U.S. patent application number 15/386052 was filed with the patent office on 2017-06-22 for heterocyclic compounds as immunomodulators.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Neil Lajkiewicz, Liangxing Wu, Wenqing Yao.
Application Number | 20170174679 15/386052 |
Document ID | / |
Family ID | 57799827 |
Filed Date | 2017-06-22 |
United States Patent
Application |
20170174679 |
Kind Code |
A1 |
Lajkiewicz; Neil ; et
al. |
June 22, 2017 |
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: |
Lajkiewicz; Neil; (Garnet
Valley, PA) ; Wu; Liangxing; (Wilmington, DE)
; Yao; Wenqing; (Chadds Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
57799827 |
Appl. No.: |
15/386052 |
Filed: |
December 21, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62385341 |
Sep 9, 2016 |
|
|
|
62324502 |
Apr 19, 2016 |
|
|
|
62270931 |
Dec 22, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 215/40 20130101;
A61P 31/00 20180101; A61P 31/12 20180101; C07D 471/04 20130101;
A61P 3/00 20180101; A61P 11/06 20180101; A61P 35/04 20180101; A61P
9/10 20180101; A61P 35/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 215/40 20060101 C07D215/40 |
Claims
1. A compound of Formula (I'): ##STR00091## or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein: 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 wherein X.sup.1, X.sup.2 and X.sup.3 are not all
simultaneously N; wherein X.sup.4, X.sup.5 and X.sup.6 are not all
simultaneously N; X.sup.7 is N or CR.sup.8a: X.sup.8 is N or
CR.sup.8b; X.sup.9 is N or CR.sup.8c; 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.9
substituents; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents; R.sup.7 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,
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.11S(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 and R.sup.11 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.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.1-4alkyl-,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl-, 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.10NR.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.10OR.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.10S(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.1-4alkyl-, C.sub.6-10 aryl,
C.sub.6-10aryl-C.sub.1-4alkyl, 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.1-4alkyl-, C.sub.6-10 aryl,
C.sub.6-10aryl-C.sub.1-4alkyl-, 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.8a, R.sup.8b, R.sup.8c and R.sup.10 are each optionally
substituted with 1, 2 or 3 independently selected R.sup.d
substituents; or two adjacent R.sup.9 substituents together with
the atoms to which they are attached, form a fused phenyl ring, a
fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or
6-membered heteroaryl ring or a fused C.sub.3-10 cycloalkyl ring,
wherein the fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-10 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.6-10aryl,
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 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; 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 iaryl-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, 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, R.sup.o, 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.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-, and (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.r 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.1-4alkyl,
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; provided that R.sup.7 is other than NH.sub.2, when
X.sup.8 is CR.sup.8b and X.sup.7 and X.sup.9 are each N; and the
compound is other than
(1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine
or
(1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.
2. The compound claim 1, or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein: 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 wherein X.sup.1,
X.sup.2 and X.sup.3 are not all simultaneously N; wherein X.sup.4,
X.sup.5 and X.sup.6 are not all simultaneously N; X.sup.7 is N or
CR.sup.8a; X.sup.8 is N or CR.sup.8b; X.sup.9 is N or CR.sup.8c; 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.9
substituents; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents; R.sup.7 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,
OR.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.1-4 alkyl,
cyclopropyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of R.sup.7 are
each optionally substituted with 1 or 2 halo, OH, CN or OCH.sub.3
substituents 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; 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.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, OR.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
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
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4
alkenyl and C.sub.2-4 alkynyl of R.sup.8 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; or two adjacent
R.sup.9 substituents together with the carbon atoms to which they
are attached, form a fused phenyl ring, a fused 5- to 7-membered
heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or
a fused C.sub.3-10 cycloalkyl ring, wherein the fused 5- to
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- to
7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl
ring and fused C.sub.3-10 cycloalkyl ring are each optionally
substituted with 1 or 2 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, phenyl, 5- or 6-membered
heteroaryl, 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, phenyl, 5- or
6-membered heteroaryl 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 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; 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, R.sup.o, 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.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR.sup.o)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-, and (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 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; provided that R.sup.7 is other than
NH.sub.2, when X.sup.8 is CR.sup.8b and X.sup.7 and X.sup.9 are
each N; and the compound is other than
(1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine
or
(1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.
3. The compound of claim 1 or 2, having Formula (I): ##STR00092##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: 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 wherein X.sup.1, X.sup.2 and
X.sup.3 are not all simultaneously N; wherein X.sup.4, X.sup.5 and
X.sup.6 are not all simultaneously N; R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6 and R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents; R.sup.7 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,
OR.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 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; each R.sup.8 is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-6 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, OR.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.10NR.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
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4
alkenyl and C.sub.2-4 alkynyl of R.sup.8 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; or two adjacent
R.sup.9 substituents together with the carbon atoms to which they
are attached, form a fused phenyl ring, a fused 5- to 7-membered
heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or
a fused C.sub.3-10 cycloalkyl ring, wherein the fused 5- to
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- to
7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl
ring and fused C.sub.3-10 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, phenyl, 5- or 6-membered
heteroaryl, 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, phenyl, 5- or
6-membered heteroaryl 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 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; 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, 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, R.sup.o, 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.sup.o)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-, and (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, 4- to 6-membered heterocycloalkyl, 5-
or 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, 4- to 6-membered heterocycloalkyl and 5- or
6-membered heteroaryl of R.sup.q are each optionally substituted
with 1 or 2 substituents independently selected from halo, OH, CN,
--COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-10
cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each
R.sup.12 is independently C.sub.1-6 alkyl; 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):
##STR00093## wherein R.sup.2 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.2 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):
##STR00094## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
6. The compound of any one of claims 1-5, having Formula (IV):
##STR00095## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
7. The compound of any one of claim 1-4, having Formula (V):
##STR00096## or a pharmaceutically acceptable salt or a
stereoisomer thereof.
8. The compound of any one of claims 1-4 and 7, having Formula
(VI): ##STR00097## 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
##STR00098## is selected from ##STR00099## ##STR00100##
10. The compound of any one of claims 1-3, having Formula (VII):
##STR00101## wherein R.sup.3 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.3 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents, or
a pharmaceutically acceptable salt or a stereoisomer thereof.
11. The compound of any one of claims 1-3 and 10, or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
the moiety ##STR00102## selected from: ##STR00103##
##STR00104##
12. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is
CR.sup.1, X.sup.3 is CR.sup.3, X.sup.4 is CR.sup.4, X.sup.5 is
CR.sup.5 and X.sup.6 is CR.sup.6.
13. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is
CR.sup.1, X.sup.3 is CR.sup.3, X.sup.4 is CR.sup.4, X.sup.5 is
CR.sup.5 and X.sup.6 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
CR.sup.1, X.sup.3 is CR.sup.3, X.sup.4 is N, X.sup.5 is CR.sup.5
and X.sup.6 is N.
15. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is
CR.sup.1, X.sup.3 is N, X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5
and X.sup.6 is N.
16. The compound of any one of claims 1-8, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein X.sup.1 is
CR.sup.1, X.sup.3 is N, X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5
and X.sup.6 is CR.sup.6.
17. The compound of any one of claims 1-9 and 12-16, or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 when applicable, are
each independently selected from H, CN, C.sub.1-6 alkyl and
halo.
18. The compound of claim 10 or 11, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.1,
R.sup.2, R.sup.4, R.sup.5 and R.sup.6, when applicable, are each
independently selected from H, CN, C.sub.1-6 alkyl and halo.
19. The compound of any one of claims 1-18, or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.2 is
--CH.sub.2--R.sup.b.
20. The compound of claim 19, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.b is
--NR.sup.cR.sup.c.
21. The compound of any one of claims 1-14 and 17-20, or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
R.sup.3 is --CH.sub.2--R.sup.b.
22. The compound of claim 21, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.b is
--NR.sup.cR.sup.c.
23. The compound of any one of claims 1-22 or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein R.sup.2 is
2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl,
(S)-2-carboxypiperidin-1-ylmethyl,
(R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
24. The compound of any one of claims 1-14, 17-21, and 23, or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein
R.sup.3 is 2-hydroxyethylaminomethyl,
2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl,
(R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
25. The compound of claim 1, wherein the compound is selected from:
2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methyl)amino]ethanol;
2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]-
ethanol;
1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl-
)piperidine-2-carboxylic acid;
1-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}methyl)pi-
peridine-2-carboxylic acid;
1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)piperid-
ine-2-carboxylic acid;
2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)amino]-
ethanol;
2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)amino]e-
thanol; and
1-({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)piperidine-2-car-
boxylic acid; or a pharmaceutically acceptable salt or a
stereoisomer thereof.
26. The compound of claim 1, wherein the compound is selected from:
2-[({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}meth-
yl)amino]ethanol;
2-[({4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}met-
hyl)amino]ethanol;
1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methy-
l)piperidine-2-carboxylic acid;
2-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-n-
aphthyridin-4-yl)methyl]amino}ethanol;
1-[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-na-
phthyridin-4-yl)methyl]piperidine-2-carboxylic acid;
2-[({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)ami-
no]ethanol;
(2S)-1-({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl-
)piperidine-2-carboxylic acid;
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-[(3-{[(2-hydroxyethyl)amino]methyl-
}-1,7-naphthyridin-8-yl)amino]benzonitrile;
2-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-n-
aphthyridin-3-yl)methyl]amino}ethanol;
2-[({8-[(3-cyclohex-1-en-1-yl-2-methylphenyl)amino]-1,7-naphthyridin-3-yl-
}methyl)amino]ethanol;
3-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]bipheny-
l-2-carbonitrile;
2-cyclohex-1-en-1-yl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyrid-
in-8-yl)amino]benzonitrile; and
2-cyclohexyl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)-
amino]benzonitrile; or a pharmaceutically acceptable salt or a
stereoisomer thereof.
27. A pharmaceutical composition comprising a compound of any one
of claims 1-26, or a pharmaceutically acceptable salt or a
stereoisomer thereof, and a pharmaceutically acceptable carrier or
excipient.
28. A method of inhibiting PD-1/PD-L1 interaction, said method
comprising administering to a patient 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
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.
31. A method of enhancing, stimulating, modulating and/or
increasing the immune response in a patient, said method comprising
administering to the patient in need thereof a therapeutically
effective amount of a compound of any one of claims 1-26, or a
pharmaceutically acceptable salt or a stereoisomer thereof, or a
composition of claim 27.
32. A method of inhibiting growth, proliferation, or metastasis of
cancer cells in a patient, said method comprising administering to
the 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.
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, PNAS2002, 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 AP1 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
Fomrula (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, compounds of
Formula (I'):
##STR00004##
[0012] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[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] wherein X.sup.1, X.sup.2 and X.sup.3 are not all
simultaneously N;
[0020] wherein X.sup.4, X.sup.5 and X.sup.6 are not all
simultaneously N;
[0021] X.sup.7 is N or CR.sup.8a;
[0022] X.sup.8 is N or CR.sup.8b;
[0023] X.sup.9 is N or CR.sup.8c;
[0024] 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.9 substituents;
[0025] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents;
[0026] R.sup.7 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, 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.11S(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 and R.sup.11 are each
optionally substituted with 1, 2 or 3 R.sup.b substituents;
[0027] 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;
[0028] 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.1-4alkyl-, C.sub.6-10aryl,
C.sub.6-10aryl-C.sub.1-4alkyl-, 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.10NR.sub.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.1-4alkyl-, C.sub.6-10 aryl,
C.sub.6-10aryl-C.sub.1-4alkyl, 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.1-4alkyl-, C.sub.6-10 aryl,
C.sub.6-10aryl-C.sub.1-4alkyl-, 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.8a, R.sup.8b, R.sup.8c and R.sup.10 are each optionally
substituted with 1, 2 or 3 independently selected R.sup.d
substituents;
[0029] or two adjacent R.sup.9 substituents together with the atoms
to which they are attached, form a fused phenyl ring, a fused 5- to
7-membered heterocycloalkyl ring, a fused 5- or 6-membered
heteroaryl ring or a fused C.sub.3-10 cycloalkyl ring, wherein the
fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-10 cycloalkyl ring are
each optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents;
[0030] 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;
[0031] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10aryl, 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.d substituents;
[0032] 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;
[0033] 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, 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, R.sup.o, 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, 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;
[0034] 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;
[0035] 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.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-, and (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;
[0036] 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;
[0037] 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;
[0038] 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;
[0039] 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;
[0040] 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;
[0041] 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
[0042] each R.sup.e, R.sup.i, R.sup.k, R.sup.o or R.sup.r 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, R.sup.k, R.sup.o or R.sup.p are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0043] 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.1-4alkyl,
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;
[0044] provided that R.sup.7 is other than NH.sub.2, when X.sup.8
is CR.sup.8b and X.sup.7 and X.sup.9 are each N; and
[0045] the compound is other than
(1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1. O]hept-3-en-3-amine
or
(1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.
[0046] The present disclosure provides compounds of Formula (I'),
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0047] X.sup.1 is N or CR.sup.1;
[0048] X.sup.2 is N or CR.sup.2;
[0049] X.sup.3 is N or CR.sup.3;
[0050] X.sup.4 is N or CR.sup.4;
[0051] X.sup.5 is N or CR.sup.5;
[0052] X.sup.6 is N or CR.sup.6
[0053] wherein X.sup.1, X.sup.2 and X.sup.3 are not all
simultaneously N;
[0054] wherein X.sup.4, X.sup.5 and X.sup.6 are not all
simultaneously N;
[0055] X.sup.7 is N or CR.sup.8a;
[0056] X.sup.8 is N or CR.sup.8b;
[0057] X.sup.9 is N or CR.sup.8c;
[0058] 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.9 substituents;
[0059] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents;
[0060] R.sup.7 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, OR.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.1-4 alkyl,
cyclopropyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of R.sup.7 are
each optionally substituted with 1 or 2 halo, OH, CN or OCH.sub.3
substituents 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;
[0061] 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.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, OR.sup.10,
NHOR.sup.10, C(O)R.sup.10, C(O)NR.sup.10R.sup.10,
C(O)OR.sup.10OC(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
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4
alkenyl and C.sub.2-4 alkynyl of R.sup.8 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN, C.sub.1-4 alkyl and C.sub.1-4 alkoxy;
[0062] or two adjacent R.sup.9 substituents together with the
carbon atoms to which they are attached, form a fused phenyl ring,
a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or
6-membered heteroaryl ring or a fused C.sub.3-10 cycloalkyl ring,
wherein the fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-10 cycloalkyl ring are
each optionally substituted with 1 or 2 independently selected
R.sup.b substituents or 1 or 2 independently selected R.sup.q
substituents;
[0063] 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;
[0064] 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, phenyl, 5- or 6-membered heteroaryl, 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, phenyl, 5- or
6-membered heteroaryl and 4-10 membered heterocycloalkyl of R.sup.d
are each further optionally substituted with 1-3 independently
selected R.sup.q substituents;
[0065] 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,
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;
[0066] 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, OR.sup.g,
SR.sup.g, C(O)R, 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, 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, R.sup.o, 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, 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;
[0067] 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;
[0068] 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,
NRC(O)OR.sup.1, 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-, and (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;
[0069] 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;
[0070] 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;
[0071] 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;
[0072] 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;
[0073] 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;
[0074] 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
[0075] 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;
[0076] 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 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;
[0077] provided that R.sup.7 is other than NH.sub.2, when X.sup.8
is CR.sup.8b and X.sup.7 and X.sup.9 are each N; and
[0078] the compound is other than
(1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine
or
(1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)p-
henyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.
[0079] In some embodiments of compounds of Formula (I'), Cy is
other than
3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. In
certain instances, when any of R.sup.8a, R.sup.8b or R.sup.8c is F,
Cy is not
3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. In
certain instances, when any of R.sup.8a, R.sup.8b or R.sup.8C is
halo, Cy is not
3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. In
certain instances, when R.sup.7 is F, Cy is not
3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. In
certain instances, when R.sup.7 is halo, Cy is not
3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl.
[0080] 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.9 substituents. In certain embodiments, Cy is phenyl
or naphthyl, each of which is optionally substituted with 1 to 4
independently selected R.sup.9 substituents. In certain
embodiments, Cy is phenyl optionally substituted with 1 to 4
independently selected R.sup.9 substituents. In certain
embodiments, Cy is unsubstituted phenyl.
[0081] 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.9 substituents. In certain
embodiments, Cy is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl or cyclooctyl, each of which is optionally
substituted with 1 to 4 independently selected R.sup.9
substituents.
[0082] 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.9 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.9 substituents.
[0083] 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.9 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.9 substituents. In some embodiments, Cy is
2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with 1 to 4
independently selected R.sup.9 substituents. In some embodiments,
Cy is unsubstituted 2,3-dihydro-1,4-benzodioxin-6-yl.
[0084] In some embodiments of compounds of Formula (I'), X.sup.7 is
CR.sup.8a, X.sup.8 is CR.sup.8b and X.sup.9 is CR.sup.8c. In
certain instances, R.sup.8a, R.sup.8b and R.sup.8c are each H.
[0085] In some embodiments of compounds of Formula (I'), X.sup.7 is
CR.sup.8a, X.sup.8 is N and X.sup.9 is N. In certain instances,
R.sup.8a is H.
[0086] In some embodiments of compounds of Formula (I'), X.sup.7 is
CR.sup.8a, X.sup.8 is N and X.sup.9 is CR.sup.8c. In certain
instances, R.sup.8a and R.sup.8c are each H.
[0087] In some embodiments of compounds of Formula (I'), X.sup.7 is
CR.sup.8a, X.sup.8 is CR.sup.8b and X.sup.9 is N. In certain
instances, R.sup.8a and R.sup.8c are each H.
[0088] In some embodiments of compounds of Formula (I'), X.sup.7 is
N, X.sup.8 is CR.sup.8b and X.sup.9 is CR.sup.8c. In certain
instances, R.sup.8a and R.sup.8c are each H.
[0089] In some embodiments of compounds of Formula (I'), X.sup.7 is
N, X.sup.8 is N and X.sup.9 is CR.sup.8c. In certain instances,
R.sup.8c is H.
[0090] In some embodiments of compounds of Formula (I'), X.sup.7 is
N, X.sup.8 is CR.sup.8b and X.sup.9 is N. In certain instances,
R.sup.8b is H.
[0091] In some embodiments of compounds of Formula (I'), X.sup.7,
X.sup.8 and X.sup.9 are each N.
[0092] In some embodiments, the present disclosure provides
compounds of Formula (I):
##STR00005##
[0093] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[0094] X.sup.1 is N or CR.sup.1;
[0095] X.sup.2 is N or CR.sup.2;
[0096] X.sup.3 is N or CR.sup.3;
[0097] X.sup.4 is N or CR.sup.4;
[0098] X.sup.5 is N or CR.sup.5;
[0099] X.sup.6 is N or CR.sup.6
[0100] wherein X.sup.1, X.sup.2 and X.sup.3 are not all
simultaneously N;
[0101] wherein X.sup.4, X.sup.5 and X.sup.6 are not all
simultaneously N;
[0102] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents;
[0103] R.sup.7 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, OR.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.1-4 alkyl,
cyclopropyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy of R.sup.7 are
each optionally substituted with 1 or 2 halo, OH, CN or OCH.sub.3
substituents 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; each R.sup.8 is independently selected from H, C.sub.1-4
alkyl, C.sub.3-6 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, OR.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
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
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4
alkenyl and C.sub.2-4 alkynyl of R.sup.8 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN, C.sub.1-4 alkyl and C.sub.1-4 alkoxy;
[0104] or two adjacent R.sup.9 substituents together with the
carbon atoms to which they are attached, form a fused phenyl ring,
a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or
6-membered heteroaryl ring or a fused C.sub.3-10 cycloalkyl ring,
wherein the fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-10 cycloalkyl ring are
each optionally substituted with 1 or 2 independently selected
R.sup.q substituents or 1 or 2 independently selected R.sup.b
substituents;
[0105] 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;
[0106] 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, phenyl, 5- or 6-membered heteroaryl, 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, phenyl, 5- or
6-membered heteroaryl and 4-10 membered heterocycloalkyl of R.sup.d
are each further optionally substituted with 1-3 independently
selected R.sup.q substituents;
[0107] 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;
[0108] 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.a substituents
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
halo, CN, R.sup.o, NHOR.sup.o, OR.sup.o, SR.sup.o, C(O)R.sup.o,
C(O)NR.sup.oR.sup.o, C(O)OR.sup.o, OC(O)R.sup.o,
OC(O)NR.sup.oR.sup.o, NHR.sup.o, NR.sup.oR.sup.o,
NR.sup.oC(O)R.sup.o, NROC(O)NR.sup.oR.sup.o, NR.sup.oC(O)OR.sup.o,
C(.dbd.NR)NR.sup.oR.sup.o, NR.sup.oC(.dbd.NR)NR.sup.oR.sup.o,
S(O)R.sup.o, S(O)NR.sup.oR.sup.o, S(O).sub.2R,
NROS(O).sub.2R.sup.o, NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and
S(O).sub.2NR.sup.oR.sup.o;
[0109] 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;
[0110] 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-, and (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;
[0111] 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;
[0112] 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;
[0113] 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;
[0114] 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;
[0115] 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;
[0116] 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
[0117] each R.sup.e, R.sup.i, R.sup.k, R.sup.i 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;
[0118] 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, 4- to 6-membered heterocycloalkyl, 5- or
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, 4- to 6-membered heterocycloalkyl and 5- or
6-membered heteroaryl of R.sup.q are each optionally substituted
with 1 or 2 substituents independently selected from halo, OH, CN,
--COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-10
cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each
R.sup.12 is independently C.sub.1-6 alkyl;
[0119] the subscript n is an integer of 1, 2, 3, 4 or 5; and
[0120] the subscript m is an integer of 1, 2 or 3.
[0121] In some embodiments, the present disclosure provides
compounds of Formula (I):
##STR00006##
[0122] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[0123] X.sup.1 is N or CR.sup.1;
[0124] X.sup.2 is N or CR.sup.2;
[0125] X.sup.3 is N or CR.sup.3;
[0126] X.sup.4 is N or CR.sup.4:
[0127] X.sup.5 is N or CR.sup.5;
[0128] X.sup.6 is N or CR.sup.6
[0129] wherein X.sup.1, X.sup.2 and X.sup.3 are not all
simultaneously N;
[0130] wherein X.sup.4, X.sup.5 and X.sup.6 are not all
simultaneously N;
[0131] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.9 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.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.9 are each optionally
substituted with 1, 2, 3, or 4 R.sup.b substituents;
[0132] R.sup.7 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, OR.sup.11, NHOR, C(O)R.sup.1, 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;
[0133] each R.sup.8 is independently selected from H, C.sub.1-4
alkyl, C.sub.3-6 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, OR.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.10NR.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
wherein the C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4
alkenyl and C.sub.2-4 alkynyl of R.sup.8 are each optionally
substituted with 1 or 2 substituents independently selected from
halo, OH, CN, C.sub.1-4 alkyl and C.sub.1-4 alkoxy;
[0134] or two adjacent R.sup.9 substituents together with the
carbon atoms to which they are attached, form a fused phenyl ring,
a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or
6-membered heteroaryl ring or a fused C.sub.3-10 cycloalkyl ring,
wherein the fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or
6-membered heteroaryl ring and fused C.sub.3-10 cycloalkyl ring are
each optionally substituted with 1 or 2 independently selected
R.sup.q substituents;
[0135] 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;
[0136] 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, phenyl, 5- or 6-membered heteroaryl, 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, phenyl, 5- or
6-membered heteroaryl and 4-10 membered heterocycloalkyl of R.sup.d
are each further optionally substituted with 1-3 independently
selected R.sup.q substituents;
[0137] 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,
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; 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, 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.a substituents
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
halo, CN, R.sup.o, 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.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR.sup.o)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;
[0138] 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;
[0139] 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,
NRC(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-, and (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;
[0140] 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;
[0141] 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;
[0142] 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;
[0143] 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;
[0144] 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;
[0145] 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
[0146] 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;
[0147] 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, 4- to 6-membered heterocycloalkyl, 5- or
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, 4- to 6-membered heterocycloalkyl and 5- or
6-membered heteroaryl of R.sup.q are each optionally substituted
with 1 or 2 substituents independently selected from halo, OH, CN,
--COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-10
cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each
R.sup.12 is independently C.sub.1-6 alkyl;
[0148] the subscript n is an integer of 1, 2, 3, 4 or 5; and
[0149] the subscript m is an integer of 1, 2 or 3.
[0150] 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.
[0151] In some embodiments, the present disclosure provides
compounds having Formula (II):
##STR00007##
or a pharmaceutically acceptable salt or a stereoisomer thereof. In
certain embodiments of compounds of Formula (II), R.sup.2 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.2 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
any embodiment of compounds of Formula (I) as described herein. In
one embodiment of compounds of Formula (II), R.sup.7 is CN or
C.sub.1-4 alkyl optionally substituted with R.sup.q. In another
embodiment, R.sup.7 is CH.sub.3 or CN.
[0152] In some embodiments, the present disclosure provides
compounds having Formula (III):
##STR00008##
or a pharmaceutically acceptable salt or a stereoisomer thereof. In
certain embodiments of compounds of Formula (III), R.sup.2 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.2 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
Other variables of Formula (III) are as defined in Formula (I) or
any embodiment of compounds of Formula (I) as described herein.
[0153] 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 any embodiment of compounds of Formula (I) as described herein.
In certain embodiments of compounds of Formula (II), R.sup.2 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.2 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
[0154] 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 any embodiment of compounds of Formula (I) as described herein.
In certain embodiments of compounds of Formula (V), R.sup.2 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.2 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
[0155] 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 any embodiment of compounds of Formula (I) as described herein.
In certain embodiments of compounds of Formula (VI), R.sup.2 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.2 are each
optionally substituted with 1, 2, 3, or 4 R.sup.b substituents.
[0156] 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 certain embodiments of compounds of Formula
(VII), 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.
[0157] 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 certain instances, R.sup.9 is H, n is 1,
X.sup.7 is CR.sup.8a, X.sup.8 is CR.sup.8b and X.sup.9 is CR.sup.c.
In some instances, X.sup.7, X.sup.8 and X.sup.9 are each CH.
[0158] In some embodiments, the present disclosure provides
compounds having Formula (IX):
##STR00014##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the variables of Formula (IX) are as defined in Formula
(I') or (I) or any embodiment of compounds of Formula (I') or (I)
as described herein. In certain instances, R.sup.9 is H, n is 1,
X.sup.7 is CR.sup.8a, X.sup.8 is CR.sup.8b and X.sup.9 is CR.sup.c.
In some instances, X.sup.7, X.sup.8 and X.sup.9 are each CH.
[0159] In some embodiments of compounds of Formula I', I, II, III,
IV, V or VI, or a pharmaceutically acceptable salt or a
stereoisomer thereof, the moiety
##STR00015##
is selected from:
##STR00016## ##STR00017##
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'), (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.3,
R.sup.4, R.sup.5 and R.sup.6 are each H.
[0160] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, the moiety
##STR00018##
is selected from:
##STR00019## ##STR00020##
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'), (I) or any
embodiment of compounds of Formula (I'), (I) as described herein.
In certain embodiments, at each occurrence, R.sup.1, R.sup.2,
R.sup.4, R.sup.5 and R.sup.6 are each H.
[0161] In some embodiments of compounds of Formula I', I, II, III,
IV, V or VI, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.3 is CR.sup.3,
X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6.
In some instances, X.sup.1, X.sup.3, X.sup.4, X.sup.5 and X.sup.6
are each CH. In one embodiment, X.sup.2 is CR.sup.2.
[0162] In some embodiments of compounds of Formula I', I, II, III,
IV, V or VI, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.3 is CR.sup.3,
X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some
instances, X.sup.1, X.sup.3, X.sup.4 and X.sup.5 are each CH. In
one embodiment, X.sup.2 is CR.sup.2.
[0163] In some embodiments of compounds of Formula I', I, II, III,
IV, V or VI, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.3 is CR.sup.3,
X.sup.4 is N, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some
instances, X.sup.1, X.sup.3 and X.sup.5 are each CH. In one
embodiment, X.sup.2 is CR.sup.2.
[0164] In some embodiments of compounds of Formula I', I, II, III,
IV, V or VI, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR, X.sup.3 is N, X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some instances,
X.sup.1, X.sup.4 and X.sup.5 are each CH. In one embodiment,
X.sup.2 is CR.sup.2.
[0165] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR, X.sup.2 is N, X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6. In some
instances, X.sup.1, X.sup.4, X.sup.5 and X.sup.6 are each CH. In
one embodiment, X.sup.2 is CR.sup.2.
[0166] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.2 is CR.sup.2,
X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6.
In some instances, X.sup.1, X.sup.2, X.sup.4, X.sup.5 and X.sup.6
are each CH. In one embodiment, X.sup.3 is CR.sup.3.
[0167] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.2 is CR.sup.2,
X.sup.4 is CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some
instances, X.sup.1, X.sup.2, X.sup.4 and X.sup.5 are each CH. In
one embodiment, X.sup.3 is CR.sup.3.
[0168] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR.sup.1, X.sup.2 is CR.sup.2,
X.sup.4 is N, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some
instances, X.sup.1, X.sup.2 and X.sup.5 are each CH. In one
embodiment, X.sup.3 is CR.sup.3.
[0169] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR, X.sup.2 is N, X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is N. In some instances,
X.sup.1, X.sup.4 and X.sup.5 are each CH. In one embodiment,
X.sup.3 is CR.sup.3.
[0170] In some embodiments of compounds of Formula I', I, VII,
VIII, or IX, or a pharmaceutically acceptable salt or a
stereoisomer thereof, X.sup.1 is CR, X.sup.2 is N, X.sup.4 is
CR.sup.4, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6. In some
instances, X.sup.1, X.sup.4, X.sup.5 and X.sup.6 are each CH. In
one embodiment, X.sup.3 is CR.sup.3.
[0171] In some embodiments, R.sup.1, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6, are each independently selected from H, C.sub.1-6 alkyl,
CN, --N(C.sub.1-6 alkyl).sub.2 and halo.
[0172] In some embodiments, R.sup.1, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6, are each independently selected from H, CN, C.sub.1-6
alkyl and halo.
[0173] In some embodiments, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
R.sup.6, are each independently selected from H, C.sub.1-6 alkyl,
CN, --N(C.sub.1-6 alkyl).sub.2 and halo.
[0174] In some embodiments, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
R.sup.6, are each independently selected from H, CN, C.sub.1-6
alkyl and halo.
[0175] In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.8 and R.sup.9 are each H.
[0176] In some embodiments, R.sup.1, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.8 and R.sup.9 are each H.
[0177] In some embodiments, R.sup.1, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, R.sup.8 and R.sup.9 are each H.
[0178] In some embodiments, R.sup.2 is --CH.sub.2--R.sup.b.
[0179] In some embodiments, R.sup.3 is --CH.sub.2--R.sup.b.
[0180] In some embodiments, R.sup.3 is H, halo or
C.sub.1-6alkyl.
[0181] In some embodiments, R.sup.3 is H, Cl or OCH.sub.3.
[0182] In some embodiments, two adjacent R.sup.9 substituents on
the phenyl ring taken together with the carbon atoms to which they
are attached form a 5-, 6- or 7-membered fused heterocycloalkyl
optionally substituted by 1 or 2 R.sup.q substituents. In some
instances, the fused heterocycloalkyl is fused dioxanyl optionally
substituted withl or 2 R.sup.q substituents. In certain instances,
the fused heterocycloalkyl has carbon and 1 or 2 heteroatoms as
ring members selected from O, N or S, wherein the carbon ring atom
is optionally oxidized to form carbonyl, the N ring atom is
optionally oxidized to form NO and the S ring atom is optionally
oxidized to form SO or SO.sub.2.
[0183] In some embodiments, the subscript n is 2 and the subscript
m is 1.
[0184] In some embodiments, R.sup.7 is C.sub.1-4 alkyl or CN.
[0185] In some embodiments, R.sup.7 is CH.sub.3 or CN.
[0186] In some embodiments, R.sup.8 and R.sup.9 are each H.
[0187] In some embodiments of compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.2 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 certain embodiments, R.sup.b is
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, each of which is optionally substituted
with 1, 2 or 3 R.sup.q substituents. 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.b is
2-hydroxyethylamino. In other embodiments, R.sup.b is
2-carboxypiperidin-1-yl. In other embodiments, R.sup.2 is C.sub.1-4
alkyl substituted with R.sup.q.
[0188] In some embodiments compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.2 is C.sub.1-4 alkoxy
substituted with R.sup.d. In certain embodiments, R.sup.d is
phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of
which is optionally substituted with 1, 2 or 3 R.sup.q
substituents.
[0189] In some embodiments compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.2 is --OCH.sub.2R.sup.d. In
certain embodiments, R.sup.d is phenyl, 3-cyanophenyl, 3-pyridyl,
2-pyridyl, 4-pyridyl, each of which is optionally substituted with
1, 2 or 3 R.sup.q substituents.
[0190] In some embodiments of compounds of Formula I', I, II, III,
III, IV, V, or VI, VII, VIII, or IX, R.sup.3 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 certain embodiments, R.sup.b is
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, each of which is optionally substituted
with 1, 2 or 3 R.sup.q substituents.
[0191] 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.b is 2-hydroxyethylamino. In other embodiments,
R.sup.b is 2-carboxypiperidin-1-yl. In other embodiments, R.sup.3
is C.sub.1-4 alkyl substituted with R.sup.q.
[0192] In some embodiments of compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.3 is C.sub.1-4 alkoxy
substituted with R.sup.d. In certain embodiments, R.sup.d is
phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of
which is optionally substituted with 1, 2 or 3 R.sup.q
substituents.
[0193] In some embodiments of compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.3 is --OCH.sub.2R.sup.d. In
certain embodiments, R.sup.d is phenyl, 3-cyanophenyl, 3-pyridyl,
2-pyridyl, 4-pyridyl, each of which is optionally substituted with
1, 2 or 3 R.sup.q substituents.
[0194] In some embodiments of compounds of Formula I', I, II, III,
III, IV, V, VI, VII, VIII, or IX, R.sup.3 is
2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl,
2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl,
(S)-2-carboxypiperidin-1-ylmethyl,
(R)-2-carboxypiperidin-1-ylmethyl, 2-carboxypiperidin-1-ylmethyl,
benzyloxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,
2-pyridylmethoxy, 3-pyridylmethoxy, or 4-pyridylmethoxy, each of
which is optionally substituted with 1, 2 or 3 R.sup.q
substituents. In certain embodiments, R.sup.3 is
2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl,
(S)-2-carboxypiperidin-1-ylmethyl,
(R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy, each of
which is optionally substituted with 1, 2 or 3 R.sup.q
substituents.
[0195] In some embodiments of compounds of Formula I, II, III, V,
or VII, R.sup.8 is H, halo, CN, N(C.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl or C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and
C.sub.1-6 alkoxy are each optionally substituted with 1-3 R.sup.q
substituents. In some embodiments of compounds of Formula I', VIII,
or IX, R.sup.8a, R.sup.8b and R.sup.8c are each independently
selected from H, halo, CN, N(C.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl and C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and
C.sub.1-6 alkoxy are each optionally substituted with 1-3 R.sup.q
substituents.
[0196] In some embodiments of compounds of Formula I, II, III, V or
VII, R.sup.8 is H, halo, CN, N(CH.sub.3).sub.2 or CH.sub.3. In some
embodiments of compounds of Formula I', VIII, or IX, R.sup.8a,
R.sup.8b and R.sup.8c are each independently selected from H, halo,
CN, N(CH.sub.3).sub.2 and CH.sub.3.
[0197] 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.
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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.
[0202] 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.
[0203] The term "alkyl," employed alone or in combination with
other terms, refers to a saturated hydrocarbon group that may be
straight-chained or branched. The term "C.sub.n-m alkyl," refers to
an alkyl group having n to m carbon atoms. An alkyl group formally
corresponds to an alkane with one C--H bond replaced by the point
of attachment of the alkyl group to the remainder of the compound.
In some embodiments, the alkyl group contains from 1 to 6 carbon
atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to
2 carbon atoms. Examples of alkyl moieties include, but are not
limited to, chemical groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher
homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,
1,2,2-trimethylpropyl and the like.
[0204] 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.
[0205] 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.
[0206] 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.
[0207] 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.
[0208] The term "alkylthio," employed alone or in combination with
other terms, refers to a group of formula --S-alkyl, wherein the
alkyl group is as defined above. The term "C.sub.n-m alkylthio"
refers to an alkylthio group, the alkyl group of which has n to m
carbons. Example alkylthio groups include methylthio, ethylthio,
etc. In some embodiments, the alkyl group of the alkylthio group
has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0209] The term "amino," employed alone or in combination with
other terms, refers to a group of formula --NH.sub.2.
[0210] 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).
[0211] The term "cyano" or "nitrile" refers to a group of formula
--C.ident.N, which also may be written as --CN.
[0212] 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.
[0213] The term "haloalkyl," employed alone or in combination with
other terms, 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-m haloalkyl" refers to a C.sub.n-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.
[0214] 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.
[0215] 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.
[0216] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0217] 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).
[0218] 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.
[0219] 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, pyridinyl (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.
[0220] 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.
[0221] 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.
[0222] 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, norbomyl,
norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl,
and the like. In some embodiments, the cycloalkyl group is
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0223] 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 quatemized. 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.
[0224] The term "arylalkyl," employed alone or in combination with
other terms, refers to an aryl-(alkylene)- group where aryl and
alkylene are as defined herein. An example arylalkyl group is
benzyl.
[0225] The term "heteroarylalkyl," employed alone or in combination
with other terms, refers to an heteroaryl-(alkylene)- group, where
heteroaryl and alkylene are as defined herein. An example
heteroarylalkyl group is pyridylmethyl.
[0226] The term "cycloalkylalkyl," employed alone or in combination
with other terms, refers to a cycloalkyl-(alkylene)- group, where
cycloalkyl and alkylene are as defined herein. An example
cycloalkylalkyl group is cyclopropylmethyl.
[0227] The term "heterocycloalkylalkyl," employed alone or in
combination with other terms, refers to a
heterocycloalkyl-(alkylene)- group, where heterocycloalkyl and
alkylene are as defined herein. An example heterocycloalkylalkyl
group is azetidinylmethyl.
[0228] 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.
[0229] 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.
[0230] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. One method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are,
e.g., optically active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,
malic acid, lactic acid or the various optically active
camphorsulfonic acids such as .beta.-camphorsulfonic acid. Other
resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of .alpha.-methylbenzylamine
(e.g., S and R forms, or diastereomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,
cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
[0231] 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.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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.
[0236] 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.
[0237] 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.
[0238] 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.
[0239] 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.
[0240] 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
[0241] 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.
[0242] 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.
[0243] 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).
[0244] 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).
[0245] 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.
[0246] Compounds of the invention of formula 8 can be synthesized
using a process shown in Scheme 1. In Scheme 1, a suitable halo
(Hal.sup.1)-substituted aromatic amine 1 can react with a suitable
coupling reagent 2 (where M is, e.g., --B(OH).sub.2) to produce
compound 3 under standard metal catalyzed cross-coupling reaction
conditions (such as Suzuki coupling reaction, e.g., in the presence
of a palladium catalyst (e.g.,
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a
base (e.g., a bicarbonate or a carbonate base)). Then the aromatic
amine 3 can selectively react with the halo group (Hal.sup.2) of
compound 4 under suitable S.sub.NAr conditions (such as acid
catalyzed, e.g., in the presence of HCl; or uncatalyzed) or
standard coupling reaction conditions (such as Buchwald-Hartwig
amination, e.g., in the presence of a palladium catalyst (e.g.,
[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphe-
nyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) and
a base (e.g., a carbonate or butoxide base)) forming compound 5.
The compound of formula 6 can be synthesized by coupling the halo
group (Hal.sup.3) of 5 with a vinyl reagent (e.g., vinyl boronic
acid pinacol ester) under standard coupling reaction conditions
(such as Suzuki coupling reaction, e.g., in the presence of a
palladium catalyst (e.g.,
1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II)) and
a base (e.g., a bicarbonate or a carbonate base)). The vinyl group
in compound 6 can be oxidatively cleaved to afford an aldehyde of
formula 7 in the presence of suitable reagents such as, but not
limited to, OsO.sub.4 and NaIO.sub.4. Then the compounds of formula
8 can be obtained by a reductive amination between the compound of
formula 7 and amine HN(R.sup.c).sub.2 in an appropriate solvent
such as THF or DCM using a reducing agent such as, but not limited
to, sodium triacetoxyborohydride, optionally in the presence of a
base such as DIPEA.
##STR00021##
[0247] Compounds of the invention of formula 8 can be alternatively
synthesized using a process shown in Scheme 2. The aromatic amine 3
can react with the halo (Hal.sup.4) of formula 9 under standard
coupling reaction conditions (such as Buchwald-Hartwig amination,
e.g., in the presence of a palladium catalyst (e.g.,
[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphe-
nyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) and
a base (e.g., a carbonate or butoxide base)). Subsequent reduction
of the carboxylic acid group in compound 10 can give an alcohol of
formula 11 using a suitable reducing agent such as, but not limited
to, lithium aluminum hydride. The alcohol unit in compound 11 can
be oxidized to give the aldehyde 7 with a suitable oxidant such as,
but not limited to, Dess-Martin periodinane. Then the compounds of
formula 8 can be obtained from compound 7 using similar conditions
as shown in Scheme 1.
##STR00022##
[0248] Compounds of the invention of formula 16 can be synthesized
using a process shown in Scheme 3. In Scheme 3, the aromatic amine
3 can selectively react with the halo group (Hal.sup.5) of compound
12 under suitable S.sub.NAr conditions (acid catalyzed, e.g., in
the presence of HCl; or uncatalyzed) or standard coupling reaction
conditions (such as Buchwald-Hartwig amination, e.g., in the
presence of a palladium catalyst (e.g.,
[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1-
'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)
methanesulfonate) and a base (e.g., a carbonate or butoxide base))
to give compound 13. The compound of formula 14 can be synthesized
by coupling the halo group (Hal.sup.6) of 13 with a vinyl reagent
(e.g., vinyl boronic acid pinacol ester) under standard coupling
reaction conditions (such as Suzuki coupling reaction, e.g., in the
presence of a palladium catalyst (e.g.,
1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II)) and
a base (e.g., a bicarbonate or a carbonate base)). The vinyl group
in compound 14 can be oxidatively cleaved to afford an aldehyde of
formula 15 in the presence of suitable reagents such as, but not
limited to, OsO.sub.4 and NaIO.sub.4. Then the compounds of formula
16 can be obtained by a reductive amination between the compound of
formula 15 and amine HN(R.sup.c).sub.2 in a proper solvent such as
THF or DCM using a reducing agent such as, but not limited to,
sodium triacetoxyborohydride, optionally in the presence of a base
such as DIPEA.
##STR00023##
[0249] Compounds of Formula 21 can be prepared using procedures as
outlined in Scheme 4. The aromatic amines of Formula 17 can
selectively react with the halo group (Hal.sup.7) of compound 18
under suitable S.sub.NAr conditions (acid catalyzed, e.g., in the
presence of HCl; or uncatalyzed) or suitable selective coupling
reaction conditions (such as Buchwald-Hartwig amination, e.g., in
the presence of a palladium catalyst (e.g.,
[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1-
'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)
methanesulfonate) and a base (e.g., a carbonate or butoxide base))
to give compounds of Formula 19. The halide (Hal.sup.8) in
compounds Formula 19 can be coupled to compounds of Formula 20, 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 21. Alternatively,
compound Formula 20 can be a cyclic amine (where M is H and
attached to an amine nitrogen in ring Cy) and the coupling of aryl
halide of Formula 19 with the cyclic amine of Formula 18 can be
performed under suitable Buchwald-Hartwig amination conditions
(e.g., in the presence of a palladium catalyst and a base such as
sodium tert-butoxide).
##STR00024##
[0250] Alternatively, compounds of Formula 21 can be prepared using
reaction sequences as outlined in Scheme 5. Coupling of aromatic
halides of Formula 17 with compounds of Formula 20 can be achieved
using similar conditions as described in Scheme 4 (e.g. conditions
used for coupling of compounds of Formula 19 with compounds of
Formula 20) to give aromatic amines of Formula 22, which can react
with the halo group (Hal.sup.7) of compounds of Formula 18 under
suitable S.sub.NAr conditions or suitable selective coupling
reaction conditions as described in Scheme 4 to give compounds of
Formula 21.
##STR00025##
III. Uses of the Compounds
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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.
[0264] 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
[0265] 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.
[0266] 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, PDGFatR,
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.
[0267] 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.
[0268] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0269] 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.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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).
[0276] 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.
[0277] Other anti-cancer agent(s) include antibody therapeutics
such as trastuzumab (Herceptin), antibodies to costimulatory
molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to
PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-.beta.,
etc.). Examples of antibodies to PD-1 and/or PD-L1 that can be
combined with compounds of the present disclosure for the treatment
of cancer or infections such as viral, bacteria, fungus and
parasite infections include, but are not limited to, nivolumab,
pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
[0278] In some embodiments, the anti-cancer 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).
[0279] 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, stereoisomers thereof can be used in
combination with an immune checkpoint inhibitor for the treatment
of cancer and viral infections.
[0280] 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.
[0281] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0282] 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.
[0283] 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.
[0284] 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.
[0285] 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.
[0286] 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.
[0287] 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.
[0288] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] 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.
[0294] 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.
[0295] 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.
[0296] 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.
[0297] 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.
[0298] 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
[0299] 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.
[0300] 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.
[0301] 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.
[0302] 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.
[0303] 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.
[0304] 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.
[0305] 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.).
[0306] 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.
[0307] 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.
[0308] 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.
[0309] 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.
[0310] 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.
[0311] 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.
[0312] 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.
[0313] 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.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] 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.
[0318] 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
[0319] 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.
[0320] 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
.sup.11C, .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.
[0321] 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
[0322] 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.
[0323] 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
[0324] 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-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methyl)amino]ethanol
##STR00026##
[0325] Step 1: 2-methylbiphenyl-3-amine
##STR00027##
[0327] A mixture of 3-bromo-2-methylaniline (Aldrich, cat#530018:
0.39 mL, 3.2 mmol), phenylboronic acid (Aldrich, cat#P20009: 0.50
g, 4.1 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#697230: 0.13 g, 0.16 mmol) and potassium carbonate
(1.32 g, 9.57 mmol) in 1,4-dioxane (20.0 mL) and water (7 mL) was
sparged with nitrogen for 5 min. The mixture was then heated and
stirred at 110.degree. C. for 1.5 h. The reaction mixture was
cooled to room temperature, quenched with saturated aqueous
NaHCO.sub.3, and extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on a silica gel column
eluting with ethyl acetate in hexanes (0.fwdarw.15%) to afford the
desired product. LC-MS calculated for C.sub.13H.sub.14N
(M+H).sup.+: m/z=184.1; found 184.1. .sup.1H NMR (400 MHz, DMSO)
.delta. 7.40 (dd, J=7.6, 6.8 Hz, 2H), 7.32 (dd, J=7.6, 7.2 Hz, 1H),
7.29-7.14 (m, 2H), 6.92 (dd, J=7.6, 7.6 Hz, 1H), 6.64 (d, J=7.2 Hz,
1H), 6.40 (d, J=7.2 Hz, 1H), 4.89 (s, 2H), 1.92 (s, 3H).
Step 2: 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carboxylic
acid
##STR00028##
[0329] To a vial was added racemic
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (Aldrich,
cat#481084: 30 mg, 0.05 mmol), 2-methylbiphenyl-3-amine (262 mg,
1.43 mmol), ethyl 8-bromoquinoline-3-carboxylate (Ark Pharm,
cat#AK-47201: 0.200 g, 0.714 mmol),
bis(dibenzylideneacetone)palladium(0) (Aldrich, cat#227994: 0.012
g, 0.021 mmol) and sodium tert-butoxide (Aldrich, cat#359270: 96.7
mg, 1.01 mmol). Toluene (3.6 mL) was added and the reaction mixture
was sparged for 5 min with nitrogen then sealed and heated at
130.degree. C. for 18 h. The reaction mixture was cooled, and
concentrated in vacuo. The resulting residue was used directly in
the next step without further purification. LC-MS calculated for
C.sub.23H.sub.19N.sub.2O.sub.2 (M+H).sup.+: m/z=355.1; found
355.4.
Step 3: {8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methanol
##STR00029##
[0331] To a solution of
8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carboxylic acid (253
mg, 0.714 mmol) in THF (3.6 mL) was added 1.0 M lithium
tetrahydroaluminate in THF (2.14 mL, 2.14 mmol) at -78.degree. C.
The resulting mixture was warmed to room temperature, and stirred
for 18 h. The mixture was cooled to 0.degree. C. and quenched using
the Fieser workup: water (80 .mu.L) was added, followed by 1 N NaOH
(240 .mu.L), and then water (80 .mu.L) was added again and the
mixture was then stirred for 1 h at room temperature. The resulting
slurry was diluted with ethyl acetate (10 mL), filtered over
Celite, and washed with water. The organic extract was then washed
with brine, dried over sodium sulfate, filtered, then concentrated
in vacuo. The resulting residue was purified by silica gel
chromatography (0.fwdarw.40% ethyl acetate/hexanes). LC-MS
calculated for C.sub.23H.sub.21N.sub.2O (M+H).sup.+: m/z=341.1;
found 341.2.
Step 4:
8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde
##STR00030##
[0333] To a solution of
{8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methanol (83.0 mg,
0.244 mmol) in methylene chloride (1.0 mL) at 0.degree. C. was
added Dess-Martin periodinane (Aldrich, cat#274623: 103 mg, 0.244
mmol). The mixture was stirred for 10 min at 0.degree. C. then
quenched at 0.degree. C. with aqueous saturated sodium thiosulfate.
The mixture was extracted with methylene chloride (3.times.10 mL).
The organic extract was then washed with aqueous saturated sodium
bicarbonate, water, then brine. The organic extract was dried over
sodium sulfate and concentrated in vacuo. The desired aldehyde was
purified by column chromatography (0 to 20% EtOAc/hexanes). LC-MS
calculated for C.sub.23H.sub.19N.sub.2O (M+H).sup.+: m/z=339.1;
found 339.3.
Step 5:
2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methyl)amino]et-
hanol
[0334] A mixture of
8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde (19 mg,
0.056 mmol) and ethanolamine (Aldrich, cat#398136: 10 .mu.L, 0.167
mmol) in methylene chloride (0.4 mL) and N,N-diisopropylethylamine
(58.1 .mu.L, 0.333 mmol) was stirred at room temperature for 1 h
then sodium triacetoxyborohydride (0.0353 g, 0.167 mmol) was
carefully added. The reaction mixture was stirred at room
temperature for 24 h. The mixture was concentrated, dissolved in
methanol then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)
to give the desired product as the TFA salt. LC-MS calculated for
C.sub.25H.sub.26N.sub.3O (M+H).sup.+: m/z=384.2; found 384.2.
.sup.1H NMR (400 MHz, DMSO) .delta. 9.06 (s, 2H), 8.94 (d, J=2.0
Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.54-7.22 (m, 8H),
7.06 (d, J=7.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 5.18 (brs, 1H),
4.43 (t, J=5.2 Hz, 2H), 3.70 (t, J=5.2 Hz, 2H), 3.08 (brs, 2H),
2.14 (s, 3H).
Example 2
2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]e-
thanol
##STR00031##
[0335] Step 1: 3-bromo-N-(2-methylbiphenyl-3-yl)-1,
7-naphthyridin-8-amine
##STR00032##
[0337] To a microwave vial was added 2-methylbiphenyl-3-amine
(Example 1, Step 1: 0.1 g, 0.546 mmol),
3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 140
mg, 0.55 mmol), tert-butyl alcohol (2.5 mL) and 4.0 M hydrogen
chloride in dioxane (0.136 mL, 0.546 mmol). The resulting mixture
was irradiated in the microwave to 100.degree. C. for 1 h. The
resulting mixture was concentrated, and the desired product was
used directly in the next step. LC-MS calculated for
C.sub.21H.sub.17N.sub.3Br (M+H).sup.+: m/z=390.1; found 390.1.
Step 2: N-(2-methylbiphenyl-3-yl)-3-vinyl-1,
7-naphthyridin-8-amine
##STR00033##
[0339] A mixture of
3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine (213 mg,
0.546 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane
(Aldrich, cat#633348: 0.185 mL, 1.09 mmol), and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#701998: 4 mg, 0.005 mmol) in tert-butyl alcohol (3.93
mL) and water (4 mL) was sparged with nitrogen then sealed. It was
stirred at 110.degree. C. for 2 h. The reaction mixture was cooled
then extracted with ethyl acetate (3.times.10 mL). The combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The crude product
was used directly in the next step without purification. LC-MS
calculated for C.sub.23H.sub.20N.sub.3(M+H).sup.+: m/z=338.2; found
338.1.
Step 3: 8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridine-3-carbaldehyde
##STR00034##
[0341] To a solution of
N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine (184 mg,
0.55 mmol) in 1,4-dioxane (11 mL) and water (11 mL) was added a 4
wt % solution of osmium tetraoxide in water (0.52 mL, 0.082 mmol).
The mixture was stirred for 5 min then sodium periodate (467 mg,
2.18 mmol) was added and stirred for 1 h. The mixture was diluted
with ethyl acetate (10 mL), and the phases were separated. The
aqueous layer was extracted with ethyl acetate (10 mL) and the
combined organic layers were washed with water, then brine and were
dried over sodium sulfate. The extract was filtered then
concentrated in vacuo. The desired aldehyde was purified by silica
gel chromatography (0.fwdarw.40% EtOAc/hexanes). LC-MS calculated
for C.sub.22H.sub.18N.sub.3O (M+H).sup.+: m/z=340.1; found
340.1.
Step 4: 2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)amino]ethanol
[0342] This compound was prepared using a similar procedure as
described for Example 1, Step 5, with
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde
(Step 3) replacing
8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde. The
reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.24H.sub.25N.sub.4O (M+H).sup.+:
m/z=385.2; found 385.2. .sup.1H NMR (400 MHz, DMSO) .delta. 9.24
(s, 2H), 9.10 (s, 1H), 8.50 (s, 1H), 7.88 (d, J=2.8 Hz, 2H),
7.52-7.35 (m, 6H), 7.28-7.18 (m, 2H), 5.02 (brs, 1H), 4.49 (s, 2H),
3.71 (t, J=5.2 Hz, 2H), 3.11 (s, 2H), 2.18 (s, 3H).
Example 3
1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidi-
ne-2-carboxylic acid
##STR00035##
[0343] Step 1: methyl 1-((8-(2-methylbiphenyl-3-ylamino)-1,
7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate
##STR00036##
[0345] A mixture of
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde
(Example 2, Step 3: 65 mg, 0.19 mmol) and methyl pipecolinate
hydrochloride (Aldrich, cat#391204: 100 mg, 0.574 mmol) in
methylene chloride (2 mL) and N,N-diisopropylethylamine (200 .mu.L,
1.15 mmol) was stirred at room temperature for 1 h. Sodium
triacetoxyborohydride (0.0353 g, 0.167 mmol) was carefully added
and the mixture was stirred at room temperature for 24 h. The
reaction mixture was quenched with saturated sodium bicarbonate
solution, and the organic layer was separated. The aqueous layer
was further extracted with methylene chloride (2.times.10 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. The desired product was obtained as an
oil and was used in the next step without further purification.
LC-MS calculated for C.sub.29H.sub.31N.sub.4O.sub.2 (M+H).sup.+:
m/z=467.2; found 467.2.
Step 2: 1-({8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)piperidine-2-carboxylic acid
[0346] To a mixture of methyl
1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidin-
e-2-carboxylate (88 mg, 0.19 mmol), tetrahydrofuran (0.66 mL),
methanol (0.66 mL), and water (0.33 mL) was added lithium hydroxide
(275 mg, 11.5 mmol). The resulting mixture was heated at 65.degree.
C. overnight. The mixture was cooled to room temperature, then
adjusted to pH=1-2 with 1N HCl 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.28H.sub.29N.sub.4O.sub.2
(M+H).sup.+: m/z=453.2; found 453.2. .sup.1H NMR (400 MHz, MeOD)
.delta. 9.21 (d, J=1.8 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 7.61 (d,
J=7.0 Hz, 1H), 7.57-7.36 (m, 8H), 7.33 (d, J=7.0 Hz, 1H), 4.80 (m,
1H), 4.39 (d, J=13.4 Hz, 1H), 3.90 (d, J=10.4 Hz, 1H), 3.48 (m,
1H), 3.16-3.00 (m, 1H), 2.34 (d, J=13.4 Hz, 1H), 2.22 (s, 3H),
1.96-1.55 (m, 6H).
Example 4
1-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}methyl)pip-
eridine-2-carboxylic acid
##STR00037##
[0348] Step 1:
7-bromo-N-(2-methylbiphenyl-3-yl)pyrido[3,2-d]pyrimidin-4-amine
##STR00038##
[0349] To a vial was added 2-methylbiphenyl-3-amine (Example 1,
Step 1: 0.4 g, 2.18 mmol), 7-bromo-4-chloropyrido[3,2-d]pyrimidine
(Ark Pharm, cat#AK-27560: 540 mg, 2.2 mmol), and isopropyl alcohol
(10. mL) The mixture was heated to 110.degree. C. for 4 h. The
mixture was cooled to room temperature, concentrated, and the crude
product was used directly in the next step without further
purification. LC-MS calculated for C.sub.20H.sub.16BrN.sub.4
(M+1).sup.+: m/z=391.1; found 391.1.
Step 2: N-(2-methylbiphenyl-3-yl)-7-vinylpyrido[3,
2-d]pyrimidin-4-amine
##STR00039##
[0351] This compound was prepared using a similar procedure as
described for Example 2, Step 2, with
7-bromo-N-(2-methylbiphenyl-3-yl)pyrido[3,2-d]pyrimidin-4-amine
(Step 1) replacing
3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine. The
crude product was used directly in the next step without further
purification. LC-MS calculated for
C.sub.22H.sub.19N.sub.4(M+1).sup.+: m/z=339.2; found 339.2.
Step 3:
4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidine-7-carbalde-
hyde
##STR00040##
[0353] This compound was prepared using a similar procedure as
described for Example 2, Step 3, with
N-(2-methylbiphenyl-3-yl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine
replacing
N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine. The
reaction mixture was stirred at room temperature for 18 h, and then
was diluted with ethyl acetate (10 mL). The organic layer was
separated and the aqueous layer was further extracted with ethyl
acetate (2.times.10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. The crude product was used directly in the next step
without further purification. LC-MS calculated for
C.sub.21H.sub.17N.sub.4O (M+1).sup.+: m/z=341.1; found 341.1.
Step 4: methyl 1-((4-(2-methylbiphenyl-3-ylamino)pyrido[3,
2-d]pyrimidin-7-yl)methyl)piperidine-2-carboxylate
##STR00041##
[0355] This compound was prepared using a similar procedure as
described for Example 3, Step 1 with
4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidine-7-carbaldehyde
(Step 3) replacing
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.
The crude product was used directly in the next step without
further purification. LC-MS calculated for C.sub.28H.sub.30N.sub.5
O.sub.2 (M+1).sup.+: m/z=468.2; found 468.2.
Step 5:
1-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}me-
thyl)piperidine-2-carboxylic acid
[0356] This compound was prepared using a similar procedure as
described for Example 3, Step 2, with methyl
1-((4-(2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pipe-
ridine-2-carboxylate (Step 4) replacing methyl
1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidin-
e-2-carboxylate. The crude product was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.27H.sub.28N.sub.5O.sub.2
(M+H).sup.+: m/z=454.2; found 454.3.
Example 5
1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)piperidi-
ne-2-carboxylic acid
##STR00042##
[0358] Step 1: 4-chloro-N-(2-methylbiphenyl-3-yl)-1,
7-naphthyridin-8-amine
##STR00043##
[0359] To a vial was added 2-methylbiphenyl-3-amine (Example 1,
Step 1: 0.2 g, 1.09 mmol), 4,8-dichloro-1,7-naphthyridine
(Synthonix, cat#D7291: 180 mg, 0.91 mmol), and isopropyl alcohol (4
mL). The mixture was heated to 100.degree. C. for 4 h. The mixture
was concentrated, and the crude product was used directly in the
next step. LC-MS calculated for C.sub.21H.sub.17ClN.sub.3
(M+1).sup.+: m/z=346.1; found 346.1.
Step 2: N-(2-methylbiphenyl-3-yl)-4-vinyl-1,
7-naphthyridin-8-amine
##STR00044##
[0361] This compound was prepared using a similar procedure as
described for Example 2, Step 2, with
4-chloro-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine (Step
1) replacing
3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine. The
crude product was used directly in the next step without further
purification. LC-MS calculated for C.sub.23H.sub.20N.sub.3
(M+1).sup.+: m/z=338.2; found 338.2.
Step 3: 8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridine-4-carbaldehyde
##STR00045##
[0363] This compound was prepared using a similar procedure as
described for Example 2, Step 3, with
N-(2-methylbiphenyl-3-yl)-4-vinyl-1,7-naphthyridin-8-amine (Step 2)
replacing
N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine. The
reaction mixture was stirred at room temperature for 18 h, and then
was diluted with ethyl acetate (10 mL). The organic layer was
separated and the aqueous layer was further extracted with ethyl
acetate (2.times.10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. The crude product was purified by silica gel
chromatography (0.fwdarw.50% EtOAc/hexanes). LC-MS calculated for
C.sub.22H.sub.18N.sub.3O (M+1).sup.+: m/z=340.1; found 340.2.
Step 4: methyl 1-((8-(2-methylbiphenyl-3-ylamino)-1,
7-naphthyridin-4-yl)methyl)piperidine-2-carboxylate
##STR00046##
[0365] This compound was prepared using a similar procedure as
described for Example 3, Step 1, with
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-4-carbaldehyde
(Step 3) replacing
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.
The crude product was used directly in the next step without
further purification. LC-MS calculated for C.sub.29H.sub.31N.sub.4
O.sub.2 (M+1).sup.+: m/z=467.2; found 467.2.
Step 5: 1-({8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-4-yl}methyl)piperidine-2-carboxylic acid
[0366] This compound was prepared using a similar procedure as
described for Example 3, Step 2, with methyl
1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-4-yl)methyl)piperidin-
e-2-carboxylate replacing methyl
1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidin-
e-2-carboxylate. The crude product 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.29N.sub.4O.sub.2
(M+H).sup.+: m/z=453.2; found 453.2. .sup.1H NMR (400 MHz, MeOD)
.delta. 9.11 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz, 1H), 7.94 (d,
J=7.2 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.55-7.37 (m, 8H), 4.73 (d,
J=13.8 Hz, 1H), 4.16 (d, J=13.8 Hz, 1H), 3.66-3.48 (m, 1H), 3.12
(m, 1H), 2.71 (m, 1H), 2.24 (s, 3H), 2.20 (m, 1H) 1.94-1.52 (m,
6H).
Example 6
2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)amino]e-
thanol
##STR00047##
[0368] A mixture of
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-4-carbaldehyde
(Example 5, Step 3: 0.022 g, 0.065 mmol) and ethanolamine in
methylene chloride (1.00 mL) and N,N-diisopropylethylamine (67.7
.mu.L, 0.389 mmol) was stirred at 50.degree. C. for 1 h then sodium
triacetoxyborohydride (0.0412 g, 0.194 mmol) was carefully added.
The reaction was stirred at 50.degree. C. for 12 h. The mixture was
cooled to room temperature, and then concentrated in vacuo. The
residue was dissolved in 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.24H.sub.25N.sub.4O (M+H).sup.+:
m/z=385.2; found 385.2. .sup.1H NMR (400 MHz, DMSO) .delta. 9.19
(s, 2H), 9.05 (d, J=4.8 Hz, 1H), 8.20-8.02 (m, 2H), 7.97 (d, J=3.6
Hz, 1H), 7.48 (dd, J=7.6, 7.2 Hz, 2H), 7.44-7.32 (m, 4H), 7.09 (m,
1H), 5.32 (brs, 1H), 4.69 (m, 2H), 3.86-3.67 (m, 2H), 3.19 (m, 2H),
2.21 (s, 3H).
Example 7
2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)amino]ethanol
##STR00048##
[0370] Step 1:
8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde
##STR00049##
[0371] A mixture of 8-bromoquinoline-4-carbaldehyde (Oakwood
Chemical, cat#042977: 100.0 mg, 0.4236 mmol),
2-methylbiphenyl-3-amine (Example 1, Step 1: 77.6 mg, 0.424 mmol),
[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphe-
nyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate
(Aldrich, cat#761605: 58 mg, 0.064 mmol) and cesium carbonate
(0.690 g, 2.12 mmol) in tert-butyl alcohol (10.0 mL) was purged
with nitrogen, and then stirred at 100.degree. C. for 2 h. The
mixture was cooled to room temperature, diluted with ethyl acetate
and water. The layers were separated and the organic layer was
washed with brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (0.fwdarw.50% EtOAc/hexanes). LC-MS calculated for
C.sub.23H.sub.19N.sub.2O (M+H).sup.+: m/z=339.1; found 339.2.
Step 2:
2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)amino]et-
hanol
[0372] This compound was prepared using a similar procedure as
described for Example 1, Step 5, with
8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde (Step 1)
replacing 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde.
The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.25H.sub.26N.sub.3O (M+H).sup.+:
m/z=384.2; found 384.2. .sup.1H NMR (400 MHz, DMSO) .delta. 9.13
(s, 2H), 8.94 (d, J=4.4 Hz, 1H), 8.43 (s, 1H), 7.73 (d, J=4.4 Hz,
1H), 7.60-7.43 (m, 4H), 7.44-7.23 (m, 4H), 7.10-6.99 (m, 2H), 5.32
(brs, 1H), 4.73 (m, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.21 (s, 2H), 2.15
(s, 3H).
Example 8
1-({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)piperidine-2-carb-
oxylic acid
##STR00050##
[0373] Step 1: methyl
1-((8-(2-methylbiphenyl-3-ylamino)quinolin-4-yl)methyl)piperidine-2-carbo-
xylate
##STR00051##
[0375] This compound was prepared using a similar procedure as
described for Example 3, Step 1, with
8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde (Example
7, Step 1) replacing
8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.
The crude product was used directly in the next step without
further purification. LC-MS calculated for
C.sub.30H.sub.32N.sub.3O.sub.2 (M+H).sup.+: m/z=466.2; found
466.2.
Step 2:
1-({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)piperidin-
e-2-carboxylic acid
[0376] This compound was prepared using a similar procedure as
described for Example 3, Step 2, with methyl
1-((8-(2-methylbiphenyl-3-ylamino)quinolin-4-yl)methyl)piperidine-2-carbo-
xylate (Step 1) replacing methyl
1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidin-
e-2-carboxylate. The crude product 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.29H.sub.30N.sub.3O.sub.2
(M+H).sup.+: m/z=452.2; found 452.3. .sup.1H NMR (400 MHz, MeOD)
.delta. 8.93 (d, J=4.4 Hz, 1H), 7.77 (d, J=4.4 Hz, 1H), 7.71 (d,
J=8.4 Hz, 1H), 7.58 (dd, J=8.0, 7.8 Hz, 1H), 7.50-7.43 (m, 4H),
7.40-7.30 (m, 4H), 7.11 (dd, J=15.2, 7.8 Hz, 2H), 5.14 (d, J=12.8
Hz, 1H), 4.65 (m, 1H), 4.16 (d, J=11.2 Hz, 1H), 3.25-3.13 (m, 1H),
2.42 (d, J=11.2 Hz, 1H), 2.20 (s, 3H), 2.02-1.62 (m, 6H).
Example 9
2-[({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methy-
l)amino]ethanol
##STR00052##
[0378] Step 1: diethyl
{[(2-chloropyridin-3-yl)amino]methylene}malonate
##STR00053##
[0379] 3-Amino-2-chloropyridine (Aldrich, cat#A46900: 5.71 g, 44.4
mmol) and (ethoxymethylene)propanedioic acid, diethyl ester (Alfa
Aesar, cat#A13776: 9.013 mL, 44.6 mmol) were combined in a vial
with a stir bar and heated at 120.degree. C. for 5 h. The resulting
mixture was concentrated and washed with hexanes to provide the
desired compound as a beige solid. LC-MS calculated for
C.sub.13H.sub.16ClN.sub.2O.sub.4(M+H).sup.+: m/z=299.1; found
299.1.
Step 2: ethyl 8-chloro-4-oxo-1, 4-dihydro-1,
7-naphthyridine-3-carboxylate
##STR00054##
[0381] A three-neck flask was charged with diethyl
{[(2-chloropyridin-3-yl)amino]methylene}malonate (6.39 g, 21.4
mmol), a stir bar, and diphenyl ether (Aldrich, cat#240834: 102
mL). The mixture was degassed for 10 min by bubbling nitrogen
through the solution. A Vigreux reflux condenser and temperature
probe were then equipped and the internal temperature of the
reaction was heated to 240-250.degree. C. for 1 h. The reaction was
then allowed to cool, and hexanes were added to precipitate the
product. The mixture was then filtered and the precipitate was
washed with hexanes. The solid was dried further using high vacuum
and used directly in the next step without further purification.
LC-MS calculated for C.sub.11H.sub.10ClN.sub.2O.sub.3(M+H).sup.+:
m/z=253.0; found 253.1.
Step 3: ethyl 8-(2-methylbiphenyl-3-ylamino)-4-oxo-1, 4-dihydro-1,
7-naphthyridine-3-carboxylate
##STR00055##
[0383] To a vial was added 2-methylbiphenyl-3-amine (Example 1,
Step 1: 0.457 g, 2.49 mmol), ethyl
8-chloro-4-hydroxy-1,7-naphthyridine-3-carboxylate (630 mg, 2.5
mmol), cesium carbonate (2.44 g, 7.48 mmol), Brettphos-Pd-G3
precatalyst (Aldrich, cat#761605: 339 mg, 0.374 mmol), then
tert-butyl alcohol (21 mL). The mixture was sparged with nitrogen
for 2 min, then sealed and heated at 100.degree. C. for 2 h. After
cooling to rt, the mixture was filtered and the solid was washed
with ethyl acetate. The filtrate was concentrated in vacuo and
purified by column chromatography (0-20% MeOH/DCM). LC-MS
calculated for C.sub.24H.sub.22N.sub.3O.sub.3 (M+H)+: m/z=400.2;
found 400.2.
Step 4: ethyl
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carboxylate
##STR00056##
[0385] A flask equipped with a Vigreux reflux condenser was charged
with ethyl
8-(2-methylbiphenyl-3-ylamino)-4-oxo-1,4-dihydro-1,7-naphthyridine--
3-carboxylate (0.480 g, 1.20 mmol), a stir bar, and phosphoryl
chloride (13 mL, 140 mmol). The mixture was stirred at 110.degree.
C. for 1 h. The mixture was concentrated in vacuo and the remaining
phosphoryl chloride was quenched with ice and slow addition of
saturated sodium bicarbonate solution. DCM was added to the
mixture, and the layers were separated. The aqueous layer was
further extracted with DCM, and the combined organic extracts were
dried over sodium sulfate, filtered, and concentrated in vacuo. The
crude residue was purified by column chromatography (0.fwdarw.40%
EtOAc/hexanes). LC-MS calculated for
C.sub.24H.sub.21ClN.sub.3O.sub.2(M+H).sup.+: m/z=418.1; found
418.2.
Step 5: {4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methanol
##STR00057##
[0387] To a solution of ethyl
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carboxylate
(0.550 g, 1.32 mmol) in tetrahydrofuran (13.8 mL, 1.70E2 mmol) was
added 1.0 M lithium tetrahydroaluminate in THF (1.32 mL, 1.32 mmol)
at -78.degree. C. dropwise. After addition, the reaction was
stirred at this temperature for 30 min. The reaction was carefully
quenched by adding aqueous saturated ammonium chloride, then
aqueous saturated Rochelle's salt was added and stirred for 1 h.
The mixture was diluted with EtOAc, and the layers were separated.
The aqueous layer was further extracted with EtOAc, and the
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. The crude solid was used directly in the
next step as a mixture of the title compound and the corresponding
aldehyde. LC-MS calculated for C.sub.22H.sub.19ClN.sub.3O
(M+H).sup.+: m/z=376.1; found 376.2.
Step 6:
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carb-
aldehyde
##STR00058##
[0389] To a solution of
{4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methanol
(464.0 mg, 1.234 mmol) in methylene chloride (11 mL) at 0.degree.
C. was added Dess-Martin periodinane (549.8 mg, 1.296 mmol). The
mixture was stirred for 1 h at 0.degree. C. The reaction was
quenched at this temperature with aqueous saturated sodium
thiosulfate, and the layers were separated. The aqueous layer was
further extracted with methylene chloride. The combined organic
layers were washed with sodium bicarbonate, water, and brine and
were dried over sodium sulfate, filtered, and concentrated in
vacuo. The crude residue was purified by chromatography using a pad
of silica gel (0.fwdarw.1:1 EtOAc/hexanes). LC-MS calculated for
C.sub.22H.sub.17ClN.sub.3O (M+H).sup.+: m/z=374.1; found 374.2.
Step 7: 2-[({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)amino]ethanol
[0390] A mixture of
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyd-
e (0.008 g, 0.02 mmol) and ethanolamine (Aldrich, cat#398136: 3.87
.mu.L, 0.0642 mmol) in methylene chloride (0.2 mL) and
N,N-diisopropylethylamine (22.4 .mu.L, 0.128 mmol) was stirred at
rt for 1 h. sodium triacetoxyborohydride (0.0136 g, 0.0642 mmol)
was carefully added in portions. The reaction was stirred at rt for
12 h. The imine was observed using LC-MS (pH=10, water+NH.sub.4OH),
and to the mixture was added sodium borohydride (4.05 mg, 0.107
mmol) and a few drops of methanol. The reaction was stirred at rt
for 2 h, then was diluted with methanol and purified by prep HPLC
(pH=2, water+TFA) to provide the desired product as the TFA salt.
LC-MS calculated for C.sub.24H.sub.24ClN.sub.4O (M+H).sup.+:
m/z=419.2; found 419.1.
Example 10
2-[({4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}meth-
yl)amino]ethanol
##STR00059##
[0391] Step 1: 4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridine-3-carbaldehyde
##STR00060##
[0393]
4-Chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carba-
ldehyde (Example 9, Step 6: 20.0 mg, 0.0535 mmol), methanol (1.0
mL), and potassium carbonate (8.87 mg, 0.0642 mmol) were combined
in a vial and heated at 60.degree. C. whilst stirring for 1 h. The
mixture was diluted with ethyl acetate, filtered, and concentrated
in vacuo. The resulting yellow residue was used directly in the
next step. LC-MS calculated for C.sub.23H.sub.20N.sub.3O.sub.2
(M+H).sup.+: m/z=370.1; found 370.2.
Step 2: 2-[({4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)amino]ethanol
[0394] This compound was prepared using a similar procedure as
described for Example 9, Step 7 with
4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehy-
de replacing
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyd-
e. The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.25H.sub.27N.sub.4O.sub.2
(M+H).sup.+: m/z=415.2; found 415.2.
Example 11
1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl-
)piperidine-2-carboxylic acid
##STR00061##
[0395] Step 1: methyl
1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)piperidine-2-carboxylate
##STR00062##
[0397] A mixture of
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyd-
e (Example 9, Step 6: 0.020 g, 0.053 mmol) and methyl
piperidine-2-carboxylate hydrochloride (Aldrich, cat#391204: 28.8
mg, 0.160 mmol) in methylene chloride (0.4 mL) and
N,N-diisopropylethylamine (55.9 .mu.L, 0.321 mmol) was stirred at
rt for 1 h. Sodium triacetoxyborohydride (0.0340 g, 0.160 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h. The resulting imine was observed by LC-MS (pH=10,
water+NH.sub.4OH) and to the reaction mixture was added a few drops
of methanol and sodium tetrahydroborate (10.1 mg, 0.267 mmol). The
mixture was stirred for 1 h, then quenched with an aqueous solution
of saturated sodium bicarbonate. The organic layer was separated
and the aqueous layer was further extracted with DCM. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude residue was used directly in the
next step. LC-MS calculated for
C.sub.29H.sub.30ClN.sub.4O.sub.2(M+H).sup.+: m/z=501.2; found
501.2.
Step 2: 1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,
7-naphthyridin-3-yl}methyl)piperidine-2-carboxylic acid
[0398] To a vial charged with methyl
1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methy-
l)piperidine-2-carboxylate (26.8 mg, 0.0535 mmol) was added lithium
hydroxide (12.81 mg, 0.5350 mmol), methanol (0.5 mL), THF (0.5 mL),
and water (0.5 mL). The mixture was heated to 60.degree. C. whilst
stirring for 2 h. After cooling to rt, the mixture was acidified
using aqueous 1 N HCl, diluted with methanol, and purified by prep
HPLC (pH=2, water+TFA) to provide the desired compound as the TFA
salt. LC-MS calculated for
C.sub.28H.sub.28ClN.sub.4O.sub.2(M+H).sup.+: m/z=487.2; found
487.2.
Example 12
2-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-na-
phthyridin-4-yl)methyl]amino}ethanol
##STR00063##
[0399] Step 1: 3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylaniline
##STR00064##
[0401] A mixture of 3-bromo-2-methylaniline (Aldrich, cat#530018:
1.00 mL, 8.12 mmol), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid
(Combi-Blocks, cat#BB-8311: 1.9 g, 10. mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (Aldrich, cat#379670: 0.05 g,
0.06 mmol) and potassium carbonate (2.72 g, 19.7 mmol) in
1,4-dioxane (41.2 mL) and water (20 mL) was degassed and recharged
with nitrogen three times. The mixture was then heated and stirred
at 110.degree. C. for 1.5 h. The reaction mixture was quenched with
saturated aqueous NaHCO.sub.3, and extracted with ethyl acetate
(3.times.10 mL). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (0.fwdarw.30% EtOAc/hexanes). LC-MS calculated for
C.sub.15H.sub.16NO.sub.2 (M+H).sup.+: m/z=242.1; found 242.2.
Step 2: 4-chloro-N-[3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylphenyl]-, 7-naphthyridin-8-amine
##STR00065##
[0403] To a vial was added
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylaniline (0.263 g, 1.09
mmol), 4,8-dichloro-1,7-naphthyridine (Synthonix, cat#D7291: 180
mg, 0.91 mmol), and acetonitrile (10.0 mL). The reaction was heated
to 100.degree. C. for 4 h. After cooling to rt, cesium carbonate
(0.296 g, 0.910 mmol) was added and the mixture was then refluxed
for 4 h. After cooling to rt, the mixture was diluted with ethyl
acetate, filtered, and concentrated in vacuo. LC-MS calculated for
C.sub.23H.sub.19ClN.sub.3O.sub.2(M+H).sup.+: m/z=404.1; found
404.1.
Step 3: N-[3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,
7-naphthyridin-8-amine
##STR00066##
[0405] A mixture of
N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-napht-
hyridin-8-amine (0.370 g, 0.936 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#633348: 1.59 mL, 9.36 mmol), sodium carbonate (0.198 g, 1.87
mmol) and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#701998: 7.1 mg, 0.0094 mmol) in tert-butyl alcohol
(6.73 mL) and water (6 mL) was degassed and sealed. The mixture was
stirred at 110.degree. C. for 2 h. The reaction mixture was cooled
then extracted with ethyl acetate (3.times.20 mL). The combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The crude residue
was used directly in the next step without further purification.
LC-MS calculated for C.sub.25H.sub.22N.sub.3O.sub.2 (M+1).sup.+:
m/z=396.2; found 396.2.
Step 4: 8-{[3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylphenyl]amino}-,
7-naphthyridine-4-carbaldehyde
##STR00067##
[0407] A flask was charged with
N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-napht-
hyridin-8-amine (370. mg, 0.936 mmol), 1,4-dioxane (20. mL), a stir
bar and water (20. mL). To this suspension was added a 4% w/w
mixture of osmium tetraoxide in water (0.89 mL, 0.14 mmol). The
reaction was stirred for 5 min then sodium periodate (2001 mg,
9.356 mmol) was added. After stirring at rt for 1 h, the reaction
was quenched with a saturated aqueous solution of sodium
thiosulfate. The mixture was then extracted with ethyl acetate
(2.times.10 mL), and the combined organic layers were separated,
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude residue was purified by column
chromatography (0.fwdarw.60% EtOAc/hexanes). LC-MS calculated for
C.sub.24H.sub.20N.sub.3O.sub.3 (M+H)+: m/z=398.1; found 398.2.
Step 5: 2-{[(8-{[3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,
7-naphthyridin-4-yl)methyl]amino}ethanol
[0408] This compound was prepared using a similar procedure as
described for Example 9, Step 7 with
8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphth-
yridine-4-carbaldehyde replacing
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyd-
e. The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.26H.sub.27N.sub.4O.sub.3
(M+H).sup.+: m/z=443.2; found 443.3.
Example 13
1-[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-nap-
hthyridin-4-yl)methyl]piperidine-2-carboxylic acid
##STR00068##
[0409] Step 1: methyl 1-((8-(3-(2, 3-dihydrobenzo[b][1,
4]dioxin-6-yl)-2-methylphenylamino)-1,
7-naphthyridin-4-yl)methyl)piperidine-2-carboxylate
##STR00069##
[0411] This compound was prepared using a similar procedure as
described for Example 11, Step 1 with
8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphth-
yridine-4-carbaldehyde (Example 12, Step 4) replacing
4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyd-
e. The crude compound was used directly in the next step without
further purification. LC-MS calculated for
C.sub.31H.sub.33N.sub.4O.sub.4 (M+H).sup.+: m/z=525.2; found
525.2.
Step 2: 1-[(8-{[3-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,
7-naphthyridin-4-yl)methyl]piperidine-2-carboxylic acid
[0412] This compound was prepared using a similar procedure as
described for Example 11, Step 2 with methyl
1-((8-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenylamino)-1,7-n-
aphthyridin-4-yl)methyl)piperidine-2-carboxylate replacing methyl
1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methy-
l)piperidine-2-carboxylate. The reaction mixture was purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.30H.sub.31N.sub.4O.sub.4 (M+H).sup.+: m/z=511.2; found
511.3.
Example 14
2-[({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)amin-
o]ethanol
##STR00070##
[0413] Step 1: 5-chloropyrido[3, 4-b]pyrazin-2(1H)-one
##STR00071##
[0415] A suspension of 2-chloropyridine-3,4-diamine (Aldrich,
cat#736376: 0.5 g, 3 mmol) and ethyl glyoxylate (1:1 w/v in
toluene, Alfa Aesar, cat#L19207: 0.73 mL, 3.6 mmol) in ethanol (5.0
mL) was heated at 90.degree. C. overnight. The mixture was then
cooled at -20.degree. C. for 2 d. The precipitate was filtered,
washed with cold ethanol, collected, and used directly in the next
step without further purification. LC-MS calculated for
C.sub.7H.sub.5ClN.sub.3O (M+H).sup.+: m/z=182.0; found 182.1.
Step 2: 5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,
4-b]pyrazin-2-ol
##STR00072##
[0417] A degassed mixture of 2-methylbiphenyl-3-amine (Example 1,
Step 1: 0.020 g, 0.11 mmol), 5-chloropyrido[3,4-b]pyrazin-2(1H)-one
(0.020 g, 0.11 mmol), cesium carbonate (0.107 g, 0.327 mmol) and
Brettphos Pd G3 precatalyst (Aldrich, cat#761605: 7.9 mg, 0.0087
mmol) in tert-butyl alcohol (0.3 mL) was heated at 100 deg .degree.
C. for 2 h. 1.0 M hydrogen chloride in water was added until the pH
was .about.5. After stirring overnight, the precipitate was
filtered, and the solid was dried and used directly in the next
step. LC-MS calculated for C.sub.20H.sub.17N.sub.4O (M+H).sup.+:
m/z=329.1; found 329.2.
Step 3:
2-chloro-N-(2-methylbiphenyl-3-yl)pyrido[3,4-b]pyrazin-5-amine
##STR00073##
[0419] A mixture of
5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-ol (0.25 g,
0.76 mmol) in phosphoryl chloride (2.5 mL, 27 mmol) was heated at
120.degree. C. in a sealed vial for 1.5 h. The reaction was cooled
and concentrated in vacuo. The resulting black residue was
dissolved in 1,2-dichloroethane and cooled to 0.degree. C. An
aqueous saturated solution of sodium bicarbonate was added and
stirred for 1 h at rt. The precipitate was filtered and the
filtrate was washed with brine, dried over sodium sulfate,
filtered, and concentrated. The black solid was then triturated
with tert-butyl methyl ether (3 mL), and the resulting precipitate
was filtered and washed to give the desired product as a dark brown
solid. The filtrate was then purified using column chromatography
(0.fwdarw.30% EtOAc/hexanes) to provide the desired product as a
dark brown solid. LC-MS calculated for C.sub.20H.sub.16ClN.sub.4
(M+H).sup.+: m/z=347.1; found 347.1.
Step 4: N-(2-methylbiphenyl-3-yl)-2-vinylpyrido[3,
4-b]pyrazin-5-amine
##STR00074##
[0421] A degassed mixture of
2-chloro-N-(2-methylbiphenyl-3-yl)pyrido[3,4-b]pyrazin-5-amine
(0.25 g, 0.72 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphen-
yl-2-yl)(chloro)palladium (1:1) (Aldrich, cat#741825: 0.063 g,
0.080 mmol), potassium phosphate (0.47 g, 2.2 mmol) and
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#663348: 0.18 mL, 1.1 mmol) in 1,4-dioxane (2.5 mL) and water
(0.8 mL) was refluxed at 120.degree. C. for 2.5 h. The mixture was
cooled to rt, and ethyl acetate and water were added. The resulting
mixture was stirred for 1 h, and the precipitate was filtered and
washed. The organic filtrate was washed with brine, dried over
sodium sulfate, filtered and concentrated in vacuo. The crude
residue was purified using flash chromatography (0.fwdarw.30%
EtOAc/hexanes) to provide the desired compound as an orange solid.
LC-MS calculated for C.sub.22H.sub.19N.sub.4(M+H).sup.+: m/z=339.2;
found 339.2.
Step 5: 5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,
4-b]pyrazine-2-carbaldehyde
##STR00075##
[0423] This compound was prepared using a similar procedure as
described for Example 12, Step 4 with
N-(2-methylbiphenyl-3-yl)-2-vinylpyrido[3,4-b]pyrazin-5-amine
replacing
N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-napht-
hyridin-8-amine. The crude compound was used directly in the next
step without further purification. LC-MS calculated for
C.sub.21H.sub.17N.sub.4O.sub.2 (M+H.sub.2O)+: m/z=359.1; found
359.2.
Step 6: 2-[({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,
4-b]pyrazin-2-yl}methyl)amino]ethanol
[0424] To a solution of
5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazine-2-carbaldehyde
(3.0 mg, 0.0088 mmol) in methylene chloride (1 mL) was added
ethanolamine (Aldrich, cat#398136: 10.0 .mu.L, 0.166 mmol) and
acetic acid (10.0 .quadrature.L, 0.176 mmol). The mixture was
stirred at rt for 20 min, then sodium triacetoxyborohydride (31 mg,
0.15 mmol) was added and stirred at rt for 1 h. Water and a
saturated solution of NaHCO.sub.3 were added. The layers were
separated and the organic layer was concentrated and dissolved in
THF/MeOH. The desired product was purified by prep HPLC (pH=10,
water+NH.sub.4OH, then a second purification using pH=2, water+TFA)
to provide the compound as the TFA salt. LC-MS calculated for
C.sub.23H.sub.24N.sub.5O (M+H).sup.+: m/z=386.2; found 386.2.
Example 15
(2S)-1-({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)-
piperidine-2-carboxylic acid
##STR00076##
[0426] A suspension of
5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazine-2-carbaldehyde
(Example 14, Step 5: 0.022 g, 0.065 mmol),
(2S)-piperidine-2-carboxylic acid (AlfaAesar, cat#L15373: 15 mg,
0.12 mmol) and acetic acid (10.0 .mu.L, 0.176 mmol) in methanol (1
mL) and tetrahydrofuran (1 mL) was stirred for 2 min. Sodium
cyanoborohydride (9.0 mg, 0.14 mmol) was added and stirred at rt
for 4.5 h. The mixture was diluted with methanol and purified by
prep HPLC (pH=10, water+NH.sub.4OH, then a second purification
using pH=2, water+TFA) to provide the desired compound as the TFA
salt. LC-MS calculated for C.sub.27H.sub.28N.sub.5O.sub.2
(M+H).sup.+: m/z=454.2; found 454.3.
Example 16
2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-[(3-{[(2-hydroxyethyl)amino]methyl}-
-1,7-naphthyridin-8-yl)amino]benzonitrile
##STR00077##
[0427] Step 1: 2-amino-6-(2,
3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
##STR00078##
[0429] A mixture of 2-amino-6-bromobenzonitrile (Combi-blocks,
cat#SS-7081: 3.0 g, 15 mmol),
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Combi-Blocks,
cat#BB-8311: 3.6 g, 20. mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (Aldrich, cat#379670: 0.1 g, 0.1
mmol) and potassium carbonate (5.11 g, 36.9 mmol) in 1,4-dioxane
(77 mL) and water (30 mL) was degassed and recharged with nitrogen
three times. The mixture was then heated and stirred at 120.degree.
C. for 1.5 h. The reaction mixture was quenched with saturated
aqueous NaHCO.sub.3, and extracted with ethyl acetate (3.times.10
mL). The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The beige solid was used directly in the next step. LC-MS
calculated for C.sub.15H.sub.13N.sub.2O.sub.2 (M+H).sup.+:
m/z=253.1; found 253.2.
Step 2: 8-chloro-3-vinyl-1, 7-naphthridine
##STR00079##
[0431] A mixture of 3-bromo-8-chloro-1,7-naphthyridine
(PharmaBlock, cat#PBLJ2743: 0.200 g, 0.821 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#663348: 153 .mu.L, 0.904 mmol), sodium carbonate (0.174 g, 1.64
mmol) and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#701998: 6.2 mg, 0.0082 mmol) in tert-butyl alcohol
(5.91 mL) and water (6 mL) was degassed and sealed. It was stirred
at 110.degree. C. for 2 h. The reaction mixture was cooled then
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude residue was used
directly in the next step without further purification. LC-MS
calculated for C.sub.10H.sub.8ClN.sub.2 (M+H).sup.+: m/z=191.0;
found 191.0.
Step 3: 8-chloro-1, 7-naphthyridine-3-carbaldehyde
##STR00080##
[0433] This compound was prepared using a similar procedure as
described for Example 12, Step 4 with
8-chloro-3-vinyl-1,7-naphthyridine replacing
N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-napht-
hyridin-8-amine. The crude compound was used directly in the next
step without further purification. LC-MS calculated for
C.sub.9H.sub.6ClN.sub.2O (M+H).sup.+: m/z=193.0; found 192.9.
Step 4: 2-{[(8-chloro-1,
7-naphthyridin-3-yl)methyl]amino}ethanol
##STR00081##
[0435] A mixture of 8-chloro-1,7-naphthyridine-3-carbaldehyde
(0.160 g, 0.831 mmol) and ethanolamine (Aldrich, cat#398136: 251
.mu.L, 4.15 mmol) in methylene chloride (6 mL) and
N,N-diisopropylethylamine (868 .mu.L, 4.98 mmol) was stirred at rt
for 1 h. Sodium triacetoxyborohydride (0.528 g, 2.49 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h. To the mixture was then carefully added sodium tetrahydroborate
(157 mg, 4.15 mmol) and methanol (1 mL) and the reaction mixture
was stirred overnight under nitrogen. The reaction was quenched
with a saturated aqueous solution of sodium bicarbonate. The
mixture was then extracted with a 3:1 mixture of
chlorofom/isopropyl alcohol. The combined organic layers were
washed with brine, dried over sodium sulfate, then concentrated in
vacuo. The crude residue was purified by column chromatography
(0.fwdarw.50% methanol/DCM) and was obtained as an off white solid.
LC-MS calculated for C.sub.11H.sub.13ClN.sub.3O (M+H).sup.+:
m/z=238.1; found 238.1.
Step 5: 2-(2, 3-dihydro-1,
4-benzodioxin-6-yl)-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,
7-naphthyridin-8-yl)amino]benzonitrile
[0436] To a vial was added
2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (0.0106 g,
0.0421 mmol),
2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol (10.00 mg,
0.04207 mmol), cesium carbonate (0.0274 g, 0.0841 mmol),
1,4-dioxane (1 mL),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Aldrich,
cat#526460: 4.9 mg, 0.0084 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (Aldrich, cat#328774: 4.4
mg, 0.0042 mmol). The mixture was sparged with nitrogen for 20 s,
then the vial was sealed and heated to 110.degree. C. for 2 h
whilst stirring. The mixture was cooled to rt, diluted with
methanol, and purified by prep HPLC (pH=2, water+TFA) to provide
the compound as the TFA salt. LC-MS calculated for
C.sub.26H.sub.24N.sub.5O.sub.3 (M+H).sup.+: m/z=454.2; found
454.2.
Example 17
2-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-na-
phthyridin-3-yl)methyl]amino}ethanol
##STR00082##
[0438] To a vial was added
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylaniline (Example 12,
Step 1: 0.0102 g, 0.0421 mmol),
2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol (Example
16, Step 4: 10.00 mg, 0.04207 mmol), cesium carbonate (0.0274 g,
0.0841 mmol), 1,4-dioxane (1.00 mL),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Aldrich,
cat#526460: 4.9 mg, 0.0084 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (Aldrich, cat#328774: 4.4
mg, 0.0042 mmol). The mixture was sparged with nitrogen for 20 s
and the vial was sealed and heated to 110.degree. C. whilst
stirring for 2 h. The reaction was cooled, diluted with methanol,
then purified by prep HPLC (pH=2, water+TFA) to provide the
compound as a TFA salt. LC-MS calculated for
C.sub.26H.sub.27N.sub.4O.sub.3 (M+H).sup.+: m/z=443.2; found
443.2.
Example 18
2-[({8-[(3-cyclohex-1-en-1-yl-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}-
methyl)amino]ethanol
##STR00083##
[0439] Step 1: 2-[({8-[(3-bromo-2-methylphenyl)amino]-1,
7-naphthyridin-3-yl}methyl)amino]ethanol
##STR00084##
[0441] To a microwave vial was added 3-bromo-2-methylaniline
(Aldrich, cat#530018: 29.5 L, 0.240 mmol),
2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol (Example
16, Step 4: 57.00 mg, 0.2398 mmol), tert-butyl alcohol (1.1 mL) and
4.0 M hydrogen chloride in dioxane (59.0 .mu.L, 0.236 mmol). The
reaction was irradiated to 100.degree. C. for 1 h in the microwave.
After cooling to rt, the mixture was concentrated in vacuo, and the
desired compound was purified by column chromatography
(0.fwdarw.50% methanol/DCM). LC-MS calculated for
C.sub.18H.sub.20BrN.sub.4O (M+H).sup.+: m/z=387.1; found 387.1.
Step 2: 2-[({8-[(3-cyclohex-1-en-1-yl-2-methylphenyl)amino]-1,
7-naphthyridin-3-yl}methyl)amino]ethanol
[0442] A mixture of
2-[({8-[(3-bromo-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}methyl)amino-
]ethanol (0.0150 g, 0.0387 mmol),
2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Aldrich, cat#650277: 0.0242 g, 0.116 mmol), sodium carbonate
(0.00821 g, 0.0775 mmol) and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II- )
(Aldrich, cat#701998: 0.29 mg, 0.00039 mmol) in tert-butyl alcohol
(0.279 mL) and water (0.3 mL) was degassed and sealed. The mixture
was stirred at 90.degree. C. for 2 h. The reaction was cooled,
diluted with methanol, then purified by prep HPLC (pH=10,
water+NH.sub.4OH). LC-MS calculated for C.sub.24H.sub.29N.sub.4O
(M+H).sup.+: m/z=389.2; found 389.3.
Example 19
3-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]biphenyl-
-2-carbonitrile
##STR00085##
[0443] Step 1: 3-aminobiphenyl-2-carbonitrile
##STR00086##
[0445] This compound was prepared using a similar procedure as
described for Example 16, Step 1 with phenylboronic acid (Aldrich,
cat#P20009) replacing 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid.
The crude compound was purified using column chromatography
(0.fwdarw.50% EtOAc/hexanes). LC-MS calculated for
C.sub.13H.sub.11N.sub.2 (M+H).sup.+: m/z=195.1; found 195.2.
Step 2: 3-[(3-{[(2-hydroxyethyl)amino]methyl}-1,
7-naphthyridin-8-yl)amino]biphenyl-2-carbonitrile
[0446] This compound was prepared using a similar procedure as
described for Example 16, Step 5 with
3-aminobiphenyl-2-carbonitrile replacing
2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. The
reaction mixture was purified using prep HPLC (pH=2, water+TFA) to
provide the compound as the TFA salt. LC-MS calculated for
C.sub.24H.sub.22N.sub.5O (M+H).sup.+: m/z=396.2; found 396.3.
Example 20
2-cyclohex-1-en-1-yl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridi-
n-8-yl)amino]benzonitrile
##STR00087##
[0447] Step 1: 2-amino-6-cyclohex-1-en-1-ylbenzonitrile
##STR00088##
[0449] This compound was prepared using a similar procedure as
described for Example 16, Step 1 with
2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Aldrich, cat#650277) replacing
2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. The crude compound
was purified using column chromatography (0.fwdarw.50%
EtOAc/hexanes). LC-MS calculated for C.sub.13H.sub.15N.sub.2
(M+H).sup.+: m/z=199.1; found 199.1.
Step 2:
2-cyclohex-1-en-1-yl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,
7-naphthyridin-8-yl)amino]benzonitrile
[0450] This compound was prepared using a similar procedure as
described for Example 16, Step 5 with
2-amino-6-cyclohex-1-en-1-ylbenzonitrile replacing
2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. The
reaction mixture was purified using prep HPLC (pH=2, water+TFA) to
provide the compound as the TFA salt. LC-MS calculated for
C.sub.24H.sub.26N.sub.5O (M+H).sup.+: m/z=400.2; found 400.3.
Example 21
2-cyclohexyl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)a-
mino]benzonitrile
##STR00089##
[0452] Step 1: 2-amino-6-cyclohexylbenzonitrile
##STR00090##
[0453] A mixture of 2-amino-6-cyclohex-1-en-1-ylbenzonitrile
(Example 20, Step 1: 100 mg, 0.5 mmol) and 10% palladium on carbon
(53 mg, 0.050 mmol) in methanol (5 mL) was stirred under an
atmosphere of hydrogen at room temperature for 1.5 h. The reaction
mixture was filtered through celite and the filtrate was
concentrated in vacuo. The desired compound was used directly in
the next step without further purification. LC-MS calculated for
C.sub.13H.sub.17N.sub.2(M+H).sup.+: m/z=201.1; found 201.2.
Step 2: 2-cyclohexyl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,
7-naphthyridin-8-yl)amino]benzonitrile
[0454] This compound was prepared using a similar procedure as
described for Example 16, Step 5 with
2-amino-6-cyclohexylbenzonitrile replacing
2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. The
reaction mixture was purified using prep HPLC (pH=2, water+TFA) to
provide the compound as the TFA salt. LC-MS calculated for
C.sub.24H.sub.28N.sub.5O (M+H).sup.+: m/z=402.2; found 402.3.
Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)
Binding Assay
[0455] 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.
[0456] Compounds of the present disclosure, as exemplified in the
Examples, showed IC.sub.50 values in the following ranges:
+=IC.sub.50.ltoreq.10 nM; ++=10 nM<IC.sub.50.ltoreq.100 nM;
+++=100 nM<IC.sub.50.ltoreq.1000 nM.
[0457] 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 ++
[0458] 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.
* * * * *