U.S. patent application number 16/005961 was filed with the patent office on 2019-05-16 for heterocyclic compounds as immunomodulators.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Jingwei Li, Zhenwu Li, Kai Liu, Bo Shen, Liangxing Wu, Wenqing Yao, Fenglei Zhang.
Application Number | 20190144439 16/005961 |
Document ID | / |
Family ID | 57206446 |
Filed Date | 2019-05-16 |
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United States Patent
Application |
20190144439 |
Kind Code |
A1 |
Wu; Liangxing ; et
al. |
May 16, 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: |
Wu; Liangxing; (Wilmington,
DE) ; Shen; Bo; (Garnet Valley, PA) ; Li;
Jingwei; (Westfield, NJ) ; Li; Zhenwu;
(Wilmington, DE) ; Liu; Kai; (Bel Air, MD)
; Zhang; Fenglei; (Ambler, PA) ; Yao; Wenqing;
(Chadds Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
57206446 |
Appl. No.: |
16/005961 |
Filed: |
June 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15792300 |
Oct 24, 2017 |
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16005961 |
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15296234 |
Oct 18, 2016 |
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15792300 |
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62385053 |
Sep 8, 2016 |
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62322949 |
Apr 15, 2016 |
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62243307 |
Oct 19, 2015 |
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Current U.S.
Class: |
514/243 ;
548/240 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 35/00 20180101; C07D 487/04 20130101; A61P 31/12 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 487/04 20060101 C07D487/04 |
Claims
1. A compound of Formula (I'): ##STR00109## or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein: one of Y.sup.1
and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is C; X.sup.1
is N or CR.sup.i; X.sup.2 is N or CR.sup.2; X.sup.3 is N 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; 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
4 independently selected R.sup.7 substituents; Z.sup.1 is N or
CR.sup.8a; Z.sup.2 is N or CR.sup.8b; Z.sup.3 is N or CR.sup.8c;
R.sup.1, R.sup.2, R.sup.8a, R.sup.8b and R.sup.8c are each
independently selected from H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, C.sub.6-10 aryl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, CN, OR.sup.10,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, NH.sub.2, --NHR.sup.10,
--NR.sup.10R.sup.10, 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, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, C.sub.6-10 aryl, C.sub.6-10
aryl-C.sub.1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and
(4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4
alkyl-, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2, R.sup.8a,
R.sup.8b, R.sup.8c and R.sup.10 are each optionally substituted
with 1, 2 or 3 independently selected R.sup.b substituents; R.sup.9
is 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.11, --SR.sup.11, --NH.sub.2, NHR.sup.11,
NR.sup.11R.sup.11, 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.iC(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 the 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- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.9 are each optionally
substituted with 1, 2 or 3 R.sup.b substituents; each R.sup.11 is
independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
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.11 are each optionally
substituted with 1, 2 or 3 independently selected R.sup.b
substituents; R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H; 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; 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.1-6 alkyl, C.sub.1-6
haloalkyl, halo, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl, 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, 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,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)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.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.3-10 cycloalkyl, 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.d are each optionally substituted with 1-3 independently
selected R.sup.h 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, 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; 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 R.sup.p
substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6
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.r, OR.sup.r, SR.sup.r, C(O)R.sup.r,
C(O)NR.sup.rR.sup.r, C(O)OR.sup.r, OC(O)R.sup.r,
OC(O)NR.sup.rR.sup.r, NHR.sup.r, NR.sup.rR.sup.r,
NR.sup.rC(O)R.sup.r, NR.sup.rC(O)NR.sup.rR.sup.r,
NR.sup.rC(O)OR.sup.r, C(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NOH)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NCN)NR.sup.rR.sup.r, S(O)R.sup.r,
S(O)NR.sup.rR.sup.r, S(O).sub.2R.sup.r, NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2NR.sup.rR.sup.r and S(O).sub.2NR.sup.rR.sup.r,
wherein the C.sub.1-6 alkyl, C.sub.1-6 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.p is optionally substituted with 1, 2 or 3
R.sup.q 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.6-10 aryl-C.sub.1-4alkyl-, 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.1-6
haloalkoxy, 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.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4alkyl-,
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, 4-7 membered heterocycloalkyl,
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,
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, and
C.sub.1-4 haloalkoxy of R.sup.j are each optionally substituted
with 1, 2 or 3 independently selected R.sup.q substituents; 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,
4-7 membered heterocycloalkyl, 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,
4-7 membered heterocycloalkyl, 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.1-6 haloalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
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 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl 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; and with the proviso that the compound is other
than
6-(6-chloro-3-methylimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-
-dimethylethoxy)-2,5-dimethyl-3-pyridineacetic acid or
6-(6-chloroimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethyl-
ethoxy)-2,5-dimethyl-3-pyridineacetic acid, or enantiomers
thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: one of Y.sup.1 and Y.sup.2 is N
and the other of Y.sup.1 and Y.sup.2 is C; X.sup.1 is N or
CR.sup.i; X.sup.2 is N or CR.sup.2; X.sup.3 is N 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; 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 4 independently
selected R.sup.7 substituents; Z.sup.1 is N or CR.sup.8a; Z.sup.2
is N or CR.sup.8b; Z.sup.3 is N or CR.sup.8c; R.sup.1, R.sup.2,
R.sup.8a, R.sup.8b and R.sup.8c 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 and C.sub.2-4 alkynyl of R.sup.1, R.sup.2,
R.sup.8a, R.sup.8b and R.sup.8c 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 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 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.3, R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H; 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; 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, 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; 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.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;
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.1-6 haloalkyl, 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; and is a single
bond or a double bond to maintain ring A being aromatic.
3. The compound of claim 1 or 2, having Formula (I): ##STR00110##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1
and Y.sup.2 is C; X.sup.1 is N or CR.sup.1; X.sup.2 is N or
CR.sup.2; X.sup.3 is N 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; R.sup.1,
R.sup.2 and R.sup.8 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 and C.sub.2-4 alkynyl of R.sup.1, R.sup.2 or
R.sup.8 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
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 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; R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H; or
two adjacent R.sup.7 substituents on the phenyl ring, taken
together with the carbon 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.5-6
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.5-6 cycloalkyl ring are each optionally substituted
with 1 or 2 independently selected R.sup.q 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, 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; 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.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;
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.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C.sub.3-6
cycloalkyl, NHR.sup.12, NR.sup.12R.sup.12, and C.sub.1-4
haloalkoxy, wherein the C.sub.1-4 alkyl, phenyl and 5-6 membered
heteroaryl of R.sup.q are each optionally substituted with OH, CN,
--COOH, NH.sub.2, C.sub.1-4 alkoxy, 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 or 5;
and the subscript m is an integer of 1, 2 or 3.
4. The compound of any one of claims 1-3, having Formula (II):
##STR00111## wherein R.sup.4 is 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.4 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents, or
a pharmaceutically acceptable salt or a stereoisomer thereof.
5. The compound of any one of claims 1-4, having Formula (III):
##STR00112## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
6. The compound of any one of claims 1-5, having Formula (IV):
##STR00113## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
7. The compound of any one of claims 1-4, having Formula (V):
##STR00114## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
8. The compound of any one of claims 1-4, having Formula (VI):
##STR00115## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
9. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein the moiety:
##STR00116## is selected from: ##STR00117## ##STR00118##
10. The compound of any one of claims 1-9, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are each H.
11. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.3, X.sup.5 and X.sup.6 are each CH, Y.sup.1 is
N and Y.sup.2 is C.
12. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is CH,
X.sup.2 is CH, X.sup.3, X.sup.5 and X.sup.6 are each CH, Y.sup.1 is
C and Y.sup.2 is N.
13. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is CH,
X.sup.2 is CH, X.sup.3 and X.sup.6 are each CH, X.sup.5 is N,
Y.sup.1 is C and Y.sup.2 is N.
14. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.3 and X.sup.6 are each N, X.sup.5 is CH,
Y.sup.1 is N and Y.sup.2 is C.
15. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.3 and X.sup.5 are each CH, X.sup.6 is N,
Y.sup.1 is N and Y.sup.2 is C.
16. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.3 and X.sup.6 are each CH, X.sup.5 is N,
Y.sup.1 is N and Y.sup.2 is C.
17. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.5 and X.sup.6 are each CH, X.sup.3 is N,
Y.sup.1 is N and Y.sup.2 is C.
18. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 and
X.sup.2 are each N, X.sup.3, X.sup.5 and X.sup.6 are each CH,
Y.sup.1 is C and Y.sup.2 is N.
19. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 and
X.sup.2 are each N, X.sup.3 is CH, X.sup.5 is N, X.sup.6 is
CR.sup.6, Y.sup.1 is C and Y.sup.2 is N.
20. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is N,
X.sup.2 is CH, X.sup.3 and X.sup.5 are each CH, X.sup.6 is
CR.sup.6, Y.sup.1 is N and Y.sup.2 is C.
21. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 and
X.sup.2 are each N, X.sup.3 and X.sup.5 are each CH, X.sup.6 is
CR.sup.6, Y.sup.1 is N and Y.sup.2 is C.
22. The compound of any one of claims 1-21, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.4 is
--CH.sub.2--R.sup.b.
23. The compound of claim 22, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.b is
--NR.sup.cR.sup.c.
24. The compound of any of claims 1-23, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.4 is
2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl,
2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl,
(S)-2-carboxypiperidin-1-ylmethyl or
(R)-2-carboxypiperidin-1-ylmethyl.
25. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the compound is selected from:
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)eth-
anol;
2-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol;
(2
S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-car-
boxylic acid;
(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}pip-
eridine-2-carboxylic acid;
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamin-
o)ethanol;
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)-
methylamino)acetonitrile;
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamin-
o)acetamide;
2-(methyl((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)met-
hyl)amino)ethanol;
2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylam-
ino)ethanol;
(S)-1-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)meth-
yl)piperidine-2-carboxylic acid;
2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylam-
ino)ethanol;
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}amino)e-
thanol;
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}am-
ino)ethanol;
(S)-1-((2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl)methyl)pipe-
ridine-2-carboxylic acid;
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl}amino)e-
thanol;
2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]m-
ethyl}amino)ethanol; (2S)-1-{[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}piperidine-2-carboxylic
acid;
2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}a-
mino)ethanol; (2S)-1-{[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}piperidine-2-carboxylic
acid; and
2-({[5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidi-
n-7-yl]methyl}amino)ethanol.
26. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the compound is selected from:
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-y-
l]methyl}amino)ethanol;
2-({[8-[(2-methoxyethyl)amino]-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1-
,5-a]pyridin-6-yl]methyl}amino)ethanol;
4-[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-8-yl]butanenitrile;
[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-8-yl]acetonitrile;
2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridi-
n-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile;
2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6-{[(2-hydroxyethy-
l)amino]methyl}[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile; and
2-(8-(cyanomethyl)-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a-
]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile.
27. A pharmaceutical composition comprising a compound of any one
of claims 1-26, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
28. A method of inhibiting PD-1/PD-L1 interaction, said method
comprising administering to an individual a compound of any one of
claims 1-26, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
29. 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 any one of claims 1-26, or a
pharmaceutically acceptable salt or a stereoisomer thereof, or a
composition of claim 27.
30. The method of claim 29, wherein the disease or disorder is a
viral infection or cancer.
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 compound of
Formula (I):
##STR00003##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein constituent variables are defined herein.
[0008] 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.
[0009] 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.
[0010] 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
[0011] The present disclosure provides, inter alia, a compound of
Formula (I'):
##STR00004##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0012] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and
Y.sup.2 is C;
[0013] X.sup.1 is N or CR.sup.1;
[0014] X.sup.2 is N or CR.sup.2;
[0015] X.sup.3 is N or CR.sup.3;
[0016] X.sup.4 is N or CR.sup.4;
[0017] X.sup.5 is N or CR.sup.5;
[0018] X.sup.6 is N or CR.sup.6;
[0019] 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 4 independently
selected R.sup.7 substituents;
[0020] Z.sup.1 is N or CR.sup.8a;
[0021] Z.sup.2 is N or CR.sup.8b;
[0022] Z.sup.3 is N or CR.sup.8c;
[0023] R.sup.1, R.sup.2, R.sup.8a, R.sup.8b and R.sup.8c are each
independently selected from H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, C.sub.6-10 aryl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, CN, OR.sup.10,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, NH.sub.2, --NHR.sup.10,
--NR.sup.10R.sup.10, 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, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, C.sub.6-10 aryl, C.sub.6-10
aryl-C.sub.1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and
(4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4
alkyl-, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2, R.sup.8a,
R.sup.8b, R.sup.8c and R.sup.10 are each optionally substituted
with 1, 2 or 3 independently selected R.sup.b substituents;
[0024] R.sup.9 is 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.11,
--SR.sup.11, NH.sub.2, NHR.sup.11, --NR.sup.11R.sup.11,
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 the 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- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.9 are each optionally
substituted with 1, 2 or 3 R.sup.b substituents; [0025] each
R.sup.11 is independently selected from H, C.sub.1-6 alkyl,
C.sub.1-6 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.11 are each optionally substituted with 1, 2 or 3
independently selected R.sup.b substituents;
[0026] R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H;
[0027] 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;
[0028] 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;
[0029] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl, 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, 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,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)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.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.3-10 cycloalkyl, 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.d are each optionally substituted with 1-3 independently
selected R.sup.h substituents;
[0030] 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;
[0031] 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;
[0032] 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 R.sup.p
substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6
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.r, OR.sup.r, SR.sup.r, C(O)R.sup.r,
C(O)NR.sup.rR.sup.r, C(O)OR.sup.r, OC(O)R.sup.r,
OC(O)NR.sup.rR.sup.r, NHR.sup.r, NR.sup.rR.sup.r,
NR.sup.rC(O)R.sup.r, NR.sup.rC(O)NR.sup.rR.sup.r,
NR.sup.rC(O)OR.sup.r, C(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NOH)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NCN)NR.sup.rR.sup.r, S(O)R.sup.r,
S(O)NR.sup.rR.sup.r, S(O).sub.2R.sup.r, NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2NR.sup.rR.sup.r and S(O).sub.2NR.sup.rR.sup.r,
wherein the C.sub.1-6 alkyl, C.sub.1-6 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.p is
optionally substituted with 1, 2 or 3 R.sup.q substituents;
[0033] 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.6-10
aryl-C.sub.1-4alkyl-, 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.1-6
haloalkoxy, 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.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4alkyl-,
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, 4-7 membered heterocycloalkyl,
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,
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, and
C.sub.1-4 haloalkoxy of R.sup.j are each optionally substituted
with 1, 2 or 3 independently selected R.sup.q substituents; 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;
[0034] 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;
[0035] 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;
[0036] 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;
[0037] 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;
[0038] 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;
[0039] 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
[0040] 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, 4-7
membered heterocycloalkyl, 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, 4-7
membered heterocycloalkyl, 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;
[0041] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-6 haloalkyl, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, 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 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6
membered heterocycloalkyl and each R.sup.12 is independently
C.sub.1-6 alkyl;
[0042] is a single bond or a double bond to maintain ring A being
aromatic; and
[0043] with the proviso that the compound is other than
6-(6-chloro-3-methylimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-
-dimethylethoxy)-2,5-dimethyl-3-pyridineacetic acid or
6-(6-chloroimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethyl-
ethoxy)-2,5-dimethyl-3-pyridineacetic acid, or enantiomers
thereof.
[0044] The present disclosure provides a compound of Formula (I'),
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0045] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and
Y.sup.2 is C;
[0046] X.sup.1 is N or CR.sup.1;
[0047] X.sup.2 is N or CR.sup.2;
[0048] X.sup.3 is N or CR.sup.3;
[0049] X.sup.4 is N or CR.sup.4;
[0050] X.sup.5 is N or CR.sup.5;
[0051] X.sup.6 is N or CR.sup.6;
[0052] 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 4 independently
selected R.sup.7 substituents;
[0053] Z.sup.1 is N or CR.sup.8a;
[0054] Z.sup.2 is N or CR.sup.8b;
[0055] Z.sup.3 is N or CR.sup.8c;
[0056] R.sup.1, R.sup.2, R.sup.8a, R.sup.8b and R.sup.8c 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 and C.sub.2-4 alkynyl of R.sup.1, R.sup.2,
R.sup.8a, R.sup.8b, or R.sup.8c are each optionally substituted
with 1 or 2 substituents independently selected from halo, OH, CN
and C.sub.1-4 alkoxy;
[0057] R.sup.9 is C.sub.1-4 alkyl, halo, CN, OH, cyclopropyl,
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 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;
[0058] R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H;
[0059] 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 1, 2
or 3 independently selected R.sup.q substituents;
[0060] 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;
[0061] 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;
[0062] 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;
[0063] 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)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;
[0064] 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;
[0065] 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.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;
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;
[0066] 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;
[0067] 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;
[0068] 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;
[0069] 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;
[0070] 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;
[0071] 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
[0072] 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;
[0073] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-6 haloalkyl, 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; and
[0074] is a single bond or a double bond to maintain ring A being
aromatic.
[0075] In some embodiments of compounds of Formula (I'), Cy is
C.sub.6-10 aryl, optionally substituted with 1 to 4 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 4
independently selected R.sup.7 substituents. In certain
embodiments, Cy is unsubstituted phenyl.
[0076] In some embodiments of compounds of Formula (I'), Cy is
C.sub.3-10 cycloalkyl, optionally substituted with 1 to 4
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 4 independently selected
R.sup.7 substituents.
[0077] In some embodiments of compounds of Formula (I'), Cy is 5-
to 14-membered heteroaryl, optionally substituted with 1 to 4
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 4 independently selected R.sup.7 substituents.
[0078] In some embodiments of compounds of Formula (I'), Cy is 4-
to 10-membered heterocycloalkyl, optionally substituted with 1 to 4
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-dihydro-1,4-benzodioxin-6-yl optionally substituted with 1 to 4
independently selected R.sup.7 substituents.
[0079] In some embodiments of compounds of Formula (I'), Z.sup.1 is
CR.sup.8a, Z.sup.2 is CR.sup.8b and Z.sup.3 is CR.sup.8c. In
certain instances, R.sup.8a, R.sup.8b and R.sup.8c are each H.
[0080] In some embodiments of compounds of Formula (I'), Z.sup.1 is
CR.sup.8a, Z.sup.2 is N and Z.sup.3 is N. In certain instances,
R.sup.8a is H.
[0081] In some embodiments of compounds of Formula (I'), Z.sup.1 is
CR.sup.8a, Z.sup.2 is N and Z.sup.3 is CR.sup.8c. In certain
instances, R.sup.8a and R.sup.8c are each H.
[0082] In some embodiments of compounds of Formula (I'), Z.sup.1 is
CR.sup.8a, Z.sup.2 is CR.sup.8b and Z.sup.3 is N. In certain
instances, R.sup.8a and R.sup.8b are each H.
[0083] In some embodiments of compounds of Formula (I'), Z.sup.1 is
N, Z.sup.2 is CR.sup.8b and Z.sup.3 is CR.sup.8c. In certain
instances, R.sup.8b and R.sup.8c are each H.
[0084] In some embodiments of compounds of Formula (I'), Z.sup.1 is
N, Z.sup.2 is N and Z.sup.3 is CR.sup.8c. In certain instances,
R.sup.8c is H.
[0085] In some embodiments of compounds of Formula (I'), Z.sup.1 is
N, Z.sup.2 is CR.sup.8b and Z.sup.3 is N. In certain instances,
R.sup.8b is H.
[0086] In some embodiments of compounds of Formula (I'), Z.sup.1,
Z.sup.2 and Z.sup.3 are each N.
[0087] In some embodiments, the present disclosure provides
compounds of Formula (I):
##STR00005##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0088] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and
Y.sup.2 is C;
[0089] X.sup.1 is N or CR.sup.1;
[0090] X.sup.2 is N or CR.sup.2;
[0091] X.sup.3 is N or CR.sup.3;
[0092] X.sup.4 is N or CR.sup.4;
[0093] X.sup.5 is N or CR.sup.5;
[0094] X.sup.6 is N or CR.sup.6;
[0095] R.sup.1, R.sup.2 and R.sup.8 are each independently selected
from H, C.sub.1-4 alkyl, C.sub.34 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
H or 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
the C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, C.sub.2-4 alkenyl and
C.sub.2-4 alkynyl of R.sup.1, R.sup.2 or R.sup.8 are each
optionally substituted with 1 or 2 substituents independently
selected from halo, OH, CN and C.sub.1-4 alkoxy;
[0096] R.sup.9 is C.sub.1-4 alkyl, halo, CN, OH, cyclopropyl,
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 each R.sup.11 is independently
H or C.sub.1-4 alkyl optionally substituted with 1 or 2 halo, OH,
CN or OCH.sub.3;
[0097] R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 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.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, or 4 R.sup.b substituents, with the proviso that at least
one of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than H;
[0098] or two adjacent R.sup.7 substituents on the phenyl ring,
taken together with the carbon atoms to which they are attached,
form a fused phenyl ring, a fused 5- or 6-membered heterocycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C.sub.5-6
cycloalkyl ring, wherein the fused 5- or 6-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- or 6-membered
heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and
fused C.sub.5-6 cycloalkyl ring are each optionally substituted
with 1 or 2 independently selected R.sup.q substituents;
[0099] 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;
[0100] 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;
[0101] 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 or
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;
[0102] 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-, and (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)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;
[0103] 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;
[0104] 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.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;
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 attach 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;
[0105] 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;
[0106] 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;
[0107] 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;
[0108] 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;
[0109] 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;
[0110] 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
[0111] 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;
[0112] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, phenyl, 5-6 membered heteroaryl, C.sub.3-6 cycloalkyl,
NHR.sup.12, NR.sup.12R.sup.12, and C.sub.1-4 haloalkoxy, wherein
the C.sub.1-4 alkyl, phenyl and 5-6 membered heteroaryl of R.sup.q
are each optionally substituted with OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkoxy, C.sub.3-10 cycloalkyl and 4-6 membered
heterocycloalkyl and each R.sup.12 is independently C.sub.1-6
alkyl;
[0113] is a single bond or a double bond to maintain ring A being
aromatic;
[0114] the subscript n is an integer of 1, 2, 3, 4 or 5; and
[0115] the subscript m is an integer of 1, 2, 3 or 4. In some
embodiments, the subscript m is an integer of 1, 2 or 3.
[0116] In some embodiments, R.sup.9 is C.sub.1-4 alkyl, halo, CN,
OH, cyclopropyl, 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 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 H or
C.sub.1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or
OCH.sub.3.
[0117] In some embodiments, two adjacent R.sup.7 substituents on
the phenyl ring, taken together with the carbon atoms to which they
are attached, form a fused phenyl ring, a fused 5- or 6-membered
heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or
a fused C.sub.5-6 cycloalkyl ring, wherein the fused 5- or
6-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- or
6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl
ring and fused C.sub.5-6 cycloalkyl ring are each optionally
substituted with 1, 2 or 3 independently selected R.sup.b
substituents or 1 or 2 independently selected R.sup.q substituents.
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.
[0118] In some embodiments, the present disclosure provides
compounds having Formula (II):
##STR00006##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein R.sup.4 is 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.1 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
Other variables of Formula (II) are as defined in Formula (I') or
(I) or any embodiment of compounds of Formula (I') or (I) as
described herein. In one embodiment of compounds of Formula (II),
R.sup.9 is CN or C.sub.1-4 alkyl optionally substituted with
R.sup.q. In another embodiment, R.sup.9 is CH.sub.3 or CN.
[0119] In some embodiments, the present disclosure provides
compounds having Formula (IIa):
##STR00007##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein R.sup.5 is 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.1 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
Other variables of Formula (IIa) are as defined in Formula (I') or
(I) or any embodiment of compounds of Formula (I) as described
herein. In one embodiment of compounds of Formula (II), R.sup.9 is
CN or C.sub.1-4 alkyl optionally substituted with R.sup.q. In
another embodiment, R.sup.9 is CH.sub.3 or CN.
[0120] In some embodiments, the present disclosure provides
compounds having Formula (III):
##STR00008##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (III) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein.
[0121] In some embodiments, the present disclosure provides
compounds having Formula (IV):
##STR00009##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (IV) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein.
[0122] In some embodiments, the present disclosure provides
compounds having Formula (V):
##STR00010##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (V) are as defined in Formula (I')
or (I) or any embodiment of compounds of Formula (I') or (I) as
described herein.
[0123] In some embodiments, the present disclosure provides
compounds having Formula (VI):
##STR00011##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (VI) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein.
[0124] In some embodiments, the present disclosure provides
compounds having Formula (VII):
##STR00012##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (VII) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein. In some instances, R.sup.7 is H, n is 1,
Z.sup.1 is CR.sup.8a, Z.sup.2 is CR.sup.8b and Z.sup.3 is
CR.sup.8c. In certain instances, Z.sup.1, Z.sup.2 and Z.sup.3 are
each H.
[0125] In some embodiments, the present disclosure provides
compounds having Formula (VIII):
##STR00013##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (VIII) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein. In some instances, R.sup.7 is H, n is 1,
Z.sup.1 is CR.sup.8a, Z.sup.2 is CR.sup.8b and Z.sup.3 is
CR.sup.8c. In certain instances, Z.sup.1, Z.sup.2 and Z.sup.3 are
each H.
[0126] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, or a pharmaceutically acceptable salt
or a stereoisomer thereof, the moiety:
##STR00014##
is selected from:
##STR00015## ##STR00016##
wherein the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are as defined in Formula (I') or (I) or any
embodiment of compounds of Formula (I') or (I) as described herein.
In certain embodiments, at each occurrence, R.sup.1, R.sup.2,
R.sup.3 and R.sup.5 are each H.
[0127] In some embodiments, the moiety:
##STR00017##
is selected from:
##STR00018## ##STR00019##
wherein the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are as defined in Formula (I') or (I) or any
embodiment of compounds of Formula (I') or (I) as described herein.
In certain embodiments, at each occurrence, R.sup.1, R.sup.2,
R.sup.3 and R.sup.5 are each H.
[0128] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is N, X.sup.2 is CH, X.sup.3,
X.sup.5 and X.sup.6 are each CH, Y.sup.1 is N and Y.sup.2 is C.
[0129] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is CH, X.sup.2 is CH,
X.sup.3, X.sup.5 and X.sup.6 are each CH, Y.sup.1 is C and Y.sup.2
is N.
[0130] In some embodiments of compounds of Formula I', I, II, III,
IV, V, VI, or VII, X.sup.1 is CH, X.sup.2 is CH, X.sup.3 and
X.sup.6 are each CH, X.sup.5 is N, Y.sup.1 is C and Y.sup.2 is
N.
[0131] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is N, X.sup.2 is CH, X.sup.3
and X.sup.6 are each N, X.sup.5 is CH, Y.sup.1 is N and Y.sup.2 is
C.
[0132] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is N, X.sup.2 is CH, X.sup.3
and X.sup.5 are each CH, X.sup.6 is N, Y.sup.1 is N and Y.sup.2 is
C.
[0133] In some embodiments of compounds of Formula I', I, II, III,
IV, V, VI, or VII, X.sup.1 is N, X.sup.2 is CH, X.sup.3 and X.sup.6
are each CH, X.sup.5 is N, Y.sup.1 is N and Y.sup.2 is C.
[0134] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is N, X.sup.2 is CH, X.sup.5
and X.sup.6 are each CH, X.sup.3 is N, Y.sup.1 is N and Y.sup.2 is
C.
[0135] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 and X.sup.2 are each N,
X.sup.3, X.sup.5 and X.sup.6 are each CH, Y.sup.1 is C and Y.sup.2
is N.
[0136] In some embodiments of compounds of Formula I', I, II, III,
IV, V, VI, or VII, X.sup.1 and X.sup.2 are each N, X.sup.3 is CH,
X.sup.5 is N, X.sup.6 is CR.sup.6, Y.sup.1 is C and Y.sup.2 is
N.
[0137] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1 is N, X.sup.2 is CH, X.sup.3
and X.sup.5 are each CH, X.sup.6 is CR.sup.6, Y.sup.1 is N and
Y.sup.2 is C.
[0138] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, or VI, VII, or VIII, X.sup.1 and X.sup.2 are each N,
X.sup.3 and X.sup.5 are each CH, X.sup.6 is CR.sup.6, Y.sup.1 is N
and Y.sup.2 is C.
[0139] In some embodiments, R.sup.9 is C.sub.1-4 alkyl or CN.
[0140] In some embodiments, R.sup.9 is CH.sub.3 or CN.
[0141] In some embodiments, R.sup.7 and R.sup.8 are each H.
[0142] In some embodiments, R.sup.8a, R.sup.8b, and R.sup.8c are
each H.
[0143] In some embodiments, R.sup.7, R.sup.8a, R.sup.8b, and
R.sup.8c are each H.
[0144] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.2, X.sup.3, X.sup.5 and X.sup.6
are each CH.
[0145] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1, X.sup.2, X.sup.3, X.sup.5
and X.sup.6 are each CH.
[0146] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.1, X.sup.2, X.sup.3 and X.sup.6
are each CH.
[0147] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.2 and X.sup.5 are each CH.
[0148] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.2, X.sup.3 and X.sup.5 are each
CH.
[0149] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.2 and X.sup.6 are each CH.
[0150] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.2, X.sup.5 and X.sup.6 are each
CH.
[0151] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.3, X.sup.5 and X.sup.6 are each
CH.
[0152] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, X.sup.3 is CH.
[0153] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, R.sup.4 is C.sub.1-4 alkyl
substituted with R.sup.b. In certain embodiments, R.sup.b is
NHR.sup.c or NR.sup.cR.sup.c. In other embodiments, R.sup.b is
2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,
2-carboxypiperidin-1-yl, (cyanomethyl)amino,
(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or
2-carboxypiperidin-1-yl. In other embodiments, R.sup.4 is C.sub.1-4
alkyl substituted with R.sup.d. In other embodiments, R.sup.4 is
C.sub.1-4 alkyl substituted with R.sup.f. In other embodiments,
R.sup.4 is C.sub.1-4 alkyl substituted with R.sup.h. In other
embodiments, R.sup.4 is C.sub.1-4 alkyl substituted with R. In
other embodiments, R.sup.4 is C.sub.1-4 alkyl substituted with
R.sup.n. In other embodiments, R.sup.4 is C.sub.1-4 alkyl
substituted with R.sup.q.
[0154] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, R.sup.4 is --CH.sub.2R.sup.b. In
certain embodiments, R.sup.b is NHR.sup.c or NR.sup.cR.sup.c. In
other embodiments, R.sup.b is 2-hydroxyethylamino,
2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl,
(cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl,
(R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl. In other
embodiments, R.sup.4 is --CH.sub.2--R.sup.d. In other embodiments,
R.sup.4 is --CH.sub.2--R.sup.f. In other embodiments, R.sup.4 is
--CH.sub.2--R.sup.h. In other embodiments, R.sup.4 is
--CH.sub.2--R.sup.j. In other embodiments, R.sup.4 is
--CH.sub.2--R.sup.n. In other embodiments, R.sup.4 is
--CH.sub.2--R.sup.q.
[0155] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, R.sup.4 is 2-hydroxyethylaminomethyl,
2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl,
(cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl,
(R)-2-carboxypiperidin-1-ylmethyl or
2-carboxypiperidin-1-ylmethyl.
[0156] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, R.sup.6 is H, halo or C.sub.1-6 alkyl
optionally substituted with 1-3 R.sup.q substituents.
[0157] In some embodiments of compounds of Formula I', I, II, IIa,
III, IV, V, VI, VII, or VIII, R.sup.6 is H, halo or CH.sub.3.
[0158] 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') or (I) can be combined in any suitable
combination.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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-malkyl", 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] The term "amino" refers to a group of formula
--NH.sub.2.
[0170] The term "carbamyl" refers to a group of formula
--C(O)NH.sub.2.
[0171] 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).
[0172] The term "cyano" or "nitrile" refers to a group of formula
--C.ident.N, which also may be written as --CN.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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.
[0177] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0178] The term "aromatic" refers to a carbocycle or heterocycle
having one or more polyunsaturated rings having aromatic character
(i.e., having (4n+2) delocalized .pi. (pi) electrons where n is an
integer).
[0179] 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. 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.
[0180] 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.
[0181] 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.
[0182] 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.
[0183] 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. 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, norbornyl,
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.
[0184] 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.
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.
[0185] 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.
[0186] 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.
[0187] 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 3-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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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. One or more constituent atoms of the compounds of the
invention can be replaced or substituted with isotopes of the atoms
in natural or non-natural abundance. In some embodiments, the
compound includes at least one deuterium atom. For example, one or
more hydrogen atoms in a compound of the present disclosure can be
replaced or substituted by deuterium. In some embodiments, the
compound includes two or more deuterium atoms. In some embodiments,
the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
deuterium atoms. Synthetic methods for including isotopes into
organic compounds are known in the art.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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
[0198] 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.
[0199] 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.
[0200] 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).
[0201] 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).
[0202] 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.
[0203] Compounds of formula (I') or (I) can be prepared, e.g.,
using a process as illustrated in Schemes 1-5.
##STR00020##
[0204] The compounds of Formula 4 can be prepared according to
Scheme 1. The halo group (e.g., Hal.sup.I=Cl, Br, I) of biphenyl
compounds 1 can be converted to the boronic esters 2 under standard
conditions [e.g., in the presence of bis(pinacolato)diboron and a
palladium catalyst, such as, tetrakis(triphenylphosphine)
palladium(0), palladium(II) acetate]. Boronates 2 can react with
the heteroaryl halides 3 (e.g., Hal.sup.2=Cl, Br, I) under standard
Suzuki coupling condition (e.g., in the presence of a palladium
catalyst and a suitable base) to give the N-bridged bicyclic
compounds 4.
##STR00021##
[0205] The N-bridged heteroaryl compounds of Formula 10 can also be
prepared according to Scheme 2. Briefly, the halo group of the
substituted phenyl ethanone 5 (e.g., Hal.sup.3=Cl, Br or I) can be
coupled with substituted phenyl boronic esters 6 under standard
Suzuki coupling condition (e.g., in the presence of a palladium
catalyst and a suitable base) to produce the biphenyl compounds 7.
Bromination of the methyl ketones 7 using brominating reagents
including, but not limited, to copper(II) bromide can generate
.alpha.-bromo ketones 8. Condensation of .alpha.-bromo ketones 8
and amino heterocycles 9 in polar solvents (e.g., isopropanol)
under heating can afford the N-bridged heteroaryl compounds 10.
##STR00022##
[0206] The triazole-containing heteroaryl halides of formula 13
(Hal.sup.4 is a halide such as Br or I) can be formed according to
Scheme 3. Coupling of amino heterocycles 9 with ethoxycarbonyl
isothiocyanate 11, followed by treatment with hydroxylamine
hydrochloride and diisopropylethylamine (DIPEA) can form N-bridged
heteroaryl amines 12. Conversion of the primary amine in 12 to
halides can be achieved under Sandmeyer reaction conditions [i.e.
in the presence of tert-butyl nitrite and a halogen sources such as
CuBr.sub.2 or I.sub.2] to generate the N-bridged heteraryl halides
13.
##STR00023##
[0207] The N-bridged heteroaryl compounds of Formula 18 can be
prepared according to Scheme 4, starting from compounds of formula
14 or 15 which can be prepared according to procedures as described
in Scheme 1 or 2. Heteroaryl esters 14 can be reduced to aldehydes
16 via a sequence of reduction (e.g., LiAlH.sub.4 or LiBH.sub.4 as
reducing reagents) and oxidation (e.g., Dess-Martin periodinane as
oxidant). The aldehydes 16 might also be formed via direct
reduction of esters 14 under mild reducing conditions [e.g., using
diisobutylaluminium hydride (DIBAL) as the reducing agent at low
temperature]. Alternatively, aldehydes 16 can be formed through a
direct reduction of nitriles 15 with DIBAL as the reducing reagent
at low temperature. Then the aldehydes 16 can react with amines 17
of formula HNR.sup.cR.sup.c under standard reductive amination
conditions (e.g., sodium triacetoxyborohydride or sodium
cyanoborohydride as reducing reagents) to generate compounds of
formula 18.
##STR00024##
[0208] Alternatively, aldehydes 16 can also be prepared using
procedures as shown in Scheme 5, starting from heteroaryl halides
19 (e.g., Hal.sup.5=Cl, Br, I) which can be synthesized according
to procedures as described in Scheme 1 or 2. The halide in
compounds 19 can be converted to vinyl group to give olefins 20,
under standard Suzuki coupling condition (e.g., with vinylboronic
acid pinaco ester in the presence of a palladium catalyst and a
suitable base). The vinyl group in compounds 20 can be oxidatively
cleaved by NaIO.sub.4 in the presence of catalytic amount of
OsO.sub.4 to form aldehydes 16.
##STR00025##
[0209] Compounds of Formula 25 can be prepared using procedures as
outlined in Scheme 6. The halo group (e.g., Hal.sup.2=Cl, Br, I) of
heteroaryl compounds 3 can be converted to the boronic esters 21
under standard conditions [e.g., in the presence of
bis(pinacolato)diboron and a palladium catalyst, such as,
tetrakis(triphenylphosphine) palladium(0), palladium(II) acetate].
Selective coupling of boronates 21 with aryl halides 22 (e.g.,
Hal.sup.6=Cl, Br, I) under suitable Suzuki coupling condition
(e.g., in the presence of a palladium catalyst and a suitable base)
can give the N-bridged bicyclic compounds 23. The halide (e.g.,
Hal.sup.7=Cl, Br, I) in compound 23 can be coupled to compounds of
formula 24, in which M is a boronic acid, boronic ester or an
appropriately substituted metal [e.g., M is B(OR).sub.2,
Sn(Alkyl).sub.4, or Zn-Hal], under Suzuki coupling conditions
(e.g., in the presence of a palladium catalyst and a suitable base)
or Stille coupling conditions (e.g., in the presence of a palladium
catalyst), or Negishi coupling conditions (e.g., in the presence of
a palladium catalyst) to give derivatives of Formula 25.
Alternatively, compound 24 can be a cyclic amine (where M is H and
attached to an amine nitrogen in ring Cy) and the coupling of aryl
halide 23 with the cyclic amine 24 can be performed under Buchwald
amination conditions (e.g., in the presence of a palladium catalyst
and a base such as sodium tert-butoxide).
##STR00026##
[0210] Alternatively, Compounds of Formula 25 can be prepared using
the procedures as outlined in Scheme 7. Selective coupling of aryl
halides 26 with compounds of formula 24 [M is a boronic acid,
boronic ester or an appropriately substituted metal, e.g., M is
B(OR).sub.2, Sn(Alkyl).sub.4, or Zn-Hal] can be achieved under
suitable Suzuki coupling, Stille coupling or Negishi coupling
conditions to give compounds of Formula 27. If compound 24 is a
cyclic amine (e.g., M is H and attached to nitrogen in ring Cy),
the coupling can be achieved under Buchwald amination conditions.
Conversion of compound 27 to the final product 25 can be achieved
using similar conditions as described in Scheme 1.
III. Uses of the Compounds
[0211] 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 immunity in cancer
or chronic infection, including enhancement of response to
vaccination. In some embodiments, the present disclosure provides a
method for inhibiting the PD-1/PD-L1 protein/protein interaction.
The method includes administering to an individual or a patient a
compound of Formula (I') or (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 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.
[0212] 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 (I) or a salt or stereoisomer thereof such that
growth of cancerous tumors is inhibited. A compound of Formula (I')
or (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 (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 (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 (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.
[0213] 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 (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.
[0214] 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.
[0215] 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.
[0216] 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.
[0217] 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
(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.
[0218] 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 (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.
[0219] 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 (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.
[0220] 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 (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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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
[0225] 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.
[0226] 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, fit-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.
[0227] 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.
[0228] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0229] 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.
[0230] 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.
[0231] 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.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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).
[0236] 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.
[0237] 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-3, 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.
[0238] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0239] The compounds of Formula (I') or (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.
[0240] The compounds of Formula (I') or (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 (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.
[0241] 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.
[0242] 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.
[0243] The compounds of Formula (I') or (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.
[0244] 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.
[0245] 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.
[0246] 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.
[0247] 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.
[0248] 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
[0249] 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 (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.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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 K00LV.TM.). In some
embodiments, the polyethylene oxide is polyethylene oxide WSR 1105
(e.g., Polyox WSR 1105.TM.).
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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.
[0264] 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.
[0265] 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.
[0266] 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.
[0267] 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.
[0268] 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.
V. Labeled Compounds and Assay Methods
[0269] 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. Accordingly, the present
invention includes PD-1/PD-L1 binding assays that contain such
labeled compounds.
[0270] The present invention further includes
isotopically-substituted compounds of the disclosure. An
"isotopically-substituted" 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). It is to be understood that a "radio-labeled" compound
is a compound that has incorporated at least one isotope that is
radioactive (e.g., radionuclide). Suitable radionuclides that may
be incorporated in compounds of the present invention include but
are not limited to .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 C,
.sup.18F, .sup.125I, .sup.123I, .sup.124I, .sup.131I, .sup.75Br,
.sup.76Br or .sup.77Br will generally be most useful. In some
embodiments the radionuclide is selected from the group consisting
of .sup.3H, .sup.14C, .sup.125I, .sup.35S and .sup.82Br. Synthetic
methods for incorporating radio-isotopes into organic compounds are
known in the art.
[0271] 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. 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
[0272] 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
(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.
[0273] 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
[0274] 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-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)etha-
nol
##STR00027##
[0275] Step 1: (2-bromoimidazo[1,2-a]pyridin-6-yl)methanol
##STR00028##
[0277] To a solution of methyl
2-bromoimidazo[1,2-a]pyridine-6-carboxylate (200 mg, 0.784 mmol)
(Ark Pharm, cat#AK-31669) in tetrahydrofuran (5.0 mL) at 0.degree.
C. was added 1.0 M diisobutylaluminum hydride in tetrahydrofuran
(862 .mu.L, 0.862 mmol). The resulting mixture was stirred at room
temperature for 1 h then it was quenched with saturated NH.sub.4Cl
aqueous solution (1 mL), stirred for 1 h then filtered through
celite. The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was used for next step without
further purification. LC-MS calculated for C.sub.8H.sub.8BrN.sub.2O
(M+H).sup.+: m/z=227.0; found 227.2.
Step 2: 2-bromoimidazo[1,2-a]pyridine-6-carbaldehyde
##STR00029##
[0279] To a suspension of the crude
(2-bromoimidazo[1,2-a]pyridin-6-yl)methanol from Step 1 in
methylene chloride (5.0 mL) was added Dess-Martin periodinane (499
mg, 1.18 mmol). The resulting mixture was stirred at room
temperature for 30 min then quenched with sat'd NaHCO.sub.3
solution. 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 10%
MeOH/DCM to give the desired product (156 mg, 88%). LC-MS
calculated for C.sub.8H.sub.6BrN.sub.2O (M+H).sup.+: m/z=225.0;
found 225.2.
Step 3:
2-{[(2-bromoimidazo[1,2-a]pyridin-6-yl)methyl]amino}ethanol
##STR00030##
[0281] To a solution of
2-bromoimidazo[1,2-a]pyridine-6-carbaldehyde (20 mg, 0.09 mmol) and
ethanolamine (7.0 mg, 0.12 mmol) in acetonitrile (1.0 mL) was added
sodium triacetoxyborohydride (28 mg, 0.13 mmol). The resulting
mixture was stirred at room temperature for overnight then
concentrated. The residue was used for next step without further
purification. LC-MS calculated for C.sub.10H.sub.13BrN.sub.3O
(M+H).sup.+: m/z=270.0; found 270.2.
Step 4:
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
##STR00031##
[0283] A mixture of 3-chloro-2-methylbiphenyl (0.440 mL, 2.47 mmol)
(Aldrich, cat#361623),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1.88 g, 7.40 mmol), palladium acetate (22.2 mg, 0.0987 mmol),
K.sub.3PO.sub.4 (1.57 g, 7.40 mmol) and
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (101 mg,
0.247 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen then
stirred at room temperature for 48 h. The reaction mixture was
diluted with dichloromethane (DCM), then washed over 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% EtOAc/DCM to give the
desired product (656 mg, 90%). LC-MS calculated for
C.sub.19H.sub.24BO.sub.2 (M+H).sup.+: m/z=295.2; found 295.2.
Step 5:
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}am-
ino)ethanol
[0284] To a mixture of
2-{[(2-bromoimidazo[1,2-a]pyridin-6-yl)methyl]amino}ethanol (9 mg,
0.03 mmol),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(10 mg, 0.03 mmol) and sodium carbonate (8.58 mg, 0.0809 mmol) in
tert-butyl alcohol (0.4 mL) and water (0.2 mL) was added
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (3
mg, 0.00324 mmol). The resulting mixture was purged with nitrogen,
then heated to 105.degree. C. and stirred for 4 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.23H.sub.24N.sub.3O
(M+H).sup.+: m/z=358.4; found 358.2.
Example 2
2-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol
##STR00032##
[0285] Step 1: ethyl 2-bromoindolizine-7-carboxylate
##STR00033##
[0287] A mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (Apollo,
cat#AS422081: 511 mg, 2.94 mmol), ethyl 4-bromocrotonate (Aldrich,
cat#E13830: 1130 mg, 5.87 mmol) and potassium carbonate (893 mg,
6.46 mmol) in N, N-dimethylformamide (DMF, 8 mL) was stirred
overnight at room temperature. The reaction mixture was diluted
with EtOAc then washed with 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% EtOAc/hexanes to give the desired product as a yellow
solid. LC-MS calculated for C.sub.11H.sub.11BrNO.sub.2 (M+H).sup.+:
m/z=268.0; found 268.0.
Step 2: (2-bromoindolizin-7-yl)methanol
##STR00034##
[0289] To a solution of ethyl 2-bromoindolizine-7-carboxylate (167
mg, 0.623 mmol) in THF (1 mL) was added lithium tetrahydroaluminate
in THF (1.0 M, 400 .mu.L, 0.4 mmol) dropwise at 0.degree. C. The
mixture was slowly warmed up to room temperature and stirred for 1
h then the mixture was quenched with EtOAc, followed by water and
sodium hydroxide solution. The mixture was extracted with EtOAc
three times. The organic phase was combined, 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 60% EtOAc/hexanes to give the desired product. LC-MS
calculated for C.sub.9H.sub.9BrNO (M+H).sup.+: m/z=226.0; found
225.9.
Step 3: 2-bromoindolizine-7-carbaldehyde
##STR00035##
[0291] To a solution of (2-bromoindolizin-7-yl)methanol (44.0 mg,
0.195 mmol) in methylene chloride (1.5 mL) was added Dess-Martin
periodinane (82.6 mg, 0.195 mmol) at room temperature. The reaction
mixture was stirred for 10 min then quenched with NaHCO.sub.3
solution and Na.sub.2S.sub.2O.sub.3 solution. The mixture was
extracted with methylene chloride. The organic phase was combined,
dried over MgSO.sub.4 and concentrated. The residue was used in the
next step without further purification. LC-MS calculated for
C.sub.9H.sub.7BrNO (M+H).sup.+: m/z=224.0; found 223.9.
Step 4: 2-{[(2-bromoindolizin-7-yl)methyl]amino}ethanol
##STR00036##
[0293] To the crude product from Step 3 was added a solution of
ethanolamine (23 .mu.L, 0.39 mmol) in methylene chloride (2 mL).
The mixture was stirred for 20 min at room temperature then sodium
triacetoxyborohydride (82 mg, 0.39 mmol) and acetic acid (1 drop)
were added. The mixture was stirred at room temperature for 2 h
then quenched by NH.sub.4OH solution and extracted with EtOAc three
times. The organic phase was combined, dried over MgSO.sub.4 and
concentrated. The residue was used in the next step without further
purification. LC-MS calculated for C.sub.11H.sub.14BrN.sub.2O
(M+H).sup.+: m/z=269.0; found 269.0.
Step 5:
2-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol
[0294] To a solution of the crude product from Step 4 in
1,4-dioxane (1 mL) and water (0.2 mL) were added
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 57 mg, 0.20 mmol), potassium phosphate (69 mg,
0.32 mmol) and
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (10
mg, 0.01 mmol). The resulting mixture was purged with N.sub.2 then
stirred at 90.degree. C. for 4 h. The reaction mixture was cooled
to room temperature then diluted with EtOAc and washed with water.
The organic phase was dried over MgSO.sub.4, filtered and
concentrated. The residue was dissolved in MeOH 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 (M+H).sup.+: m/z=357.2; found 357.2.
Example 3
(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carbo-
xylic acid
##STR00037##
[0295] Step 1: methyl
(2S)-1-[(2-bromoindolizin-7-yl)methyl]piperidine-2-carboxylate
##STR00038##
[0297] To a mixture of methyl (2S)-piperidine-2-carboxylate
hydrogen chloride (180 mg, 1.0 mmol) and
2-bromoindolizine-7-carbaldehyde (75 mg, 0.33 mmol) in
CH.sub.2Cl.sub.2 (2 mL) at room temperature was added
N,N-diisopropylethylamine (170 .mu.L, 1.0 mmol), followed by acetic
acid (100 .mu.L, 2 mmol). The reaction mixture was stirred for 1 h
then sodium triacetoxyborohydride (280 mg, 1.3 mmol) was added.
After stirring at room temperature for 4 h, the reaction mixture
was quenched with NH.sub.4OH solution then extracted with
CH.sub.2Cl.sub.2 three times. The organic phase was combined, dried
over MgSO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 40% EtOAc/hexanes to give the desired product. LC-MS
calculated for C.sub.16H.sub.20BrN.sub.2O.sub.2 (M+H).sup.+:
m/z=351.1; found 351.0.
Step 2: methyl
(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carb-
oxylate
##STR00039##
[0299] To a solution of methyl
(2S)-1-[(2-bromoindolizin-7-yl)methyl]piperidine-2-carboxylate
(product from Step 1) in 1,4-dioxane (0.3 mL) and water (0.06 mL)
was added
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 18 mg, 0.060 mmol), potassium phosphate (17 mg,
0.078 mmol) and
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (2
mg, 0.003 mmol). The mixture was purged with N.sub.2, then heated
at 90.degree. C. for 4 h. The reaction mixture was cooled to room
temperature, diluted with EtOAc then washed with water and brine.
The organic phase was dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography on a
silica gel column eluting with 0 to 50% EtOAc/Hexanes to give the
desired product. LC-MS calculated for
C.sub.29H.sub.31N.sub.2O.sub.2 (M+H).sup.+: m/z=439.2; found
439.2.
Step 3: (2S)-1-{[2-(2-methylbiphenyl-3-yl)
indolizin-7-yl]methyl}piperidine-2-carboxylic acid
[0300] To a mixture of methyl
(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carb-
oxylate (14 mg, 0.032 mmol) in tetrahydrofuran (THF, 0.3 mL) and
MeOH (0.3 mL) was added lithium hydroxide monohydrate (20 mg, 0.4
mmol) and water (0.3 mL). The resulting mixture was stirred at room
temperature overnight. The reaction mixture was diluted with MeOH
then purified by prep-HPLC (pH=10, acetonitrile/water+NH.sub.4OH)
to give the desired product. LC-MS calculated for
C.sub.28H.sub.29N.sub.2O.sub.2 (M+H).sup.+: m/z=425.2; found
425.2.
Example 4
(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}pipe-
ridine-2-carboxylic acid
##STR00040##
[0301] Step 1: 6-bromopyrrolo[1,2-c]pyrimidine-3-carbaldehyde
##STR00041##
[0303] To a solution of ethyl
6-bromopyrrolo[1,2-c]pyrimidine-3-carboxylate (D-L chiral
chemicals, cat#ST-KS-041: 119 mg, 0.442 mmol) in CH.sub.2Cl.sub.2
(4 mL) was added diisobutylaluminum hydride in CH.sub.2Cl.sub.2
(1.0 M, 440 .mu.L, 0.44 mmol) dropwise at -78 OC. The mixture was
slowly warmed up to room temperature and stirred for 3 h. Then the
reaction mixture was quenched with EtOAc followed by
(NH.sub.4).sub.2SO.sub.4 solution then extracted with EtOAc three
times. The organic phase was combined, dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatography on a silica gel column eluting with 0 to 50%
EtOAc/Hexanes to give the desired product. LC-MS calculated for
C.sub.8H.sub.6BrN.sub.2O (M+H).sup.+: m/z=225.0; found 224.9.
Step 2: methyl
(2S)-1-[(6-bromopyrrolo[1,2-c]pyrimidin-3-yl)methyl]piperidine-2-carboxyl-
ate
##STR00042##
[0305] To a solution of
6-bromopyrrolo[1,2-c]pyrimidine-3-carbaldehyde (9.0 mg, 0.040 mmol)
and methyl (2S)-piperidine-2-carboxylate[1.0]-hydrogen chloride (18
mg, 0.10 mmol) in CH.sub.2Cl.sub.2 (0.2 mL) were added
diisopropylethylamine (17.4 .mu.L, 0.10 mmol) and acetic acid (7
.mu.L, 0.1 mmol) at room temperature. The mixture was stirred for 2
h then sodium triacetoxyborohydride (30 mg, 0.2 mmol) was added.
The reaction mixture was stirred at room temperature for 3 h then
quenched by NH.sub.4OH solution and extracted with CH.sub.2Cl.sub.2
three times. The organic phase was combined, dried over MgSO.sub.4,
filtered and concentrated. The residue was used in the next step
without further purification. LC-MS calculated for
C.sub.15H.sub.19BrN.sub.3O.sub.2(M+H).sup.+: m/z=352.1; found
352.0.
Step 3: Methyl
(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}pip-
eridine-2-carboxylate
##STR00043##
[0307] To the mixture of the crude product from Step 2 in
1,4-dioxane (0.3 mL) and water (0.07 mL) was added
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 21 mg, 0.070 mmol), potassium phosphate (20.
mg, 0.092 mmol) and dichloro[1,1'-bis(dicyclohexylphosphino)
ferrocene]palladium(II) (3 mg, 0.004 mmol). The mixture was purged
with N.sub.2, then heated at 90.degree. C. for 4 h. The reaction
mixture was cooled to room temperature, diluted with EtOAc then
washed with water and brine. The organic phase was dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
flash chromatography on a silica gel column eluting with 0 to 60%
EtOAc/hexanes to give the desired product. LC-MS calculated for
C.sub.28H.sub.30N.sub.3O.sub.2 (M+H).sup.+: m/z=440.2; found
440.2.
Step 4:
(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]met-
hyl}piperidine-2-carboxylic acid
[0308] To a solution of methyl
(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}pip-
eridine-2-carboxylate (6.7 mg, 0.015 mmol) in THF (0.1 mL) and MeOH
(0.1 mL) was added lithium hydroxide monohydrate (8 mg, 0.2 mmol)
and water (0.1 mL). The resulting mixture was stirred at room
temperature overnight then diluted with MeOH 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.27H.sub.28N.sub.3O.sub.2 (M+H).sup.+: m/z=426.2; found
426.2.
Example 5
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino-
)ethanol
##STR00044##
[0309] Step 1: 1-(2-methylbiphenyl-3-yl)ethanone
##STR00045##
[0311] To a solution of 1-(3-bromo-2-methylphenyl)ethanone
(AstaTech, cat#CL9266: 4.2 g, 20. mmol) in water (10 mL) and
1,4-dioxane (45 mL) were added potassium phosphate (8.4 g, 39
mmol), phenylboronic acid (2.6 g, 22 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (0.8 g, 1 mmol). The resulting
mixture was purged with nitrogen then stirred at 100.degree. C. for
30 mins. The reaction mixture was cooled to room temperature then
diluted with ethyl acetate, washed with water and brine. The
organic layer was dried over MgSO.sub.4, filtered, then
concentrated. The residue was purified by silica gel chromatography
eluting with 0-50% ethyl acetate in hexanes to afford the desired
product (3.95 g, 95%) as light yellowish oil. LC-MS calculated for
C.sub.15H.sub.15O (M+H).sup.+: m/z=211.3; found 211.3.
Step 2: 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
##STR00046##
[0313] 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). The reaction mixture was stirred at 80.degree. C.
for 2 hours then cooled to room temperature, filtered and
concentrated to dryness under reduced pressure. The residue was
purified by silica gel chromatography using 0-50% ethyl acetate in
hexanes to afford desired product (1.51 g, 87%) as light yellowish
oil. LC-MS calculated for C.sub.15H.sub.14BrO (M+H).sup.+:
m/z=289.0; found 289.0.
Step 3: 6-bromo-1,2,4-triazin-3-amine
##STR00047##
[0315] To a solution of 1,2,4-triazin-3-amine (Aldrich, cat#100625:
5.0 g, 52 mmol) in acetonitrile (50 mL) and water (70 mL) was added
N-bromosuccinimide (9.72 g, 54.6 mmol). The resulting mixture was
stirred at room temperature for 2 hours then diluted with 100 mL
saturated NaHCO.sub.3 solution, and stirred for another 1 hour,
then extracted with ethyl acetate. The organic layer was washed
with brine, dried over MgSO.sub.4 then filtered and concentrated to
dryness to afford the desired product (4.5 g, 49%) as a brownish
solid, which was used for the next step without further
purification.
Step 4: 6-vinyl-1,2,4-triazin-3-amine
##STR00048##
[0317] To a solution of 6-bromo-1,2,4-triazin-3-amine (1.0 g, 5.7
mmol) in water (3 mL) and 1,4-dioxane (17 mL) were added potassium
phosphate (2.4 g, 11 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#633348: 0.97 g, 6.3 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.09 g, 0.1 mmol). The
resulting mixture was purged with nitrogen then stirred at
80.degree. C. for 30 mins. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate then washed with water and
brine. Then organic layer was dried over MgSO.sub.4, filtered, then
concentrated to dryness to afford the desired product (580 mg, 83%)
as a brownish solid which was used for next step without further
purification.
Step 5:
6-(2-methylbiphenyl-3-yl)-2-vinylimidazo[1,2-b][1,2,4]triazine
##STR00049##
[0319] To a solution of 6-vinyl-1,2,4-triazin-3-amine (200 mg, 2
mmol) in isopropyl alcohol (6.3 mL) was added
2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (470 mg, 1.6 mmol). The
resulting mixture was warmed up to 90.degree. C. and stirred for 2
hours. The reaction mixture was cooled to room temperature then
concentrated to dryness. The residue was purified by silica gel
chromatography using 0-50% ethyl acetate in hexanes to afford
desired product (200 mg, 40%) as a yellowish solid. LC-MS
calculated for C.sub.20H.sub.17N.sub.4(M+H).sup.+: m/z=313.1; found
313.4.
Step 6:
6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazine-2-carbaldeh-
yde
##STR00050##
[0321] To a solution of
6-(2-methylbiphenyl-3-yl)-2-vinylimidazo[1,2-b][1,2,4]triazine (340
mg, 1.1 mmol) in tetrahydrofuran (10 mL) and water (20 mL) was
added potassium osmate, dihydrate (80 mg, 0.2 mmol) and sodium
periodate (880 mg, 4.1 mmol). The resulting mixture was stirred at
room temperature for 2 hours then diluted with ethyl acetate,
washed with water and brine. The organic layer was dried over
MgSO.sub.4, filtered, then concentrated to dryness. The residue was
purified by silica gel chromatography using 0-80% ethyl acetate in
hexanes to afford the desired product (220 mg, 64%) as a yellowish
solid. LC-MS calculated for C.sub.19H.sub.15N.sub.4O (M+H).sup.+:
m/z=315.1; found 315.2.
Step 7:
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)met-
hylamino)ethanol
[0322] To a solution of
6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazine-2-carbaldehyde
(20 mg, 0.06 mmol) in N,N-dimethylformamide (500 .mu.L) was added
ethanolamine (19 .mu.L, 0.32 mmol) and acetic acid (18 .mu.L, 0.32
mmol). The resulting mixture was stirred at room temperature for 30
min then sodium cyanoborohydride (8.0 mg, 0.13 mmol) was added. The
mixture was stirred at room temperature for 2 hours then diluted
with methanol 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.5O (M+H).sup.+:
m/z=360.2; found 360.2.
Example 6
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino-
)acetonitrile
##STR00051##
[0324] This compound was prepared using similar procedures as
described for Example 5 with aminoacetonitrile replacing
ethanolamine in Step 7. 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.21H.sub.19N.sub.6(M+H).sup.+: m/z=355.2; found 355.2.
Example 7
2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino-
)acetamide
##STR00052##
[0326] This compound was prepared using similar procedures as
described for Example 5 with glycinamide replacing ethanolamine in
Step 7. 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.21H.sub.21N.sub.6O (M+H).sup.+:
m/z=373.2; found 373.2.
Example 8
2-(methyl((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)meth-
yl)amino)ethanol
##STR00053##
[0328] This compound was prepared using similar procedures as
described for Example 5 with 2-(methylamino)ethanol replacing
ethanolamine in Step 7. 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.22H.sub.24N.sub.5O (M+H).sup.+: m/z=374.2; found 374.2.
Example 9
2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylami-
no)ethanol
##STR00054##
[0329] Step 1:
6-bromo-8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
##STR00055##
[0331] To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
(Example 5, Step 2: 500 mg, 2 mmol) in isopropyl alcohol (7 mL) was
added 5-bromo-3-methylpyridin-2-amine (Aldrich, cat#525537: 320 mg,
1.7 mmol). The resulting mixture was stirred at 90.degree. C. for 1
hour then cooled to room temperature and concentrated to dryness.
The residue was purified by silica gel chromatography using 0-60%
ethyl acetate in hexanes to afford the desired product (299 mg,
40%) as a white solid. LC-MS calculated for
C.sub.21H.sub.18BrN.sub.2 (M+H).sup.+: m/z=377.1; found 377.0.
Step 2:
8-methyl-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
##STR00056##
[0333] To a solution of
6-bromo-8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
(229 mg, 0.607 mmol) in water (0.5 mL) and 1,4-dioxane (2.5 mL) was
added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#633348: 100 mg, 0.67 mmol), potassium phosphate (0.26 g, 1.2
mmol) and
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',4',6'-triisopropylbipheny-
l-2-yl)phosphoranylidene]palladium (0.05 g, 0.06 mmol). The mixture
was purged with nitrogen then stirred at 90.degree. C. for 1 hour.
The reaction mixture was cooled to room temperature then
concentrated. The residue was purified by silica gel chromatography
using 0-60% ethyl acetate in hexanes to afford the desired product
(197 mg, 82%) as a yellowish solid. LC-MS calculated for
C.sub.23H.sub.21N.sub.2 (M+H).sup.+: m/z=325.2; found 325.1.
Step 3:
8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbald-
ehyde
##STR00057##
[0335] To a solution of
8-methyl-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
(162 mg, 0.499 mmol) in 1,4-dioxane (3.5 mL) and water (6 mL) was
added potassium osmate, dihydrate (20 mg, 0.05 mmol) and sodium
metaperiodate (210 mg, 1.0 mmol). The resulting mixture was stirred
at room temperature for 2 hours then diluted with water, quenched
with sodium sulfite, then extracted with ethyl acetate. The
combined extract was dried over Na.sub.2SO.sub.4, filtered, then
concentrated to dryness under reduced pressure. The residue was
purified by silica gel chromatography using 0-80% ethyl acetate in
hexanes to afford the desired product (57 mg, 35%) as a yellowish
solid. LC-MS calculated for C.sub.22H.sub.19N.sub.2O (M+H).sup.+:
m/z=327.1; found 327.1.
Step 4:
2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)m-
ethylamino)ethanol
[0336] To a solution of
8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbaldehyde
(28 mg, 0.086 mmol) in N,N-dimethylformamide (700 .mu.L) was added
ethanolamine (10. L, 0.17 mmol) and acetic acid (50 .mu.L, 0.8
mmol). The mixture was stirred at room temperature overnight then
sodium cyanoborohydride (0.027 g, 0.43 mmol) was added. The
reaction mixture was stirred at room temperature for another 30
mins then diluted with methanol and purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to afford desired product as TFA salt.
LC-MS calculated for C.sub.24H.sub.26N.sub.3O (M+H).sup.+:
m/z=372.2; found 372.2.
Example 10
[0337]
(S)-1-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-y-
l)methyl)piperidine-2-carboxylic acid
##STR00058##
[0338] This compound was prepared using similar procedures as
described for Example 9 with (S)-piperidine-2-carboxylic acid
replacing ethanolamine in Step 4. 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.28H.sub.30N.sub.3O.sub.2 (M+H).sup.+: m/z=440.2; found
440.3.
Example 11
2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylami-
no)ethanol
##STR00059##
[0339] Step 1: 5-bromo-3-chloropyridin-2-amine
##STR00060##
[0341] To a solution of 2-amino-5-bromopyridine (Aldrich,
cat#122858: 5.0 g, 29 mmol) in N,N-dimethylformamide (60 mL) was
added N-chlorosuccinimide (4.2 g, 32 mmol). The resulting mixture
was stirred at room temperature for 1 hour then saturated
NaHCO.sub.3 aqueous solution was added. The mixture was stirred for
10 min then extracted with ethyl acetate. The combined extracts
were dried over MgSO.sub.4, filtered, and concentrated to dryness
under reduced pressure. The residue was purified by silica gel
chromatography using 0-100% ethyl acetate in hexanes to afford the
desired product (4.8 g, 80%) as a yellowish solid. LC-MS calculated
for C.sub.5H.sub.5BrClN.sub.2 (M+H).sup.+: m/z=206.9; found
206.9.
Step 2:
6-bromo-8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
##STR00061##
[0343] To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
(Example 5, Step 2: 560 mg, 1.9 mmol) in isopropyl alcohol (7 mL)
was added 5-bromo-3-chloropyridin-2-amine (400 mg, 2 mmol). The
resulting mixture was stirred at 90.degree. C. for 4 hours then
cooled to room temperature and concentrated to dryness under
reduced pressure. The residue was purified by silica gel
chromatography using 0-50% ethyl acetate in hexanes to afford the
desired product (82 mg, 10%) as a yellowish solid. LC-MS calculated
for C.sub.20H.sub.15BrClN.sub.2 (M+H).sup.+: m/z=397.0; found
397.0.
Step 3:
8-chloro-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
##STR00062##
[0345] To a solution of
6-bromo-8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
(82 mg, 0.21 mmol) in water (0.2 mL) and 1,4-dioxane (2 mL) was
added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#633348: 35 mg, 0.23 mmol), potassium phosphate (88 mg, 0.41
mmol) and
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',4',6'-triisopropylbipheny-
l-2-yl)phosphoranylidene]palladium (8 mg, 0.01 mmol). The resulting
mixture was purged with nitrogen then warmed up to 70.degree. C.
and stirred for 30 mins. The reaction mixture was then cooled to
room temperature, diluted with brine, and extracted with ethyl
acetate. The combined extracts were dried over MgSO.sub.4,
filtered, and then concentrated to dryness under reduced pressure.
The residue was purified with silica gel chromatography using 0-80%
ethyl acetate in hexanes to afford the desired product (59 mg, 83%)
as a yellowish solid. LC-MS calculated for
C.sub.22H.sub.18ClN.sub.2 (M+H).sup.+: m/z=345.1; found 345.0.
Step 4:
8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbald-
ehyde
##STR00063##
[0347] To a solution of
8-chloro-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
(59 mg, 83%) in 1,4-dioxane (2 mL) and water (3 mL) was added
sodium periodate (0.13 g, 0.62 mmol) and potassium osmate dihydrate
(20 mg, 0.04 mmol). The resulting mixture was stirred at room
temperature for 2 hours then diluted with water, quenched with
sodium sulfite, and extracted with ethyl acetate. The combined
extracts were dried over MgSO.sub.4, filtered, and concentrated to
dryness under reduced pressure. The residue was used for next step
without further purification. LC-MS calculated for
C.sub.21H.sub.16ClN.sub.2O (M+H).sup.+: m/z=347.1; found 347.0.
Step 5:
2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)m-
ethylamino)ethanol
[0348] To a solution of the crude product from Step 4 in
N,N-dimethylformamide (2 mL) was added ethanolamine (50 .mu.L, 0.82
mmol) and acetic acid (0.2 mL, 3.5 mmol). The resulting mixture was
stirred at room temperature overnight then sodium cyanoborohydride
(0.065 g, 1.0 mmol) was added. The mixture was stirred at room
temperature for another 30 mins then diluted with methanol and
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to afford
desired product as the TFA salt. LC-MS calculated for
C.sub.23H.sub.23ClN.sub.3O (M+H).sup.+: m/z=392.2; found 392.1.
Example 12
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}amino)et-
hanol
##STR00064##
[0349] Step 1: 5-(1,3-dioxolan-2-yl)pyrimidin-2-amine
##STR00065##
[0351] To a solution of 2-aminopyrimidine-5-carbaldehyde (Aldrich,
cat#734845: 200 mg, 1.62 mmol) in toluene (5 mL) were added
1,2-ethanediol (120 .mu.L, 2.1 mmol) and p-toluenesulfonic acid
monohydrate (30 mg, 0.2 mmol), followed by molecular sieves (400
mg). The mixture was heated to reflux overnight. The reaction
mixture was cooled to room temperature and filtered. The filtrate
was concentrated to dryness under reduced pressure and the residue
was used in the next step without further purification. LC-MS
calculated for C.sub.7H.sub.10N.sub.3O.sub.2 (M+H).sup.+:
m/z=168.1; found 168.0.
Step 2:
6-(1,3-dioxolan-2-yl)-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrim-
idine
##STR00066##
[0353] To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
(Example 5, Step 2: 138 mg, 0.48 mmol) in isopropyl alcohol (2 mL)
was added 5-(1,3-dioxolan-2-yl)pyrimidin-2-amine (80. mg, 0.48
mmol) and dipotassium hydrogen phosphate (170 mg, 0.96 mmol). The
reaction mixture was stirred at 110.degree. C. overnight. The
mixture was then cooled to room temperature, poured into water and
extracted with dichloromethane twice (20 mL). The combined organic
phase was washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography on a
silica gel column eluting with 0 to 25% ethyl acetate/DCM to give
the desired product. LC-MS calculated for
C.sub.22H.sub.20N.sub.3O.sub.2 (M+H).sup.+: m/z=358.2; found
358.1.
Step 3:
2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine-6-carbaldehyde
##STR00067##
[0355] To a solution of
6-(1,3-dioxolan-2-yl)-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine
(40 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added 1.0 M
hydrogen chloride in water (450 .mu.L, 0.45 mmol). The reaction
solution was stirred at 50.degree. C. for 2 hour then cooled to
room temperature, diluted with DCM, washed with NaHCO.sub.3 aqueous
solution and brine. The organic layer was dried over MgSO.sub.4,
filtered and concentrated. The residue was used in the next step
without further purification. LC-MS calculated for
C.sub.20H.sub.16N.sub.3O (M+H).sup.+: m/z=314.1; found 314.1.
Step 4:
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}-
amino)ethanol
[0356] To a solution of
2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine-6-carbaldehyde
(15.0 mg, 0.0479 mmol) in 1,2-dichloroethane (1 mL) was added
ethanolamine (5.8 .mu.L, 0.096 mmol). The mixture was stirred at
room temperature for 30 min, then sodium triacetoxyborohydride (30
mg, 0.14 mmol) was added. The resulting mixture was stirred at room
temperature overnight then concentrated. The residue was diluted
with MeOH and purified by prep-HPLC (pH=10,
acetonitrile/water+NH.sub.4OH) to give the desired product. LC-MS
calculated for C.sub.22H.sub.23N.sub.4O (M+H).sup.+: m/z=359.2;
found 359.1.
Example 13
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}amino)etha-
nol
##STR00068##
[0357] Step 1: 2-(2-methylbiphenyl-3-yl)
imidazo[1,2-a]pyrazine-6-carbonitrile
##STR00069##
[0359] To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone
(Example 5, Step 2: 782 mg, 2.71 mmol) in isopropyl alcohol (10 mL)
was added 5-aminopyrazine-2-carbonitrile (Ark Pharm, cat#AK-21935:
325. mg, 2.71 mmol). The resulting mixture was heated at
110.degree. C. overnight then cooled to room temperature and
concentrated. The residue was purified by flash chromatography on a
silica gel column eluting with 0 to 25% ethyl acetate/DCM to give
the desired product. LC-MS calculated for
C.sub.20H.sub.15N.sub.4(M+H).sup.+: m/z=311.1; found 311.1.
Step 2:
[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methanol
##STR00070##
[0361] To a solution of
2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (110
mg, 0.35 mmol) in methylene chloride (3 mL) was added 1.0 M
diisobutylaluminum hydride in DCM (0.71 mL, 0.71 mmol) dropwise at
-78 OC. The mixture was stirred at -78 OC for 2 hours then quenched
with a few drops of saturated NH.sub.4Cl aqueous solution and
diluted with saturated sodium potassium tartrate solution. The
suspension was stirred at room temperature overnight then extracted
with DCM. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatography on a silica gel column eluting with 0 to 25% ethyl
acetate/DCM to give the desired product. LC-MS calculated for
C.sub.20H.sub.18N.sub.3O (M+H).sup.+: m/z=316.1; found 316.1.
Step 3:
2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbaldehyde
##STR00071##
[0363] Dimethyl sulfoxide (27 .mu.L, 0.38 mmol) was added to a
solution of 2.0 M oxalyl chloride in DCM (0.095 mL, 0.19 mmol) in
methylene chloride (1 mL) at -78 OC. To the above solution,
[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methanol (30.
mg, 0.095 mmol) in methylene chloride (1 mL) was slowly added and
then continued to stir at -78.degree. C. for 30 mins. Then
N,N-diisopropylethylamine (0.13 mL, 0.76 mmol) was added. The
reaction mixture was slowly warmed to 0.degree. C. then poured into
NaHCO.sub.3 aqueous solution and extracted with DCM. The combined
extracts were washed with water and brine. The organic layer was
dried over MgSO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel column eluting
with 0 to 25% ethyl acetate/DCM to give the desired product. LC-MS
calculated for C.sub.20H.sub.16N.sub.3O (M+H).sup.+: m/z=314.1;
found 314.1.
Step 4:
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}am-
ino)ethanol
[0364] To a solution of
2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbaldehyde
(15.0 mg, 0.0479 mmol) in 1,2-dichloroethane (1 mL) was added
N,N-diisopropylethylamine (17 .mu.L, 0.096 mmol) and ethanolamine
(5.8 .mu.L, 0.096 mmol). The mixture was stirred at room
temperature for 20 min, then sodium triacetoxyborohydride (30. mg,
0.14 mmol) was added. The reaction mixture was stirred at room
temperature for 3 h then concentrated. The residue was dissolved in
MeOH 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.23N.sub.4O (M+H).sup.+: m/z=359.2; found 359.1.
Example 14
(S)-1-((2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl)methyl)piper-
idine-2-carboxylic acid
##STR00072##
[0365] Step 1: methyl
2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate
##STR00073##
[0367] Methyl 6-aminopyridazine-3-carboxylate (Accela ChemBio,
cat#SY006049: 87 mg, 0.57 mmol) was added to the solution of
2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5, Step 2: 181
mg, 0.626 mmol) in isopropyl alcohol (2.3 mL). The mixture was
stirred at 90.degree. C. for 2 h then cooled to room temperature
and concentrated. The residue was purified by chromatography
(15-30% EtOAc/hexanes) on silica gel to give the desired product 85
mg (43% yield). LC-MS calculated for C.sub.21H.sub.18N.sub.3O.sub.2
(M+H).sup.+: m/z=344.1; found: 344.1.
Step 2:
[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methanol
##STR00074##
[0369] 1.0 M Diisobutylaluminum hydride in DCM (0.33 mL, 0.33 mmol)
was added to a solution of methyl
2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate
(104 mg, 0.303 mmol) in methylene chloride (1.5 mL) at -40 OC. The
mixture was warmed to -5.degree. C. and stirred for 40 min and then
stirred at room temperature overnight. The mixture was quenched
with aqueous NH.sub.4Cl and potassium sodium tartrate, and
extracted with DCM. The combined extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by chromatography (90-100% EtOAc) on silica gel to give
the desire product (35 mg). LC-MS calculated for
C.sub.20H.sub.18N.sub.3O (M+H).sup.+: m/z=316.1; found: 316.1.
Step 3:
2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carbaldehyde
##STR00075##
[0371] Dess-Martin periodinane (66.6 mg, 0.157 mmol) was added to
the solution of
[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methanol
(33.0 mg, 0.105 mmol) in DCM (3 mL). The mixture was stirred at
room temperature for 15 min then quenched with aqueous sodium
bisulfite and extracted with Et.sub.2O. The organic phase was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by chromatography (20-30% EtOAc/Hex) on silica gel to give
the desired product (24 mg). LC-MS calculated for
C.sub.20H.sub.16N.sub.3O (M+H).sup.+: m/z=314.1; found: 314.1.
Step 4:
(2S)-1-{[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]met-
hyl}piperidine-2-carboxylic acid
[0372] (2S)-piperidine-2-carboxylic acid (26.8 mg, 0.207 mmol) was
added to a solution of
2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carbaldehyde
(13.0 mg, 0.0415 mmol) in N,N-dimethylformamide (0.41 mL), followed
by acetic acid (3.54 .mu.L, 0.0622 mmol). The reaction mixture was
stirred at room temperature for 10 min. Then sodium
cyanoborohydride (7.9 mg, 0.12 mmol) was added. The reaction
mixture was stirred at room temperature overnight then diluted with
MeOH and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
afford the desired product as the TFA salt. LC-MS calculated for
C.sub.26H.sub.27N.sub.4O.sub.2 (M+H).sup.+: m/z=427.2; found:
427.2.
Example 15
2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl}amino)et-
hanol
##STR00076##
[0374] This compound was prepared using similar procedures as
described for Example 14 with ethanolamine replacing
(2S)-piperidine-2-carboxylic acid in Step 4. 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.22H.sub.23N.sub.4O (M+H).sup.+: m/z=359.2; found 359.2.
Example 16
2-({[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}amino)ethanol
##STR00077##
[0375] Step 1:
(2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol
##STR00078##
[0377] Ethoxycarbonyl isothiocyanate (606 .mu.L, 5.36 mmol) was
added to a solution of (2-aminopyridin-4-yl)methanol (Aldrich,
cat#714577: 555 mg, 4.47 mmol) in 1,4-dioxane (22.4 mL). The
reaction mixture was stirred at room temperature for 15 h. The
mixture was concentrated and the residue was dissolved in methanol
(16.0 mL)/ethanol (16.0 mL), then N,N-diisopropylethylamine (1.56
mL, 8.94 mmol) was added, followed by hydroxylamine hydrochoride
(932 mg, 13.4 mmol). The reaction mixture was stirred at 45.degree.
C. for 2 h then cooled to room temperature and concentrated. The
residue was used in the next step without further purification.
LC-MS calculated for C.sub.7H.sub.9N.sub.4O (M+H).sup.+: m/z=165.1;
found: 165.1.
Step 2: (2-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol
##STR00079##
[0379] tert-Butyl nitrite (1.28 mL, 10.7 mmol) was added to a
suspension of (2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol
(734 mg, 4.47 mmol) and copper(II) bromide (2.00 g, 8.94 mmol) in
acetonitrile (55 mL). The reaction mixture was stirred at room
temperature for 2 h then diluted with DCM and washed with water.
The organic phase was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by chromatography on silica
gel to give the desired product as a yellow solid (842 mg, 83%
yield). LC-MS calculated for C.sub.7H.sub.7BrN.sub.3O (M+H).sup.+:
m/z=228.0; found: LC/MS: 228.0.
Step 3:
[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]metha-
nol
##STR00080##
[0381] A mixture of
(2-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol (128 mg, 0.564
mmol),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 199 mg, 0.676 mmol),
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',4',6'-triisopropylbipheny-
l-2-yl)phosphoranylidene]palladium (44.4 mg, 0.0564 mmol) and
K.sub.3PO.sub.4 (215 mg, 1.01 mmol) in 1,4-dioxane (2.6 mL)/water
(0.3 mL) was purged with nitrogen then stirred at 90.degree. C. for
18 h. The mixture was cooled to room temperature then diluted with
DCM, dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by chromatography (40-100% EtOAc/hexanes) on
silica gel to give the desired product as an off-white solid (85.0
mg). LC-MS calculated for C.sub.20H.sub.18N.sub.3O (M+H).sup.+:
m/z=316.1; found: 316.1.
Step 4:
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-7-carbalde-
hyde
##STR00081##
[0383] Dess-Martin periodinane (80.7 mg, 0.190 mmol) was added to
the solution of
[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methanol
(40.0 mg, 0.127 mmol) in dichloromethane (3 mL). The mixture was
stirred at room temperature for 1.5 h and more Dess-Martin
periodinane (1.5 equiv) was added. The mixture was stirred for
another 3.5 h then quenched with aqueous sodium bisulfite and
extracted with dichloromethane. The combined extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified with chromatography on silica gel to give the desired
product (29 mg). LC-MS calculated for C.sub.20H.sub.16N.sub.3O
(M+H).sup.+: m/z=314.1; found: 314.1.
Step 5:
2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]m-
ethyl}amino)ethanol
[0384] Ethanolamine (7.3 mg, 0.12 mmol) was added to a solution of
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde
(7.5 mg, 0.024 mmol) in N,N-dimethylformamide (0.24 mL), followed
by acetic acid (2.0 .mu.L, 0.036 mmol). The reaction mixture was
stirred at room temperature for 10 min then sodium cyanoborohydride
(4.5 mg, 0.072 mmol) was added. The mixture was stirred at room
temperature overnight then diluted with MeOH and purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to afford the desired
product as the TFA salt. LC-MS calculated for
C.sub.22H.sub.23N.sub.4O (M+H).sup.+: m/z=359.2; found: 359.2.
Example 17
(2S)-1-{[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}piperidine-2-carboxylic
acid
##STR00082##
[0386] This compound was prepared using similar procedures as
described for Example 16 with (2S)-piperidine-2-carboxylic acid
replacing ethanolamine in Step 5. 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.27N.sub.4O.sub.2 (M+H).sup.+: m/z=427.2; found
427.2.
Example 18
2-({[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol
##STR00083##
[0387] Step 1: methyl
2-amino[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
##STR00084##
[0389] To a solution of methyl 6-aminonicotinate (Aldrich,
cat#648736: 699 mg, 4.59 mmol) in 1,4-dioxane (23.0 mL) was added
ethoxycarbonyl isothiocyanate (623 .mu.L, 5.51 mmol). The reaction
mixture was stirred at room temperature for 15 h. The crude was
concentrated and the residue was dissolved in methanol (17
mL)/ethanol (17 mL) then N,N-diisopropylethylamine (1.6 mL, 9.2
mmol) was added, followed by hydroxyaminehydrochoride (958 mg, 13.8
mmol). The resulting mixture was stirred at 45.degree. C. for 2 h
then cooled to room temperature and concentrated. The residue was
directly used for the next step without further purification. LC-MS
calculated for C.sub.8H.sub.9N.sub.4O.sub.2(M+H).sup.+: m/z=193.1;
found: 193.0.
Step 2: methyl
2-bromo[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
##STR00085##
[0391] tert-Butyl nitrite (1.31 mL, 11.0 mmol) was added to a
suspension of methyl
2-amino[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (883 mg, 4.59
mmol) and copper(II) bromide (2.05 g, 9.19 mmol) in acetonitrile
(44 mL). The mixture was stirred at room temperature for 2 h then
diluted with dichloromethane and washed with water. The organic
phase was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by chromatography on silica gel to give
the desired product as a white solid (483 mg, 41% yield). LC-MS
calculated for C.sub.8H.sub.7BrN.sub.3O.sub.2(M+H).sup.+:
m/z=256.0; found: 256.0.
Step 3: methyl
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
##STR00086##
[0393] A mixture of methyl
2-bromo[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (188 mg, 0.734
mmol),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 259 mg, 0.881 mmol),
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',4',6'-triisopropylbipheny-
l-2-yl)phosphoranylidene]palladium (57.8 mg, 0.0734 mmol) and
K.sub.3PO.sub.4 (280 mg, 1.32 mmol) in 1,4-dioxane (3.4 mL)/water
(0.3 mL) was purged with nitrogen then stirred at 90.degree. C. for
15 h. The reaction mixture was cooled to room temperature and
concentrated. The residue was purified by chromatography (20-25%
EtOAc/Hex) on silica gel to give the desired product as an
off-white solid (188 mg, 75% yield). LC-MS calculated for
C.sub.21H.sub.18N.sub.3O.sub.2 (M+H).sup.+: 344.1; found:
344.1.
Step 4:
[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]metha-
nol
##STR00087##
[0395] Diisobutylaluminum hydride in DCM (643 .mu.L, 0.643 mmol)
was added to the solution of methyl
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
(184 mg, 0.536 mmol) in Et.sub.2O (5 mL) at 0.degree. C. The
mixture was stirred at room temperature for 3 h then another
portion of diisobutylaluminum hydride (1M in DCM, 1 mL, 1 mmol) was
added. The mixture was stirred at room temperature for another 2 h
then quenched with aqueous NH.sub.4Cl and stirred with Rochelle
salt, and then extracted with DCM. The combined extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by chromatography (50-100% EtOAc) on silica gel to give
the desired product (86 mg, 51% yield). LC-MS calculated for
C.sub.20H.sub.18N.sub.3O (M+H).sup.+: 316.1; found: 316.1.
Step 5:
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbalde-
hyde
##STR00088##
[0397] Dess-Martin periodinane (171 mg, 0.404 mmol) was added to a
solution of
[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol
(85 mg, 0.27 mmol) in dichloromethane (3 mL). The mixture was
stirred at room temperature for 1 h then quenched with aqueous
sodium bisulfite, and extracted with dichloromethane. The combined
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified with chromatography (20-40%
EtOAc/Hex) on silica gel to give the desired product (70 mg). LC-MS
calculated for C.sub.20H.sub.16N.sub.3O (M+H).sup.+: m/z=314.1;
found: 314.1.
Step 6:
2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]m-
ethyl}amino)ethanol
[0398] Ethanolamine (8.7 .mu.L, 0.15 mmol) was added to a solution
of
2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde
(9.0 mg, 0.029 mmol) in N,N-dimethylformamide (0.28 mL), followed
by acetic acid (2.5 .mu.L, 0.04 mmol). The reaction mixture was
stirred at room temperature for 10 min then sodium cyanoborohydride
(5.4 mg, 0.087 mmol) was added. The mixture was stirred at room
temperature overnight then diluted with MeOH and purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to afford the desired
product as the TFA salt. LC-MS calculated for
C.sub.22H.sub.23N.sub.4O (M+H).sup.+: m/z=359.2; found: 359.2.
Example 19
(2S)-1-{[2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}piperidine-2-carboxylic
acid
##STR00089##
[0400] The title compound was prepared using similar procedures as
described for Example 18 with (2S)-piperidine-2-carboxylic acid
replacing ethanolamine in Step 6. 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.27N.sub.4O.sub.2 (M+H).sup.+: m/z=427.2; found
427.2.
Example 20
2-({[5-methyl-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]methyl}amino)ethanol
##STR00090##
[0401] Step 1:
7-chloro-5-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-amine
##STR00091##
[0403] To a solution of 6-chloro-2-methylpyrimidin-4-amine (AK
Scientific, cat#W3822: 585 mg, 4.07 mmol) in 1,4-dioxane (20.4 mL)
was added ethoxycarbonyl isothiocyanate (553 .mu.L, 4.89 mmol). The
reaction mixture was heated at 50.degree. C. for 6 h then cooled to
room temperature and concentrated. The residue was dissolved in
methanol (15 mL)/ethanol (15 mL) then N,N-diisopropylethylamine
(1.42 mL, 8.15 mmol) was added, followed by hydroxylamine
hydrochoride (849 mg, 12.2 mmol). The mixture was stirred at
50.degree. C. for 3 h then cooled to room temperature and
concentrated. The residue was directly used for the next step
without further purification. LC-MS calculated for
C.sub.6H.sub.7ClN.sub.5 (M+H).sup.+: m/z=184.0; found 184.0.
Step 2:
7-chloro-2-iodo-5-methyl[1,2,4]triazolo[1,5-c]pyrimidine
##STR00092##
[0405] tert-Butyl nitrite (1.16 mL, 9.78 mmol) was added to a
suspension of
7-chloro-5-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (crude
product from Step 1) and copper(I) iodide (1.55 g, 8.15 mmol) in
acetonitrile (39.4 mL). The mixture was heated at 70.degree. C. for
2 h then cooled to room temperature, diluted with dichloromethane
and washed with water. The organic phase was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by chromatography on silica gel to give the desired
product as a yellow solid (61.0 mg). LC-MS calculated for
C.sub.6H.sub.5ClN.sub.4 (M+H).sup.+: m/z=294.9; found 294.9.
Step 3:
5-methyl-2-(2-methylbiphenyl-3-yl)-7-vinyl[1,2,4]triazolo[1,5-c]py-
rimidine
##STR00093##
[0407] A mixture of
7-chloro-2-iodo-5-methyl[1,2,4]triazolo[1,5-c]pyrimidine (61 mg,
0.21 mmol),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 67 mg, 0.23 mmol),
(2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2',4',6'-triisopropylbipheny-
l-2-yl)phosphoranylidene]palladium (16 mg, 0.02 mmol) and
K.sub.3PO.sub.4 (79 mg, 0.37 mmol) in 1,4-dioxane (0.96 mL)/water
(75 .mu.L) was purged with nitrogen then heated at 90.degree. C.
for 3 h. The reaction mixture was cooled to room temperature then
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (105 .mu.L, 0.62
mmol) was added, followed by (2'-aminobiphenyl-2-yl)(chloro)
[dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphoranylidene]pallad-
ium (16 mg, 0.02 mmol) and K.sub.3PO.sub.4 (79 mg, 0.37 mmol). The
mixture was purged with nitrogen again and stirred at 90.degree. C.
for 3 h. The reaction mixture was cooled to room temperature,
diluted with dichloromethane then dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by
chromatography (8-15% EtOAc/Hex) on silica gel to give the desired
product as an off-white solid. LC-MS calculated for
C.sub.21H.sub.19N.sub.4 (M+H).sup.+: m/z=327.2; found 327.1.
Step 4: 5-methyl-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-c]pyrimidine-7-carbaldehyde
##STR00094##
[0409] Potassium osmate dihydrate (0.96 mg, 0.0026 mmol) and sodium
periodate (5.85 mg, 0.0273 mmol) were added to the solution of
5-methyl-2-(2-methylbiphenyl-3-yl)-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidin-
e (8.5 mg, 0.026 mmol) in tetrahydrofuran (0.07 mL) and water (0.11
mL). The mixture was stirred at room temperature for 1 h then
diluted with ethyl acetate and washed with water. The organic phase
was dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was directly used for the next step without further
purification. LC-MS calculated for C.sub.20H.sub.17N.sub.4O
(M+H).sup.+: m/z=329.1; found 329.2.
Step 5:
2-({[5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrim-
idin-7-yl]methyl}amino)ethanol
[0410] Ethanolamine (5.9 .mu.L, 0.097 mmol) was added to the
solution of
5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidine-7-carb-
aldehyde (6.4 mg, 0.019 mmol) in N,N-dimethylformamide (0.19 mL),
followed by acetic acid (1.7 .mu.L, 0.029 mmol). The mixture was
stirred at room temperature for 10 min then sodium cyanoborohydride
(3.7 mg, 0.059 mmol) was added. The mixture was stirred at room
temperature overnight then diluted with MeOH and purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to afford the desired
product as the TFA salt. LC-MS calculated for
C.sub.22H.sub.24N.sub.5O (M+H).sup.+: m/z=374.2; found: 374.2.
Example 21
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl-
]methyl}amino)ethanol
##STR00095##
[0411] Step 1: ethyl
({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate
##STR00096##
[0413] To a solution of (6-amino-5-chloropyridin-3-yl)methanol (551
mg, 3.47 mmol) in 1,4-dioxane (8.8 mL) was added ethoxycarbonyl
isothiocyanate (471 .mu.L, 4.17 mmol). The reaction mixture was
stirred at room temperature for 15 h. The precipitate was filtered
and washed with dichloromethane. The mother liquor was concentrated
and filtered again. Two crops of the solid were collected and dried
to give the desired product 599 mg (60% yield). LC-MS calculated
for C.sub.10H.sub.13ClN.sub.3O.sub.3S (M+H).sup.+: m/z=290.0;
found: 290.0.
Step 2:
(2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol
##STR00097##
[0415] Hydroxyaminehydrochloride (423 mg, 6.09 mmol) was added to a
solution of ethyl
({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate
(588 mg, 2.03 mmol) in methanol (7.5 mL)/ethanol (7.5 mL), followed
by N,N-diisopropylethylamine (0.707 mL, 4.06 mmol). The reaction
mixture was then heated at 50.degree. C. for 1.5 h. The crude was
concentrated. The residue was directly used in the next step. LC-MS
calculated for C.sub.7H.sub.8ClN.sub.4O (M+H).sup.+: m/z=199.0;
found: 199.0.
Step 3:
(2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol
##STR00098##
[0417] tert-Butyl nitrite (579 .mu.L, 4.87 mmol) was added to a
suspension of
(2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (403
mg, 2.03 mmol) and copper(II) bromide (906 mg, 4.06 mmol) in
acetonitrile (19.6 mL). The mixture was stirred at room temperature
for 3 h. The reaction mixture was diluted with dichloromethane and
washed with water. The organic phase was dried, filtered and
concentrated. The residue was purified by chromatography on silica
gel (50-75% EtOAc/Hex) to give the desired product as a white solid
(428 mg, 82% yield, two steps). LC-MS calculated for
C.sub.7H.sub.6BrClN.sub.3O (M+H).sup.+: m/z=261.9; found:
261.9.
Step 4: [8-chloro-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol
##STR00099##
[0419] A mixture of
(2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (350
mg, 1.33 mmol),
4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
(Example 1, Step 4: 392 mg, 1.33 mmol), K.sub.3PO.sub.4 (509 mg,
2.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (385 mg,
0.333 mmol) in 1,4-dioxane (6.18 mL)/water (480 .mu.L) was stirred
and heated at 110.degree. C. for 4 h. The crude mixture was dried
over a drying agent and filtered. The filtrate was concentrated.
The residue was purified by chromatography (40-60% EtOAc/Hex) on
silica gel to give the desired product 291 mg (63% yield). LC-MS
calculated for C.sub.20H.sub.17ClN.sub.3O (M+H).sup.+: m/z=350.1;
found: 350.1.
Step 5: 8-chloro-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde
##STR00100##
[0421] Dess-Martin periodinane (706 mg, 1.66 mmol) was added to a
solution of [8-chloro-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol (291 mg, 0.832 mmol) in
dichloromethane (3.94 mL). The mixture was stirred at room
temperature for 1 h. The mixture was quenched with aq. sodium
bisulfite and extracted with dichloromethane. The organic phase was
dried over a drying agent and filtered. The filtrate was
concentrated. The residue was purified by chromatography (15-25%
EtOAc/Hex) on silica gel to give the desired product (215 mg, 74%
yield) as a white solid. LC-MS calculated for
C.sub.20H.sub.15ClN.sub.3O (M+H).sup.+: m/z=348.1; found:
348.1.
Step 6:
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyrid-
in-6-yl]methyl}amino)ethanol
[0422] Ethanolamine (186 .mu.L, 3.09 mmol) was added to a solution
of
8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbal-
dehyde (215 mg, 0.618 mmol) in N,N-dimethylformamide (3.87 mL),
followed by trifluoroacetic acid (143 .mu.L). The reaction mixture
was stirred at room temperature for 10 min. Then sodium
cyanoborohydride (116 mg, 1.85 mmol) was added. The reaction
mixture was stirred at room temperature overnight. The crude was
diluted with water and extracted with dichloromethane. The organic
phase was concentrated. The residue was purified by chromatography
on silica gel (5-15% MeOH/DCM) to give the desired product 188 mg
(77% yield). LC-MS calculated for C.sub.22H.sub.22ClN.sub.4O
(M+H).sup.+: m/z=393.1; found: 393.1.
Example 22
2-({[8-[(2-methoxyethyl)amino]-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol
##STR00101##
[0424]
[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-
-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)
methanesulfonate methanesulfonate (Brettphos-Pd-G3, Aldrich,
cat#761605: 3.7 mg, 0.0041 mmol) was added to a mixture of
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl-
]methyl} amino)ethanol (8.0 mg, 0.020 mmol), cesium carbonate (13.3
mg, 0.0407 mmol) and 2-methoxyethylamine (5.3 .mu.L, 0.061 mmol) in
1,4-dioxane (152 .mu.L). The mixture was stirred at 100.degree. C.
for 45 min. The crude was diluted with MeOH and filtered. The
filtrate was purified by prep-HPLC (pH=2, acetonitrile/water+TFA)
to afford the desired product as the TFA salt. LC-MS calculated for
C.sub.25H.sub.30N.sub.5O.sub.2 (M+H).sup.+: m/z=432.2; found:
432.2.
Example 23
4-[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-8-yl]butanenitrile
##STR00102##
[0426]
Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2--
(2'-amino-1,1'-biphenyl)]palladium(II) (RuPhos-Pd-G2, Aldrich,
cat#753246: 1.6 mg, 0.0020 mmol) was added to a mixture of
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl-
]methyl} amino)ethanol (Example 21: 8.0 mg, 0.02 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butanenitrile (7.9
mg, 0.041 mmol) and cesium carbonate (13.3 mg, 0.0407 mmol) in
1,4-dioxane (94.5 .mu.L)/water (31.1 .mu.L). The mixture was
stirred at 100.degree. C. for 1 h. The crude was diluted with MeOH
and filtered. The filtrate was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to afford the desired product as the TFA
salt. LC-MS calculated for C.sub.26H.sub.28N.sub.5O (M+H).sup.+:
m/z=426.2; found: 426.3.
Example 24
[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)
[1,2,4]triazolo[1,5-a]pyridin-8-yl]acetonitrile
##STR00103##
[0428]
Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, Aldrich,
cat#741825: 4.8 mg, 0.0061 mmol) was added to a mixture of
2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl-
]methyl} amino)ethanol (Example 21: 12.0 mg, 0.0305 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (8.94 mg,
0.0458 mmol) and potassium phosphate (19.4 mg, 0.0916 mmol) in
1,4-dioxane (188 .mu.L, 2.41 mmol)/water (11.0 .mu.L, 0.611 mmol).
The mixture was stirred at 100.degree. C. for 2 h. The crude was
diluted with MeOH and filtered through Celite. The filtrate was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to afford the
desired product as the TFA salt. LC-MS calculated for
C.sub.24H.sub.24N.sub.5O (M+H).sup.+: m/z=398.2; found: 398.2.
Example 25
2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-
-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
##STR00104##
[0429] Step 1:
2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
##STR00105##
[0431] A mixture of 2-bromo-6-iodobenzonitrile (3.01 g, 9.78 mmol),
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (1.60 g, 8.89 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (363 mg, 0.444 mmol) and
potassium carbonate (3.07 g, 22.2 mmol) in 1,4-dioxane (36.0 mL,
462 mmol) and water (1.60 mL, 88.9 mmol) was degassed and recharged
with nitrogen. The mixture was then heated and stirred at
75.degree. C. for 4 h. The reaction mixture was dried over a drying
agent and filtered. The filtrate was concentrated. The residue was
purified by chromatography on silica gel (10-15% EtOAc/Hex) to
afford the desired product 1.48 g. LC-MS calculated for
C.sub.15H.sub.11BrNO.sub.2 (M+H).sup.+: m/z=316.0 and 318.0; found:
316.0 and 318.0.
Step 2:
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)benzonitrile
##STR00106##
[0433] A mixture of
2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (1.20 g,
3.80 mmol), Bis(pinacolato)diboron (1.06 g, 4.18 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (150 mg, 0.19 mmol), potassium
acetate (1.1 g, 11 mmol) in 1,4-dioxane (30 mL, 400 mmol) was
degassed for 5 min, and then stirred at 90.degree. C. for 4 h. The
crude was diluted with dichloromethane and then filtered. The
filtrate was concentrated. The residue was purified by
chromatography on silica gel to afford the desired product. LC-MS
calculated for C.sub.21H.sub.23BNO.sub.4 (M+H).sup.+: m/z=364.2;
found: 364.2.
Step 3:
2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a-
]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
[0434] This compound was prepared using similar procedures as
described for Example 21. The resulting crude 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.21ClN.sub.5O.sub.3(M+H).sup.+: m/z=462.1; found:
462.1.
Example 26
2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6-{[(2-hydroxyethyl-
)amino]methyl}[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile
##STR00107##
[0436] A mixture of
2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridi-
n-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (Example
25: 6.0 mg, 0.013 mmol), potassium hexacyanoferrate(II) trihydrate
(5.49 mg, 0.0130 mmol), and potassium acetate (0.255 mg, 0.00260
mmol) in 1,4-dioxane (32.2 .mu.L)/water (32.2 .mu.L) was stirred
and heated at 100.degree. C. for 1 h. The resulting crude was
diluted with MeOH and filtered. The filtrate 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.25H.sub.21N.sub.6O.sub.3 (M+H).sup.+: m/z=453.2; found:
453.2.
Example 27
2-(8-(cyanomethyl)-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]-
pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
##STR00108##
[0438] This compound was prepared using similar procedures as
described for Example 24. The resulting crude 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.23N.sub.6O.sub.3 (M+H).sup.+: m/z=467.2; found:
467.2.
Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)
Binding Assay
[0439] 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.
[0440] Compounds of the present disclosure, as exemplified in
Examples 1-20, 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
[0441] 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 +
[0442] 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.
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