4-dioxane (30 mL) was degassed and stirred at r.t.
for 48 h. The reaction mixture was diluted with methylene chloride,
washed with saturated NaHCO.sub.3, water and brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by flash chromatography on a silica gel
column eluting with 0 to 5% ethyl acetate in methylene chloride to
give the desired product (1.60 g, 68%). LCMS calculated for
C.sub.19H.sub.24BO.sub.2 (M+H).sup.+: m/z=295.2; found 295.1.
Step 2: tert-butyl
2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-c-
arboxylate
##STR00034##
[0223] To a solution of tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
(9.9 mg, 31 .mu.mol) (Astatech, cat#27671),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(10 mg, 34 .mu.mol) and sodium carbonate (8.2 mg, 77.2 .mu.mol) in
tert-butyl alcohol (0.3 mL) and water (0.1 mL) was added
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II)
(Pd-127: 4.7 mg, 6.2 .mu.mol). The mixture was purged with N.sub.2,
then heated at 110.degree. C. for 2 h. The reaction mixture was
diluted with methylene chloride, washed with saturated NaHCO.sub.3,
water and brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was used in the next step
without further purification. LC-MS calculated for
C.sub.24H.sub.27N.sub.2O.sub.2S (M+H).sup.+: m/z=407.2; found
407.2.
Step 3:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]py-
ridine
[0224] The crude product from Step 2 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.19N.sub.2S (M+H).sup.+:
m/z=307.2; found 307.2.
Example 2
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
##STR00035##
[0225] Step 1: tert-butyl
2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-c-
arboxylate
##STR00036##
[0227] This compound was prepared using similar procedures as
described for Example 1, Step 2 with tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(Astatech, cat#AB1021) replacing tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5 (4H)-carboxylate.
The reaction mixture was diluted with methylene chloride, washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.24H.sub.27N.sub.2O.sub.2S (M+H).sup.+:
m/z=407.2; found 407.2.
Step 2:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]py-
ridine
[0228] The crude product from Step 1 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.19N.sub.2S (M+H).sup.+:
m/z=307.2; found 307.2.
Example 3
5-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]p-
yridine
##STR00037##
[0230] Formaldehyde (37 wt. % in water, 16 .mu.L, 0.2 mmol) was
added to a solution of
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
(Example 2: 15 mg, 0.049 mmol) and N,N-diisopropylethylamine (20
.mu.L, 0.1 mmol) in methylene chloride (1.0 mL), then the reaction
mixture was allowed to stir at r.t. for 5 min before sodium
triacetoxyborohydride (30 mg, 0.1 mmol) was added to the reaction
mixture. The resulting mixture was stirred for another 2 h then
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.20H.sub.21N.sub.2S (M+H).sup.+:
m/z=321.2; found 321.2.
Example 4
2-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)--
yl]ethanol
##STR00038##
[0232] To a solution of
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
(Example 2: 5.0 mg, 16 .mu.mol) and bromoethanol (5.7 .mu.L, 80
.mu.mol) in N,N-dimethylformamide (0.5 mL) was added potassium
carbonate (11 mg, 80 .mu.mol). The resulting mixture was stirred at
r.t. for 16 h, and then purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.21H.sub.23N.sub.2OS (M+H).sup.+:
m/z=351.2; found 351.2.
Example 5
(2S)-1-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5-
(4H)-yl]propan-2-ol
##STR00039##
[0234] To a solution of
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
(Example 2: 10.0 mg, 32.6 .mu.mol) and N,N-diisopropylethylamine
(11.4 .mu.L, 0.653 mmol) in methanol (1.3 mL) was added
(S)-(-)-methyloxirane (TCI, Cat#:P0951: 22.9 .mu.L, 0.326 mmol).
The reaction mixture was stirred at r.t. for 12 h, then diluted
with methanol then purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.22H.sub.25N.sub.2OS (M+H).sup.+:
m/z=365.2; found 365.2.
Example 6
2-(2-methylbiphenyl-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro[-
1,3]thiazolo[5,4-c]pyridine
##STR00040##
[0236] This compound was prepared using similar procedures as
described for Example 3 with tetrahydro-4H-pyran-4-one (Aldrich,
Cat#198242) replacing formaldehyde. The resulting mixture was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.24H.sub.27N.sub.2OS (M+H).sup.+: m/z=391.2; found 391.2.
Example 7
4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)--
yl]cyclohexanecarboxylic Acid
##STR00041##
[0238] This compound was prepared using similar procedures as
described for Example 3 with 4-oxocyclohexanecarboxylic acid
(Aldrich, Cat#751294) replacing formaldehyde. The resulting mixture
was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give
the desired product as the TFA salt. LC-MS calculated for
C.sub.26H.sub.29N.sub.2O.sub.2S (M+H).sup.+: m/z=433.2; found
433.2.
Example 8
4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)--
yl]butanoic Acid
##STR00042##
[0240] This compound was prepared using similar procedures as
described for Example 3 with 4-oxobutanoic acid (Aldrich,
Cat#14075) replacing formaldehyde. The resulting mixture was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.23H.sub.25N.sub.2O.sub.2S (M+H).sup.+: m/z=393.2; found
393.2.
Example 9
Trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-
-5(4H)-yl]methyl}cyclopropanecarboxylic Acid
##STR00043##
[0241] Step 1: ethyl
trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridi-
n-5(4H)-yl]methyl}cyclopropanecarboxylate
##STR00044##
[0243] This compound was prepared using similar procedures as
described for Example 3 with trans-ethyl
2-formylcyclopropanecarboxylate (Aldrich, Cat#157279) replacing
formaldehyde. The resulting mixture was concentrated to dryness and
used in the next step without further purification. LC-MS
calculated for C.sub.26H.sub.29N.sub.2O.sub.2S (M+H).sup.+:
m/z=433.2; found 433.2.
Step 2:
trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c-
]pyridin-5(4H)-yl]methyl}cyclopropanecarboxylic Acid
[0244] The crude product in Step 1 was treated with 1 N aq. NaOH
(0.5 mL) in methanol (1.0 mL) at 50.degree. C. and stirred for 15
h. The reaction mixture was cooled to room temperature then
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.24H.sub.25N.sub.2O.sub.2S (M+H).sup.+: m/z=405.2; found
405.2.
Example 10
2-(2-methylbiphenyl-3-yl)-5-(1H-pyrazol-4-ylmethyl)-4,5,6,7-tetrahydro[1,3-
]thiazolo[5,4-c]pyridine
##STR00045##
[0246] This compound was prepared using similar procedures as
described for Example 3 with 1H-pyrazole-4-carbaldehyde (Ark Pharm,
Cat#AK-25836) replacing formaldehyde. The resulting mixture was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.23H.sub.23N.sub.4S (M+H).sup.+: m/z=387.2; found 387.2.
Example 11
{4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-
-yl]cyclohexyl}acetonitrile
##STR00046##
[0248] This compound was prepared using similar procedures as
described for Example 3 with (4-oxocyclohexyl)acetonitrile
(ArkPharm, Cat#AK-46872) replacing formaldehyde. The resulting
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for
C.sub.27H.sub.30N.sub.3S (M+H).sup.+: m/z=428.2; found 428.2.
Example 12
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine
##STR00047##
[0249] Step 1: tert-butyl
2-(2-methylbiphenyl-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbox-
ylate
##STR00048##
[0251] This compound was prepared using similar procedures as
described for Example 1, Step 2 with tert-butyl
2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Aurum
Pharmatech, cat#10451833) replacing tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate.
The reaction mixture was diluted with methylene chloride, washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.24H.sub.28N.sub.3O.sub.2 (M+H).sup.+:
m/z=390.2; found 390.2.
Step 2:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e
[0252] The crude product from Step 1 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.3(M+H).sup.+:
m/z=290.2; found 290.2.
Example 13
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,5,6,7-tetrahydro[1,3]thiazolo[5,-
4-c]pyridin-2-yl)benzonitrile
##STR00049##
[0253] Step 1:
2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
##STR00050##
[0255] To a solution of 2-bromo-6-iodobenzonitrile (207 mg, 0.674
mmol) (Astatech, cat#CL8155),
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (127 mg, 0.707 mmol)
(Aldrich, cat#635995) and sodium carbonate (178 mg, 1.68 mmol) in
tert-butyl alcohol (3 mL) and water (1 mL) was added Pd-127 (51 mg,
67 .mu.mol). The reaction mixture was purged with N.sub.2, and then
heated at 90.degree. C. for 2 h. The reaction mixture was diluted
with methylene chloride, washed with saturated NaHCO.sub.3, water
and brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatography on a silica gel column eluting with 10 to 20% ethyl
acetate in hexanes to give the desired product (130 mg, 61%). LCMS
calculated for C.sub.15H.sub.11BrNO.sub.2 (M+H).sup.+: m/z=316.2;
found 316.2.
Step 2:
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)benzonitrile
##STR00051##
[0257] A mixture of
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (106
mg, 0.418 mmol),
2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (120 mg,
0.380 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (20 mg, 20 .mu.mol) and
potassium acetate (112 mg, 1.14 mmol) in 1,4-dioxane (3 mL) was
purges with nitrogen and heated at 90.degree. C. for 16 h. The
reaction mixture was diluted with methylene chloride, washed with
saturated NaHCO.sub.3, water and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 50% ethyl acetate in hexanes to give the desired product
(70 mg, 51%). LCMS calculated for C.sub.21H.sub.23BNO.sub.4
(M+H).sup.+: m/z=364.2; found 364.2.
Step 3: tert-butyl
2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6,7-dihydro[1,3]th-
iazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00052##
[0259] This compound was prepared using similar procedures as
described for Example 2, Step 1 with
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)benzonitrile (Step 2) replacing
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane.
The reaction mixture was diluted with methylene chloride, washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.26H.sub.26N.sub.3O.sub.4S (M+H).sup.+:
m/z=476.2; found 476.2.
Step 4:
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,5,6,7-tetrahydro[1,3]thi-
azolo[5,4-c]pyridin-2-yl)benzonitrile
[0260] The crude product from Step 3 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.21H.sub.18N.sub.3O.sub.2S
(M+H).sup.+: m/z=376.2; found 376.2.
Example 14
2-(3-methyl-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]py-
ridine
##STR00053##
[0261] Step 1: 2-chloro-3-methyl-4-phenylpyridine
##STR00054##
[0263] To a solution of 2-chloro-4-iodo-3-methylpyridine (303 mg,
1.20 mmol) (Aldrich, cat#724092), phenylboronic acid (160 mg, 1.32
mmol) (Aldrich, cat#78181) and sodium carbonate (317 mg, 2.99 mmol)
in tert-butyl alcohol (10 mL) and water (6 mL) was added Pd-127
(181 mg, 0.239 mmol). The resulting mixture was purged with
N.sub.2, and then heated at 80.degree. C. for 2 h. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 10 to 20% ethyl acetate in hexanes to give the desired product
(225 mg, 92%). LCMS calculated for C.sub.12H.sub.11C.sub.1N
(M+H).sup.+: m/z=204.2; found 204.2.
Step 2: tert-butyl
2-(3-methyl-4-phenylpyridin-2-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-
-5(4H)-carboxylate
##STR00055##
[0265] A solution of 2-chloro-3-methyl-4-phenylpyridine (40.0 mg,
0.196 mmol) in 1,4-dioxane (2.0 mL) was bubbled with N.sub.2, then
hexabutyldistannane (129 .mu.L, 0.255 mmol), lithium chloride (51.6
mg, 1.22 mmol), dichloro[bis(triphenylphosphoranyl)]palladium (14
mg, 20 .mu.mol) and tetrakis(triphenylphosphine)palladium(0) (23
mg, 20 .mu.mol) were added in sequence. The resulting mixture was
heated at 90.degree. C. for 90 min before a solution of tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(94.0 mg, 0.294 mmol) in 1,4-dioxane (1.5 mL) was pumped in over
1.5 h at 95.degree. C. The resulted mixture was stirred at the same
temperature for another 12 h, then cooled to room temperature,
diluted with methylene chloride, washed with saturated NaHCO.sub.3,
water and brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was used in the next step
without further purification. LC-MS calculated for
C.sub.23H.sub.26N.sub.3O.sub.2S (M+H).sup.+: m/z=408.2; found
408.2.
Step 3:
2-(3-methyl-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[-
5,4-c]pyridine
[0266] The crude product from Step 2 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.18H.sub.18N.sub.3S (M+H).sup.+:
m/z=308.2; found 308.2. .sup.1H NMR (600 MHz, DMSO) .delta. 9.35
(s, 1H), 8.56-8.50 (m, 1H), 7.55-7.51 (m, 2H), 7.50-7.46 (m, 1H),
7.44-7.40 (m, 2H), 7.34 (d, J=4.8 Hz, 1H), 4.52 (br, 2H), 3.54 (br,
2H), 3.09 (t, J=6.1 Hz, 2H), 2.62 (s, 3H).
Example 15
2-[4-(3-methoxyphenyl)-3-methylpyridin-2-yl]-4,5,6,7-tetrahydro[1,3]thiazo-
lo[5,4-c]pyridine
##STR00056##
[0268] This compound was prepared using similar procedures as
described for Example 14, Step 1-3 with 3-methoxyphenylboronic acid
(Aldrich, cat#441686) replacing phenylboronic acid in Step 1. The
reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.30S (M+H).sup.+:
m/z=338.2; found 338.2.
Example 16
2-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-2-yl]-4,5,6,7-tetr-
ahydro[1,3]thiazolo[5,4-c]pyridine
##STR00057##
[0269] This compound was prepared using similar procedures as
described for Example 14, Step 1-3 with
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Combi-blocks,
cat#BB-8311) replacing phenylboronic acid in Step 1. The reaction
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for
C.sub.20H.sub.20N.sub.3O.sub.2S (M+H).sup.+: m/z=366.2; found
366.2.
Example 17
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
##STR00058##
[0270] Step 1: 3-bromo-2-methylbiphenyl
##STR00059##
[0272] This compound was prepared using similar procedures as
described for Example 13, Step 1 with
1-bromo-3-iodo-2-methylbenzene (Oakwood, cat#037475) replacing
2-bromo-6-iodobenzonitrile, and phenylboronic acid replacing
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. The reaction mixture
was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 5% ethyl acetate in hexanes to give the desired
product.
Step 2: tert-butyl
2-(2-methylbiphenyl-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-
-carboxylate
##STR00060##
[0274] To a mixture of 3-bromo-2-methylbiphenyl (100 mg, 0.405
mmol), tert-butyl
1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Ark
Pharm, Cat#AK-24984: 180 mg, 0.81 mmol),
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',6'-diisopropoxybiphenyl-2-
-yl)phosphoranyl]palladium (30.9 mg, 39.7 .mu.mol) (RuPhos G2,
Aldrich, cat#753246) in 1,4-dioxane (1.1 mL) was added sodium
tert-butoxide (76.4 mg, 0.795 mmol). The resulting mixture was
heated at 110.degree. C. under the atmosphere of N.sub.2 for 15 h,
then diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.24H.sub.28N.sub.3O.sub.2 (M+H).sup.+: m/z=390.2; found
390.2.
Step 3:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyr-
idine
[0275] The crude product from Step 2 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.3(M+H).sup.+:
m/z=290.2; found 290.2.
Example 18
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine
##STR00061##
[0276] Step 1: tert-butyl
2-(2-methylbiphenyl-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-
-carboxylate
##STR00062##
[0278] This compound was prepared using similar procedures as
described for Example 17, Step 2 with tert-butyl
1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Ark
Pharm, cat#AK-39955) replacing tert-butyl
1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. The
resulting mixture was diluted with methylene chloride, washed with
saturated NaHCO.sub.3, water and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
used in the next step without further purification. LC-MS
calculated for C.sub.24H.sub.28N.sub.3O.sub.2 (M+H).sup.+:
m/z=390.2; found 390.2.
Step 2:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyr-
idine
[0279] The crude product from Step 1 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.3 (M+H).sup.+:
m/z=290.2; found 290.2.
Example 19
7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
-c]pyridine
##STR00063##
[0280] Step 1: tert-butyl
5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate
##STR00064##
[0282] To a solution of tert-butyl
3,3-dimethyl-4-oxopiperidine-1-carboxylate (107 mg, 469 .mu.mol)
(Combi-blocks, cat#QA-1430) in chloroform (2.0 mL) was added
bromine (24.2 .mu.L, 469 .mu.mol) in chloroform (0.5 mL) at
0.degree. C. After stirred at the same temperature for 15 min, it
was allowed to warm up to r.t. and stirred for another 30 min. The
resulted mixture was concentrated to dryness and used in the next
step without further purification. LC-MS calculated for
C.sub.12H.sub.21BrNO.sub.3 (M+H).sup.+: m/z=306.2; found 306.2.
Step 2: tert-butyl
2-amino-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate
##STR00065##
[0284] To a solution of above crude product in ethanol (0.5 mL) was
added thiourea (53.5 mg, 703 .mu.mol). The resulted mixture was
heated at 80.degree. C. for 3 h then concentrated to dryness and
used in the next step without further purification. LC-MS
calculated for C.sub.13H.sub.22N.sub.3O.sub.2S (M+H).sup.+:
m/z=284.2; found 284.2.
Step 3: tert-butyl
2-bromo-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate
##STR00066##
[0286] To a solution of the crude product from Step 2 in
acetonitrile (1.0 mL) was added tert-butyl nitrite (94.8 .mu.L, 797
.mu.mol) and copper(II) bromide (157 mg, 703 .mu.mol). After the
reaction mixture was stirred for 3 h, it was diluted with methylene
chloride and washed over water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.13H.sub.20BrN.sub.2O.sub.2S (M+H).sup.+: m/z=347.2; found
347.2.
Step 4: tert-butyl
7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyr-
idine-5(4H)-carboxylate
##STR00067##
[0288] This compound was prepared using similar procedures as
described for Example 1, Step 2 with tert-butyl
2-bromo-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate (Step 3) replacing tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate.
The reaction mixture was diluted with methylene chloride, washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.26H.sub.31N.sub.2O.sub.2S (M+H).sup.+:
m/z=435.2; found 435.2.
Step 5:
7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thia-
zolo[5,4-c]pyridine
[0289] The crude product from Step 4 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.21H.sub.23N.sub.2S (M+H).sup.+:
m/z=335.2; found 335.2.
Example 20
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine
##STR00068##
[0290] Step 1: 1-(2-methylbiphenyl-3-yl)ethanone
##STR00069##
[0292] To a solution of 1-(3-bromo-2-methylphenyl)ethanone (500 mg,
2.35 mmol) (Astatech, cat#CL9266), phenylboronic acid (300 mg, 2.46
mmol) and sodium carbonate (622 mg, 5.87 mmol) in tert-butyl
alcohol (10 mL) and water (4 mL) was added Pd-127 (178 mg, 235
.mu.mol). The resulted mixture was heated at 105.degree. C. for 2
h, and then was diluted with methylene chloride, washed with
saturated NaHCO.sub.3, water and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 50% ethyl acetate in hexanes to give the desired product
(400 mg, 80%). LC-MS calculated for C.sub.15H.sub.15O (M+H).sup.+:
m/z=211.2; found 211.2.
Step 2: 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
##STR00070##
[0294] To a solution of 1-(2-methylbiphenyl-3-yl)ethanone (1.25 g,
5.94 mmol) in ethyl acetate (30 mL) was added copper(II) bromide
(5.3 g, 24 mmol) then stirred at 80.degree. C. for 2 hours, then it
was filtered and concentrated to dryness under reduced pressure.
The residue was purified by flash chromatography on a silica gel
column eluting with 0 to 50% ethyl acetate in hexanes to give the
desired product (1.50 g, 87%). LC-MS calculated for
C.sub.15H.sub.14BrO (M+H).sup.+: m/z=289.2; found 289.2.
Step 3: 2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine
##STR00071##
[0296] A solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (20
mg, 69 .mu.mol), aminopyrazine (9.87 mg, 104 .mu.mol) in
acetonitrile (0.4 mL) was heated at 100.degree. C. for 2 h, then it
was concentrated to dryness under reduced pressure. The residue was
used in the next step without further purification. LC-MS
calculated for C.sub.19H.sub.16N.sub.3(M+H).sup.+: m/z=286.2; found
286.2.
Step 4:
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine
[0297] To the solution of the crude product from Step 3 in methanol
(2.0 mL) was added Pd/C (10 mg) and the resulting mixture was
stirred at r.t. for 4 h under an atmosphere of H.sub.2. The
resulting mixture was filtered and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.3(M+H).sup.+:
m/z=290.2; found 290.2.
Example 21
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine
##STR00072##
[0298] Step 1: 2-methylbiphenyl-3-carbaldehyde
##STR00073##
[0300] To a solution of (2-methylbiphenyl-3-yl)methanol (TCI,
Cat#:H0777: 4.12 g, 20.8 mmol) in methylene chloride (60 mL) was
slowly added Dess-Martin periodinane (9.25 g, 21.8 mmol). The
resulting mixture was stirred at r.t. for 30 min, and then washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by flash chromatography on a silica gel column eluting
with 0 to 30% ethyl acetate in hexanes to give the desired product
(3.30 g, 80%). LC-MS calculated for C.sub.14H.sub.13O (M+H).sup.+:
m/z=197.2; found 197.2.
Step 2: 2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine
##STR00074##
[0302] To a solution of pyridine-3,4-diamine (15 mg, 0.14 mmol) and
2-methylbiphenyl-3-carbaldehyde (30 mg, 0.15 mmol) in methanol
(0.69 mL) was added catalytic amount of zinc triflate (5 mg), then
heated at 70.degree. C. for 36 h. The resulting mixture was
filtered and purified by prep-HPLC (pH=2, acetonitrile/water+TFA)
to give the desired product as the TFA salt. LC-MS calculated for
C.sub.19H.sub.16N.sub.3(M+H).sup.+: m/z=286.2; found 286.2.
Step 3:
5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4-
,5-c]pyridine
##STR00075##
[0304] To a solution of
2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine (10 mg, TFA
salt) in DMF (0.3 mL) was added benzylbromide (10 .mu.L) and DIPEA
(10 .mu.L). The resulting mixture was heated at 100.degree. C. for
2 h, then concentrated to dryness. The crude mixture was dissolved
in methanol (2.0 mL) and NaBH.sub.4 (10 mg) was added at r.t. The
resulting mixture was stirred for 30 min and purified by prep-HPLC
(pH=2, acetonitrile/water+TFA) to give the desired product as the
TFA salt. LC-MS calculated for C.sub.26H.sub.26N.sub.3(M+H).sup.+:
m/z=380.2; found 380.2.
Step 4:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyri-
dine
[0305] To a solution of
5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]py-
ridine (5 mg, TFA salt) in methanol (2.0 mL) was added Pd/C (10 mg)
and stirred at r.t. for 4 h under under an atmosphere of H.sub.2.
The resulting mixture was filtered and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.3(M+H).sup.+:
m/z=290.2; found 290.2.
Example 22
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine
##STR00076##
[0306] Step 1:
2-(2-methylbiphenyl-3-yl)[1,3]oxazolo[5,4-c]pyridine
##STR00077##
[0308] To a mixture of 2-methylbiphenyl-3-carboxylic acid (100 mg,
471 .mu.mol) (Combi-Blocks, cat#YA-8643) and triethylamine (65.7
.mu.L, 471 .mu.mol) in methylene chloride (2.0 mL) was added
cyanuric chloride (28.9 mg, 157 .mu.mol). The resulting mixture was
heated at 60.degree. C. for 20 min then 4-aminopyridin-3-ol (51.9
mg, 471 .mu.mol) was added. The resulting mixture was heated at the
same temperature for 18 h then cooled to room temperature and
concentrated. The residue was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.15N.sub.20 (M+H).sup.+:
m/z=287.2; found 287.2.
Step 2:
5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[-
5,4-c]pyridine
##STR00078##
[0310] This compound was prepared using similar procedures as
described for Example 21, Step 3 with
2-(2-methylbiphenyl-3-yl)[1,3]oxazolo[5,4-c]pyridine (Step 1)
replacing 2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine. The
resulting mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.26H.sub.25N.sub.20 (M+H).sup.+:
m/z=381.2; found 381.3.
Step 3:
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyr-
idine
[0311] This compound was prepared using similar procedures as
described for Example 21, Step 4 with
5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]p-
yridine (Step 2) replacing
5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]py-
ridine. The resulting mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.19N.sub.20 (M+H).sup.+:
m/z=291.2; found 291.2.
Example 23
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine
##STR00079##
[0313] This compound was prepared using similar procedures as
described for Example 22 with 3-aminopyridin-4-ol replacing
4-aminopyridin-3-ol in Step 1. The reaction mixture was purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.19H.sub.19N.sub.20 (M+H).sup.+: m/z=291.2; found 291.2.
Example 24
5-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]py-
ridine
##STR00080##
[0315] This compound was prepared using similar procedures as
described for Example 3 with
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine
(Example 23) replacing
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine.
The resulting mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.20H.sub.21N.sub.2O (M+H).sup.+:
m/z=305.2; found 305.2.
Example 25
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine
##STR00081##
[0316] Step 1: ethyl
[(pyrazin-2-ylamino)carbonothioyl]carbamate
##STR00082##
[0318] To a solution of aminopyrazine (200 mg, 2.10 mmol) in
1,4-dioxane (10 mL) was added ethoxycarbonyl isothiocyanate (273
.mu.L, 2.42 mmol). The reaction mixture was stirred at r.t. for 15
h. The resulted mixture was concentrated to dryness and used in the
next step without further purification. LC-MS calculated for
C.sub.8H.sub.11N.sub.4O.sub.2S (M+H).sup.+: m/z=227.2; found
227.2.
Step 2: [1,2,4]triazolo[1,5-a]pyrazin-2-amine
##STR00083##
[0320] To a solution of the crude product from Step 1 in methanol
(7.0 mL) and ethanol (7.0 mL) was added hydroxyaminehydrochoride
(438 mg, 6.31 mmol) and N,N-diisopropylethylamine (733 .mu.L, 4.20
mmol). The resulting mixture was heated at 75.degree. C. for 7 h.
After cooled to room temperature, the precipitated product (yellow
solid) was filtered and washed with small amount of methanol. LC-MS
calculated for C.sub.8H.sub.6N.sub.5(M+H).sup.+: m/z=136.2; found
136.2.
Step 3: 2-bromo[1,2,4]triazolo[1,5-a]pyrazine
##STR00084##
[0322] This compound was prepared using similar procedures as
described for Example 19, Step 3 with
[1,2,4]triazolo[1,5-a]pyrazin-2-amine (Step 2) replacing tert-butyl
2-amino-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate. After stirred for 3 h, the reaction mixture was diluted with
methylene chloride and washed over water. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.5H.sub.4BrN.sub.4 (M+H).sup.+: m/z=199.2;
found 199.2.
Step 4: 2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyrazine
##STR00085##
[0324] This compound was prepared using similar procedures as
described for Example 1, Step 2 with
2-bromo[1,2,4]triazolo[1,5-a]pyrazine (Step 3) replacing tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5 (4H)-carboxylate.
The reaction mixture was diluted with methylene chloride, washed
with saturated NaHCO.sub.3, water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was used in the next step without further purification. LC-MS
calculated for C.sub.18H.sub.15N.sub.4(M+H).sup.+: m/z=287.2; found
287.2.
Step 5:
2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]-
pyrazine
[0325] The crude product from Step 4 was dissolved in methanol (1.0
mL) then treated with LiBH.sub.4 (10 mg) at 50.degree. C. for 30
min. The resulting mixture was quenched with TFA before
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.18H.sub.19N.sub.4(M+H).sup.+:
m/z=291.2; found 291.2.
Example 26
2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-4,5,6,7-tetr-
ahydro[1,3]thiazolo[5,4-c]pyridine
##STR00086##
[0326] Step 1: (2-chloro-3-methylpyridin-4-yl)boronic Acid
##STR00087##
[0328] A mixture of 2-chloro-4-iodo-3-methylpyridine (250 mg, 986
.mu.mol) (AstaTech, cat#22441) and boric acid, trimethyl ester (224
.mu.L, 1.97 mmol) in tetrahydrofuran (5.0 mL) was added 2.5 M
n-butyllithium in hexanes (789 .mu.L, 1.97 mmol) dropwise at
-78.degree. C. The reaction mixture was allowed to warm up to r.t.
after 90 min and stirred for another 30 min. The resulting mixture
was concentrated and acetonitrile (5 mL) was added. The resulting
suspension was filtered through celite then concentrated to give
the desired product. LCMS calculated for C.sub.6H.sub.8BClNO.sub.2
(M+H).sup.+: m/z=172.2; found 172.2.
Step 2: tert-butyl
2-(2-chloro-3-methylpyridin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-
-5(4H)-carboxylate
##STR00088##
[0330] To a solution of (2-chloro-3-methylpyridin-4-yl)boronic acid
(Example 26, Step 1: 170 mg, 1.0 mmol), tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(AstaTech, cat#AB1021: 320 mg, 1.0 mmol) and sodium carbonate (314
mg, 2.96 mmol) in tert-butyl alcohol (10 mL) and water (5 mL) was
added Pd-127 (75 mg, 0.10 mmol). The resulting mixture was purged
with N.sub.2, then heated at 105.degree. C. for 2 h. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.17H.sub.21C.sub.1N.sub.3O.sub.2S (M+H).sup.+: m/z=366.1;
found 366.2.
Step 3: tert-butyl
2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-6,7-dihydro-
[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00089##
[0332] To a solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic
acid (Combi-blocks, Cat#BB-8311: 36 mg, 0.20 mmol), tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(Example 26, Step 2: 32 mg, 0.10 mmol) and sodium carbonate (31 mg,
0.30 mmol) in tert-butyl alcohol (1.0 mL) and water (0.6 mL) was
added Pd-127 (15 mg, 0.020 mmol). The resulting mixture was purged
with N.sub.2, then heated at 105.degree. C. for 1.5 h. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.25H.sub.28N.sub.3O.sub.4S (M+H).sup.+: m/z=466.1; found
466.2.
Step 4:
2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-4,5,-
6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
[0333] The crude product from Step 3 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min then
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.20H.sub.20N.sub.3O.sub.2S
(M+H).sup.+: m/z=366.2; found 366.2.
Example 27
2-[2-methyl-3-(3-thienyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyr-
idine
##STR00090##
[0334] Step 1: tert-butyl
2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-
-carboxylate
##STR00091##
[0336] To a solution of (3-chloro-2-methylphenyl)boronic acid
(Combi-blocks, cat#BB-2035: 64 mg, 0.38 mmol), tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(AstaTech, cat#AB1021: 100 mg, 0.31 mmol) and sodium carbonate (100
mg, 0.94 mmol) in tert-butyl alcohol (3.2 mL) and water (2 mL) was
added Pd-127 (47 mg, 0.063 mmol). The resulting mixture was purged
with N.sub.2, then heated at 105.degree. C. for 2 h. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 40% ethyl acetate in hexanes to give the desired product
(114 mg, 83%). LC-MS calculated for
C.sub.18H.sub.22C.sub.1N.sub.2O.sub.2S (M+H).sup.+: m/z=365.1;
found 365.2.
Step 2: tert-butyl
2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6,7-di-
hydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00092##
[0338] A mixture of tert-butyl
2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-
-carboxylate (Example 26, Step 1: 95 mg, 0.26 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (200
mg, 0.78 mmol), palladium acetate (2.5 mg, 0.014 mmol),
K.sub.3PO.sub.4 (170 mg, 0.78 mmol) and
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (11 mg,
0.026 mmol) in 1,4-dioxane (1 mL) was degassed and stirred at r.t.
for 3 d. The reaction mixture was diluted with methylene chloride,
washed with saturated NaHCO.sub.3, water and brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by flash chromatography on a silica gel
column eluting with 0 to 5% ethyl acetate in methylene chloride to
give the desired product (108 mg, 90%). LC-MS calculated for
C.sub.24H.sub.34BN.sub.2O.sub.4S (M+H).sup.+: m/z=457.2; found
457.2.
Step 3: tert-butyl
2-[2-methyl-3-(3-thienyl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine--
5(4H)-carboxylate
##STR00093##
[0340] To a solution of tert-butyl
2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6,7-di-
hydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (Example 26,
Step 2: 15 mg, 0.033 mmol), thiophene, 3-bromo- (6.2 .mu.L, 0.066
mmol) and sodium carbonate (8.7 mg, 0.082 mmol) in tert-butyl
alcohol (0.3 mL) and water (0.2 mL) was added Pd-127 (5.0 mg,
0.0066 mmol). The resulting mixture was purged with N.sub.2, then
heated at 105.degree. C. for 1.5 h. The reaction mixture was
diluted with methylene chloride, washed with saturated NaHCO.sub.3,
water and brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was used in the next step
without further purification. LC-MS calculated for
C.sub.22H.sub.25N.sub.2O.sub.2S.sub.2(M+H).sup.+: m/z=413.1; found
413.2.
Step 4:
2-[2-methyl-3-(3-thienyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5-
,4-c]pyridine
[0341] The crude product from Step 3 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min then
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.17H.sub.17N.sub.2S.sub.2
(M+H).sup.+: m/z=313.1; found 313.2.
Example 28
2-(3'-methoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c-
]pyridine
##STR00094##
[0343] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with 1-bromo-3-methoxybenzene
replacing 3-bromothiophene in Step 3. The reaction mixture was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.20H.sub.21N.sub.2OS (M+H).sup.+: m/z=337.2; found 337.2.
Example 29
2-[3-(3,6-dihydro-2H-pyran-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]th-
iazolo[5,4-c]pyridine
##STR00095##
[0345] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with
4-bromo-3,6-dihydro-2H-pyran (Combi-blocks, cat#OT-0686) replacing
3-bromothiophene in Step 3. The reaction mixture was purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.18H.sub.21N.sub.2OS (M+H).sup.+: m/z=313.2; found 313.2.
Example 30
2-[3-(2-methoxypyridin-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazo-
lo[5,4-c]pyridine
##STR00096##
[0347] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with 4-bromo-2-methoxypyridine
(Ark Pharm, cat#AK-47404) replacing 3-bromothiophene in Step 3. The
reaction mixture purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.19H.sub.20N.sub.30S (M+H).sup.+:
m/z=338.2; found 338.2.
Example 31
2-[3-(5-fluoropyridin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazol-
o[5,4-c]pyridine
##STR00097##
[0349] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with 2-bromo-5-fluoropyridine
(Aldrich, cat#595675) replacing 3-bromothiophene in Step 3. The
reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.18H.sub.17FN.sub.3S (M+H).sup.+:
m/z=326.2; found 326.2.
Example 32
2-(3-cyclohex-1-en-1-yl-2-methylphenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,-
4-c]pyridine
##STR00098##
[0351] This compound was prepared using similar procedures as
described for Example 27 with 1-bromocyclohexene (Combi-blocks,
cat#OT-0350) replacing 3-bromothiophene in Step 3. The reaction
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for
C.sub.19H.sub.23N.sub.2S (M+H).sup.+: m/z=311.2; found 311.2.
Example 33
2-(3'-ethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-
pyridine
##STR00099##
[0353] This compound was prepared using similar procedures as
described for Example 27 with 1-bromo-3-ethoxybenzene (Aldrich,
cat#453250) replacing 3-bromothiophene in Step 3. The reaction
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for
C.sub.21H.sub.23N.sub.2OS (M+H).sup.+: m/z=351.2; found 351.2.
Example 34
2-(3',5'-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[-
5,4-c]pyridine
##STR00100##
[0355] This compound was prepared using similar procedures as
described for Example 27 with 3,5-dimethoxybromobenzene (Aldrich,
cat#569313) replacing 3-bromothiophene in Step 3. The reaction
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for
C.sub.21H.sub.23N.sub.2O.sub.2S (M+H).sup.+: m/z=367.2; found
367.2.
Example 35
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4,5,6,7-tetrahydro[1,3]thiazolo[5,-
4-c]pyridin-2-yl)nicotinonitrile
##STR00101##
[0357] This compound was prepared using similar procedures as
described for Example 16 with 2-chloro-4-iodonicotinonitrile (Aurum
Pharmatech, cat#A-6061) replacing 2-chloro-4-iodo-3-methylpyridine.
The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.20H.sub.17N.sub.4O.sub.2S
(M+H).sup.+: m/z=377.2; found 377.2.
Example 36
2-{[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphe-
nyl-3-yl]oxy}ethanol
##STR00102##
[0358] Step 1: 2-(3-bromophenoxy)ethanol
##STR00103##
[0360] To a solution of 3-bromophenol (100 mg, 0.58 mmol) and
2-bromoethanol (36 mg, 0.29 mmol) in methanol (1 mL) was added
potassium carbonate (80 mg, 0.58 mmol). The reaction mixture was
heated at 55.degree. C. for 4 h, and then diluted with methylene
chloride, washed with water and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
used in the next step without further purification.
Step 2:
2-{[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2--
yl)biphenyl-3-yl]oxy}ethanol
[0361] This compound was prepared using similar procedures as
described for Example 27, Steps 1-4 with 2-(3-bromophenoxy)ethanol
(Step 1) replacing 3-bromothiophene in Step 3. The reaction mixture
was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give
the desired product as the TFA salt. LC-MS calculated for
C.sub.21H.sub.23N.sub.2O.sub.2S (M+H).sup.+: m/z=367.2; found
367.2.
Example 37
2-(2',6'-difluoro-3',5'-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydr-
o[1,3]thiazolo[5,4-c]pyridine
##STR00104##
[0362] Step 1: 2,4-difluoro-3-iodo-1,5-dimethoxybenzene
##STR00105##
[0364] To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline
(500 mg, 2.64 mmol) in 6.0 M hydrogen chloride in water (4 mL, 24
mmol) was added a solution of sodium nitrite (191 mg, 2.78 mmol) in
water (1 mL) dropwise over 15 min at 0.degree. C. After stirring
the resulting mixture at 0.degree. C. for another 15 min, a
solution of potassium iodide (1.8 g, 10. mmol) in water (2 mL) was
slowly added to the resulting orange-red slurry at 0.degree. C.
with vigorus stirring. After completion of the addition, the
reaction mixture was allowed to warm up to r.t. for 1 hour. The
solid was collected by filtration, washed with water and dried
under vacuum. 570 mg solid was collected and used directly in the
next step.
Step 2:
2-(2',6'-difluoro-3',5'-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-t-
etrahydro[1,3]thiazolo[5,4-c]pyridine
[0365] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with
2,4-difluoro-3-iodo-1,5-dimethoxybenzene (Step 1) replacing
3-bromothiophene in Step 3. The reaction mixture was purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.21H.sub.21F.sub.2N.sub.2O.sub.2S (M+H).sup.+: m/z=403.2;
found 403.2.
Example 38
2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl--
3-carboxamide
##STR00106##
[0366] Step 1: tert-butyl
2-[3'-(aminocarbonyl)-2-methylbiphenyl-3-yl]-6,7-dihydro[1,3]thiazolo[5,4-
-c]pyridine-5(4H)-carboxylate
##STR00107##
[0368] This compound was prepared using similar procedures as
described for Example 27, Step 3 with 3-bromobenzoic acid nitrile
(Aldrich, cat#B58202) replacing 3-bromothiophene. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.25H.sub.28N.sub.3O.sub.3S (M+H).sup.+: m/z=450.2; found
450.2.
Step 2:
2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)b-
iphenyl-3-carboxamide
[0369] The crude product from Step 1 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min then
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.20H.sub.20N.sub.3OS (M+H).sup.+:
m/z=350.2; found 350.2.
Example 39
2-[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphen-
yl-3-yl]acetamide
##STR00108##
[0370] Step 1: tert-butyl
2-[3'-(2-amino-2-oxoethyl)-2-methylbiphenyl-3-yl]-6,7-dihydro[1,3]thiazol-
o[5,4-c]pyridine-5(4H)-carboxylate
##STR00109##
[0372] This compound was prepared using similar procedures as
described for Example 27, Step 3 with (3-bromophenyl)acetonitrile
(Aldrich, cat#260088) replacing 3-bromothiophene. The reaction
mixture was diluted with methylene chloride, washed with saturated
NaHCO.sub.3, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was used
in the next step without further purification. LC-MS calculated for
C.sub.26H.sub.30N.sub.3O.sub.3S (M+H).sup.+: m/z=464.2; found
464.2.
Step 2:
2-[2'-methyl-3'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-y-
l)biphenyl-3-yl]acetamide
[0373] The crude product from Step 1 was dissolved in methylene
chloride (0.6 mL) then treated with TFA (0.3 mL). The resulting
mixture was stirred at room temperature for 30 min then
concentrated and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.21H.sub.22N.sub.30S (M+H).sup.+:
m/z=364.2; found 364.2. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.57-7.53 (m, 1H), 7.43-7.38 (m, 1H), 7.38-7.32 (m, 3H), 7.31-7.27
(m, 1H), 7.24-7.20 (m, 1H), 4.62-4.54 (m, 2H), 3.71-3.64 (m, 2H),
3.58 (s, 2H), 3.21 (t, J=6.2 Hz, 2H), 2.31 (s, 3H).
Example 40
2-[2-methyl-3-(1-methyl-1H-indazol-4-yl)phenyl]-4,5,6,7-tetrahydro[1,3]thi-
azolo[5,4-c]pyridine
##STR00110##
[0374] Step 1: 4-bromo-1-methyl-1H-indazole
##STR00111##
[0376] To a solution of 4-bromo-1H-indazole (Aldrich, cat#776610:
100. mg, 0.508 mmol) in acetone (2.5 mL) was added potassium
hydroxide (85.4 mg, 1.52 mmol). The resulting mixture was stirred
at room temperature for 10 min then methyl iodide (63.2 .mu.L, 1.02
mmol) was added. The mixture was stirred at room temperature
overnight then concentrated to give a mixture of
4-bromo-2-methyl-2H-indazole and 4-bromo-1-methyl-1H-indazole,
which was used in the next step without further purification. LC-MS
calculated for CsHsBrN.sub.2 (M+H).sup.+: m/z=211.0; found
211.1.
Step 2:
2-[2-methyl-3-(1-methyl-1H-indazol-4-yl)phenyl]-4,5,6,7-tetrahydro-
[1,3]thiazolo[5,4-c]pyridine
[0377] This compound was prepared using similar procedures as
described for Example 27, Step 1-4 with
4-bromo-1-methyl-1H-indazole (crude product from Step 1) replacing
3-bromothiophene in Step 3. The reaction mixture was purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.21H.sub.21N.sub.4S (M+H).sup.+: m/z=361.1; found 361.2.
.sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 7.69-7.67 (m, 1H),
7.66-7.63 (m, 1H), 7.61-7.58 (m, 1H), 7.55-7.51 (m, 1H), 7.46-7.41
(m, 2H), 7.08 (d, J=6.9 Hz, 1H), 4.62-4.56 (m, 2H), 4.12 (s, 3H),
3.67 (t, J=6.2 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.23 (s, 3H).
Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)
Binding Assay
[0378] The assays were conducted in a standard black 384-well
polystyrene plate with a final volume of 20 .mu.L. Inhibitors were
first serially diluted in DMSO and then added to the plate wells
before the addition of other reaction components. The final
concentration of DMSO in the assay was 1%. The assays were carried
out at 25.degree. C. in the PBS buffer (pH 7.4) with 0.05% Tween-20
and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a
His-tag at the C-terminus was purchased from AcroBiosystems
(PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at
the C-terminus was also purchased from AcroBiosystems (PD1-H5257).
PD-L1 and PD-1 proteins were diluted in the assay buffer and 10
.mu.L was added to the plate well. Plates were centrifuged and
proteins were preincubated with inhibitors for 40 minutes. The
incubation was followed by the addition of 10 .mu.L of HTRF
detection buffer supplemented with Europium cryptate-labeled
anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His
antibody conjugated to SureLight.RTM.-Allophycocyanin (APC,
PerkinElmer-AD0059H). After centrifugation, the plate was incubated
at 25.degree. C. for 60 min. before reading on a PHERAstar FS plate
reader (665 nm/620 nm ratio). Final concentrations in the assay
were--3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG and 20 nM
anti-His-Allophycocyanin. IC.sub.50 determination was performed by
fitting the curve of percent control activity versus the log of the
inhibitor concentration using the GraphPad Prism 5.0 software.
[0379] Compounds of the present disclosure, as exemplified in
Examples 1-40, showed IC.sub.50 values in the following ranges:
+=IC.sub.50.ltoreq.100 nM; ++=100 nM<IC.sub.50.ltoreq.500 nM;
+++=500 nM<IC.sub.50.ltoreq.10000 nM
[0380] Data obtained for the Example compounds using the PD-1/PD-L1
homogenous time-resolved fluorescence (HTRF) binding assay
described in Example A is provided in Table 1.
TABLE-US-00001 TABLE 1 PD-1/PD-L1 HTRF Example IC.sub.50 (nM) 1 +++
2 + 3 + 4 + 5 + 6 ++ 7 + 8 + 9 ++ 10 ++ 11 ++ 12 ++ 13 + 14 + 15 +
16 + 17 ++ 18 + 19 +++ 20 +++ 21 +++ 22 + 23 + 24 + 25 ++ 26 +++ 27
++ 28 + 29 +++ 30 ++ 31 +++ 32 + 33 + 34 + 35 ++ 36 ++ 37 + 38 + 39
+ 40 +
[0381] 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 without limitation all patent, patent applications, and
publications, cited in the present application is incorporated
herein by reference in its entirety.
* * * * *