U.S. patent application number 15/850985 was filed with the patent office on 2018-06-28 for heterocyclic compounds as immunomodulators.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Chunhong He, Leah C. Konkol, Neil Lajkiewicz, Zhenwu Li, Song Mei, Chao Qi, Liangxing Wu, Kaijiong Xiao, Wenqing Yao, Wenyu Zhu.
Application Number | 20180179202 15/850985 |
Document ID | / |
Family ID | 60991627 |
Filed Date | 2018-06-28 |
United States Patent
Application |
20180179202 |
Kind Code |
A1 |
Wu; Liangxing ; et
al. |
June 28, 2018 |
HETEROCYCLIC COMPOUNDS AS IMMUNOMODULATORS
Abstract
Disclosed are compounds of Formula (I), methods of using the
compounds as immunomodulators, and pharmaceutical compositions
comprising such compounds. The compounds are useful in treating,
preventing or ameliorating diseases or disorders such as cancer or
infections. ##STR00001##
Inventors: |
Wu; Liangxing; (Wilmington,
DE) ; Lajkiewicz; Neil; (Garnet Valley, PA) ;
He; Chunhong; (Chadds Ford, PA) ; Xiao; Kaijiong;
(Clark, NJ) ; Zhu; Wenyu; (Media, PA) ; Li;
Zhenwu; (Wilmington, DE) ; Mei; Song;
(Wilmington, DE) ; Qi; Chao; (Newwark, DE)
; Konkol; Leah C.; (Wilmington, DE) ; Yao;
Wenqing; (Chadds Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
60991627 |
Appl. No.: |
15/850985 |
Filed: |
December 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62438038 |
Dec 22, 2016 |
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62487362 |
Apr 19, 2017 |
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62551011 |
Aug 28, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/00 20180101;
C07D 519/00 20130101; C07D 471/04 20130101; A61P 37/02 20180101;
C07D 401/04 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 519/00 20060101 C07D519/00; A61P 37/02 20060101
A61P037/02 |
Claims
1. A compound of Formula (I): ##STR00313## or a pharmaceutically
acceptable salt or a stereoisomer thereof, wherein: ring A is 5- to
14-membered heteroaryl, 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein the 5- to
14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each
has 1-4 heteroatoms as ring members selected from B, P, N, O and S,
wherein the P, N or S atom as ring members is optionally oxidized
and one or more carbon atoms as ring members are each optionally
replaced by a carbonyl group; and wherein ring A is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.6 substituents; L is a bond,
--C(O)NR.sup.13--, --NR.sup.13C(O)--, --C(.dbd.S)NR.sup.13--,
--NR.sup.13C(.dbd.S)--, --C(.dbd.NR.sup.13)NR.sup.13--,
--NR.sup.13C(.dbd.NR.sup.13)--, --C(.dbd.NOR.sup.13)NR.sup.13--,
--NR.sup.13C(.dbd.NOR.sup.13)--, --C(.dbd.NCN)NR.sup.13--,
--NR.sup.13C(.dbd.NCN)--, O, --(CR.sup.14R.sup.15).sub.q--,
--(CR.sup.14R.sup.15).sub.q--O--, --O(CR.sup.14R.sup.15).sub.q--,
--(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--; X is N or
CR.sup.17; R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl or --N(C.sub.1-4 alkyl).sub.2; R.sup.5 is C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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, C(O)NR.sup.aS(O).sub.2R.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(.dbd.NR.sup.a)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,
S(O).sub.2NR.sup.aC(O)R.sup.a, --P(O)R.sup.aR.sup.a,
--P(O)(OR.sup.a)(OR.sup.a), --B(OH).sub.2, --B(OR.sup.a).sub.2 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents; or two R.sup.6
substituents attached to the same ring carbon atom taken together
with the ring carbon atom to which they are attached form spiro
C.sub.3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,
each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents; each R.sup.13 is
independently H, C.sub.1-6 haloalkyl or C.sub.1-6 alkyl optionally
substituted with a substituent selected from C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl and --N(C.sub.1-4
alkyl).sub.2; R.sup.14 and R.sup.15 are each independently selected
from H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents; or R.sup.14 and R.sup.15 taken together with
the carbon atom to which they are attached form 3-, 4-, 5- or
6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl,
each of which is 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, 5-14 membered heteroaryl, 4-14 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 (4-14 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, 5-14 membered heteroaryl,
4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3, 4, or 5 independently selected 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, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
C(O)NR.sup.eS(O).sub.2R.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(.dbd.NR.sup.e)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,
S(O).sub.2NR.sup.eC(O)R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), --B(OH).sub.2, --B(OR.sup.e).sub.2 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, 5-14 membered heteroaryl, C.sub.3-10
cycloalkyl, 4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each optionally
substituted with 1, 2, or 3 independently selected R.sup.f
substituents; each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents; each R.sup.b substituent is independently selected
from 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, 5-10 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, C(O)NR.sup.cS(O).sub.2R.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(.dbd.NR.sup.c)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,
S(O).sub.2NR.sup.cC(O)R.sup.c, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), --B(OH).sub.2, --B(OR.sup.e).sub.2 and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 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
independently selected R.sup.f substituents; each R.sup.f is
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, C(O)NR.sup.gR.sup.g,
C(O)OR.sup.g, C(O)NR.sup.gS(O).sub.2R.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(.dbd.NR.sup.g)R.sup.g,
NR.sup.gC(O)NR.sup.gR.sup.g, NR.sup.iC(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,
S(O).sub.2NR.sup.gC(O)R.sup.g, NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), --B(OH).sub.2, --B(OR.sup.g).sub.2 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
independently selected R.sup.n substituents; each R.sup.n is
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.o, OR.sup.o, SR.sup.o, C(O)R.sup.o,
C(O)NR.sup.oR.sup.o, C(O)OR.sup.o, C(O)NR.sup.oS(O).sub.2R.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(.dbd.NR.sup.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,
S(O).sub.2NR.sup.oC(O)R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), --B(OH).sub.2, --B(OR.sup.o).sub.2 and
S(O).sub.2NR.sup.oR.sup.o, 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.n are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents; 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, 2, or 3 independently selected R.sup.p
substituents; each R.sup.p is 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,
C(O)NR.sup.rS(O).sub.2R.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(.dbd.NR.sup.r)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,
S(O).sub.2NR.sup.rC(O)R.sup.r, NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2NR.sup.rR.sup.r, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), --B(OH).sub.2, --B(OR.sup.r).sub.2 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 independently
selected R.sup.q substituents; or any two R.sup.a substituents
together with the boron, phosphorus or 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
independently selected R.sup.h substituents; each R.sup.h is
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.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered heteroaryl)-C.sub.1-4
alkyl-, (4-7 membered heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, halo, CN, OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, C(O)NR.sup.iS(O).sub.2R,
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(.dbd.NR.sup.i)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.1)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i,
S(O).sub.2NR.sup.iC(O)R.sup.1, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, --P(O)R.sup.iR.sup.i,
--P(O)(OR)(OR), --B(OH).sub.2, --B(OR.sup.i).sub.2 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents; each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, C(O)NR.sup.kS(O).sub.2R.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(.dbd.NR.sup.k)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,
S(O).sub.2NR.sup.kC(O)R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), --B(OH).sub.2, --B(OR.sup.k).sub.2 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, 4-7
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 boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.e substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.g substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.i substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents, or 1,
2, or 3 independently selected R.sup.q substituents; or any two
R.sup.k substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents, or 1,
2, or 3 independently selected R.sup.q substituents; or any two
R.sup.o substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.r substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; each
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.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents; each R.sup.q is
independently selected from halo, OH, CN, --COOH, NH.sub.2,
--NH--C.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered
heterocycloalkyl and C.sub.3-6 cycloalkyl, 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 1, 2, or 3 substituents selected from halo, OH,
CN, --COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl; the
subscript m is an integer of 0, 1, 2 or 3; the subscript n is an
integer of 0, 1, 2 or 3; each subscript q is independently an
integer of 1, 2, 3 or 4; and the subscript s is an integer of 1, 2,
or 3.
2. The compound of claim 1, having Formula (I): ##STR00314## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from B, P, N, O and S, wherein the P, N or S atom as ring members
is optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents; L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--; X is N or
CR.sup.17; R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl or --N(C.sub.1-4 alkyl).sub.2; R.sup.5 is C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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,
--P(O)R.sup.aR.sup.a, --P(O)(OR.sup.a)(OR.sup.a), --B(OH).sub.2,
--B(OR.sup.a).sub.2 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.6, R.sup.7, R.sup.17
and R.sup.18 are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents; or two R.sup.6
substituents attached to the same ring carbon atom taken together
with the ring carbon atom to which they are attached form spiro
C.sub.3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,
each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents; each R.sup.13 is
independently H, C.sub.1-6 haloalkyl or C.sub.1-6 alkyl optionally
substituted with a substituent selected from C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl and --N(C.sub.1-4
alkyl).sub.2; R.sup.14 and R.sup.15 are each independently selected
from H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents; or R.sup.14 and R.sup.15 taken together with
the carbon atom to which they are attached form 3-, 4-, 5- or
6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl,
each of which is 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, 5-14 membered heteroaryl, 4-14 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 (4-14 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, 5-14 membered heteroaryl,
4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3, 4, or 5 independently selected 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, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), --B(OH).sub.2, --B(OR.sup.e).sub.2 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, 5-14 membered heteroaryl, C.sub.3-10
cycloalkyl, 4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each optionally
substituted with 1, 2, or 3 independently selected R.sup.f
substituents; each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents; each R.sup.b substituent is independently selected
from 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, 5-10 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,
--P(O)R.sup.cR.sup.c, --P(O)(OR.sup.c)(OR.sup.c), --B(OH).sub.2,
--B(OR.sup.c).sub.2 and S(O).sub.2NR.sup.cR.sup.c; wherein the
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
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.b are each further optionally substituted with 1, 2, or 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 independently selected R.sup.f
substituents; each R.sup.f is 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, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), --B(OH).sub.2, --B(OR.sup.g).sub.2 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
independently selected R.sup.n substituents; each R.sup.n is
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.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, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), --B(OH).sub.2, --B(OR.sup.o).sub.2 and
S(O).sub.2NR.sup.oR.sup.o, 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.n are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents; 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, 2, or 3 independently selected R.sup.p
substituents; each R.sup.p is 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, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), --B(OH).sub.2, --B(OR.sup.r).sub.2 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 independently
selected R.sup.q substituents; or any two R.sup.a substituents
together with the boron, phosphorus or 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
independently selected R
.sup.h substituents; each R.sup.h is 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR)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, --P(O)R.sup.iR.sup.i,
--P(O)(OR)(OR), --B(OH).sub.2, --B(OR.sup.i).sub.2 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents; each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), --B(OH).sub.2, --B(OR.sup.k).sub.2 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, 4-7
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 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 boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.e substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.g substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.i substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents, or 1,
2, or 3 independently selected R.sup.q substituents; or any two
R.sup.k substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents, or 1,
2, or 3 independently selected R.sup.q substituents; or any two
R.sup.o substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; or any
two R.sup.r substituents together with the boron, phosphorus or
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 independently selected R.sup.h substituents; each
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.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents; each R.sup.q is
independently selected from halo, OH, CN, --COOH, NH.sub.2,
--NH--C.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered
heterocycloalkyl and C.sub.3-6 cycloalkyl, 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 1, 2, or 3 substituents selected from halo, OH,
CN, --COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl; the
subscript m is an integer of 0, 1, 2 or 3; the subscript n is an
integer of 0, 1, 2 or 3; each subscript q is independently an
integer of 1, 2, 3 or 4; and the subscript s is an integer of 1, 2,
or 3.
3. The compound of claim 1, having Formula (I): ##STR00315## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents; L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--; X is N or
CR.sup.17; R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl or --N(C.sub.1-4 alkyl).sub.2; R.sup.5 is C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents; or two R.sup.6
substituents attached to the same ring carbon atom taken together
with the ring carbon atom to which they are attached form spiro
C.sub.3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,
each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents; each R.sup.13 is
independently H, C.sub.1-6 haloalkyl or C.sub.1-6 alkyl optionally
substituted with a substituent selected from C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl and --N(C.sub.1-4
alkyl).sub.2; R.sup.14 and R.sup.15 are each independently selected
from H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents; or R.sup.14 and R.sup.15 taken together with
the carbon atom to which they are attached form 3-, 4-, 5- or
6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl,
each of which is 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, 5-14 membered heteroaryl, 4-14 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 (4-14 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, 5-14 membered heteroaryl,
4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3, 4, or 5 independently selected 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, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents; each R.sup.e 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.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.e are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.f substituents; each R.sup.b substituent is independently
selected from 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, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 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
independently selected R.sup.f substituents; each R.sup.f is
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 independently selected
R.sup.n substituents; each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents; 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, 2, or 3
independently selected R.sup.p substituents; each R.sup.p is
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 independently selected
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 independently selected R.sup.h substituents; each
R.sup.h is 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.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered heteroaryl)-C.sub.1-4
alkyl-, (4-7 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, halo, CN, OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, OC(O)R.sup.i,
OC(O)NR.sup.iR.sup.i, NHR.sup.i, NR.sup.iR.sup.i,
NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents; each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, 4-7 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-, 7-, 8-, 9- or 10-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-, 7-, 8-,
9- or 10-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-, 7-, 8-, 9- or 10-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-, 7-, 8-, 9- or 10-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-, 7-, 8-, 9- or 10-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-, 7-, 8-, 9- or 10-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents; or any two R.sup.r
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
independently selected R.sup.h substituents; each 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.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, 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.i, R.sup.k,
R.sup.o or R.sup.r are each optionally substituted with 1, 2 or 3
R.sup.q substituents; each R.sup.q is independently selected from
halo, OH, CN, --COOH, NH.sub.2, --NH--C.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and
C.sub.3-6 cycloalkyl, 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
1, 2, or 3 substituents selected from halo, OH, CN, --COOH,
NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered
heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an
integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2
or 3; each subscript q is independently an integer of 1, 2, 3 or 4;
and the subscript s is an integer of 1, 2, or 3.
4. The compound of claim 1, having Formula (I): ##STR00316## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-10 cycloalkyl, wherein
the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.6 substituents; L is a bond, --C(O)NR.sup.13--,
--NR.sup.13C(O)--, O, --(CR.sup.14R.sup.15).sub.q--,
--(CR.sup.14R.sup.15).sub.q--O--, --O(CR.sup.14R.sup.15).sub.q--,
--NR.sup.13--, --(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O-- or
--NR.sup.13C(O)NR.sup.13--; X is N or CR.sup.17; R.sup.3 is methyl,
halo, CN or C.sub.1-4 haloalkyl; R.sup.4 is C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH,
NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents; each R.sup.13
is independently H, C.sub.1-6 haloalkyl or C.sub.1-6 alkyl
optionally substituted with a substituent selected from C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl and
--N(C.sub.1-4 alkyl).sub.2; R.sup.14 and R.sup.15 are each
independently selected from H, halo, CN, OH, --COOH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered
heterocycloalkyl, wherein the C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl
of R.sup.14 or R.sup.15 are each optionally substituted with 1, 2,
or 3 independently selected independently selected R.sup.q
substituents; or R.sup.14 and R.sup.15 taken together with the
carbon atom to which they are attached form 3-, 4-, 5- or
6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl,
each of which is 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, 5-14 membered heteroaryl, 4-14 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 (4-14 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, 5-14 membered heteroaryl,
4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3, 4, or 5 independently selected 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, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.q substituents; each R.sup.e 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.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.e are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents; each R.sup.b substituent is independently
selected from 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, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 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
independently selected R.sup.d 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
independently selected R.sup.h substituents; or any two R.sup.c
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
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-, 7-, 8-, 9- or 10-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents; each R.sup.h is
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.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered heteroaryl)-C.sub.1-4
alkyl-, (4-7 membered heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, halo, CN, OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, OC(O)R.sup.i,
OC(O)NR.sup.iR.sup.i, NHR.sup.i, NR.sup.iR.sup.i,
NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents; each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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; each of
R.sup.i and R.sup.k 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.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, 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.i or R.sup.k are
each optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents; each R.sup.q is independently selected from
halo, OH, CN, --COOH, NH.sub.2, --NH--C.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and
C.sub.3-6 cycloalkyl, 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
1, 2, or 3 substituents selected from halo, OH, CN, --COOH,
NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered
heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an
integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2
or 3; each subscript q is independently an integer of 1, 2, 3 or 4;
and the subscript s is an integer of 1, 2, or 3.
5. The compound of claim 1, having Formula (I): ##STR00317## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-10 cycloalkyl, wherein
the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents; L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13C(O)O-- or --NR.sup.13C(O)NR.sup.13--; X is N or
CR.sup.17; R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl or --N(C.sub.1-4 alkyl).sub.2; R.sup.5 is C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 R.sup.b substituents; or two R.sup.6 substituents attached
to the same ring carbon atom taken together with the ring carbon
atom to which they are attached form spiro C.sub.3-6 cycloalkyl or
spiro 4- to 7-membered heterocycloalkyl, each of which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.f substituents; each R.sup.13 is independently H, C.sub.1-6
haloalkyl or C.sub.1-6 alkyl optionally substituted with a
substituent selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH,
NH.sub.2, --NHC.sub.1-4 alkyl and --N(C.sub.1-4 alkyl).sub.2;
R.sup.14 and R.sup.15 are each independently selected from H, halo,
CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, --NHC.sub.1-4
alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl, wherein the C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6
membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents; or R.sup.14 and R.sup.15 taken together with
the carbon atom to which they are attached form 3-, 4-, 5- or
6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl,
each of which is optionally substituted with 1 or 2 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.1-6 alkyl, C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN,
NH.sub.2, NHOR.sup.e, OR.sup.e, SR.sup.e, C(O)R.sup.e,
C(O)NR.sup.eR.sup.e, C(O)OR.sup.e, OC(O)R.sup.e,
OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)NR.sup.eR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents; each R.sup.e 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.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.e are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.f substituents; each R.sup.b substituent is independently
selected from 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, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 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; each R.sup.f is 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;
each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents; 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, 2, or 3 R.sup.p
substituents; each R.sup.p is 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; each R.sup.h is 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR
.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents; each
R.sup.j is 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; or any two R.sup.r 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; each 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.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents; each R.sup.q is
independently selected from halo, OH, CN, --COOH, NH.sub.2,
--NH--C.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered
heterocycloalkyl and C.sub.3-6 cycloalkyl, 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 1, 2, or 3 substituents selected from halo, OH,
CN, --COOH, NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl; the
subscript m is an integer of 0, 1, 2 or 3; the subscript n is an
integer of 0, 1, 2 or 3; each subscript q is independently an
integer of 1, 2, 3 or 4; and the subscript s is an integer of 1, 2,
or 3.
6. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: any two R.sup.i 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 independently selected
R.sup.q substituents; or any two R.sup.k 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 independently selected R.sup.q substituents.
7. The compound of claim 1, having Formula (Ia): ##STR00318## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: R.sup.17 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH,
NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2,
wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each
optionally substituted with 1 or 2 substituents independently
selected from CN, halo and --C(O)NH.sub.2; one of R.sup.1 and
R.sup.2 is --(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the
other is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl or --N(C.sub.1-4 alkyl).sub.2, wherein the C.sub.1-4 alkyl
and C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally
substituted with 1 or 2 substituents independently selected from
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, --C(O)NH.sub.2, NH.sub.2, --NHC.sub.1-4 alkyl and
--N(C.sub.1-4 alkyl).sub.2; R.sup.7 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are
each optionally substituted with 1 or 2 substituents independently
selected from CN, halo or --C(O)NH.sub.2; R.sup.8 and R.sup.9 are
each independently selected from H, halo, CN, OH, --COOH, C.sub.1-4
alkyl, C.sub.1 4 alkoxy, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered
heterocycloalkyl, wherein the C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl
of R.sup.8 or R.sup.9 are each optionally substituted with 1, 2 or
3 independently selected R.sup.q substituents; or R.sup.8 and
R.sup.9 taken together with the carbon atom to which they are
attached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or
7-membered heterocycloalkyl, each of which is optionally
substituted with 1 or 2 R.sup.q substituents; or R.sup.8 and
R.sup.10 taken together with the atoms to which they are attached
form 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to one
additional heteroatoms as ring members selected from O, N or S,
wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed by
R.sup.8 and R.sup.10 are each optionally substituted with 1 or 2
R.sup.q substituents; R.sup.10 and R.sup.11 are each independently
selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, --C(O)R.sup.g, --C(O)OR.sup.g,
--C(O)NR.sup.gR.sup.g, --SO.sub.2R.sup.g and
--SO.sub.2NR.sup.gR.sup.g, wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-6 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.10 or R.sup.11 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents; or R.sup.10 and R.sup.11 taken together with
the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-,
8-, 9-, 10-, or 11-membered heterocycloalkyl, wherein the 4-1
membered heterocycloalkyl is each optionally substituted with 1, 2
or 3 R.sup.f substituents; R.sup.12 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4
alkyl).sub.2; and the subscript p is an integer of 1, 2, 3 or
4.
8. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein (1) when L is --C(O)NH--, ring A
is not 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L
is a bond, ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3)
when L is a bond, ring A is not 2-benzoxazolyl; or (4) when L is
--C(O)NH--, ring A is not 2-pyridyl.
9. The compound of claim 7, having Formula (II): ##STR00319## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
10. The compound of claim 7, having Formula (IIa): ##STR00320## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
11. The compound of claim 7, having Formula (IIb): ##STR00321## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
12. The compound of claim 7, having Formula (III): ##STR00322## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
13. The compound of claim 7, having Formula (IIIa): ##STR00323## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
14. The compound of claim 7, having Formula (IIIb): ##STR00324## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
15. The compound of claim 7, having Formula (IIc): ##STR00325## or
a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.6
are each independently N or CH, with the proviso that X.sup.1,
X.sup.5 and X.sup.6 are not simultaneously N; R.sup.13 is H or
C.sub.1-4 alkyl; and the subscript r is an integer of 1, 2 or
3.
16. The compound of claim 7, having Formula (IIc-1): ##STR00326##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
17. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.13 is H.
18. The compound of claim 7, having Formula (IIa-1): ##STR00327##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl or C.sub.6-10 aryl, wherein the 5- to 10-membered
heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4
heteroatoms as ring members selected from N, O and S, wherein the N
or S atom as ring members is optionally oxidized and one or more
carbon atoms as ring members are each optionally replaced by a
carbonyl group; and wherein ring A is optionally substituted with
1, 2 or 3 R.sup.6 substituents; L is a bond, --C(O)NH--, --NH-- or
--OCH.sub.2--, wherein the carbonyl group in the --C(O)NH-- linkage
or the oxygen atom in the --OCH.sub.2-- linkage is attached to ring
A; and X is CH or N.
19. The compound of claim 7, having Formula (IIa-2): ##STR00328##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
20. The compound of claim 7, having Formula (IId): ##STR00329## or
a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: R.sup.13 is H or C.sub.1-4 alkyl; R.sup.19 is 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-, or (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.18 are each optionally substituted with 1, 2, or 3 R.sup.b
substituents; and the subscript t is an integer of 0, 1 or 2.
21. The compound of claim 7, having Formula (IId-1): ##STR00330##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
22. The compound of claim 7, having Formula (IIe): ##STR00331## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
23. The compound of claim 7, having Formula (IIf): ##STR00332## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
24. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein ring A is selected from:
##STR00333## ##STR00334## wherein each subscript r is an integer of
1, 2, 3, 4 or 5; R.sup.16 is C.sub.1-6 alkyl; and the wavy line
indicates the point of attachment to L.
25. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein ring A is selected from:
##STR00335## wherein each subscript r is an integer of 1, 2 or
3.
26. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein ring A is selected from:
##STR00336## wherein each subscript r is an integer of 1, 2 or
3.
27. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.6 is H, C.sub.1-6 alkyl,
(3-carboxypyrrolidin-1-yl)methyl,
(R)-(3-carboxypyrrolidin-1-yl)methyl,
(S)-(3-carboxypyrrolidin-1-yl)methyl,
(3-hydroxypyrrolidin-1-yl)methyl,
(R)-(3-hydroxypyrrolidin-1-yl)methyl,
(S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl,
(2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl,
2-(3-carboxyazetidin-1-yl)ethanoyl,
(R)-2-(3-carboxyazetidin-1-yl)ethanoyl,
(S)-2-(3-carboxyazetidin-1-yl)ethanoyl,
2-(2-carboxypiperidin-1-yl)ethanoyl,
(R)-2-(2-carboxypiperidin-1-yl)ethanoyl,
(S)-2-(2-carboxypiperidin-1-yl)ethanoyl,
2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(5-cyanopyridin-3-yl)methoxy, halo or CN.
28. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.6 is
(4-carboxycyclohexyl)methyl, trans-(4-carboxycyclohexyl)methyl,
cis-(4-carboxycyclohexyl)methyl, 1-carboxy-2-propyl,
(R)-1-carboxy-2-propyl, (S)-1-carboxy-2-propyl,
(4-carboxy-4-methylcyclohexyl)methyl, 2-pyrrolidinyl,
2-(3-hydroxypyrrolidin-1-yl)acetyl,
2-((R)-3-hydroxypyrrolidin-1-yl)acetyl,
2-((S)-3-hydroxypyrrolidin-1-yl)acetyl,
2-(3-hydroxyazetidin-1-yl)acetyl,
2-((2-hydroxyethyl)(methyl)amino)acetyl,
(4-carboxycyclohexyl)ethyl, 4-carboxycyclohexyl,
4-carboxy-4-methylcyclohexyl, dimethylglycyl, or
N-ethyl-N-methylglycyl.
29. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein L is a bond, --NH--,
--CH.dbd.CH-- or --C(O)NH--, wherein the carbonyl group in the
--C(O)NH-- linkage is attached to ring A.
30. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein L is --C(O)NH--.
31. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein L is --NH--.
32. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein L is a bond, --NH-- or
--C(O)NH--.
33. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the subscript m is 0.
34. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the subscript n is 1 and R.sup.5
is halo or C.sub.1-4 alkyl.
35. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.3 is methyl, CN or Cl.
36. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.12 is H, halo, CN,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy.
37. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.7 is H, halo, CN,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy, wherein
the C.sub.1-4 alkyl and C.sub.1-4 alkoxy of R.sup.7 are each
optionally substituted with CN.
38. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.2 is H.
39. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.2, R.sup.7 and R.sup.12
are each H.
40. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.3 and R.sup.5 are each
independently halo, methyl or CN.
41. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.1 is H.
42. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the subscript p is 1.
43. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.8 and R.sup.9 are each
H.
44. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.10 is H.
45. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.11 is 2-hydroxyethyl,
[1-(hydroxymethyl)cyclopropyl]methyl,
[1-(hydroxymethyl)cyclobutyl]methyl or
2-(dimethylamino)-2-oxo-ethyl.
46. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.11 is 1-hydroxy-2-propyl,
2-carboxyethyl, or 2-hydroxycyclopentyl.
47. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
(R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1-yl, (R)-3-carboxypyrrolidin-1l-yl,
(S)-3-carboxypyrrolidin-1-yl, 3-carboxyazetidin-1l-yl,
(S)-3-carboxyazetidin-1l-yl, (R)-3-carboxyazetidin-1l-yl,
2-carboxy-1-piperidinyl, (R)-2-carboxy-1-piperidinyl,
(S)-2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino,
[2-(dimethylamino)-2-oxo-ethyl]amino,
3-(dimethylaminocarbonyl)pyrrolidin-1-yl,
(R)-3-(dimethylaminocarbonyl)pyrrolidin-1-yl,
(S)-3-(dimethylaminocarbonyl)pyrrolidin-1-yl, 2-hydroxypropylamino,
2-hydroxy-2-methylpropylamino, or
3-methyl-3-carboxypyrrolidin-1-yl.
48. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1-yl, 3-carboxyazetidin-1-yl,
(S)-3-carboxyazetidin-1-yl, (R)-3-carboxyazetidin-1-yl,
2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino or
[2-(dimethylamino)-2-oxo-ethyl]amino.
49. The compound of claim 7, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein --NR.sup.10R.sup.11 is
1-pyrrolidinyl, (3-carboxy-3-methyl)pyrrolidin-1-yl,
(R)-(3-carboxy-3-methyl)pyrrolidin-1-yl,
(S)-(3-carboxy-3-methyl)pyrrolidin-1-yl, (1-hydroxy-2-propyl)amino,
(R)-(1-hydroxy-2-propyl)amino, (S)-(1-hydroxy-2-propyl)amino,
(3-hydroxy-3-methyl)pyrrolidin-1-yl,
(R)-(3-hydroxy-3-methyl)pyrrolidin-1-yl,
(S)-(3-hydroxy-3-methyl)pyrrolidin-1-yl,
(2-hydroxycyclopentyl)amino, ((1R,2S)-2-hydroxycyclopentyl)amino,
((1R,2R)-2-hydroxycyclopentyl)amino,
((1S,2S)-2-hydroxycyclopentyl)amino,
((1S,2R)-2-hydroxycyclopentyl)amino, 2-carboxyethylamino,
3-(carboxymethyl)pyrrolidin-1-yl, or
5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl.
50. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein ring A is 2-pyridyl, optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.6
substituents.
51. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein X is N or CH.
52. The compound of claim 1 selected from:
2-(((8-((2-chloro-2'-methyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin--
2-yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-
-1-ol;
1-(((6-(2-fluoro-3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyrid-
in-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)amino)cy-
clobutanecarboxylic acid;
(S)-1-((6-((2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyri-
din-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)meth-
yl)piperidine-2-carboxylic acid;
N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)pi-
colinamide;
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)pi-
colinamide;
N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin--
1-yl)methyl)picolinamide;
(R)-1-((8-((2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolin-
amido)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)p-
yrrolidine-3-carboxylic acid; and
(R)-1-((8-((2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamid-
o)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)azeti-
dine-3-carboxylic acid; or a pharmaceutically acceptable salt or a
stereoisomer thereof.
53. The compound of claim 1 selected from:
(R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid;
(S)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)met-
hyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid; and
(S)-1-((8-((3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid; or a pharmaceutically
acceptable salt or a stereoisomer thereof.
54. The compound of claim 1 selected from:
1-((8-(2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyri-
dine-2-carboxamido)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)met-
hyl)azetidine-3-carboxylic acid;
(R)-1-((5-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-di-
hydropyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-(2,2'-dichloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methy-
l-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyr-
idin-3-yl)methyl)azetidine-3-carboxylic acid;
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxyethylamino)methyl)-1-methyl-2-oxo-1-
,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl-
)methyl)azetidine-3-carboxylic acid;
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxy-2-methylpropylamino)methyl)-1-meth-
yl-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthy-
ridin-3-yl)methyl)azetidine-3-carboxylic acid;
2,2'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(1,7--
naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol);
(3R,3'R)-1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))-
bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol);
(R)-1-((8-(3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino-
)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-
-3-ol;
(3R,3'R)-1,1'-((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(azane-
diyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol);
(R)-1-((4-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin--
8-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)met-
hyl)pyrrolidin-3-ol;
(R)-1-((8-(3'-(7-((2-hydroxyethylamino)methyl)pyrido[3,2-d]pyrimidin-4-yl-
amino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol;
(R)-1-((8-(3'-(7-(((2-hydroxyethyl)(methyl)amino)methyl)pyrido[3,2-d]pyri-
midin-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol;
(R)-1-((8-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin--
8-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)--
N,N-dimethylpyrrolidine-3-carboxamide
(R)-1-((8-(3'-(7-(((S)-2-hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin-
-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-
pyrrolidin-3-ol;
(R)-1-((8-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,-
2-dihydropyridine-3-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naph-
thyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-(3'-(7-(((R)-2-hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin-
-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-
pyrrolidin-3-ol;
(R)-1-((8-(3'-(7-((2-hydroxy-2-methylpropylamino)methyl)pyrido[3,2-d]pyri-
midin-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol;
(R)-1-((8-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c-
]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl-
)methyl)pyrrolidine-3-carboxylic acid;
(S)--N-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-ylamino)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-im-
idazo[4,5-c]pyridine-2-carboxamide;
(R)-1-((8-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c-
]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl-
)methyl)-3-methylpyrrolidine-3-carboxylic acid;
(R)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2--
yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-
-carboxylic acid;
(R)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2--
yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3--
ol;
(5)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-
-2-yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-
-3-ol;
(R)-2-(dimethylamino)-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methy-
l)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-di-
hydro-5H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one;
(S)-2-(dimethylamino)-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-
-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro--
5H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one;
(R)-1-(2-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4--
d]oxazol-5-yl)-2-oxoethyl)azetidine-3-carboxylic acid;
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[-
3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid;
(R)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[-
3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid;
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[-
3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((3-(((R)-3-hydro-
xypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid; and
(R)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((3-(((R)-3-hydro-
xypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-
-biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-3-carboxylic acid; or a
pharmaceutically acceptable salt or a stereoisomer thereof.
55. The compound of claim 1 selected from:
(R)-1-((8-(2'-Chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[-
4,5-c]pyridine-2-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)met-
hyl)-3-methylpyrrolidine-3-carboxylic acid;
(R)-1-((8-(3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine--
2-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)meth-
yl)pyrrolidine-3-carboxylic acid;
trans-4-((2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1l-yl)methyl)-1,7-n-
aphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid;
cis-4-((2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1l-yl)methyl)-1,7-nap-
hthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-
-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid;
cis-4-((2-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyri-
din-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5--
c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;
trans-4-((2-(2-chloro-3'-(3-(((5)-1-hydroxypropan-2-ylamino)methyl)-1,7-n-
aphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5 (41f)-yl)methyl)cyclohexanecarboxylic
acid; trans-4-((2-(2-chloro-3'-(3-(((1 S,2
S)-2-hydroxycyclopentylamino)methyl)-1,7-naphthyridin-8-ylamino)-2'-methy-
lbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5
(41f)-yl)methyl)cyclohexanecarboxylic acid; trans
4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;
cis
4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;
3-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyri-
din-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-im-
idazo[4,5-c]pyridin-5(4H)-yl)butanoic acid; cis
4-((2-(2-chloro-3'-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyr-
idin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-i-
midazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;
cis
4-((2-(2-chloro-3'-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-
-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dih-
ydro-1H-imidazo[4,5-c]pyridin-5
(41f)-yl)methyl)cyclohexanecarboxylic acid;
(R)-4-(2-(2-chloro-3'-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl-
)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,-
7-dihydro-1H-imidazo[4,5-c]pyridin-5 (41f)-yl)cyclohexanecarboxylic
acid;
(S)-4-(2-(2-chloro-3'-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7--
naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihy-
dro-1H-imidazo[4,5-c]pyridin-5 (41f)-yl)cyclohexanecarboxylic acid;
trans
4-(2-(2-(2-chloro-3'-(3-(((R)-1-hydroxypropan-2-ylamino)methyl)-1,7-napht-
hyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5 (41f)-yl)ethyl)cyclohexanecarboxylic
acid; trans
4-(2-(2-(2-chloro-3'-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-napht-
hyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5 (41f)-yl)ethyl)cyclohexanecarboxylic
acid;
trans-4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)met-
hyl)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-
-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5
(41f)-yl)ethyl)cyclohexanecarboxylic acid;
(R)-4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yla-
mino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo-
[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic acid;
trans-4-(2-(2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyri-
din-8-yl
amino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro--
1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;
(R)-4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yla-
mino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo-
[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid;
Trans-4-(2-(2-(2,2'-dichloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-
-1,7-naphthyridin-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;
trans
4-(2-(2-(2'-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5 (41f)-yl)ethyl)cyclohexanecarboxylic acid;
(R)-1-((4-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c-
]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-
-7-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid
(R)-4-(2-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]p-
yrimidin-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro--
1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic
acid; trans
4-((2-(2-chloro-3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[-
3,2-d]pyrimidin-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-d-
ihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid;
(R)-1-((5-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthy-
ridin-8-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[4,3-b]pyrazin-2-yl-
)methyl)pyrrolidine-3-carboxylic acid;
(3R)-1-((8-(2,2'-dimethyl-3'-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylam-
ino)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxy-
lic acid;
(R)-1-((8-(2,2'-dichloro-3'-(3-((2-hydroxyethylamino)methyl)imid-
azo[1,2-a]pyrazin-8-ylamino)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)meth-
yl)pyrrolidin-3-ol;
(R)-1-((8-((2,2'-dimethyl-3'-((3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-
-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrr-
olidin-3-ol;
(S)-1-((8-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyri-
din-3-yl)methyl)pyrrolidin-3-ol;
(R)-1-((8-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin--
3-yl)methyl)azetidine-3-carboxylic acid;
(R)-1-((8-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)-3-methylpyrrolidin-3-ol;
(R)-1-((8-((2,2'-dichloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naph-
thyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)met-
hyl)pyrrolidin-3-ol;
(R)-1-((8-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyri-
din-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin--
3-yl)methyl)azetidine-3-carboxylic acid;
(R)-3-(((8-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-
-3-yl)methyl)amino)propanoic acid;
(R)-1-((8-((2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid;
(S)-1-((8-((2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2--
yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl-
)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-
-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methy-
l)pyrrolidine-3-carboxylic acid;
2-((R)-3-hydroxypyrrolidin-1-yl)-1-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-
-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-y-
l)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one;
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-
-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methy-
l)-3-methylpyrrolidine-3-carboxylic acid;
1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-
-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)az-
etidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]-
thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)-
methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrol-
o[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyrid-
in-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-2-(1-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-
-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidin-3-yl)acetic acid;
2-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thia-
zol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)meth-
yl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid;
(R)-2-(1-((8-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4-
H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridi-
n-3-yl)methyl)pyrrolidin-3-yl)acetic acid;
2-((8-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrro-
lo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)-
methyl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-d-
ihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino-
)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(N-(2-hydroxyethyl)-N-methylglycyl)-5,6-dihydr-
o-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-
-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-d-
ihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino-
)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((8-((2-chloro-3'-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-
-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7--
naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid; and
Cis-4-((2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin--
8-ylamino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-im-
idazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid; or
a pharmaceutically acceptable salt or a stereoisomer thereof.
56. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: ring A is 5- to 10-membered
heteroaryl, 4- to 11-membered heterocycloalkyl, or C.sub.6-10 aryl,
wherein the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2 or 3 R.sup.6 substituents; L
is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--,
--(CR.sup.14R.sup.15).sub.q--O--, --O(CR.sup.14R.sup.15).sub.q--,
--NR.sup.13--, or CH.dbd.CH--; X is N or CR.sup.17, wherein
R.sup.17 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each optionally
substituted with 1 or 2 substituents independently selected from
CN, halo and --C(O)NH.sub.2; one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, and
OH; R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl; R.sup.4 is
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkyl; R.sup.5
is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, or OH; each R.sup.6 is
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, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, (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, 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, or NR.sup.aC(O)OR.sup.a, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents; R.sup.7 is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH; R.sup.8 and R.sup.9 are each
independently selected from H, halo, CN, OH, --COOH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, and C.sub.1-4 haloalkyl; R.sup.10 and R.sup.11 are
each independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, --C(O)R.sup.g, --C(O)OR.sup.g, and
--C(O)NR.sup.gR.sup.g, wherein the C.sub.1-6 alkyl and C.sub.1-6
haloalkyl of R.sup.10 or R.sup.11 are each optionally substituted
with 1 or 2 independently selected R.sup.f substituents; or
R.sup.10 and R.sup.11 taken together with the nitrogen atom to
which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents; R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH; each
R.sup.13 is independently H, C.sub.1-6 haloalkyl or C.sub.1-6
alkyl; R.sup.14 and R.sup.15 are each independently selected from
H, halo, or C.sub.1-4 alkyl; 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, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3 or independently selected R.sup.d
substituents; each R.sup.d is independently selected from C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, halo, CN, NH.sub.2, OR.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, and
NR.sup.eC(O)R.sup.e; each R.sup.e is independently selected from H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; each R.sup.b substituent is independently
selected from halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, CN, OH, NH.sub.2, NO.sub.2, OR.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, and NR.sup.cC(O)OR.sup.c;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy of R.sup.b are each further optionally substituted with
1 or 2 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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1, 2, or 3 R.sup.f substituents; each
R.sup.f is independently selected from C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.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.iC(O)R, and NR.sup.gC(O)OR.sup.g; each R.sup.j is
independently selected from H, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; each R.sup.h
is independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, halo, CN, OR.sup.i, 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, and NR.sup.iC(O)OR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl of R.sup.h are each further optionally substituted by 1, 2,
or 3 R.sup.j substituents; each R.sup.j is independently selected
from C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, and CN; 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; each R.sup.i is independently selected from H,
C.sub.1-4 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; the subscript m is an
integer of 0, 1, or 2; the subscript n is an integer of 0, 1, or 2;
and the subscript p is an integer of 1, 2, or 3.
57. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: ring A is 5- to 10-membered
heteroaryl or 4- to 11-membered heterocycloalkyl, wherein the 5- to
10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each
has 1-4 heteroatoms as ring members selected from N, O and S,
wherein the N or S atom as ring members is optionally oxidized and
one or more carbon atoms as ring members are each optionally
replaced by a carbonyl group; and wherein ring A is optionally
substituted with 1, 2 or 3 R.sup.6 substituents; L is a bond,
--C(O)NR.sup.13--, --NR.sup.13C(O)--, --NR.sup.13--, or
CH.dbd.CH--; X is N or CR.sup.17, wherein R.sup.17 is H, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
CN, halo, or OH, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy
are each optionally substituted with 1 or 2 substituents
independently selected from CN, halo and --C(O)NH.sub.2; one of
R.sup.1 and R.sup.2 is --(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11
and the other is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is
optionally substituted with 1 or 2 substituents independently
selected from C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, and OH; R.sup.3 is methyl, halo, CN or
C.sub.1-4 haloalkyl; R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
or C.sub.1-4 haloalkyl; R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
each R.sup.6 is 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, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, (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, 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, or NR.sup.aC(O)OR.sup.a, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents; R.sup.7 is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH; R.sup.8 and R.sup.9 are each
independently selected from H, halo, CN, OH, --COOH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, and C.sub.1-4 haloalkyl; R.sup.10 and R.sup.11 are
each independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, --C(O)R.sup.g, --C(O)OR.sup.g, and
--C(O)NR.sup.gR.sup.g, wherein the C.sub.1-6 alkyl and C.sub.1-6
haloalkyl of R.sup.10 or R.sup.11 are each optionally substituted
with 1 or 2 independently selected R.sup.f substituents; or
R.sup.10 and R.sup.11 taken together with the nitrogen atom to
which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents; R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH; each
R.sup.13 is independently H, C.sub.1-6 haloalkyl or C.sub.1-6
alkyl; 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, and C.sub.2-6
alkynyl; each R.sup.d is independently selected from C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, halo, CN, NH.sub.2, OR.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, and
NR.sup.eC(O)R.sup.e; each R.sup.e is independently selected from H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; each R.sup.b substituent is independently
selected from halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, CN, OH, NH.sub.2, NO.sub.2, OR.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, and NR.sup.cC(O)OR.sup.c;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy of R.sup.b are each further optionally substituted with
1 or 2 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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1, 2, or 3 R.sup.f substituents; each
R.sup.f is independently selected from C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.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.iC(O)R, and NR.sup.iC(O)OR.sup.g; each R.sup.g is
independently selected from H, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; each R.sup.h
is independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, halo, CN, OR.sup.i, 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, and NR.sup.iC(O)OR.sup.i, wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl of
R.sup.h are each further optionally substituted by 1, 2, or 3
R.sup.j substituents; each R.sup.j is independently selected from
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, and CN; 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; each R.sup.i is independently selected from H,
C.sub.1-4 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; the subscript m is an
integer of 0, 1, or 2; the subscript n is an integer of 0, 1, or 2;
and the subscript p is an integer of 1, 2, or 3.
58. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: ring A is 5- to 10-membered
heteroaryl or 4- to 11-membered heterocycloalkyl, wherein the 5- to
10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each
has 1-4 heteroatoms as ring members selected from N, O and S,
wherein the N or S atom as ring members is optionally oxidized and
one or more carbon atoms as ring members are each optionally
replaced by a carbonyl group; and wherein ring A is optionally
substituted with 1, 2 or 3 R.sup.6 substituents; L is a bond,
--C(O)NR.sup.13--, --NR.sup.13--, or --NR.sup.13C(O)--; X is
CR.sup.17, wherein R.sup.17 is H or C.sub.1-4 alkyl; one of R.sup.1
and R.sup.2 is --(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the
other is H, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sup.3 is
methyl, or halo; R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or halo; each R.sup.6
is independently selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, (5-14 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, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents; R.sup.7 is H or
C.sub.1-4 alkyl; R.sup.8 and R.sup.9 are each independently
selected from H and C.sub.1-4 alkyl; R.sup.10 and R.sup.11 are each
independently selected from H and C.sub.1-6 alkyl optionally
substituted with 1 or 2 independently selected R.sup.f
substituents; or R.sup.10 and R.sup.11 taken together with the
nitrogen atom to which they are attached form 4-, 5-, 6- or
7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents; R.sup.12 is H or C.sub.1-4 alkyl; each R.sup.13 is
independently H or C.sub.1-6 alkyl; each R.sup.b substituent is
independently selected from halo, C.sub.1-6 alkyl, OH, NH.sub.2,
C(O)OR.sup.c, NHR.sup.c, and NR.sup.cR.sup.c; each R.sup.c is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, and C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, and C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each optionally
substituted with 1 or 2 R.sup.f substituents; each R.sup.f is
independently selected from C.sub.1-4 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halo, OR.sup.g, and C(O)OR.sup.g; each R.sup.g
is independently selected from H and C.sub.1-6 alkyl; each R.sup.h
is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halo, CN, OR.sup.i, and C(O)OR.sup.i; 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; each R.sup.i is independently selected from H
and C.sub.1-4 alkyl; the subscript m is an integer of 0 or 1; the
subscript n is an integer of 0 or 1; and the subscript p is an
integer of 1 or 2.
59. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein: ring A is 5- to 10-membered
heteroaryl, wherein the 5- to 10-membered heteroaryl has 1-4
heteroatoms as ring members selected from N, O and S, wherein the N
or S atom as ring members is optionally oxidized and one or more
carbon atoms as ring members are each optionally replaced by a
carbonyl group; and wherein ring A is optionally substituted with 1
or 2 R.sup.6 substituents; L is a bond, --C(O)NR.sup.13--,
--NR.sup.13--, or --NR.sup.13C(O)--; X is CR.sup.17, wherein
R.sup.17 is H; one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H;
R.sup.3 is methyl, or halo; R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4
alkoxy; R.sup.5 is C.sub.1-4 alkyl or halo; each R.sup.6 is
independently selected from H, C.sub.1-6 alkyl, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl and
(4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are
each optionally substituted with 1 or 2 R.sup.b substituents;
R.sup.7 is H; R.sup.8 and R.sup.9 are each independently selected
from H and C.sub.1-4 alkyl; R.sup.10 and R.sup.11 are each
independently selected from H and C.sub.1-6 alkyl optionally
substituted with 1 or 2 independently selected R.sup.f
substituents; or R.sup.10 and R.sup.11 taken together with the
nitrogen atom to which they are attached form 4-, 5-, 6- or
7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents; R.sup.12 is H; R.sup.13 is H; each R.sup.b
substituent is independently selected from OH, C(O)OR.sup.c,
NHR.sup.c, and NR.sup.cR.sup.c; each R.sup.c is independently
selected from H, C.sub.1-6 alkyl, and C.sub.3-10 cycloalkyl,
wherein the C.sub.1-6 alkyl, and C.sub.3-10 cycloalkyl of R.sup.c
are each optionally substituted with 1 or 2 R.sup.f substituents;
each R.sup.f is independently selected from OR.sup.g, and
C(O)OR.sup.g; R.sup.g is H; each R.sup.h is independently selected
from OR.sup.i and C(O)OR.sup.i; 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; R.sup.i is H; the subscript m is an integer of 0 or
1; the subscript n is an integer of 0 or 1; and the subscript p is
an integer of 1 or 2.
60. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or a stereoisomer thereof,
and one or more pharmaceutically acceptable excipient or
carrier.
61. A method of inhibiting PD-1/PD-L1 interaction, said method
comprising administering to a patient a compound of claim 1, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
62. A method of treating a disease or disorder associated with
inhibition of PD-1/PD-L1 interaction, said method comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt or a stereoisomer thereof.
63. A method of enhancing, stimulating and/or increasing the immune
response in a patient, said method comprising administering to the
patient in need thereof a therapeutically effective amount of a
compound of claim 1, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
Description
FIELD OF THE INVENTION
[0001] The present application is concerned with pharmaceutically
active compounds. The disclosure provides compounds as well as
their compositions and methods of use. The compounds modulate
PD-1/PD-L1 protein/protein interaction and are useful in the
treatment of various diseases including infectious diseases and
cancer.
BACKGROUND OF THE INVENTION
[0002] The immune system plays an important role in controlling and
eradicating diseases such as cancer. However, cancer cells often
develop strategies to evade or to suppress the immune system in
order to favor their growth. One such mechanism is altering the
expression of co-stimulatory and co-inhibitory molecules expressed
on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9).
Blocking the signaling of an inhibitory immune checkpoint, such as
PD-1, has proven to be a promising and effective treatment
modality.
[0003] Programmed cell death-1 (PD-1), also known as CD279, is a
cell surface receptor expressed on activated T cells, natural
killer T cells, B cells, and macrophages (Greenwald et al, Annu.
Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol
2006, (4): 195-201). It functions as an intrinsic negative feedback
system to prevent the activation of T-cells, which in turn reduces
autoimmunity and promotes self-tolerance. In addition, PD-1 is also
known to play a critical role in the suppression of
antigen-specific T cell response in diseases like cancer and viral
infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al,
J. Clinical Oncol 2015, 1-9).
[0004] The structure of PD-1 consists of an extracellular
immunoglobulin variable-like domain followed by a transmembrane
region and an intracellular domain (Parry et al, Mol Cell Biol
2005, 9543-9553). The intracellular domain contains two
phosphorylation sites located in an immunoreceptor tyrosine-based
inhibitory motif and an immunoreceptor tyrosine-based switch motif,
which suggests that PD-1 negatively regulates T cell
receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2
(Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat
Immunol 2001, 2, 261-268), and they differ in their expression
patterns. PD-L1 protein is upregulated on macrophages and dendritic
cells in response to lipopolysaccharide and GM-CSF treatment, and
on T cells and B cells upon T cell receptor and B cell receptor
signaling. PD-L1 is also highly expressed on almost all tumor
cells, and the expression is further increased after IFN-.gamma.
treatment (Iwai et al, PNAS 2002, 99(19):12293-7; Blank et al,
Cancer Res 2004, 64(3):1140-5). In fact, tumor PD-L1 expression
status has been shown to be prognostic in multiple tumor types
(Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015;
Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2
expression, in contrast, is more restricted and is expressed mainly
by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73).
Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells
delivers a signal that inhibits IL-2 and IFN-.gamma. production, as
well as cell proliferation induced upon T cell receptor activation
(Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J
Exp Med 2000, 192(7): 1027-34). The mechanism involves recruitment
of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling
such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol
2007, 8, 239-245). Activation of the PD-1 signaling axis also
attenuates PKC-.theta. activation loop phosphorylation, which is
necessary for the activation of NF-.kappa.B and API pathways, and
for cytokine production such as IL-2, IFN-.gamma. and TNF (Sharpe
et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol
2002, 32(3):634-43; Freeman et al, J Exp Med 2000,
192(7):1027-34).
[0005] Several lines of evidence from preclinical animal studies
indicate that PD-1 and its ligands negatively regulate immune
responses. PD-1-deficient mice have been shown to develop
lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura
et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001,
291:319-322). Using an LCMV model of chronic infection, it has been
shown that PD-1/PD-L1 interaction inhibits activation, expansion
and acquisition of effector functions of virus-specific CD8 T cells
(Barber et al, Nature 2006, 439, 682-7). Together, these data
support the development of a therapeutic approach to block the
PD-1-mediated inhibitory signaling cascade in order to augment or
"rescue" T cell response. Accordingly, there is a need for new
compounds that block PD-1/PD-L1 protein/protein interaction.
SUMMARY
[0006] The present disclosure provides, inter alia, a compound of
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein constituent variables are defined herein.
[0007] The present disclosure further provides a pharmaceutical
composition comprising a compound disclosed herein, or a
pharmaceutically acceptable salt or a stereoisomer thereof, and one
or more pharmaceutically acceptable excipient or carrier.
[0008] The present disclosure further provides methods of
inhibiting PD-1/PD-L1 interaction, said method comprising
administering to a patient a compound disclosed herein, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
[0009] The present disclosure further provides methods of treating
a disease or disorder associated with inhibition of PD-1/PD-L1
interaction, said method comprising administering to a patient in
need thereof a therapeutically effective amount of a compound of
disclosed herein, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
[0010] The present disclosure further provides methods of
enhancing, stimulating and/or increasing the immune response in a
patient, said method comprising administering to the patient in
need thereof a therapeutically effective amount of a compound
disclosed herein, or a pharmaceutically acceptable salt or a
stereoisomer thereof.
DETAILED DESCRIPTION
I. Compounds
[0011] This disclosure provides, inter alia, a compound of Formula
(I):
##STR00003##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0012] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from B, P, N, O and S, wherein the P, N or S atom as ring members
is optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0013] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--,
--C(.dbd.S)NR.sup.13--, --NR.sup.13C(.dbd.S)--,
--C(.dbd.NR.sup.13)NR.sup.13--, --NR.sup.13C(.dbd.NR.sup.13)--,
--C(.dbd.NOR.sup.13)NR.sup.13--, --NR.sup.13C(.dbd.NOR.sup.13)--,
--C(.dbd.NCN)NR.sup.13--, --NR.sup.13C(.dbd.NCN)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0014] X is N or CR.sup.17;
[0015] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0016] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0017] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0018] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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, C(O)NR.sup.aS(O).sub.2R.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(.dbd.NR.sup.a)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,
S(O).sub.2NR.sup.aC(O)R.sup.a, --P(O)R.sup.aR.sup.a,
--P(O)(OR.sup.a)(OR.sup.a), --B(OH).sub.2, --B(OR.sup.a).sub.2 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents;
[0019] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0020] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0021] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0022] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0023] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0024] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
C(O)NR.sup.eS(O).sub.2R.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(.dbd.NR.sup.e)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,
S(O).sub.2NR.sup.eC(O)R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), --B(OH).sub.2, --B(OR.sup.e).sub.2 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, 5-14 membered heteroaryl, C.sub.3-10
cycloalkyl, 4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each optionally
substituted with 1, 2, or 3 independently selected R.sup.f
substituents; each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0025] each R.sup.b substituent is independently selected from
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, 5-10 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, C(O)NR.sup.cS(O).sub.2R.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(.dbd.NR.sup.c)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,
S(O).sub.2NR.sup.cC(O)R.sup.c, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), --B(OH).sub.2, --B(OR.sup.c).sub.2 and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0026] 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
independently selected R.sup.f substituents;
[0027] each R.sup.f is 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,
C(O)NR.sup.gS(O).sub.2R.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(.dbd.NR.sup.g)R.sup.g, NR.sup.gC(O)NR.sup.gR.sup.g,
NR.sup.iC(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,
S(O).sub.2NR.sup.gC(O)R.sup.g, NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), --B(OH).sub.2, --B(OR.sup.g).sub.2 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
independently selected R.sup.n substituents;
[0028] each R.sup.n is 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.o, OR.sup.o,
SR.sup.o, C(O)R.sup.o, C(O)NR.sup.oR.sup.o, C(O)OR.sup.o,
C(O)NR.sup.oS(O).sub.2R.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(.dbd.NR.sup.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,
S(O).sub.2NR.sup.oC(O)R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), --B(OH).sub.2, --B(OR.sup.o).sub.2 and
S(O).sub.2NR.sup.oR.sup.o, 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.n are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0029] each R.sup.g is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.g are each optionally substituted with 1, 2, or 3
independently selected R.sup.p substituents;
[0030] each R.sup.p is 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,
C(O)NR.sup.rS(O).sub.2R.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(.dbd.NR.sup.r)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,
S(O).sub.2NR.sup.rC(O)R.sup.r, NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2NR.sup.rR.sup.r, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), --B(OH).sub.2, --B(OR.sup.r).sub.2 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 independently
selected R.sup.q substituents;
[0031] or any two R.sup.a substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0032] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, C(O)NR.sup.iS(O).sub.2R.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(.dbd.NR.sup.i)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)NR.sup.iR.sup.i,
S(O)R.sup.i, S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i,
S(O).sub.2NR.sup.iC(O)R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, --P(O)R.sup.iR.sup.i,
--P(O)(OR.sup.i)(OR.sup.i), --B(OH).sub.2, --B(OR.sup.i).sub.2 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0033] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, C(O)NR.sup.kS(O).sub.2R.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(.dbd.NR.sup.k)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,
S(O).sub.2NR.sup.kC(O)R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), --B(OH).sub.2, --B(OR.sup.k).sub.2 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, 4-7
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;
[0034] 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;
[0035] or any two R.sup.c substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0036] or any two R.sup.e substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0037] or any two R.sup.g substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0038] or any two R.sup.i substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents, or 1, 2, or 3 independently selected R.sup.q
substituents;
[0039] or any two R.sup.k substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents, or 1, 2, or 3 independently selected R.sup.q
substituents;
[0040] or any two R.sup.o substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0041] or any two R.sup.r substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0042] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0043] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0044] the subscript m is an integer of 0, 1, 2 or 3;
[0045] the subscript n is an integer of 0, 1, 2 or 3;
[0046] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0047] the subscript s is an integer of 1, 2, or 3.
[0048] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0049] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from B, P, N, O and S, wherein the P, N or S atom as ring members
is optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0050] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0051] X is N or CR.sup.17;
[0052] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0053] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0054] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0055] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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,
--P(O)R.sup.aR.sup.a, --P(O)(OR.sup.a)(OR.sup.a), --B(OH).sub.2,
--B(OR.sup.a).sub.2 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.6, R.sup.7, R.sup.17
and R.sup.18 are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents;
[0056] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0057] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0058] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0059] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0060] each R.sup.a is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0061] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), --B(OH).sub.2, --B(OR.sup.e).sub.2 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, 5-14 membered heteroaryl, C.sub.3-10
cycloalkyl, 4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each optionally
substituted with 1, 2, or 3 independently selected R.sup.f
substituents;
[0062] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0063] each R.sup.b substituent is independently selected from
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, 5-10 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)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR)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,
--P(O)R.sup.cR.sup.c, --P(O)(OR.sup.c)(OR.sup.c), --B(OH).sub.2,
--B(OR.sup.c).sub.2 and S(O).sub.2NR.sup.cR.sup.c; wherein the
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
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.b are each further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents;
[0064] 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
independently selected R.sup.f substituents;
[0065] each R.sup.f is 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, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), --B(OH).sub.2, --B(OR.sup.g).sub.2 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
independently selected R.sup.n substituents;
[0066] each R.sup.n is 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.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, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), --B(OH).sub.2, --B(OR.sup.o).sub.2 and
S(O).sub.2NR.sup.oR.sup.o, 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.n are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[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, 2, or 3
independently selected R.sup.p substituents;
[0068] each R.sup.p is 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, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), --B(OH).sub.2, --B(OR.sup.r).sub.2 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 independently
selected R.sup.q substituents;
[0069] or any two R.sup.a substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0070] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, --P(O)R.sup.iR.sup.i,
--P(O)(OR.sup.i)(OR.sup.i), --B(OH).sub.2, --B(OR.sup.i).sub.2 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0071] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), --B(OH).sub.2, --B(OR.sup.k).sub.2 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, 4-7
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;
[0072] 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;
[0073] or any two R.sup.c substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0074] or any two R.sup.e substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0075] or any two R.sup.g substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0076] or any two R.sup.i substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents, or 1, 2, or 3 independently selected R.sup.q
substituents;
[0077] or any two R.sup.k substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents, or 1, 2, or 3 independently selected R.sup.q
substituents;
[0078] or any two R.sup.o substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0079] or any two R.sup.r substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0080] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0081] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0082] the subscript m is an integer of 0, 1, 2 or 3;
[0083] the subscript n is an integer of 0, 1, 2 or 3;
[0084] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0085] the subscript s is an integer of 1, 2, or 3.
[0086] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0087] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from B, P, N, O and S, wherein the P, N or S atom as ring members
is optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0088] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0089] X is N or CR.sup.17;
[0090] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0091] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0092] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0093] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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,
--P(O)R.sup.aR.sup.a, --P(O)(OR.sup.a)(OR.sup.a), --B(OH).sub.2,
--B(OR.sup.a).sub.2 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.6, R.sup.7, R.sup.17
and R.sup.18 are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents;
[0094] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0095] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0096] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0097] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0098] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0099] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), --B(OH).sub.2, --B(OR.sup.e).sub.2 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, 5-14 membered heteroaryl, C.sub.3-10
cycloalkyl, 4-14 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 (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each optionally
substituted with 1, 2, or 3 independently selected R.sup.f
substituents;
[0100] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0101] each R.sup.b substituent is independently selected from
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, 5-10 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)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR)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,
--P(O)R.sup.cR.sup.c, --P(O)(OR.sup.c)(OR.sup.c), --B(OH).sub.2,
--B(OR.sup.c).sub.2 and S(O).sub.2NR.sup.cR.sup.c; wherein the
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
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.b are each further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents;
[0102] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.c are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.f substituents;
[0103] each R.sup.f is 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, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), --B(OH).sub.2, --B(OR.sup.g).sub.2 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
independently selected R.sup.n substituents;
[0104] each R.sup.n is 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.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, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), --B(OH).sub.2, --B(OR.sup.o).sub.2 and
S(O).sub.2NR.sup.oR.sup.o, 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.n are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0105] 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, 2, or 3
independently selected R.sup.p substituents;
[0106] each R.sup.p is 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, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), --B(OH).sub.2, --B(OR.sup.r).sub.2 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 independently
selected R.sup.q substituents;
[0107] or any two R.sup.a substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0108] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, --P(O)R.sup.iR.sup.i,
--P(O)(OR.sup.i)(OR.sup.i), --B(OH).sub.2, --B(OR.sup.i).sub.2 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.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0109] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), --B(OH).sub.2, --B(OR.sup.k).sub.2 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, 4-7
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;
[0110] 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 boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0112] or any two R.sup.e substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0113] or any two R.sup.g substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0114] or any two R.sup.i substituents together with the boron,
phosphorus or 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 independently selected R.sup.q
substituents;
[0115] or any two R.sup.k substituents together with the boron,
phosphorus or 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 independently selected R.sup.q
substituents;
[0116] or any two R.sup.o substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0117] or any two R.sup.r substituents together with the boron,
phosphorus or 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 independently selected R.sup.h
substituents;
[0118] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0119] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0120] the subscript m is an integer of 0, 1, 2 or 3;
[0121] the subscript n is an integer of 0, 1, 2 or 3;
[0122] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0123] the subscript s is an integer of 1, 2, or 3.
[0124] In some embodiments, provided herein is a compound of
Formula (I):
##STR00004##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0125] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0126] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0127] X is N or CR.sup.17;
[0128] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0129] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0130] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0131] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents;
[0132] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0133] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0134] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0135] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0136] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0137] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents;
[0138] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0139] each R.sup.b substituent is independently selected from
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, 5-10 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)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR)NR.sup.cR.sup.c, NHR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0140] 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
independently selected R.sup.f substituents;
[0141] each R.sup.f is 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 independently selected
R.sup.n substituents;
[0142] each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0143] 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, 2, or 3
independently selected R.sup.p substituents;
[0144] each R.sup.p is 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 independently selected
R.sup.q substituents;
[0145] 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 independently selected R.sup.h substituents;
[0146] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0147] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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.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, 4-7 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;
[0148] 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;
[0149] or any two R.sup.c 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 independently selected R.sup.h substituents;
[0150] or any two R.sup.e 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 independently selected R.sup.h substituents;
[0151] or any two R.sup.g 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 independently selected R.sup.h substituents;
[0152] or any two R.sup.i 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 independently selected R.sup.h substituents, or 1, 2, or 3
independently selected R.sup.q substituents;
[0153] or any two R.sup.k 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 independently selected R.sup.h substituents, or 1, 2, or 3
independently selected R.sup.q substituents;
[0154] or any two R.sup.o 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 independently selected R.sup.h substituents;
[0155] or any two R.sup.r 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 independently selected R.sup.h substituents;
[0156] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0157] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0158] the subscript m is an integer of 0, 1, 2 or 3;
[0159] the subscript n is an integer of 0, 1, 2 or 3;
[0160] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0161] the subscript s is an integer of 1, 2, or 3.
[0162] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0163] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0164] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0165] X is N or CR.sup.17;
[0166] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0167] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0168] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0169] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents;
[0170] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0171] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0172] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0173] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0174] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0175] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents;
[0176] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0177] each R.sup.b substituent is independently selected from
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, 5-10 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)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR)NR.sup.cR.sup.c, NHR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0178] 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
independently selected R.sup.f substituents;
[0179] each R.sup.f is 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 independently selected
R.sup.n substituents;
[0180] each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0181] 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, 2, or 3
independently selected R.sup.p substituents;
[0182] each R.sup.p is 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 independently selected
R.sup.q substituents;
[0183] 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 independently selected R.sup.h substituents;
[0184] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0185] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, 4-7 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;
[0186] 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;
[0187] or any two R.sup.c 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 independently selected R.sup.h substituents;
[0188] or any two R.sup.e 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 independently selected R.sup.h substituents;
[0189] or any two R.sup.g 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 independently selected R.sup.h substituents;
[0190] or any two R.sup.i 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 independently selected R.sup.h substituents;
[0191] or any two R.sup.k 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 independently selected R.sup.h substituents;
[0192] or any two R.sup.o 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 independently selected R.sup.h substituents;
[0193] or any two R.sup.r 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 independently selected R.sup.h substituents;
[0194] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0195] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0196] the subscript m is an integer of 0, 1, 2 or 3;
[0197] the subscript n is an integer of 0, 1, 2 or 3;
[0198] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0199] the subscript s is an integer of 1, 2, or 3.
[0200] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0201] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-14 cycloalkyl, wherein
the 5- to 14-membered heteroaryl and 4- to 14-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0202] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.dbd.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O--,
--OC(O)NR.sup.13 or --NR.sup.13C(O)NR.sup.13--;
[0203] X is N or CR.sup.17;
[0204] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0205] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0206] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0207] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents;
[0208] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0209] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0210] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0211] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0212] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0213] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents;
[0214] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0215] each R.sup.b substituent is independently selected from
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, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH,
NH.sub.2, NO.sub.2, NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0216] 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
independently selected R.sup.f substituents;
[0217] each R.sup.f is 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 independently selected
R.sup.n substituents;
[0218] each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0219] 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, 2, or 3
independently selected R.sup.p substituents;
[0220] each R.sup.p is 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 independently selected
R.sup.q substituents;
[0221] 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 independently selected R.sup.h substituents;
[0222] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0223] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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, 4-7 membered heterocycloalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl and
C.sub.1-4haloalkoxy of R.sup.j are each optionally substituted with
1, 2 or 3 independently selected R.sup.q substituents;
[0224] 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;
[0225] or any two R.sup.c 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 independently selected R.sup.h substituents;
[0226] or any two R.sup.e 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 independently selected R.sup.h substituents;
[0227] or any two R.sup.g 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 independently selected R.sup.h substituents;
[0228] or any two R.sup.i 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 independently selected R.sup.q substituents;
[0229] or any two R.sup.k 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 independently selected R.sup.q substituents;
[0230] or any two R.sup.o 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 independently selected R.sup.h substituents;
[0231] or any two R.sup.r 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 independently selected R.sup.h substituents;
[0232] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0233] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0234] the subscript m is an integer of 0, 1, 2 or 3;
[0235] the subscript n is an integer of 0, 1, 2 or 3;
[0236] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0237] the subscript s is an integer of 1, 2, or 3.
[0238] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0239] ring A is 5- to 14-membered heteroaryl, 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-10 cycloalkyl, wherein
the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.6 substituents;
[0240] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13SO.sub.2NR.sup.13--, --NR.sup.13C(O)O-- or
--NR.sup.13C(O)NR.sup.13--;
[0241] X is N or CR.sup.17;
[0242] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0243] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0244] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0245] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 independently selected R.sup.b substituents;
[0246] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0247] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
independently selected R.sup.q substituents;
[0248] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.q
substituents;
[0249] 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, 5-14 membered heteroaryl,
4-14 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 (4-14 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, 5-14 membered heteroaryl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.d substituents;
[0250] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-14 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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-, (4-14 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,
5-14 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-14 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 (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.q substituents;
[0251] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.q
substituents;
[0252] each R.sup.b substituent is independently selected from
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, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH,
NH.sub.2, NO.sub.2, NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0253] 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
independently selected R.sup.d substituents;
[0254] 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 independently selected R.sup.h substituents;
[0255] or any two R.sup.c 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 independently selected R.sup.h substituents;
[0256] or any two R.sup.e 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 independently selected R.sup.h substituents;
[0257] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0258] each R.sup.j is 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, C.sub.1-4 haloalkoxy,
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;
[0259] each of R.sup.i and R.sup.k 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.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.i or R.sup.k are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0260] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0261] the subscript m is an integer of 0, 1, 2 or 3;
[0262] the subscript n is an integer of 0, 1, 2 or 3;
[0263] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0264] the subscript s is an integer of 1, 2, or 3.
[0265] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0266] ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-10 cycloalkyl, wherein
the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0267] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, --NR.sup.13SO.sub.2--,
--NR.sup.13C(O)O-- or --NR.sup.13C(O)NR.sup.13--;
[0268] X is N or CR.sup.17;
[0269] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0270] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0271] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0272] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6, R.sup.7,
R.sup.17 and R.sup.18 are each optionally substituted with 1, 2, 3,
4 or 5 R.sup.b substituents;
[0273] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0274] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0275] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0276] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 R.sup.q substituents;
[0277] 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;
[0278] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NH.sub.2, NHOR.sup.e,
OR.sup.e, SR.sup.e, C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e,
OC(O)R.sup.e, OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)NR.sup.eR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents;
[0279] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0280] each R.sup.b substituent is independently selected from
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, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH,
NH.sub.2, NO.sub.2, NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0281] 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;
[0282] each R.sup.f is 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, 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;
[0283] each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0284] 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-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, 2, or 3 R.sup.p
substituents;
[0285] each R.sup.p is 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;
[0286] 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;
[0287] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents;
[0288] each R.sup.j is 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;
[0289] 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;
[0290] 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;
[0291] 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;
[0292] 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;
[0293] 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 1, 2, or 3
independently selected R.sup.q substituents;
[0294] 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 1, 2, or 3
independently selected R.sup.q substituents;
[0295] 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;
[0296] or any two R.sup.r 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;
[0297] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.r are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0298] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0299] the subscript m is an integer of 0, 1, 2 or 3;
[0300] the subscript n is an integer of 0, 1, 2 or 3;
[0301] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0302] the subscript s is an integer of 1, 2, or 3.
[0303] In some embodiments, provided herein is a compound of
Formula (I) or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[0304] ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl, C.sub.6-10 aryl or C.sub.3-10 cycloalkyl, wherein
the 5- to 10-membered heteroaryl and 4- to 11-membered
heterocycloalkyl each has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1, 2, 3, 4 or 5 R.sup.6
substituents;
[0305] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, O,
--(CR.sup.14R.sup.15).sub.q, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.q--NR.sup.13--,
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, --CH.dbd.CH--,
--C.ident.C--, --SO.sub.2NR.sup.13--, NR.sup.13SO.sub.2,
--NR.sup.13C(O)O-- or --NR.sup.13C(O)NR.sup.13--;
[0306] X is N or CR.sup.17;
[0307] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0308] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0309] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2;
[0310] R.sup.6, R.sup.7, R.sup.17 and R.sup.18 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.6 are each
optionally substituted with 1, 2, 3, 4 or 5 R.sup.b
substituents;
[0311] or two R.sup.6 substituents attached to the same ring carbon
atom taken together with the ring carbon atom to which they are
attached form spiro C.sub.3-6 cycloalkyl or spiro 4- to 7-membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, or 3 independently selected R.sup.f substituents;
[0312] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl optionally substituted with a substituent selected
from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4
alkyl and --N(C.sub.1-4 alkyl).sub.2;
[0313] R.sup.14 and R.sup.15 are each independently selected from
H, halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.14 or R.sup.15 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents;
[0314] or R.sup.14 and R.sup.15 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 R.sup.q substituents;
[0315] 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;
[0316] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NH.sub.2, NHOR.sup.e,
OR.sup.e, SR.sup.e, C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e,
OC(O)R.sup.e, OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)NR.sup.eR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.d are each optionally substituted with 1, 2, or 3
independently selected R.sup.f substituents;
[0317] each R.sup.e 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.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.e are each optionally
substituted with 1, 2 or 3 independently selected R.sup.f
substituents;
[0318] each R.sup.b substituent is independently selected from
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, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH,
NH.sub.2, NO.sub.2, NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c, NHR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0319] 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;
[0320] each R.sup.f is 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, 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;
[0321] each R.sup.n is 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.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,
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.n are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0322] 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, 2, or 3 R.sup.p
substituents;
[0323] each R.sup.p is 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;
[0324] 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;
[0325] each R.sup.h is 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.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
OR.sup.i, SR.sup.i, NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i,
C(O)OR.sup.i, OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i,
NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents;
[0326] each R.sup.j is 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;
[0327] 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;
[0328] 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;
[0329] 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;
[0330] 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 1, 2, or 3
independently selected R.sup.q substituents;
[0331] 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 1, 2, or 3
independently selected R.sup.q substituents;
[0332] 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;
[0333] or any two R.sup.r 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;
[0334] each 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.1-6 haloalkyl, C.sub.1-6 haloalkoxy, 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.i, R.sup.k, R.sup.o or R.sup.p are each optionally
substituted with 1, 2 or 3 R.sup.q substituents;
[0335] each R.sup.q is independently selected from halo, OH, CN,
--COOH, NH.sub.2, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, phenyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl and C.sub.3-6
cycloalkyl, 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 1, 2, or
3 substituents selected from halo, OH, CN, --COOH, NH.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, phenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl;
[0336] the subscript m is an integer of 0, 1, 2 or 3;
[0337] the subscript n is an integer of 0, 1, 2 or 3;
[0338] the subscript p is an integer of 1, 2, 3 or 4;
[0339] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0340] the subscript s is an integer of 1, 2, or 3.
[0341] In some embodiments, any two R.sup.i 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 independently selected R.sup.q
substituents;
[0342] or any two R.sup.k 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 independently selected R.sup.q substituents.
[0343] In some embodiments, provided herein is a compound of
Formula (I) or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein (1) when L is --C(O)NH--, ring A is not
4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a
bond, ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L
is a bond, ring A is not 2-benzoxazolyl; and (4) when L is
--C(O)NH--, ring A is not 2-pyridyl.
[0344] In some embodiments, provided herein is a compound of
Formula (I) or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein (1) when L is --C(O)NH--, ring A is not
4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a
bond, ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L
is a bond, ring A is not 2-benzoxazolyl; or (4) when L is
--C(O)NH--, ring A is not 2-pyridyl.
[0345] In some embodiments, provided herein is a compound of
Formula (Ia):
##STR00005##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0346] R.sup.17 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each optionally
substituted with 1 or 2 substituents independently selected from
CN, halo and --C(O)NH.sub.2; one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or
--N(C.sub.1-4 alkyl).sub.2, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH,
--COOH, --C(O)NH.sub.2, NH.sub.2, --NHC.sub.1-4 alkyl and
--N(C.sub.1-4 alkyl).sub.2;
[0347] R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each optionally
substituted with 1 or 2 substituents independently selected from
CN, halo or --C(O)NH.sub.2;
[0348] R.sup.8 and R.sup.9 are each independently selected from H,
halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.8 or R.sup.9 are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0349] or R.sup.8 and R.sup.9 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 4-, 5-, 6- or 7-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 R.sup.q substituents;
[0350] or R.sup.8 and R.sup.10 taken together with the atoms to
which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, having zero to one additional heteroatoms as ring
members selected from O, N or S, wherein the 4-, 5-, 6- or
7-membered heterocycloalkyl formed by R.sup.8 and R.sup.10 are each
optionally substituted with 1 or 2 R.sup.q substituents;
[0351] R.sup.10 and R.sup.11 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
--C(O)R.sup.g, --C(O)OR.sup.g, --C(O)NR.sup.gR.sup.g, --SO.sub.2R
and --SO.sub.2NR.sup.gR.sup.g, wherein the C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-6 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.10 or R.sup.11 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0352] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, 10-,
or 11-membered heterocycloalkyl, wherein the 4-1 membered
heterocycloalkyl is each optionally substituted with 1, 2 or 3
R.sup.f substituents;
[0353] R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2; and
[0354] the subscript p is an integer of 1, 2, 3 or 4.
[0355] In some embodiments, provided herein is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0356] R.sup.17 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each optionally
substituted with 1 or 2 substituents independently selected from
CN, halo and --C(O)NH.sub.2;
[0357] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, OH, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or
--N(C.sub.1-4 alkyl).sub.2, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH,
--COOH, --C(O)NH.sub.2, NH.sub.2, --NHC.sub.1-4 alkyl and
--N(C.sub.1-4 alkyl).sub.2;
[0358] R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2, wherein the
C.sub.1-4 alkyl and C.sub.1-4 alkoxy are each optionally
substituted with 1 or 2 substituents independently selected from
CN, halo or --C(O)NH.sub.2;
[0359] R.sup.8 and R.sup.9 are each independently selected from H,
halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-6 membered heterocycloalkyl of R.sup.8 or R.sup.9 are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0360] or R.sup.8 and R.sup.9 taken together with the carbon atom
to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl
or 4-, 5-, 6- or 7-membered heterocycloalkyl, each of which is
optionally substituted with 1 or 2 R.sup.q substituents;
[0361] or R.sup.8 and R.sup.10 taken together with the atoms to
which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, having zero to one additional heteroatoms as ring
members selected from O, N or S, wherein the 4-, 5-, 6- or
7-membered heterocycloalkyl formed by R.sup.8 and R.sup.10 are each
optionally substituted with 1 or 2 R.sup.q substituents;
[0362] R.sup.10 and R.sup.11 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
--C(O)R.sup.g, --C(O)OR.sup.g, --C(O)NR.sup.gR.sup.g,
--SO.sub.2R.sup.g and --SO.sub.2NR.sup.gR.sup.g, wherein the
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-6
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.10 or R.sup.11 are each optionally substituted with 1, 2, or
3 independently selected R.sup.d substituents;
[0363] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, 10-,
or 11-membered heterocycloalkyl, wherein the 4-1 membered
heterocycloalkyl is each optionally substituted with 1, 2 or 3
R.sup.f substituents; and
[0364] R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH, NH.sub.2,
--NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2.
[0365] In some embodiments, the compound provided herein is a
compound having Formula (II):
##STR00006##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0366] In some embodiments, the compound provided herein is a
compound having Formula (IIa):
##STR00007##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0367] In some embodiments, the compound provided herein is a
compound having Formula (IIa-1):
##STR00008##
[0368] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[0369] ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl or C.sub.6-10 aryl, wherein the 5- to 10-membered
heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4
heteroatoms as ring members selected from N, O and S, wherein the N
or S atom as ring members is optionally oxidized and one or more
carbon atoms as ring members are each optionally replaced by a
carbonyl group; and wherein ring A is optionally substituted with
1, 2 or 3 R.sup.6 substituents; L is a bond, --C(O)NH--, --NH-- or
--OCH.sub.2--, wherein the carbonyl group in the --C(O)NH-- linkage
or the oxygen atom in the --OCH.sub.2-- linkage is attached to ring
A; and
[0370] X is CH or N.
[0371] In some embodiments, the compound provided herein is a
compound having Formula (IIa-2):
##STR00009##
[0372] or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0373] In some embodiments, the compound provided herein is a
compound having Formula (IIb):
##STR00010##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0374] In some embodiments, the compound provided herein is a
compound having Formula (IIc):
##STR00011##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0375] X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are
each independently N or CH, with the proviso that X.sup.1, X.sup.5
and X.sup.6 are not simultaneously N;
[0376] R.sup.13 is H or C.sub.1-4 alkyl; and
[0377] the subscript r is an integer of 1, 2 or 3.
[0378] In some embodiments, the compound provided herein is a
compound having Formula (IIc-1):
##STR00012##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0379] In some embodiments, R.sup.13 is H.
[0380] In some embodiments, the compound provided herein is a
compound having Formula (IId):
##STR00013##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0381] R.sup.13 is H or C.sub.1-4 alkyl;
[0382] R.sup.19 is 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-, or (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.18 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents; and
[0383] the subscript t is an integer of 0, 1 or 2.
[0384] In some embodiments, the compound provided herein is a
compound having Formula (IId-1):
##STR00014##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0385] In some embodiments, the compound provided herein is a
compound having Formula (IIe):
##STR00015##
or a pharmaceutically acceptable salt or a stereoisomer thereof. In
some embodiments, the compound provided herein is a compound having
Formula (IIf):
##STR00016##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0386] In some embodiments, the compound provided herein is a
compound having Formula (III):
##STR00017##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0387] In some embodiments, the compound provided herein is a
compound having Formula (IIIa):
##STR00018##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0388] In some embodiments, the compound provided herein is a
compound having Formula (IIIb):
##STR00019##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0389] In some embodiments, provided herein are compounds having
Formula (IV):
##STR00020##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5. In some embodiments, X
is N or CH. In one embodiment, ring A is pyridyl, for example,
2-pyridyl. In some embodiments, the subscript n is 0, 1 or 2 and
each R.sup.5 is independently C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, OH, --COOH,
NH.sub.2, --NHC.sub.1-4 alkyl or --N(C.sub.1-4 alkyl).sub.2. In
certain instances, R.sup.5 is halo or C.sub.1-4 alkyl. In some
embodiments, the subscript m is 0. In some embodiments, the
subscript r is 1 or 2. In some embodiments, R.sup.12 is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, --COOH, NH.sub.2, --NHC.sub.1-4 alkyl or
--N(C.sub.1-4 alkyl).sub.2. In one embodiment, R.sup.2 is H. In
some embodiments, the subscript p is 1 and R.sup.8 and R.sup.9 are
each H. In one embodiment, R.sup.10 is H. In some embodiments,
R.sup.8 and R.sup.10 taken together form 4- to 6-membered
heterocycloalkyl, optionally substituted with 1 or 2 R.sup.q
substituents. In some embodiments, R.sup.10 and R.sup.11 taken
together form 4- to 6-membered heterocycloalkyl, optionally
substituted with 1 or 2 R.sup.q substituents.
[0390] In some embodiments, provided herein are compounds having
Formula (V):
##STR00021##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5, the other variables of
Formula (V) are as defined in any embodiment disclosed herein. In
some embodiments, the subscript r is 1 or 2.
[0391] In some embodiments, provided herein are compounds having
Formula (VI):
##STR00022##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5, the other variables of
Formula (VI) are as defined in any embodiment disclosed herein. In
some embodiments, the subscript r is 1 or 2.
[0392] In some embodiments, provided herein are compounds having
Formula (VIIa) or (VIIb):
##STR00023##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5, the other variables of
Formula (VIIa) or (VIIb) are as defined in any embodiment disclosed
herein. In some embodiments, the subscript r is 1 or 2.
[0393] In some embodiments, provided herein are compounds having
Formula (VIIIa) or (VIIIb):
##STR00024##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5, the other variables of
Formula (VIIIa) or (VIIIb) are as defined in any embodiment
disclosed herein. In some embodiments, the subscript r is 1 or
2.
[0394] In some embodiments, ring A is 5- to 14-membered heteroaryl,
4- to 14-membered heterocycloalkyl or C.sub.6-10 aryl, wherein the
5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl
each has 1-4 heteroatoms as ring members selected from N, O and S,
wherein the N or S atom as ring members is optionally oxidized and
one or more carbon atoms as ring members are each optionally
replaced by a carbonyl group; and wherein ring A is optionally
substituted with 1, 2, 3, or 4 R.sup.6 substituents. In some
embodiments, ring A is 5- to 14-membered heteroaryl or 4- to
14-membered heterocycloalkyl, wherein the 5- to 14-membered
heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4
heteroatoms as ring members selected from N, O and S, wherein the N
or S atom as ring members is optionally oxidized and one or more
carbon atoms as ring members are each optionally replaced by a
carbonyl group; and wherein ring A is optionally substituted with
1, 2, or 3 R.sup.6 substituents. In some embodiments, ring A is 5-
to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl
has 1-4 heteroatoms as ring members selected from N, O and S,
wherein the N or S atom as ring members is optionally oxidized and
one or more carbon atoms as ring members are each optionally
replaced by a carbonyl group; and wherein ring A is optionally
substituted with 1, 2, or 3 R.sup.6 substituents. In some
embodiments, ring A is 4- to 14-membered heterocycloalkyl, wherein
the 4- to 14-membered heterocycloalkyl has 1-4 heteroatoms as ring
members selected from N, O and S, wherein the N or S atom as ring
members is optionally oxidized and one or more carbon atoms as ring
members are each optionally replaced by a carbonyl group; and
wherein ring A is optionally substituted with 1, 2, or 3 R.sup.6
substituents.
[0395] In some embodiments, ring A is selected from:
##STR00025##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R.sup.16
is C.sub.1-6 alkyl; and the wavy line indicates the point of
attachment to L.
[0396] In some embodiments, ring A is selected from:
##STR00026##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0397] In some embodiments, ring A is selected from:
##STR00027##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0398] In some embodiments, ring A is selected from:
##STR00028##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0399] In some embodiments, ring A is
##STR00029##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0400] In some embodiments, ring A is selected from:
##STR00030##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R.sup.16
is C.sub.1-6 alkyl; and the wavy line indicates the point of
attachment to L.
[0401] In some embodiments, ring A is selected from:
##STR00031##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0402] In some embodiments, ring A is
##STR00032##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0403] In some embodiments, ring A is 2-pyridyl, optionally
substituted with 1, 2, 3, or 4 independently selected R.sup.6
substituents.
[0404] In some embodiments, ring A is
##STR00033##
wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the
wavy line indicates the point of attachment to L.
[0405] In some embodiments, ring A is selected from:
##STR00034##
wherein each subscript r is an integer of 1, 2 or 3.
[0406] In some embodiments, ring A is selected from:
##STR00035##
[0407] In some embodiments, L is a bond, --C(O)NR.sup.13--,
--NR.sup.13C(O)--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, --NR.sup.13--, or --CH.dbd.CH--. In
some embodiments, L is a bond, --C(O)NR.sup.13--,
--NR.sup.13C(O)--, --(CR.sup.14R.sup.15).sub.q--O--,
--O(CR.sup.14R.sup.15).sub.q--, or --NR.sup.13--. In some
embodiments, L is --C(O)NR.sup.13, --NR.sup.13C(O)--,
--(CR.sup.14R.sup.15).sub.q--O--, --O(CR.sup.14R.sup.15).sub.q--,
or --NR.sup.13--. In some embodiments, L is a bond,
--C(O)NR.sup.13--, --NR.sup.13C(O)--, --NR.sup.13--, or
--CH.dbd.CH--. In some embodiments, L is a bond, --NH--,
--CH.dbd.CH-- or --C(O)NH--, wherein the carbonyl group in the
--C(O)NH-- linkage is attached to ring A. In some embodiments, L is
a bond. In some embodiments, L is --C(O)NR.sup.13-- (e.g.,
--C(O)NH--), wherein the carbonyl group is attached to ring A. In
some embodiments, L is a bond, --NR.sup.13--,
--(CR.sup.14R.sup.15).sub.qO--, --O(CR.sup.14R.sup.15).sub.q--,
--(CR.sup.14R.sup.15).sub.qNR.sup.13-- or
--NR.sup.13--(CR.sup.14R.sup.15).sub.q--, wherein the subscript q
is 1, 2 or 3. In certain instances, R.sup.14 and R.sup.15 are each
independently H or C.sub.1-4 alkyl. In other instances, R.sup.14
and R.sup.15 taken together form C.sub.3-6 cycloalkyl or
4-6-membered heterocycloalkyl, each of which is optionally
substituted with 1 or 2 R.sup.q substituents.
[0408] In some embodiments, L is a bond.
[0409] In some embodiments, L is --NR.sup.13--. In certain
instances, R.sup.13 is H or C.sub.1-4 alkyl.
[0410] In some embodiments, L is --CH.sub.2O-- or
--OCH.sub.2--.
[0411] In some embodiments, L is --NR.sup.13CH.sub.2-- or
--CH.sub.2NR.sup.13. In certain instances, R.sup.13 is H or
C.sub.1-4 alkyl.
[0412] In some embodiments, L is --C(O)NH--.
[0413] In some embodiments, L is --NH--.
[0414] In some embodiments, the subscript m is 0, 1, or 2. In some
embodiments, the subscript m is 0 or 1. In some embodiments, the
subscript m is 0.
[0415] In some embodiments, R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH.
In some embodiments, R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, halo, or OH. In some embodiments, R.sup.5 is C.sub.1-4 alkyl or
halo. In some embodiments, R.sup.5 is C.sub.1-4 alkyl (e.g.,
methyl). In some embodiments, R.sup.5 is halo (e.g., C.sub.1).
[0416] In some embodiments, the subscript n is an integer of 0, 1,
or 2. In some embodiments, the subscript n is an integer of 1 or 2.
In some embodiments, the subscript n is an integer of 1.
[0417] In some embodiments, the subscript n is 1 and R.sup.5 is
halo or C.sub.1-4 alkyl. In some embodiments, the subscript n is 1
and R.sup.5 is halo. In some embodiments, the subscript n is 1 and
R.sup.5 is C.sub.1-4 alkyl.
[0418] In some embodiments, R.sup.3 is methyl, halo, or CN. In some
embodiments, R.sup.3 is methyl. In some embodiments, R.sup.3 is
halo (e.g., Cl). In some embodiments, R.sup.3 is CN. In some
embodiments, R.sup.3 is methyl, CN or Cl.
[0419] In some embodiments, R.sup.12 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, or OH. In some embodiments, R.sup.12 is H, halo, CN,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy. In some embodiments, R.sup.12
is H, halo, or C.sub.1-4 alkoxy. In some embodiments, R.sup.12 is
H.
[0420] In some embodiments, R.sup.7 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, or OH, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are
each optionally substituted with 1 or 2 substituents independently
selected from CN, halo and --C(O)NH.sub.2. In some embodiments,
R.sup.7 is H, halo, CN, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or
C.sub.1-4 haloalkoxy, wherein the C.sub.1-4 alkyl and C.sub.1-4
alkoxy of R.sup.7 are each optionally substituted with CN. In some
embodiments, R.sup.7 is H, halo, CN, or C.sub.1-4 alkyl. In some
embodiments, R.sup.7 is H or C.sub.1-4 alkyl. In some embodiments,
R.sup.7 is H.
[0421] In some embodiments, one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, and
OH. In some embodiments, one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or
C.sub.1-4 haloalkoxy. In some embodiments, one of R.sup.1 and
R.sup.2 is --(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the
other is H or C.sub.1-4 alkyl. In some embodiments, one of R.sup.1
and R.sup.2 is --(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the
other is H.
[0422] In some embodiments, R.sup.2 is H.
[0423] In some embodiments, R.sup.1 is H.
[0424] In some embodiments, R.sup.2, R.sup.7 and R.sup.12 are each
H.
[0425] In some embodiments, R.sup.3 and R.sup.5 are each
independently halo, methyl or CN.
[0426] In some embodiments, the subscript p is an integer of 1, 2,
or 3. In some embodiments, the subscript p is an integer of 1 or 2.
In some embodiments, the subscript p is 1.
[0427] In some embodiments, R.sup.8 and R.sup.9 are each
independently selected from H, halo, CN, OH, --COOH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 haloalkyl, and C.sub.1-4 haloalkoxy,
wherein the C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
and C.sub.1-4 haloalkoxy of R.sup.8 or R.sup.9 are each optionally
substituted with 1 or 2 independently selected R.sup.q
substituents. In some embodiments, R.sup.8 and R.sup.9 are each
independently selected from H, halo, CN, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy
of R.sup.8 or R.sup.9 are each optionally substituted with 1 or 2
independently selected R.sup.q substituents. In some embodiments, R
and R.sup.9 are each independently selected from H and C.sub.1-4
alkyl. In some embodiments, R.sup.8 is H. In some embodiments,
R.sup.9 is H.
[0428] In some embodiments, R.sup.8 and R.sup.9 are each H.
[0429] In some embodiments, R.sup.10 and R.sup.11 are each
independently selected from H, C.sub.1-6 alkyl, and C.sub.1-6
haloalkyl, wherein the C.sub.1-6 alkyl and C.sub.1-6 haloalkyl of
R.sup.10 or R.sup.11 are each optionally substituted with 1, 2, or
3 independently selected R.sup.f substituents;
[0430] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents.
[0431] In some embodiments, R.sup.10 and R.sup.11 are each
independently selected from H and C.sub.1-6 alkyl optionally
substituted with 1 or 2 independently selected R.sup.f
substituents;
[0432] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents.
[0433] In some embodiments, R.sup.10 and R.sup.11 are each
independently selected from H and C.sub.1-6 alkyl optionally
substituted with 1 or 2 independently selected R.sup.f
substituents. In some embodiments, R.sup.10 and R.sup.11 taken
together with the nitrogen atom to which they are attached form 4-,
5-, 6- or 7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or
7-membered heterocycloalkyl is optionally substituted with 1, 2 or
3 R.sup.h substituents.
[0434] In some embodiments, R.sup.10 is H.
[0435] In some embodiments, R.sup.11 is 2-hydroxyethyl,
[1-(hydroxymethyl)cyclopropyl]methyl,
[1-(hydroxymethyl)cyclobutyl]methyl or
2-(dimethylamino)-2-oxo-ethyl.
[0436] In some embodiments, R.sup.11 is 1-hydroxy-2-propyl,
2-carboxyethyl, or 2-hydroxycyclopentyl.
[0437] In some embodiments, --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
(R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1-yl, (R)-3-carboxypyrrolidin-1-yl,
(S)-3-carboxypyrrolidin-1-yl, 3-carboxyazetidin-1-yl,
(S)-3-carboxyazetidin-1-yl, (R)-3-carboxyazetidin-1-yl,
2-carboxy-1-piperidinyl, (R)-2-carboxy-1-piperidinyl,
(S)-2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino,
[2-(dimethylamino)-2-oxo-ethyl]amino,
3-(dimethylaminocarbonyl)pyrrolidin-1-yl,
(R)-3-(dimethylaminocarbonyl)pyrrolidin-1-yl,
(S)-3-(dimethylaminocarbonyl)pyrrolidin-1-yl, 2-hydroxypropylamino,
2-hydroxy-2-methylpropylamino, or
3-methyl-3-carboxypyrrolidin-1-yl.
[0438] In some embodiments, --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1l-yl, 3-carboxyazetidin-1l-yl,
(S)-3-carboxyazetidin-1l-yl, (R)-3-carboxyazetidin-1-yl,
2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino or
[2-(dimethylamino)-2-oxo-ethyl]amino.
[0439] In some embodiments, --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1l-yl, 3-carboxyazetidin-1l-yl,
(S)-3-carboxyazetidin-1l-yl, (R)-3-carboxyazetidin-1-yl,
2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino,
[2-(dimethylamino)-2-oxo-ethyl]amino,
3-(dimethylaminocarbonyl)pyrrolidin-1-yl, 2-hydroxypropylamino,
2-hydroxy-2-methylpropylamino, or
3-methyl-3-carboxypyrrolidin-1-yl.
[0440] In some embodiments, --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl,
3-carboxypyrrolidin-1l-yl, 3-carboxyazetidin-1l-yl,
2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino or
[2-(dimethylamino)-2-oxo-ethyl]amino.
[0441] In some embodiments, --NR.sup.10R.sup.11 is 1-pyrrolidinyl,
(3-carboxy-3-methyl)pyrrolidin-1-yl,
(R)-(3-carboxy-3-methyl)pyrrolidin-1l-yl,
(S)-(3-carboxy-3-methyl)pyrrolidin-1l-yl,
(1-hydroxy-2-propyl)amino, (R)-(1-hydroxy-2-propyl)amino,
(S)-(1-hydroxy-2-propyl)amino, (3-hydroxy-3-methyl)pyrrolidin-1-yl,
(R)-(3-hydroxy-3-methyl)pyrrolidin-1-yl,
(S)-(3-hydroxy-3-methyl)pyrrolidin-1-yl,
(2-hydroxycyclopentyl)amino, ((1R,2S)-2-hydroxycyclopentyl)amino,
((1R,2R)-2-hydroxycyclopentyl)amino,
((1S,2S)-2-hydroxycyclopentyl)amino,
((1S,2R)-2-hydroxycyclopentyl)amino, 2-carboxyethylamino,
3-(carboxymethyl)pyrrolidin-1-yl, or
5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl.
[0442] In some embodiments, X is N or CR.sup.17, wherein R.sup.17
is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, CN, or halo. In some embodiments, X is N or
CR.sup.17, wherein R.sup.17 is H or C.sub.1-4 alkyl. In some
embodiments, X is N or CH. In some embodiments, X is N. In some
embodiments, X is CR.sup.17 (e.g., CH).
[0443] In some embodiments, R.sup.6, R.sup.7, R.sup.17 and R.sup.18
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, OR.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, and NR.sup.aC(O)OR.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.6, R.sup.7, R.sup.17
and R.sup.18 are each optionally substituted with 1, 2, or 3
independently selected R.sup.b substituents.
[0444] In some embodiments, R.sup.6, R.sup.7, R.sup.17 and R.sup.18
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.1-6haloalkoxy, 5-14 membered heteroaryl, 4-10 membered
heterocycloalkyl, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-,
(4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OR.sup.a,
C(O)R.sup.a, C(O)NR.sup.aR.sup.a, C(O)OR.sup.a, NHR.sup.a,
NR.sup.aR.sup.a, NR.sup.aC(O)R.sup.a, and NR.sup.aC(O)OR.sup.a,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14
membered heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6, R.sup.7, R.sup.17
and R.sup.18 are each optionally substituted with 1, 2, or 3
independently selected R.sup.b substituents.
[0445] In some embodiments, R.sup.6, R.sup.7, R.sup.17 and R.sup.18
are each independently selected from H, halo, C.sub.1-6 alkyl,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OR.sup.a, and C(O)R.sup.a,
wherein the C.sub.1-6 alkyl, (5-14 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.6, R.sup.7, R.sup.17 and R.sup.18 are each optionally
substituted with 1, 2, or 3 independently selected R.sup.b
substituents.
[0446] In some embodiments, R.sup.6 is H, C.sub.1-6 alkyl,
(3-carboxypyrrolidin-1-yl)methyl,
(R)-(3-carboxypyrrolidin-1-yl)methyl,
(S)-(3-carboxypyrrolidin-1-yl)methyl,
(3-hydroxypyrrolidin-1-yl)methyl,
(R)-(3-hydroxypyrrolidin-1-yl)methyl,
(S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl,
(2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl,
2-(3-carboxyazetidin-1-yl)ethanoyl,
(R)-2-(3-carboxyazetidin-1-yl)ethanoyl,
(S)-2-(3-carboxyazetidin-1-yl)ethanoyl,
2-(2-carboxypiperidin-1-yl)ethanoyl,
(R)-2-(2-carboxypiperidin-1-yl)ethanoyl,
(S)-2-(2-carboxypiperidin-1-yl)ethanoyl,
2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,
(5-cyanopyridin-3-yl)methoxy, halo or CN.
[0447] In some embodiments, R.sup.6 is (4-carboxycyclohexyl)methyl,
trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl,
1-carboxy-2-propyl, (R)-1-carboxy-2-propyl, (S)-1-carboxy-2-propyl,
(4-carboxy-4-methylcyclohexyl)methyl, 2-pyrrolidinyl,
2-(3-hydroxypyrrolidin-1-yl)acetyl,
2-((R)-3-hydroxypyrrolidin-1-yl)acetyl,
2-((S)-3-hydroxypyrrolidin-1-yl)acetyl,
2-(3-hydroxyazetidin-1-yl)acetyl,
2-((2-hydroxyethyl)(methyl)amino)acetyl,
(4-carboxycyclohexyl)ethyl, 4-carboxycyclohexyl,
4-carboxy-4-methylcyclohexyl, dimethylglycyl, or
N-ethyl-N-methylglycyl.
[0448] In some embodiments, 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, 5-14 membered heteroaryl, 4-14 membered
heterocycloalkyl, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and
(4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14
membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents. In some embodiments, each R.sup.a is independently
selected from H, CN, C.sub.1-6 alkyl, 5-14 membered heteroaryl,
4-14 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14
membered heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1 or 2 independently selected R.sup.d
substituents. In some embodiments, each R.sup.a is independently
selected from H, CN, C.sub.1-6 alkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1 or 2 independently selected R.sup.d
substituents.
[0449] In some embodiments, each R.sup.d is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, CN, NH.sub.2,
OR.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, and
NR.sup.eC(O)R.sup.e, wherein the C.sub.1-6 alkyl of R.sup.d are
each optionally substituted with 1 or 2 independently selected
R.sup.f substituents. In some embodiments, each R.sup.d is
independently selected from C.sub.1-6 alkyl, CN, NH.sub.2,
OR.sup.e, C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e,
NHR.sup.e, or NR.sup.eR.sup.e.
[0450] In some embodiments, each R.sup.e is independently selected
from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl. In some embodiments, each R.sup.e is
independently selected from H and C.sub.1-6 alkyl.
[0451] In some embodiments, each R.sup.b substituent is
independently selected from 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, 5-10 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, OR.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, NHR.sup.c, NR.sup.cR.sup.c, and
NR.sup.cC(O)R.sup.c; wherein the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkoxy, 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.b are each further
optionally substituted with 1 or 2 independently selected R.sup.d
substituents. In some embodiments, each R.sup.b substituent is
independently selected from 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, CN, OH, NH.sub.2, OR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, NHR.sup.c, and NR.sup.cR.sup.c;
wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl of R.sup.b are
each further optionally substituted with 1 or 2 independently
selected R.sup.d substituents. In some embodiments, each R.sup.b
substituent is independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, OH, NH.sub.2, OR.sup.c,
C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, NHR.sup.c, and
NR.sup.cR.sup.c; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl of R.sup.b are each further optionally
substituted with 1 or 2 independently selected R.sup.d
substituents.
[0452] In some embodiments, each R.sup.c is independently selected
from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl of R.sup.c are each optionally
substituted with 1 or 2 independently selected R.sup.f
substituents. In some embodiments, each R.sup.c is independently
selected from H and C.sub.1-6 alkyl optionally substituted with 1
or 2 independently selected R.sup.f substituents.
[0453] In some embodiments, each R.sup.f is independently selected
from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halo, CN, OR.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 and
NR.sup.gC(O)R.sup.g; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl of R.sup.f are
each optionally substituted with 1 or 2 independently selected
R.sup.n substituents. In some embodiments, each R.sup.f is
independently selected from C.sub.1-4 alkyl, halo, CN, OR.sup.g,
C(O)R.sup.g, NHR.sup.g, and NR.sup.gR.sup.g; wherein the C.sub.1-4
alkyl is optionally substituted with 1 or 2 independently selected
R.sup.n substituents. In some embodiments, each R.sup.f is
independently selected from C.sub.1-4 alkyl, halo, and
OR.sup.g.
[0454] In some embodiments, each R.sup.g is independently selected
from H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl of R.sup.g are each optionally
substituted with 1 or 2 independently selected R.sup.p
substituents. In some embodiments, each R.sup.g is independently
selected from H and C.sub.1-6 alkyl.
[0455] In some embodiments, provided herein is a compound of
Formula (I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0456] ring A is 5- to 10-membered heteroaryl, 4- to 11-membered
heterocycloalkyl, or C.sub.6-10 aryl, wherein the 5- to 10-membered
heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4
heteroatoms as ring members selected from N, O and S, wherein the N
or S atom as ring members is optionally oxidized and one or more
carbon atoms as ring members are each optionally replaced by a
carbonyl group; and wherein ring A is optionally substituted with
1, 2 or 3 R.sup.6 substituents;
[0457] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--,
--(CR.sup.14R.sup.15).sub.q--O--, --O(CR.sup.14R.sup.15).sub.q--,
--NR.sup.13--, or CH.dbd.CH--;
[0458] X is N or CR.sup.17, wherein R.sup.17 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, or OH, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are
each optionally substituted with 1 or 2 substituents independently
selected from CN, halo and --C(O)NH.sub.2;
[0459] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, and
OH;
[0460] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0461] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or C.sub.1-4
haloalkyl;
[0462] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0463] each R.sup.6 is 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, 5-14 membered heteroaryl, 4-10
membered heterocycloalkyl, (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, 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, or NR.sup.aC(O)OR.sup.a, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents;
[0464] R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0465] R.sup.8 and R.sup.9 are each independently selected from H,
halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, and C.sub.1-4
haloalkyl;
[0466] R.sup.10 and R.sup.11 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, --C(O)R.sup.g,
--C(O)OR.sup.g, and --C(O)NR.sup.gR.sup.g, wherein the C.sub.1-6
alkyl and C.sub.1-6 haloalkyl of R.sup.10 or R.sup.11 are each
optionally substituted with 1 or 2 independently selected R.sup.f
substituents;
[0467] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0468] R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0469] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl;
[0470] R.sup.14 and R.sup.15 are each independently selected from
H, halo, or C.sub.1-4 alkyl;
[0471] 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,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a are each optionally
substituted with 1, 2, 3 or independently selected R.sup.d
substituents;
[0472] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, CN, NH.sub.2, OR.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, and
NR.sup.eC(O)R.sup.e;
[0473] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0474] each R.sup.b substituent is independently selected from
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
CN, OH, NH.sub.2, NO.sub.2, OR.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, and NR.sup.cC(O)OR.sup.c;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy of R.sup.b are each further optionally substituted with
1 or 2 independently selected R.sup.d substituents;
[0475] 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, C.sub.6-10 aryl-C.sub.1-4
alkyl-, and C.sub.3-10 cycloalkyl-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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1, 2, or 3 R.sup.f substituents;
[0476] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo,
CN, OR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.gC(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.iC(O)R, and NR.sup.gC(O)OR.sup.g;
[0477] each R.sup.g is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0478] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halo, CN, OR.sup.i, 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, and NR.sup.iC(O)OR.sup.i, wherein the
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl of
R.sup.h are each further optionally substituted by 1, 2, or 3
R.sup.j substituents;
[0479] each R.sup.j is independently selected from C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and CN;
[0480] 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;
[0481] each R.sup.i is independently selected from H, C.sub.1-4
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl;
[0482] the subscript m is an integer of 0, 1, or 2;
[0483] the subscript n is an integer of 0, 1, or 2; and
the subscript p is an integer of 1, 2, or 3.
[0484] In some embodiments, provided herein is a compound of
Formula (I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0485] ring A is 5- to 10-membered heteroaryl or 4- to 11-membered
heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4-
to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring
members selected from N, O and S, wherein the N or S atom as ring
members is optionally oxidized and one or more carbon atoms as ring
members are each optionally replaced by a carbonyl group; and
wherein ring A is optionally substituted with 1, 2 or 3 R.sup.6
substituents;
[0486] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--,
--NR.sup.13--, or CH.dbd.CH--;
[0487] X is N or CR.sup.17, wherein R.sup.17 is H, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN,
halo, or OH, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are
each optionally substituted with 1 or 2 substituents independently
selected from CN, halo and --C(O)NH.sub.2;
[0488] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, CN, halo, or OH, wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy of R.sup.1 or R.sup.2 is optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, and
OH;
[0489] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0490] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or C.sub.1-4
haloalkyl;
[0491] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0492] each R.sup.6 is 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, 5-14 membered heteroaryl, 4-10
membered heterocycloalkyl, (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, 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, or NR.sup.aC(O)OR.sup.a, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents;
[0493] R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0494] R.sup.8 and R.sup.9 are each independently selected from H,
halo, CN, OH, --COOH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, and C.sub.1-4
haloalkyl;
[0495] R.sup.10 and R.sup.11 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, --C(O)R.sup.g,
--C(O)OR.sup.g, and --C(O)NR.sup.gR.sup.g, wherein the C.sub.1-6
alkyl and C.sub.1-6 haloalkyl of R.sup.10 or R.sup.11 are each
optionally substituted with 1 or 2 independently selected R.sup.f
substituents;
[0496] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0497] R.sup.12 is H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH;
[0498] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl;
[0499] 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, and C.sub.2-6
alkynyl;
[0500] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, CN, NH.sub.2, OR.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, and
NR.sup.eC(O)R.sup.e;
[0501] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0502] each R.sup.b substituent is independently selected from
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
CN, OH, NH.sub.2, NO.sub.2, OR.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, and NR.sup.cC(O)OR.sup.c;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy of R.sup.b are each further optionally substituted with
1 or 2 independently selected R.sup.d substituents;
[0503] 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, C.sub.6-10 aryl-C.sub.1-4
alkyl-, and C.sub.3-10 cycloalkyl-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, C.sub.6-10 aryl-C.sub.1-4 alkyl-, and
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1, 2, or 3 R.sup.f substituents;
[0504] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo,
CN, OR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.gC(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.iC(O)R, and NR.sup.iC(O)OR.sup.g;
[0505] each R.sup.g is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0506] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halo, CN, OR.sup.i, C(O)R.sup.i,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, OC(O)R, OC(O)NR.sup.iR.sup.i,
NHR.sup.i, NR.sup.iR.sup.i, NR.sup.iC(O)R, and
NR.sup.iC(O)OR.sup.i, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents;
[0507] each R.sup.j is independently selected from C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and CN;
[0508] 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;
[0509] each R.sup.i is independently selected from H, C.sub.1-4
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl;
[0510] the subscript m is an integer of 0, 1, or 2;
[0511] the subscript n is an integer of 0, 1, or 2; and
[0512] the subscript p is an integer of 1, 2, or 3.
[0513] In some embodiments provided herein is a compound of Formula
(I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0514] ring A is 5- to 10-membered heteroaryl or 4- to 11-membered
heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4-
to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring
members selected from N, O and S, wherein the N or S atom as ring
members is optionally oxidized and one or more carbon atoms as ring
members are each optionally replaced by a carbonyl group; and
wherein ring A is optionally substituted with 1, 2 or 3 R.sup.6
substituents;
[0515] L is a bond, --C(O)NR.sup.13-- or --NR.sup.13C(O)--;
[0516] X is CR.sup.17, wherein R.sup.17 is H or C.sub.1-4
alkyl;
[0517] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, or C.sub.1-4 alkoxy;
[0518] R.sup.3 is methyl, or halo;
[0519] R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
[0520] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or halo;
[0521] each R.sup.6 is independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 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, 5-14 membered heteroaryl,
4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents;
[0522] R.sup.7 is H or C.sub.1-4 alkyl;
[0523] R.sup.8 and R.sup.9 are each independently selected from H
and C.sub.1-4 alkyl;
[0524] R.sup.10 and R.sup.11 are each independently selected from H
and C.sub.1-6 alkyl optionally substituted with 1 or 2
independently selected R.sup.f substituents;
[0525] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0526] R.sup.12 is H or C.sub.1-4 alkyl;
[0527] each R.sup.13 is independently H or C.sub.1-6 alkyl;
[0528] each R.sup.b substituent is independently selected from
halo, C.sub.1-6 alkyl, OH, NH.sub.2, C(O)OR.sup.c, NHR.sup.c, and
NR.sup.cR.sup.c;
[0529] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1 or 2 R.sup.f substituents;
[0530] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, OR.sup.g, and
C(O)OR.sup.g;
[0531] each R.sup.g is independently selected from H and C.sub.1-6
alkyl;
[0532] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, and
C(O)OR.sup.i;
[0533] 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;
[0534] each R.sup.i is independently selected from H and C.sub.1-4
alkyl;
[0535] the subscript m is an integer of 0 or 1;
[0536] the subscript n is an integer of 0 or 1; and
[0537] the subscript p is an integer of 1 or 2.
[0538] In some embodiments provided herein is a compound of Formula
(I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0539] ring A is 5- to 10-membered heteroaryl, wherein the 5- to
10-membered heteroaryl has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1 or 2 R.sup.6 substituents;
[0540] L is a bond, --C(O)NR.sup.13-- or --NR.sup.13C(O)--;
[0541] X is CR.sup.17, wherein R.sup.17 is H;
[0542] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is
H;
[0543] R.sup.3 is methyl, or halo;
[0544] R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
[0545] R.sup.5 is C.sub.1-4 alkyl or halo;
[0546] each R.sup.6 is independently selected from H, C.sub.1-6
alkyl, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1 or 2 R.sup.b substituents;
[0547] R.sup.7 is H;
[0548] R.sup.8 and R.sup.9 are each independently selected from H
and C.sub.1-4 alkyl;
[0549] R.sup.10 and R.sup.11 are each independently selected from H
and C.sub.1-6 alkyl optionally substituted with 1 or 2
independently selected R.sup.f substituents;
[0550] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0551] R.sup.12 is H;
[0552] R.sup.13 is H;
[0553] each R.sup.b substituent is independently selected from OH,
C(O)OR.sup.c, NHR.sup.c, and NR.sup.cR.sup.c;
[0554] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, and C.sub.3-10 cycloalkyl, wherein the C.sub.1-6 alkyl, and
C.sub.3-10 cycloalkyl of R.sup.c are each optionally substituted
with 1 or 2 R.sup.f substituents;
[0555] each R.sup.f is independently selected from OR.sup.g, and
C(O)OR.sup.g;
[0556] R.sup.g is H;
[0557] each R.sup.h is independently selected from OR.sup.i and
C(O)OR.sup.i;
[0558] 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;
[0559] R.sup.i is H;
[0560] the subscript m is an integer of 0 or 1;
[0561] the subscript n is an integer of 0 or 1; and
[0562] the subscript p is an integer of 1 or 2.
[0563] In some embodiments provided herein is a compound of Formula
(I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0564] ring A is 5- to 10-membered heteroaryl or 4- to 11-membered
heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4-
to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring
members selected from N, O and S, wherein the N or S atom as ring
members is optionally oxidized and one or more carbon atoms as ring
members are each optionally replaced by a carbonyl group; and
wherein ring A is optionally substituted with 1, 2 or 3 R.sup.6
substituents;
[0565] L is a bond, --C(O)NR.sup.13--, --NR.sup.13--, or
--NR.sup.13C(O)--;
[0566] X is CR.sup.17, wherein R.sup.17 is H or C.sub.1-4
alkyl;
[0567] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is H,
C.sub.1-4 alkyl, or C.sub.1-4 alkoxy;
[0568] R.sup.3 is methyl, or halo;
[0569] R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
[0570] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or halo;
[0571] each R.sup.6 is independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 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, 5-14 membered heteroaryl,
4-10 membered heterocycloalkyl, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents;
[0572] R.sup.7 is H or C.sub.1-4 alkyl;
[0573] R.sup.8 and R.sup.9 are each independently selected from H
and C.sub.1-4 alkyl;
[0574] R.sup.10 and R.sup.11 are each independently selected from H
and C.sub.1-6 alkyl optionally substituted with 1 or 2
independently selected R.sup.f substituents;
[0575] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0576] R.sup.12 is H or C.sub.1-4 alkyl;
[0577] each R.sup.13 is independently H or C.sub.1-6 alkyl;
[0578] each R.sup.b substituent is independently selected from
halo, C.sub.1-6 alkyl, OH, NH.sub.2, C(O)OR.sup.c, NHR.sup.c, and
NR.sup.cR.sup.c;
[0579] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl- of R.sup.c are each
optionally substituted with 1 or 2 R.sup.f substituents;
[0580] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, OR.sup.g, and
C(O)OR.sup.g;
[0581] each R.sup.g is independently selected from H and C.sub.1-6
alkyl;
[0582] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, and
C(O)OR.sup.i;
[0583] 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;
[0584] each R.sup.i is independently selected from H and C.sub.1-4
alkyl;
[0585] the subscript m is an integer of 0 or 1;
[0586] the subscript n is an integer of 0 or 1; and
[0587] the subscript p is an integer of 1 or 2.
[0588] In some embodiments provided herein is a compound of Formula
(I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0589] ring A is 5- to 10-membered heteroaryl, wherein the 5- to
10-membered heteroaryl has 1-4 heteroatoms as ring members selected
from N, O and S, wherein the N or S atom as ring members is
optionally oxidized and one or more carbon atoms as ring members
are each optionally replaced by a carbonyl group; and wherein ring
A is optionally substituted with 1 or 2 R.sup.6 substituents;
[0590] L is a bond, --C(O)NR.sup.13--, --NR.sup.13--, or
--NR.sup.13C(O)--;
[0591] X is CR.sup.17, wherein R.sup.17 is H;
[0592] one of R.sup.1 and R.sup.2 is
--(CR.sup.8R.sup.9).sub.p--NR.sup.10R.sup.11 and the other is
H;
[0593] R.sup.3 is methyl, or halo;
[0594] R.sup.4 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
[0595] R.sup.5 is C.sub.1-4 alkyl or halo;
[0596] each R.sup.6 is independently selected from H, C.sub.1-6
alkyl, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.6 are each optionally
substituted with 1 or 2 R.sup.b substituents;
[0597] R.sup.7 is H;
[0598] R.sup.8 and R.sup.9 are each independently selected from H
and C.sub.1-4 alkyl;
[0599] R.sup.10 and R.sup.11 are each independently selected from H
and C.sub.1-6 alkyl optionally substituted with 1 or 2
independently selected R.sup.f substituents;
[0600] or R.sup.10 and R.sup.11 taken together with the nitrogen
atom to which they are attached form 4-, 5-, 6- or 7-membered
heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered
heterocycloalkyl is optionally substituted with 1, 2 or 3 R.sup.h
substituents;
[0601] R.sup.12 is H;
[0602] R.sup.13 is H;
[0603] each R.sup.b substituent is independently selected from OH,
C(O)OR.sup.c, NHR.sup.c, and NR.sup.cR.sup.c;
[0604] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, and C.sub.3-10 cycloalkyl, wherein the C.sub.1-6 alkyl, and
C.sub.3-10 cycloalkyl of R.sup.c are each optionally substituted
with 1 or 2 R.sup.f substituents;
[0605] each R.sup.f is independently selected from OR.sup.g, and
C(O)OR.sup.g;
[0606] R.sup.g is H;
[0607] each R.sup.h is independently selected from OR.sup.i and
C(O)OR.sup.i;
[0608] 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;
[0609] R.sup.i is H;
[0610] the subscript m is an integer of 0 or 1;
[0611] the subscript n is an integer of 0 or 1; and
[0612] the subscript p is an integer of 1 or 2.
[0613] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment (while the embodiments are intended to be
combined as if written in multiply dependent form). Conversely,
various features of the invention which are, for brevity, described
in the context of a single embodiment, can also be provided
separately or in any suitable subcombination. Thus, it is
contemplated as features described as embodiments of the compounds
of Formula (I) can be combined in any suitable combination.
[0614] 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.
[0615] 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.
[0616] 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.
[0617] 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.
[0618] 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.
[0619] 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.
[0620] 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.
[0621] 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.
[0622] 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.
[0623] 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.
[0624] 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.
[0625] The term "amino," employed alone or in combination with
other terms, refers to a group of formula --NH.sub.2.
[0626] 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).
[0627] The term "cyano" or "nitrile" refers to a group of formula
--C.dbd.N, which also may be written as --CN.
[0628] 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.
[0629] 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.
[0630] 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.
[0631] 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.
[0632] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0633] 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).
[0634] 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.
[0635] The term "heteroatom" used herein is meant to include boron,
phosphorus, sulfur, oxygen and nitrogen.
[0636] 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 boron, phosphorus, 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 5-14, or
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.
[0637] 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.
[0638] 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.
[0639] 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, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons
(C.sub.3-14). In some embodiments, the cycloalkyl group has 3 to 14
members, 3 to 10 members, 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, norcamyl, 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.
[0640] 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 boron, nitrogen, sulfur
oxygen and phosphorus, and which has 4-14 ring members, 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 or polycyclic (e.g., having two or three fused or
bridged rings) ring systems or spirorcycles. In some embodiments,
the heterocycloalkyl group is a monocyclic group having 1, 2 or 3
heteroatoms independently selected from nitrogen, sulfur and
oxygen. Ring-forming carbon atoms and heteroatoms of a
heterocycloalkyl group can be optionally oxidized to form an oxo or
sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or
S(O).sub.2, N-oxide etc.) or a nitrogen atom can be quaternized.
The heterocycloalkyl group can be attached through a ring-forming
carbon atom or a ring-forming heteroatom. In some embodiments, the
heterocycloalkyl group contains 0 to 3 double bonds. In some
embodiments, the heterocycloalkyl group contains 0 to 2 double
bonds. Also included in the definition of heterocycloalkyl are
moieties that have one or more aromatic rings fused (i.e., having a
bond in common with) to the heterocycloalkyl ring, e.g., benzo or
thienyl derivatives of piperidine, morpholine, azepine, etc. A
heterocycloalkyl group containing a fused aromatic ring can be
attached through any ring-forming atom including a ring-forming
atom of the fused aromatic ring. Examples of heterocycloalkyl
groups include azetidinyl, azepanyl, dihydrobenzofuranyl,
dihydrofuranyl, dihydropyranyl, morpholino,
3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,
piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,
1,2,3,4-tetrahydroquinolinyl, tropanyl, tetrahydrothiazolopyridinyl
(e.g., 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) and
thiomorpholino.
[0641] 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.
[0642] 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.
[0643] 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.
[0644] 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.
[0645] 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.
[0646] 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.
[0647] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. One method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are,
e.g., optically active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,
malic acid, lactic acid or the various optically active
camphorsulfonic acids such as 3-camphorsulfonic acid. Other
resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of .alpha.-methylbenzylamine
(e.g., S and R forms, or diastereomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,
cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
[0648] 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.
[0649] 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.
[0650] 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.
[0651] 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.
[0652] 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.
[0653] 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.
[0654] 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.
[0655] 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.
[0656] 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.
[0657] 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
[0658] 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.
[0659] 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.
[0660] 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).
[0661] 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).
[0662] 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.
[0663] Compounds of Formula I can be synthesized using a process
shown in Scheme 1. In Scheme 1, a suitable halo
(Hal.sup.1)-substituted [4.4.0] aromatic heterocycle 1-1 is reacted
with a suitable halo (Hal.sup.2)-substituted aniline 1-2 to produce
compound 1-3 under standard S.sub.NAr conditions using an acid such
as, but not limited to, sulfuric acid, or base such as, but not
limited to, potassium tert-butoxide. Compounds of formula 1-3 may
also be synthesized under standard metal catalyzed cross-coupling
reaction conditions (such as Buchwald-Hartwig coupling reaction,
e.g., in the presence of a palladium catalyst (e.g.,
[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphe-
nyl)]palladium(II) methanesulfonate) and a base (e.g., cesium
carbonate)). Then the aromatic halide 1-3 can be reacted with a
suitable coupling reagent 1-4 (where M is, e.g., --B(OH).sub.2) to
provide the product of formula I 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)).
##STR00036##
[0664] Compounds of formula II can be synthesized using a process
shown in Scheme 2. A suitable halo (Hal.sup.1)-substituted [4.4.0]
aromatic heterocycle 2-1 can be reacted with a suitable halo
(Hal.sup.2)-substituted aniline 2-2 to produce formula 2-3 under
S.sub.NAr conditions using an acid such as, but not limited to,
sulfuric acid, or base such as, but not limited to, potassium
tert-butoxide. Compounds of formula 2-3 may also be synthesized
under standard metal catalyzed cross-coupling reaction conditions
(such as Buchwald-Hartwig coupling reaction, e.g., in the presence
of a palladium catalyst (e.g.,
[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphe-
nyl)]palladium(II) methanesulfonate) and a base (e.g., cesium
carbonate)). Then the aromatic halide 2-3 is reacted with a
suitable coupling reagent 2-4 (where M is, e.g., --B(OH).sub.2) to
form the bi-aryl bond of formula 2-5 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)). The vinyl group in
compound 2-5 can be oxidatively cleaved to afford an aldehyde in
the presence of suitable reagents such as, but not limited to,
OsO.sub.4 and NaIO.sub.4. Then the compound of formula II can be
obtained by a reductive amination between the aldehyde derivative
and a suitable amine 2-6 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 an acid such
as acetic acid or a base such as DIPEA.
##STR00037##
[0665] Compounds of formula II can be alternatively synthesized
using a process shown in Scheme 3. The vinyl group of a suitable
halo (Hal.sup.1)-substituted [4.4.0] aromatic heterocycle 3-1 can
be oxidatively cleaved to afford an aldehyde in the presence of
suitable reagents such as, but not limited to, OsO.sub.4 and
NaIO.sub.4. Then the compound of formula 3-3 can be obtained by a
reductive amination between the aldehyde derivative and a suitable
amine 3-2 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 an acid such as acetic acid or a base
such as DIPEA. The compound of formula 3-5 can be synthesized by
reacting formula 3-3 with a suitable halo (Hal.sup.2)-substituted
aniline 3-4 under standard S.sub.NAr conditions using an acid such
as, but not limited to, sulfuric acid, or base such as, but not
limited to, potassium tert-butoxide. Compounds of formula 3-5 may
also be synthesized under standard metal catalyzed cross-coupling
reaction conditions (such as Buchwald-Hartwig coupling reaction,
e.g., in the presence of a palladium catalyst (e.g.,
[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphe-
nyl)]palladium(II) methanesulfonate) and a base (e.g., cesium
carbonate)). Then the aromatic halide 3-5 is reacted with a
suitable coupling reagent 3-6 (where M is, e.g., --B(OH).sub.2) to
provide compounds of formula II 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)).
##STR00038##
[0666] Compounds of formula III can be synthesized using a process
shown in Scheme 4. A suitable halo (Hal.sup.1)-substituted [4.4.0]
aromatic heterocycle 4-1 can be reacted with a suitable halo
(Hal.sup.2)-substituted aniline 4-2 to produce a compound of
formula 4-3 under standard S.sub.NAr conditions using an acid such
as, but not limited to, sulfuric acid, or base such as, but not
limited to, potassium tert-butoxide. Compounds of formula 4-3 may
also be synthesized under standard metal catalyzed cross-coupling
reaction conditions (such as Buchwald-Hartwig coupling reaction,
e.g., in the presence of a palladium catalyst (e.g.,
[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphe-
nyl)]palladium(II) methanesulfonate) and a base (e.g., cesium
carbonate)). Then the aromatic halide 4-3 can be reacted with a
suitable coupling reagent 4-4 (where M is, e.g., --B(OH).sub.2) to
form the bi-aryl bond of formula 4-5 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)). The vinyl group in
compound 4-5 can be oxidatively cleaved to afford an aldehyde in
the presence of suitable reagents such as, but not limited to,
OsO.sub.4 and NaIO.sub.4. Then the compound of formula III is
obtained by a reductive amination between the aldehyde derivative
and a suitable amine 4-6 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 an acid such
as acetic acid or a base such as DIPEA.
##STR00039##
[0667] Compounds of formula III can be alternatively synthesized
using a process shown in Scheme 5. The vinyl group of a suitable
halo (Hal.sup.1)-substituted [4.4.0] aromatic heterocycle 5-1 can
be oxidatively cleaved to afford an aldehyde in the presence of
suitable reagents such as, but not limited to, OsO.sub.4 and
NaIO.sub.4. Then the compound of formula 5-3 is obtained by a
reductive amination between the aldehyde derivative and a suitable
amine 5-2 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 an acid such as acetic acid or a base
such as DIPEA. The compound of formula 5-5 can be synthesized by
reacting formula 5-3 with a suitable halo (Hal.sup.2)-substituted
aniline 5-4 under standard S.sub.NAr conditions using an acid such
as, but not limited to, sulfuric acid, or base such as, but not
limited to, potassium tert-butoxide. Compounds of formula 5-5 may
also be synthesized under standard metal catalyzed cross-coupling
reaction conditions (such as Buchwald-Hartwig coupling reaction,
e.g., in the presence of a palladium catalyst (e.g.,
[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphe-
nyl)]palladium(II) methanesulfonate) and a base (e.g., cesium
carbonate)). Then the aromatic halide 5-5 is reacted with a
suitable coupling reagent 5-6 (where M is, e.g., --B(OH).sub.2) to
provide compounds of formula II 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)).
##STR00040##
III. Uses of the Compounds
[0668] 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, chronic infection or sepsis, 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 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.
[0669] The compounds of the present disclosure inhibit the
PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway
blockade. The blockade of PD-1 can enhance the immune response to
cancerous cells and infectious diseases in mammals, including
humans. In some embodiments, the present disclosure provides
treatment of an individual or a patient in vivo using a compound of
Formula (I) or a salt or stereoisomer thereof such that growth of
cancerous tumors is inhibited. A compound of Formula (I) or of any
of the formulas as described herein, or a compound as recited in
any of the claims and described herein, or a salt or stereoisomer
thereof, can be used to inhibit the growth of cancerous tumors.
Alternatively, a compound of Formula (I) or of any of the formulas
as described herein, or a compound as recited in any of the claims
and described herein, or a salt or stereoisomer thereof, can be
used in conjunction with other agents or standard cancer
treatments, as described below. In one embodiment, the present
disclosure provides a method for inhibiting growth of tumor cells
in vitro. The method includes contacting the tumor cells in vitro
with a compound of Formula (I) or of any of the formulas as
described herein, or of a compound as recited in any of the claims
and described herein, or of a salt or stereoisomer thereof. In
another embodiment, the present disclosure provides a method for
inhibiting growth of tumor cells in an individual or a patient. The
method includes administering to the individual or patient in need
thereof a therapeutically effective amount of a compound of Formula
(I) or of any of the formulas as described herein, or of a compound
as recited in any of the claims and described herein, or a salt or
a stereoisomer thereof.
[0670] In some embodiments, provided herein is a method for
treating cancer. The method includes administering to a patient in
need thereof, a therapeutically effective amount of a compound of
Formula (I) or any of the formulas as described herein, a compound
as recited in any of the claims and described herein, or a salt
thereof. Examples of cancers include those whose growth may be
inhibited using compounds of the disclosure and cancers typically
responsive to immunotherapy.
[0671] 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-Ll.
[0672] 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, lung cancer (e.g. non-small cell lung cancer
and small cell lung cancer), squamous cell head and neck cancer,
urothelial cancer (e.g. bladder and cancers with high
microsatellite instability (MSI.sup.high). Additionally, the
disclosure includes refractory or recurrent malignancies whose
growth may be inhibited using the compounds of the disclosure.
[0673] 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.
[0674] In some embodiments, cancers that are treatable using the
compounds of the present disclosure include, but are not limited
to, cholangiocarcinoma, bile duct cancer, triple negative breast
cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma,
hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain
tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell
carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer,
Fallopian tube cancer, gastrointestinal cancer, gastrointestinal
stromal tumors, hairy cell leukemia, intestinal cancer, islet cell
cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer,
lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular
cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell
carcinoma, salivary gland cancer, sinus cancer, spinal cancer,
tongue cancer, tubular carcinoma, urethral cancer, and ureteral
cancer.
[0675] In some embodiments, the compounds of the present disclosure
can be used to treat sickle cell disease and sickle cell
anemia.
[0676] In some embodiments, diseases and indications that are
treatable using the compounds of the present disclosure include,
but are not limited to hematological cancers, sarcomas, lung
cancers, gastrointestinal cancers, genitourinary tract cancers,
liver cancers, bone cancers, nervous system cancers, gynecological
cancers, and skin cancers.
[0677] Exemplary hematological cancers include lymphomas and
leukemias such as acute lymphoblastic leukemia (ALL), acute
myelogenous leukemia (AML), acute promyelocytic leukemia (APL),
chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia
(CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma,
Non-Hodgkin lymphoma (including relapsed or refractory NHL and
recurrent follicular), Hodgkin lymphoma, myeloproliferative
diseases (e.g., primary myelofibrosis (PMF), polycythemia vera
(PV), essential thrombocytosis (ET)), myelodysplasia syndrome
(MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple
myeloma (MM).
[0678] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,
osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma,
liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma,
harmatoma, and teratoma.
[0679] Exemplary lung cancers include non-small cell lung cancer
(NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous
cell, undifferentiated small cell, undifferentiated large cell,
adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial
adenoma, chondromatous hamartoma, and mesothelioma.
[0680] Exemplary gastrointestinal cancers include cancers of the
esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,
lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas
(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma,
carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma,
carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,
neurofibroma, fibroma), large bowel (adenocarcinoma, tubular
adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal
cancer.
[0681] Exemplary genitourinary tract cancers include cancers of the
kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and
urethra (squamous cell carcinoma, transitional cell carcinoma,
adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis
(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,
choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
fibroadenoma, adenomatoid tumors, lipoma).
[0682] Exemplary liver cancers include hepatoma (hepatocellular
carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,
hepatocellular adenoma, and hemangioma.
[0683] Exemplary bone cancers include, for example, osteogenic
sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous
histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma
(reticulum cell sarcoma), multiple myeloma, malignant giant cell
tumor chordoma, osteochronfroma (osteocartilaginous exostoses),
benign chondroma, chondroblastoma, chondromyxofibroma, osteoid
osteoma, and giant cell tumors Exemplary nervous system cancers
include cancers of the skull (osteoma, hemangioma, granuloma,
xanthoma, osteitis deformans), meninges (meningioma,
meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma,
glioma, ependymoma, germinoma (pinealoma), glioblastoma,
glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), and spinal cord (neurofibroma,
meningioma, glioma, sarcoma), as well as neuroblastoma and
Lhermitte-Duclos disease.
[0684] Exemplary gynecological cancers include cancers of the
uterus (endometrial carcinoma), cervix (cervical carcinoma,
pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous
cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified
carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell
tumors, dysgerminoma, malignant teratoma), vulva (squamous cell
carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma,
melanoma), vagina (clear cell carcinoma, squamous cell carcinoma,
botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes
(carcinoma).
[0685] Exemplary skin cancers include melanoma, basal cell
carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles
dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In
some embodiments, diseases and indications that are treatable using
the compounds of the present disclosure include, but are not
limited to, sickle cell disease (e.g., sickle cell anemia),
triple-negative breast cancer (TNBC), myelodysplastic syndromes,
testicular cancer, bile duct cancer, esophageal cancer, and
urothelial carcinoma.
[0686] PD-1 pathway blockade with compounds of the present
disclosure can also be used for treating infections such as viral,
bacteria, fungus and parasite infections. The present disclosure
provides a method for treating infections such as viral infections.
The method includes administering to a patient in need thereof, a
therapeutically effective amount of a compound of Formula (I) or
any of the formulas as described herein, a compound as recited in
any of the claims and described herein, a salt thereof. Examples of
viruses causing infections treatable by methods of the present
disclosure include, but are not limit to, human immunodeficiency
virus, human papillomavirus, influenza, hepatitis A, B, C or D
viruses, adenovirus, poxvirus, herpes simplex viruses, human
cytomegalovirus, severe acute respiratory syndrome virus, ebola
virus, and measles virus. In some embodiments, viruses causing
infections treatable by methods of the present disclosure include,
but are not limit to, hepatitis (A, B, or C), herpes virus (e.g.,
VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus),
adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,
coxsackie virus, cornovirus, 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.
[0687] The present disclosure provides a method for treating
bacterial infections. The method includes administering to a
patient in need thereof, a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein,
a compound as recited in any of the claims and described herein, or
a salt thereof. Non-limiting examples of pathogenic bacteria
causing infections treatable by methods of the disclosure include
chlamydia, rickettsial bacteria, mycobacteria, staphylococci,
streptococci, pneumonococci, meningococci and conococci,
klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,
salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,
leptospirosis, and Lyme's disease bacteria.
[0688] The present disclosure provides a method for treating fungus
infections. The method includes administering to a patient in need
thereof, a therapeutically effective amount of a compound of
Formula (I) or any of the formulas as described herein, a compound
as recited in any of the claims and described herein, or a salt
thereof. Non-limiting examples of pathogenic fungi causing
infections treatable by methods of the disclosure include Candida
(albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus
neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales
(mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces
dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis
and Histoplasma capsulatum.
[0689] The present disclosure provides a method for treating
parasite infections. The method includes administering to a patient
in need thereof, a therapeutically effective amount of a compound
of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or a
salt thereof. Non-limiting examples of pathogenic parasites causing
infections treatable by methods of the disclosure include Entamoeba
histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0690] It is believed that compounds of Formula (I), or any of the
embodiments thereof, may possess satisfactory pharmacological
profile and promising biopharmaceutical properties, such as
toxicological profile, metabolism and pharmacokinetic properties,
solubility, and permeability. It will be understood that
determination of appropriate biopharmaceutical properties is within
the knowledge of a person skilled in the art, e.g., determination
of cytotoxicity in cells or inhibition of certain targets or
channels to determine potential toxicity.
[0691] 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.
[0692] 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.
[0693] 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.
[0694] 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
[0695] 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.
[0696] The compounds of the present disclosure can be used in
combination with one or more other enzyme/protein/receptor
inhibitors or one or more therapies for the treatment of diseases,
such as cancer or infections. Examples of diseases and indications
treatable with combination therapies include those as described
herein. Examples of cancers include solid tumors and liquid tumors,
such as blood cancers. Examples of infections include viral
infections, bacterial infections, fungus infections or parasite
infections. For example, the compounds of the present disclosure
can be combined with one or more inhibitors of the following
kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-.beta.R,
PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK,
mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF.alpha.R,
PDGF.beta.R, PI3K (alpha, beta, gamma, delta), CSFIR, KIT, FLK-II,
KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,
Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), 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, NLG919, BMS-986205), an LSD1 inhibitor (e.g.,
INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor
(e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor such as
PI3K-gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914),
a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl,
and Mer), an adenosine receptor antagonist (e.g., A2a/A2b receptor
antagonist), an HPK1 inhibitor, an histone deacetylase inhibitor
(HDAC) such as an HDAC8 inhibitor, 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), a poly ADP ribose
polymerase (PARP) inhibitor such as rucaparib, olaparib, niraparib,
veliparib, or talazoparib, an arginase inhibitor (INCB01158), and
an adenosine receptor antagonist or combinations thereof.
[0697] 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.
[0698] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0699] 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.
[0700] 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.
[0701] 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 or
tremelimumab.
[0702] 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, LAG525 or
INCAGN2385.
[0703] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In
some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or
TSR-022.
[0704] 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, MK-4166,
INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.
[0705] 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, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In
some embodiments, the OX40L fusion protein is MEDI6383.
[0706] 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).
[0707] 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, Toll receptor
agonists, STING agonists, 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, olaparib, oxaliplatin, paclitaxel, pamidronate,
panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium,
pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,
rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib,
streptozocin, sunitinib, sunitinib maleate, tamoxifen,
temozolomide, teniposide, testolactone, thalidomide, thioguanine,
thiotepa, topotecan, toremifene, tositumomab, trastuzumab,
tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,
vinorelbine, vorinostat, niraparib, veliparib, talazoparib and
zoledronate.
[0708] 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 (e.g. urelumab,
utomilumab), 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.
[0709] 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).
[0710] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts, stereoisomers thereof can be used in
combination with an immune checkpoint inhibitor for the treatment
of cancer and viral infections.
[0711] 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.
[0712] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0713] 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.
[0714] 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.
[0715] 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.
[0716] 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.
[0717] 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.
[0718] 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.
[0719] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0720] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be combined with another
immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate
molecules), cells, and cells transfected with genes encoding immune
stimulating cytokines. Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0721] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
a vaccination protocol for the treatment of cancer. In some
embodiments, the tumor cells are transduced to express GM-CSF. In
some embodiments, tumor vaccines include the proteins from viruses
implicated in human cancers such as Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present
disclosure can be used in combination with tumor specific antigen
such as heat shock proteins isolated from tumor tissue itself. In
some embodiments, the compounds of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or salts thereof can be combined with
dendritic cells immunization to activate potent anti-tumor
responses.
[0722] 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.
[0723] 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.
[0724] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
vaccines, to stimulate the immune response to pathogens, toxins,
and self antigens. Examples of pathogens for which this therapeutic
approach may be particularly useful, include pathogens for which
there is currently no effective vaccine, or pathogens for which
conventional vaccines are less than completely effective. These
include, but are not limited to, HIV, Hepatitis (A, B, & C),
Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus
aureus, Pseudomonas Aeruginosa.
[0725] 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, cornovirus, 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.
[0726] 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.
[0727] 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.
[0728] Pathogenic parasites causing infections treatable by methods
of the disclosure include, but are not limited to, Entamoeba
histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0729] 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
[0730] When employed as pharmaceuticals, the compounds of the
present disclosure can be administered in the form of
pharmaceutical compositions. Thus the present disclosure provides a
composition comprising a compound of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or a pharmaceutically acceptable salt
thereof, or any of the embodiments thereof, and at least one
pharmaceutically acceptable carrier or excipient. These
compositions can be prepared in a manner well known in the
pharmaceutical art, and can be administered by a variety of routes,
depending upon whether local or systemic treatment is indicated and
upon the area to be treated. Administration may be topical
(including transdermal, epidermal, ophthalmic and to mucous
membranes including intranasal, vaginal and rectal delivery),
pulmonary (e.g., by inhalation or insufflation of powders or
aerosols, including by nebulizer; intratracheal or intranasal),
oral or parenteral. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal intramuscular or
injection or infusion; or intracranial, e.g., intrathecal or
intraventricular, administration. Parenteral administration can be
in the form of a single bolus dose, or may be, e.g., by a
continuous perfusion pump. Pharmaceutical compositions and
formulations for topical administration may include transdermal
patches, ointments, lotions, creams, gels, drops, suppositories,
sprays, liquids and powders. Conventional pharmaceutical carriers,
aqueous, powder or oily bases, thickeners and the like may be
necessary or desirable.
[0731] 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.
[0732] 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.
[0733] 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.
[0734] 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.
[0735] 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.
[0736] 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.
[0737] 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.).
[0738] 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.
[0739] 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.
[0740] 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.
[0741] 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.
[0742] 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.
[0743] 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.
[0744] 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.
[0745] 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.
[0746] 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.
[0747] 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.
[0748] 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.
[0749] 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.
[0750] 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
[0751] 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.
[0752] 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 the same atomic number but different atomic mass or mass
number e.g., a different atomic mass or mass number 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.
[0753] It is understood that a "radio-labeled" or "labeled
compound" is a compound that has incorporated at least one
radionuclide. In some embodiments the radionuclide is selected from
the group consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and
.sup.82Br. Synthetic methods for incorporating radio-isotopes into
organic compounds are applicable to compounds provided herein and
are well known in the art.
[0754] A radio-labeled compound of the invention can be used in a
screening assay to identify and/or evaluate compounds. In general
terms, 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 (radio-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.
V. Kits
[0755] The present disclosure also includes pharmaceutical kits
useful, e.g., in the treatment or prevention of diseases or
disorders associated with the activity of PD-L1 including its
interaction with other proteins such as PD-1 and B7-1 (CD80), such
as cancer or infections, which include one or more containers
containing a pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula (I), or
any of the embodiments thereof. Such kits can further include one
or more of various conventional pharmaceutical kit components, such
as, e.g., containers with one or more pharmaceutically acceptable
carriers, additional containers, etc., as will be readily apparent
to those skilled in the art. Instructions, either as inserts or as
labels, indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, can also be included in the kit.
[0756] 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
[0757] 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-chloro-2'-methyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)a-
mino)ethan-1-ol
##STR00041##
[0758] Step 1: 8-chloro-3-vinyl-1,7-naphthyridine
##STR00042##
[0760] 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, 61.8 mmol) and water (6 mL, 300 mmol) 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 2: 8-chloro-1,7-naphthyridine-3-carbaldehyde
##STR00043##
[0762] A flask was charged with 8-chloro-3-vinyl-1,7-naphthyridine
(391. mg, 2.05 mmol), 1,4-dioxane (40. mL), a stir bar and water
(40. mL). To this suspension was added a 4% w/w mixture of osmium
tetraoxide in water (0.84 mL, 0.132 mmol). The reaction was stirred
for 5 min then sodium periodate (3.23 g, 15.11 mmol) was added and
stirred for 3 h. The mixture was diluted with water (20 mL) and
EtOAc (20 mL). The layers were separated and the aqueous layer was
further extracted with EtOAc (2.times.20 mL). The combined organic
extracts were washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude aldehyde was
purified by silica gel chromatography (0.fwdarw.60% EtOAc/hexanes).
LC-MS calculated for C.sub.9H.sub.6ClN.sub.2O (M+H).sup.+:
m/z=193.0; found 192.9.
Step 3:
2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol
##STR00044##
[0764] 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, 100 mmol) 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
chloroform/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 4:
2-(((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methy-
l)amino)ethan-1-ol
##STR00045##
[0766] To a vial was added 3-bromo-2-chloroaniline (Enamine, cat#
EN300-105778: 0.021 g, 0.101 mmol) and
2-(((8-chloro-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol (0.020
g, 0.084 mmol). The solids were suspended in isopropanol (0.421
ml). Sulfuric acid (4.48 .mu.l, 0.084 mmol) was added to the
reaction mixture and then heated to 100.degree. C. for 1 h. After
cooling, the mixture was quenched with a saturated aqueous sodium
bicarbonate solution, and extracted with 3:1 chloroform/isopropyl
alcohol. The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. The crude residue was
purified using silica gel chromatography (1:1 DCM/MeOH) to afford a
yellow solid. LC-MS calculated for C.sub.17H.sub.17BrClN.sub.4O
(M+H).sup.+: m/z=407.0; found 407.2.
Step 5: tert-butyl
2-(3-chloro-2-methylphenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carb-
oxylate
##STR00046##
[0768] To a vial was added (3-chloro-2-methylphenyl)boronic acid
(Combi-blocks, cat#BB-2035: 640 mg, 3.76 mmol), tert-butyl
2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
(AstaTech, cat#AB1021: 1000. mg, 3.133 mmol), sodium carbonate (996
mg, 9.40 mmol), tert-butyl alcohol (160 mmol), water (600 mmol)
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#701998: 240 mg, 0.31 mmol). The mixture was sparged
with nitrogen, then heated at 105.degree. C. for 1.5 h. The mixture
was concentrated, dissolved with DCM, and purified using silica gel
chromatography (40% EtOAc/hexanes). LC-MS calculated for
C.sub.18H.sub.22ClN.sub.2O.sub.2S (M+H).sup.+: m/z=365.1; found
365.1.
Step 6: tert-butyl
2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-di-
hydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00047##
[0770] A mixture of tert-butyl
2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-
-carboxylate (261 mg, 0.715 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(Aldrich, cat#473294: 545 mg, 2.14 mmol), palladium acetate (6.42
mg, 0.0286 mmol), K.sub.3PO.sub.4 (455 mg, 2.14 mmol) and
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (Strem
Chemicals, cat#15-1143: 29.4 mg, 0.0715 mmol) in 1,4-Dioxane was
degassed and stirred at rt for 16 h. The mixture was diluted with
DCM, and washed with water. The organic layer was concentrated in
vacuo and purified by silica-gel chromatography (5% EtOAc/DCM).
LC-MS calculated for C.sub.24H.sub.34BN.sub.2O.sub.4S (M+H).sup.+:
m/z=457.2; found 457.3.
Step 7: tert-butyl
2-(2'-chloro-3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylami-
no)-2-methylbiphenyl-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate
##STR00048##
[0772] To a vial was added tert-butyl
2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-di-
hydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.013 g, 0.029
mmol),
2-(((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino-
)ethan-1-ol (0.008 g, 0.020 mmol), sodium carbonate (6.24 mg, 0.059
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1.436 mg, 1.962 .mu.mol), 1,4-dioxane (0.346 ml), and water (0.046
ml). The mixture was degassed, sealed, and heated to 90.degree. C.
whilst stirring for 4 h. After cooling, the mixture was diluted
with DCM and water. The layers were separated and the aqueous layer
was further extracted. The combined organic layers were dried over
magnesium sulfate, filtered, concentrated in vacuo, and purified by
silica gel chromatography (MeOH/DCM). LC-MS calculated for
C.sub.35H.sub.38ClN.sub.6O.sub.3S (M+H).sup.+: m/z=657.2; found
657.5.
Step 8:
2-(((8-((2-chloro-2'-methyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridin-2-yl)-[,
1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol
[0773] A vial was charged with tert-butyl
2-(2'-chloro-3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylami-
no)-2-methylbiphenyl-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carbox-
ylate (13 mg, 0.020 mmol), DCM (0.4 mL) and TFA (0.010 mL, 1 mmol).
The resulting mixture was stirred for 1 h, open to air. The mixture
was then dissolved in MeOH and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the compound as the TFA salt.
LC-MS calculated for C.sub.30H.sub.30ClN.sub.6OS (M+H).sup.+:
m/z=557.2; found 557.3.
Example 2:
1-(((6-(2-fluoro-3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphth-
yridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)amin-
o)cyclobutanecarboxylic acid
##STR00049##
[0774] Step 1:
2-(((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino-
)ethan-1-ol
##STR00050##
[0776] This compound was prepared using a similar procedure as
described for Example 1, Step 4 with 3-bromo-2-methylaniline
(Aldrich, cat#530018) replacing 3-bromo-2-chloroaniline. The crude
compound was purified using column chromatography (0.fwdarw.50%
MeOH/DCM). LC-MS calculated for C.sub.18H.sub.20BrN.sub.4O
(M+H).sup.+: m/z=387.1; found 387.2.
Step 2:
5-(dimethoxymethyl)-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)phenyl)picolinamide
##STR00051##
[0778] To a solution of
2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-5021: 200 mg, 0.844 mmol) and methyl
5-(dimethoxymethyl)picolinate (Combi-Blocks, cat#QY-1318: 196 mg,
0.928 mmol) in THF (8436 .mu.l) was added 1.0 M potassium
tert-butoxide in THF (1265 .mu.l, 1.265 mmol) at rt. The mixture
was stirred at rt for 2 h. Water and EtOAc were added, and the
layers were separated. The aqueous layer was further extracted with
ethyl acetate, and the combined organic layers were washed with
brine, dried over magnesium sulfate, filtered, and concentrated in
vacuo. The crude residue was purified using silica gel
chromatography (30% EtOAc/hexanes). LC-MS calculated for
C.sub.21H.sub.27BFN.sub.2O.sub.5 (M+H).sup.+: m/z=417.2; found
417.3.
Step 3:
5-(dimethoxymethyl)-N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)met-
hyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)picolinam-
ide
##STR00052##
[0780] To a vial was added
5-(dimethoxymethyl)-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)picolinamide (0.161 g, 0.387 mmol),
2-(((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino-
)ethan-1-ol (0.10 g, 0.258 mmol), sodium carbonate (0.041 g, 0.387
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(0.019 g, 0.026 mmol), 1,4-dioxane (4.56 ml), and water (0.608 ml).
The mixture was degassed, sealed, and heated to 90.degree. C.
whilst stirring for 4 h. After cooling, the mixture was diluted
with DCM and water, and the layers were separated. The aqueous
layer was further extracted with DCM, and the combined organic
layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (20% MeOH/DCM) to provide the desired product. LC-MS
calculated for C.sub.33H.sub.34FN.sub.6O.sub.4 (M+H).sup.+:
m/z=597.3; found 597.2.
Step 4:
N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
##STR00053##
[0782] To a solution of
5-(dimethoxymethyl)-N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,-
7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)picolinamide
(0.068 g, 0.114 mmol) in DCM (1.899 ml) was added TFA (0.439 ml,
5.70 mmol). The mixture was stirred at for 2 h. The mixture was
concentrated and the residue was dissolved in DCM, and washed with
a saturated aqueous NaHCO.sub.3 solution. The layers were separated
and the aqueous layer was further extracted with DCM. The combined
organic layers were dried over magnesium 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.31H.sub.28FN.sub.6O.sub.3 (M+H).sup.+: m/z=551.2; found
551.2.
Step 5:
1-(((6-(2-fluoro-3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyri-
din-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)amino)c-
yclobutanecarboxylic acid
[0783] To a vial was added
N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide (0.030
g, 0.054 mmol), 1-aminocyclobutane-1-carboxylic acid (Aldrich,
cat#652369: 0.019 g, 0.163 mmol), dichloromethane (0.893 ml) and
triethylamine (0.016 ml, 0.115 mmol). The reaction was stirred at
rt for 2 h, then sodium triacetoxyborohydride (0.058 g, 0.272 mmol)
and acetic acid (9.36 .mu.l, 0.163 mmol) were added. The reaction
was stirred for 2 h, then the mixture was diluted with methanol and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as the TFA salt. LC-MS calculated for
C.sub.36H.sub.37FN.sub.7O.sub.4 (M+H).sup.+: m/z=650.3; found
650.3.
Example 3:
(S)-1-((6-((2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-
-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-
-3-yl)methyl)piperidine-2-carboxylic acid
##STR00054##
[0785] This compound was prepared using a similar procedure as
described for Example 2, Step 5 with L-pipecolinic acid (Alfa
Aesar, cat# L15373) replacing 1-aminocyclobutane-1-carboxylic acid.
LC-MS calculated for C.sub.37H.sub.39FN.sub.7O.sub.4 (M+H).sup.+:
m/z=664.3; found 664.3.
Example 4:
N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyr-
idin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino-
)methyl)picolinamide
##STR00055##
[0787] This compound was prepared using a similar procedure as
described for Example 2, Step 5 with ethanolamine (Aldrich,
cat#398136) replacing 1-aminocyclobutane-1-carboxylic acid. LC-MS
calculated for C.sub.33H.sub.35FN.sub.7O.sub.3 (M+H).sup.+:
m/z=596.3; found 596.2.
Example 5:
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyr-
idin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino-
)methyl)picolinamide
##STR00056##
[0788] Step 1:
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
##STR00057##
[0790]
4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1.48 g, 5.81 mmol), potassium acetate (0.428 g, 4.36 mmol),
3-bromo-2-chloroaniline (Enamine, cat# EN300-105778: 0.300 g, 1.453
mmol), 1,4-dioxane (7.27 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.053
g, 0.073 mmol) was stirred in a closed vial flushed with argon at
110.degree. C. for 2 h. The mixture was cooled, diluted with EtOAc,
and filtered over celite. The filtrate was concentrated and
purified by silica gel chromatography (20% EtOAc/hexanes). LC-MS
calculated for C.sub.12H.sub.18BClNO.sub.2 (M+H).sup.+: m/z=254.1;
found 254.1.
Step 2:
N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
-5-(dimethoxymethyl)picolinamide
##STR00058##
[0792] This compound was prepared using a similar procedure as
described for Example 2, Step 2 with
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
replacing
2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
LC-MS calculated for C.sub.21H.sub.27BClN.sub.2O.sub.5 (M+H).sup.+:
m/z=433.2; found 433.1.
Step 3:
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinam-
ide
##STR00059##
[0794] This compound was prepared using a similar procedure as
described for Example 2, Step 3 with
N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(dim-
ethoxymethyl)picolinamide replacing
5-(dimethoxymethyl)-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)picolinamide. LC-MS calculated for
C.sub.33H.sub.34ClN.sub.6O.sub.4 (M+H).sup.+: m/z=613.2; found
613.2.
Step 4:
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
##STR00060##
[0796] This compound was prepared using a similar procedure as
described for Example 2, Step 4 with
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide
replacing
5-(dimethoxymethyl)-N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)-
methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)picoli-
namide. LC-MS calculated for C.sub.31H.sub.28ClN.sub.6O.sub.3
(M+H).sup.+: m/z=567.2; found 567.2.
Step 5:
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)me-
thyl)picolinamide
[0797] To a vial was added
N-(2-chloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-
amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide (0.015
g, 0.026 mmol), ethanolamine (Aldrich, cat#398136: 0.0049 g, 0.163
mmol), dichloromethane (0.893 ml) and N,N-diisopropylethylamine
(0.028 mL, 0.159 mmol). The reaction was stirred at rt for 2 h,
then sodium triacetoxyborohydride (0.058 g, 0.272 mmol) was added.
The reaction was stirred for 2 h, then the mixture was diluted with
methanol and purified by prep HPLC (pH=2, acetonitrile/water+TFA;
then pH=10, acetonitrile/water+NH.sub.4OH). LC-MS calculated for
C.sub.33H.sub.35ClN.sub.7O.sub.3 (M+H).sup.+: m/z=612.2; found
612.2.
Example 6:
N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxyp-
yrrolidin-1-yl)methyl)picolinamide
##STR00061##
[0798] Step 1:
N-(3-bromo-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine
##STR00062##
[0800] In a vial, 3-bromo-2-methylaniline (Aldrich, cat#530018:
0.931 ml, 7.55 mmol) and 8-chloro-3-vinyl-1,7-naphthyridine
(Example 1, Step 1: 1.20 g, 6.29 mmol) were suspended in
isopropanol (31.5 ml). Sulfuric acid (0.336 ml, 6.29 mmol) was
added to the reaction mixture. The resulting mixture was heated to
100.degree. C. for 1 h whilst stirring. The mixture was cooled,
quenched with aqueous saturated sodium bicarbonate, and diluted
with DCM. The layers were separated and the water layer was further
extracted with DCM. The combined organic layers were dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
solid was purified by column chromatography (0.fwdarw.1%
Methanol/DCM) to provide the desired compound as a yellow solid.
LC-MS calculated for C.sub.17H.sub.15BrN.sub.3 (M+H).sup.+:
m/z=340.0; found 340.1.
Step 2:
2'-chloro-2-methyl-N3-(3-vinyl-1,7-naphthyridin-8-yl)-[1,1'-biphen-
yl]-3,3'-diamine
##STR00063##
[0802] To a flask was added
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Example 5, Step 1: 1.414 g, 5.58 mmol),
N-(3-bromo-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine (1.2646
g, 3.72 mmol), sodium carbonate (0.591 g, 5.58 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.272
g, 0.372 mmol), 1,4-dioxane (32.8 ml), and water (4.37 ml). The
mixture was degassed, sealed, and heated to 90.degree. C. whilst
stirring for 4 h. The mixture was cooled, diluted with EtOAc, and
the layers were separated. The aqueous layer was further extracted
with EtOAc, and the combined organic layers were washed with brine,
dried of magnesium sulfate, filtered, and concentrated in vacuo.
The crude residue was then purified by silica gel chromatography
(20% EtOAc/hexanes) to provide the desired compound as a yellow
solid. LC-MS calculated for C.sub.23H.sub.20ClN.sub.4 (M+H).sup.+:
m/z=387.1; found 387.1.
Step 3:
N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1-
,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide
##STR00064##
[0804] To a solution of
2'-chloro-2-methyl-N3-(3-vinyl-1,7-naphthyridin-8-yl)-[1,1'-biphenyl]-3,3-
'-diamine (0.682 g, 1.763 mmol) and methyl
5-(dimethoxymethyl)picolinate (Combi-Blocks, cat#QY-1318: 0.372 g,
1.763 mmol) in THF (17.63 ml) was added 1.0 M Potassium
tert-butoxide in THF (2.64 ml, 2.64 mmol) at rt. The mixture was
stirred at rt for 2 h. Water was added to quench the reaction. The
layers were separated and the water layer was further extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over magnesium sulfate, filtered and concentrated in
vacuo. The crude orange foam was used directly in the next step
without further purification. LC-MS calculated for
C.sub.32H.sub.29ClN.sub.5O.sub.3 (M+H).sup.+: m/z=566.2; found
566.3.
Step 4:
N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1-
,1'-biphenyl]-3-yl)-5-formylpicolinamide
##STR00065##
[0806] This compound was prepared using a similar procedure as
described for Example 2, Step 4 with
N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1'-bip-
henyl]-3-yl)-5-(dimethoxymethyl)picolinamide replacing
5-(dimethoxymethyl)-N-(2-fluoro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,-
7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)picolinamide.
LC-MS calculated for C.sub.30H.sub.23ClN.sub.5O.sub.2 (M+H).sup.+:
m/z=520.2; found 520.2.
Step 5:
(R)--N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amin-
o)-[1,1'-biphenyl]-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
##STR00066##
[0808] A mixture of
N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1'-bip-
henyl]-3-yl)-5-formylpicolinamide (0.180 g, 0.346 mmol) and
(R)-3-hydroxypyrrolidine (Combi-Blocks, cat#AM-2005: 0.090 g, 1.038
mmol) in methylene chloride (1.731 ml) and
N,N-diisopropylethylamine (0.301 ml, 1.731 mmol) was stirred at rt
for 1 h. Sodium triacetoxyborohydride (0.220 g, 1.038 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h. The reaction was quenched with a saturated aqueous solution of
sodium bicarbonate. The mixture was then extracted with a 3:1
mixture of chloroform/IPA. The combined organic layers were washed
with brine, dried over sodium sulfate, and then concentrated in
vacuo. The crude residue was purified by column chromatography
(0.fwdarw.20% methanol/DCM). LC-MS calculated for
C.sub.34H.sub.32ClN.sub.6O.sub.2 (M+H).sup.+: m/z=591.2; found
591.4.
Step 6:
(R)--N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-met-
hyl-[1,1'-biphenyl]-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
##STR00067##
[0810] A flask was charged with
(R)--N-(2-chloro-2'-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1-
'-biphenyl]-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
(0.241 g, 0.408 mmol), 1,4-dioxane (4.5 mL) and water (2.3 mL). A
4% osmium tetroxide solution in water (0.181 ml, 0.029 mmol) was
added to the reaction mixture. After 5 min of stirring, sodium
periodate (0.349 g, 1.631 mmol) was added and the mixture was
stirred for 3 h. The mixture was diluted with water (2 mL) and
EtOAc (5 mL), and the layers were separated. The aqueous layer was
further extracted with EtOAc. The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The crude aldehyde was purified by silica
gel chromatography (20% MeOH/DCM). LC-MS calculated for
C.sub.33H.sub.30ClN.sub.6O.sub.3 (M+H).sup.+: m/z=593.2; found
593.1.
Step 7:
N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrr-
olidin-1-yl)methyl)picolinamide
[0811] To a vial was added
(R)--N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,-
1'-biphenyl]-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
(0.030 g, 0.051 mmol), ethanolamine (Aldrich, cat#398136: 9.3 mg,
0.152 mmol), dichloromethane (0.829 ml) and
N,N-diisopropylethylamine (0.053 ml, 0.303 mmol). The reaction was
stirred at rt for 2 h, then sodium triacetoxyborohydride (0.054 g,
0.253 mmol) was added. The reaction was stirred for 2 h, then the
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as the TFA
salt. LC-MS calculated for C.sub.37H.sub.39ClN.sub.7O.sub.3
(M+H).sup.+: m/z=664.3; found 664.2.
Example 7:
(R)-1-((8-((2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)meth-
yl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-y-
l)methyl)pyrrolidine-3-carboxylic acid
##STR00068##
[0813] To a vial was added
(R)--N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,-
1'-biphenyl]-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
(Example 6, Step 6: 0.030 g, 0.051 mmol),
(R)-pyrrolidine-3-carboxylic acid (Combi-Blocks, cat#ST-7698: 0.017
g, 0.152 mmol), dichloromethane (0.829 ml) and triethylamine (0.016
ml, 0.115 mmol). The reaction was stirred at rt for 2 h, then
sodium triacetoxyborohydride (0.054 g, 0.253 mmol) and acetic acid
(8.69 .mu.l, 0.152 mmol) were added. The reaction was stirred for 2
h, then the mixture was diluted with methanol and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide the compound as the
TFA salt. LC-MS calculated for C.sub.38H.sub.39ClN.sub.7O.sub.4
(M+H).sup.+: m/z=692.3; found 692.2.
Example 8:
(R)-1-((8-((2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)p-
icolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)me-
thyl)azetidine-3-carboxylic acid
##STR00069##
[0815] This compound was prepared using a similar procedure as
described for Example 7 with azetidine-3-carboxylic acid (Aldrich,
cat#391131) replacing (R)-pyrrolidine-3-carboxylic acid. LC-MS
calculated for C.sub.37H.sub.37ClN.sub.7O.sub.4 (M+H).sup.+:
m/z=678.3; found 678.3.
Example 9
(R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00070##
[0816] Step 1:
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
##STR00071##
[0818] A suspension of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, #ARI-0169: 300.0 mg, 0.872 mmol) and
manganese dioxide (1515 mg, 17.43 mmol) in DCM (8716 .mu.l) was
stirred at 45.degree. C. for 1 h. The reaction was filtered through
Celite.RTM. and the filtrate was concentrated to yield a crude
residue, which was used directly in the next step without further
purification. LC-MS calculated for C.sub.16H.sub.13BrN.sub.3O
(M+H).sup.+: m/z=342.0; found 342.0.
Step 2:
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol
##STR00072##
[0820] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(0.100 g, 0.292 mmol) and (R)-3-hydroxypyrrolidine (Combi-Blocks,
#AM-2005: 0.025 g, 0.292 mmol) in 1,2-dichloroethane (1.46 ml) and
N,N-diisopropylethylamine (0.051 ml, 0.292 mmol) was stirred at rt
for 1 h. Sodium triacetoxyborohydride (0.093 g, 0.438 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h, then quenched with a saturated aqueous solution of sodium
bicarbonate. The mixture was then extracted with a 3:1 mixture of
chloroform/IPA. The combined organic layers were dried over sodium
sulfate, then concentrated in vacuo. The crude residue was purified
by silica gel chromatography (0.fwdarw.30% methanol/DCM) to give
the desired product. LC-MS calculated for
C.sub.20H.sub.22BrN.sub.4O (M+H).sup.+: m/z=413.1; found 413.1.
Step 3:
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methanol
##STR00073##
[0822] A mixture of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, #ARI-0169: 0.300 g, 0.872 mmol),
bis(pinacolato)diboron (Aldrich, #473294: 0.266 g, 1.046 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.071 g, 0.087 mmol) and potassium acetate
(0.214 g, 2.179 mmol) was charged with nitrogen and stirred at
110.degree. C. for 2 h. The crude was diluted with DCM, and then
filtered through Celite.RTM.. The filtrate was concentrated, and
the resulting residue was used directly in the next step without
further purification. LC-MS calculated for
C.sub.22H.sub.27BN.sub.3O.sub.3 (M+H).sup.+: m/z=392.2; found
392.3.
Step 4:
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,-
2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol
##STR00074##
[0824] To a vial was added
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (0.162 g, 0.414 mmol),
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (0.163 g, 0.394 mmol), 1 M aqueous sodium carbonate
(0.789 mmol),
[1,1'-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium (II)
(0.029 g, 0.039 mmol), and 1,4-dioxane (3.48 ml). The mixture was
purged with nitrogen, sealed, and heated to 90.degree. C. whilst
stirring for 2 h. The mixture was cooled, diluted with EtOAc and
filtered through Celite.RTM.. The filtrate was concentrated and
purified using silica gel chromatography (20% MeOH/DCM) to provide
the desired compound as an orange solid. LC-MS calculated for
C.sub.36H.sub.36N.sub.7O.sub.2 (M+H).sup.+: m/z=598.3; found
598.4.
Step 5:
(R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-
-carbaldehyde
##STR00075##
[0826] To a solution of
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol (0.0715 g, 0.12 mmol) in DCM (1.20 ml) was added manganese
dioxide (0.208 g, 2.392 mmol). The resulting mixture was heated at
45.degree. C. for 30 min. After cooling, the mixture was filtered
through Celite.RTM. and the filtrate was concentrated. The crude
orange solid was used directly in the next step. LC-MS calculated
for C.sub.36H.sub.34N.sub.7O.sub.2 (M+H).sup.+: m/z=596.3; found
596.5.
Step 6:
(R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthy-
ridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
[0827] To a vial was added
(R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbal-
dehyde (0.013 g, 0.022 mmol), (R)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, #ST-7698: 7.5 mg, 0.065 mmol), 1,2-dichloroethane
(0.336 ml) and triethylamine (9.13 .mu.l, 0.065 mmol). The reaction
was stirred at rt for 2 h, then sodium triacetoxyborohydride (0.023
g, 0.109 mmol) and acetic acid (3.75 .mu.l, 0.065 mmol) were added.
The reaction was stirred for 2 h, then the mixture was diluted with
methanol and purified by prep HPLC (pH=2, acetonitrile/water+TFA)
to give the desired product as the TFA salt. LC-MS calculated for
C.sub.41H.sub.43N.sub.8O.sub.3 (M+H).sup.+: m/z=695.3; found 695.3.
.sup.1H NMR (500 MHz, DMSO) .delta. 10.72 (br s, 2H), 9.11 (m, 2H),
8.54 (m, 2H), 8.02 (m, 4H), 7.42 (m, 2H), 7.26 (m, 2H), 7.11 (m,
2H), 4.70 (m, 4H), 4.47 (m, 1H), 3.82-3.08 (m, 10H), 2.38-2.18 (m,
2H), 2.10 (s, 6H), 2.05-1.82 (n, 2H).
Example 10
(S)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00076##
[0829] This compound was prepared using similar procedures as
described for Example 9 with (S)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, #ST-1381) replacing (R)-pyrrolidine-3-carboxylic
acid in Step 6. The reaction was diluted with MeOH and then
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for
C.sub.41H.sub.43N.sub.8O.sub.3 (M+H).sup.+: m/z=695.3; found
695.3.
Example 11
(R)-1-((8-((3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)meth-
yl)pyrrolidine-3-carboxylic acid
##STR00077##
[0831] This compound was prepared using similar procedures as
described for Example 9 with ethanolamine (Aldrich, #411000)
replacing (R)-3-hydroxypyrrolidine in Step 2. The reaction mixture
was diluted with MeOH and then purified by prep-HPLC (pH=6.5,
acetonitrile/water+NH.sub.4OAc) to give the desired product. LC-MS
calculated for C.sub.39H.sub.41N.sub.8O.sub.3 (M+H).sup.+:
m/z=669.3; found 669.4.
Example 12
(R)-1-((8-((3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00078##
[0833] This compound was prepared using similar procedures as
described for Example 9 with (S)-3-hydroxypyrrolidine
(Combi-Blocks, #SS-7948) replacing (R)-3-hydroxypyrrolidine in Step
2. The reaction was diluted with MeOH and then purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.41H.sub.43N.sub.8O.sub.3 (M+H).sup.+: m/z=695.3; found
695.4.
Example 13
(S)-1-((8-((3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00079##
[0835] This compound was prepared using similar procedures as
described for Example 9 with (S)-3-hydroxypyrrolidine replacing
(R)-3-hydroxypyrrolidine in Step 2 and (S)-pyrrolidine-3-carboxylic
acid replacing (R)-pyrrolidine-3-carboxylic acid in Step 6. The
reaction mixture was diluted with MeOH and then purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.41H.sub.43N.sub.8O.sub.3 (M+H).sup.+: m/z=695.3; found
695.3.
Example 14
1-((8-(2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyrid-
ine-2-carboxamido)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)meth-
yl)azetidine-3-carboxylic acid
##STR00080##
[0836] Step 1: tert-butyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
##STR00081##
[0838] A solution of
1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Accela,
cat#SY032476: 2.0 g, 14.58 mmol) and (Boc).sub.2O (3.38 mL, 14.58
mmol) in dichloromethane (60.0 mL) was stirred at room temperature
for 1 h. The reaction was quenched with saturated aqueous
NaHCO.sub.3 solution, and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was used for next step without further
purification. LC-MS calculated for C.sub.12H.sub.20N.sub.3O.sub.2
(M+H).sup.+: m/z=238.2; found 238.2.
Step 2: 5-tert-butyl 2-methyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate
##STR00082##
[0840] To a solution of tert-butyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
(Crude product from Step 1) in tetrahydrofuran (60.0 mL) was added
n-Butyllithium in hexanes (2.5 M, 7.00 mL, 17.49 mmol) at
-78.degree. C., dropwise. The reaction mixture was stirred at
-78.degree. C. for 10 min prior to the addition of methyl
chloroformate (1.7 mL, 21.9 mmol). After being stirred at
-78.degree. C. for 15 min, the reaction was then quenched with
saturated aqueous NaHCO.sub.3 solution, and extracted with ethyl
acetate, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on a silica gel column eluting with 80% ethyl
acetate in hexanes to afford the desired product ( ). LC-MS
calculated for C.sub.14H.sub.22N.sub.3O.sub.4 (M+H).sup.+:
m/z=296.2; found 296.3.
Step 3: tert-butyl
1-methyl-2-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)carbamoyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
##STR00083##
[0842] Potassium tert-butoxide (0.122 ml, 0.122 mmol) was added to
a solution of 5-tert-butyl 2-methyl
1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate
(30 mg, 0.102 mmol) and
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127: 23.68 mg, 0.102 mmol) in THF (0.2 ml).
After being stirred at rt for 2 h, the reaction mixture was
quenched with water, and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on a silica gel column with ethyl
acetate in hexanes (0-40%) to afford the product. LC-MS calculated
for C.sub.26H.sub.38BN.sub.4O.sub.5 (M+H).sup.+: m/z=497.3; found
497.2.
Step 4: 8-chloro-3-vinyl-1,7-naphthyridine
##STR00084##
[0844] 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, 61.8 mmol) and water (6 mL, 300 mmol) 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 5:
N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine
##STR00085##
[0846] In a vial, 3-bromo-2-chloroaniline (Enamine, cat#
EN300-105778: 0.476 g, 2.304 mmol) and
8-chloro-3-vinyl-1,7-naphthyridine (0.366 g, 1.920 mmol) were
suspended in isopropanol (9.60 ml). Sulfuric acid (0.102 ml, 1.920
mmol) was added to the reaction mixture. The resulting mixture was
heated to 100.degree. C. for 1 h. The mixture was cooled to rt then
quenched with aqueous saturated sodium bicarbonate, and diluted
with DCM. The layers were separated and the water layer was further
extracted with DCM. The combined organic layers were dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
solid was purified by column chromatography (0.fwdarw.2%
methanol/DCM). LC-MS calculated for C.sub.16H.sub.12BrClN.sub.3
(M+H).sup.+: m/z=360.0; found 360.0.
Step 6:
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
##STR00086##
[0848] A flask was charged with
N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine (0.586
g, 1.625 mmol), 1,4-dioxane (40 mL) and water (40 mL). A 4% osmium
tetroxide solution in water (0.207 ml, 0.032 mmol) was added to the
reaction mixture. After 5 min, sodium periodate (1.390 g, 6.50
mmol) was added. The mixture was stirred overnight at rt. The
reaction was diluted with water and ethyl acetate. The layers were
separated and the aqueous layer was further extracted with EtOAc.
The combined organic extracts were washed with brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by silica gel chromatography (0.fwdarw.60%
EtOAc/hexanes). LC-MS calculated for C.sub.15H.sub.10BrClN.sub.3O
(M+H).sup.+: m/z=362.0; found 362.0.
Step 7: methyl
1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)azetid-
ine-3-carboxylate
##STR00087##
[0850] A mixture of
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(0.272 g, 0.750 mmol) and methyl azetidine-3-carboxylate, HCl
(Combi-Blocks, cat#SS-3302:125 mg, 0.825 mmol) in methylene
chloride (3.75 ml) and N,N-diisopropylethylamine (0.392 ml, 2.250
mmol) was stirred at rt for 1 h. Sodium triacetoxyborohydride
(0.477 g, 2.250 mmol) was added in portions. The reaction was
stirred at rt for 2 h, then sodium tetrahydroborate (0.060 ml,
1.500 mmol) and methanol (6 mL) were added carefully. After
stirring overnight, the reaction was quenched with a saturated
solution of sodium bicarbonate. The mixture was then extracted with
a 3:1 mixture of chloroform/isopropanol. The combined organic
layers were washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The crude residue was purified
by column chromatography (methanol/DCM). LC-MS calculated for
C.sub.20H.sub.19BrClN.sub.4O.sub.2 (M+H).sup.+: m/z=461.0; found
461.1.
Step 8: tert-butyl
2-((2'-chloro-3'-((3-((3-(methoxycarbonyl)azetidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,-
6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
##STR00088##
[0852] To a vial was added tert-butyl
1-methyl-2-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)carbamoyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(Step 3: 0.037 g, 0.074 mmol), methyl
1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)azetid-
ine-3-carboxylate (0.034 g, 0.074 mmol), sodium carbonate (8.58 mg,
0.081 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (5.39
mg, 7.36 .mu.mol), 1,4-dioxane (0.650 ml), and water (0.087 ml).
The mixture was degassed, sealed, and heated to 90.degree. C.
whilst stirring for 18 h. The mixture was cooled, diluted with
water and methylene chloride, and the layers were separated. The
aqueous layer was further extracted with methylene chloride and the
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (15% MeOH/DCM) to provide the desired product. LC-MS
calculated for C.sub.40H.sub.44ClN.sub.8O.sub.5 (M+H).sup.+:
m/z=751.3; found 751.3.
Step 9: methyl
1-((8-(2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5--
c]pyridine-2-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-
azetidine-3-carboxylate
##STR00089##
[0854] To a vial was added tert-butyl
2-((2'-chloro-3'-((3-((3-(methoxycarbonyl)azetidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,-
6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (0.041 g,
0.055 mmol), DCM (0.6 mL), and TFA (0.084 mL, 1.091 mmol). The
reaction was stirred at rt for 1 h. The mixture was concentrated
under reduced pressure, and the resulting residue was redissolved
in DCM and washed with a saturated aqueous solution of sodium
bicarbonate. The layers were separated, and the organic layer was
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The crude residue was then used directly in the next step
without further purification. LC-MS calculated for
C.sub.35H.sub.36ClN.sub.8O.sub.3 (M+H).sup.+: m/z=651.3; found
651.4.
Step 10: methyl
1-((8-(2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyri-
dine-2-carboxamido)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)met-
hyl)azetidine-3-carboxylate
##STR00090##
[0856] A mixture of methyl
1-((8-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-
-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)azetidine-3-carboxylate (0.032 g, 0.049 mmol) and 12.3 M
formaldehyde in water (7.99 .mu.l, 0.098 mmol) in methylene
chloride (0.430 ml) and methanol (0.061 ml) was stirred at rt for
30 min after which time, acetic acid (0.017 ml, 0.295 mmol) and
sodium triacetoxyborohydride (0.052 g, 0.246 mmol) were added. The
mixture was stirred at rt for 45 min and the reaction was quenched
with a saturated aqueous sodium bicarbonate solution. The mixture
was extracted with a 3:1 mixture of chloroform/isopropanol, and the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (0.fwdarw.30% methanol/DCM).
LC-MS calculated for C.sub.36H.sub.38ClN.sub.8O.sub.3 (M+H).sup.+:
m/z=665.3; found 665.4.
Step 11:
1-((8-(2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,-
5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin--
3-yl)methyl)azetidine-3-carboxylic acid
[0857] To a solution of methyl
1-((8-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyr-
idine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)azetidine-3-carboxylate (27 mg, 0.041 mmol) in THF
(203 .mu.l) was added lithium hydroxide (3.89 mg, 0.162 mmol) in
water (203 .mu.l). The mixture was stirred at rt for 30 min. The
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the compound as its TFA salt.
LC-MS calculated for C.sub.35H.sub.36ClN.sub.8O.sub.3 (M+H).sup.+:
m/z=651.3; found 651.3.
Example 15
(R)-1-((5-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dih-
ydropyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00091##
[0858] Step 1:
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
##STR00092##
[0860] In a vial was combined:
4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl](6.15
g, 24.22 mmol), potassium acetate (2.85 g, 29.1 mmol),
3-bromo-2-chloroaniline (Enamine, cat# EN300-105778: 2.00 g, 9.69
mmol), 1,4-dioxane (48.4 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.354
g, 0.484 mmol). The vial was flushed with nitrogen and was stirred
at 110.degree. C. for 2 h. The mixture was cooled, and filtered
through Celite.RTM., and concentrated under reduced pressure. The
crude residue was purified by silica gel chromatography
(EtOAc/hexanes) to provide the desired compound as a white solid.
LC-MS calculated for C.sub.12H.sub.18BClNO.sub.2 (M+H).sup.+:
m/z=254.1; found 254.1.
Step 2:
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
##STR00093##
[0862] A suspension of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, #ARI-0169: 300.0 mg, 0.872 mmol) and
manganese dioxide (1515 mg, 17.43 mmol) in DCM (8716 .mu.l) was
stirred at 45.degree. C. for 1 h. The reaction was filtered through
Celite.RTM. and the filtrate was concentrated to yield a crude
residue, which was used directly in the next step without further
purification. LC-MS calculated for C.sub.16H.sub.13BrN.sub.3O
(M+H).sup.+: m/z=342.0; found 342.0.
Step 3:
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol
##STR00094##
[0864] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(0.100 g, 0.292 mmol) and (R)-3-hydroxypyrrolidine (Combi-Blocks,
#AM-2005: 0.025 g, 0.292 mmol) in 1,2-dichloroethane (1.46 ml) and
N,N-diisopropylethylamine (0.051 ml, 0.292 mmol) was stirred at rt
for 1 h. Sodium triacetoxyborohydride (0.093 g, 0.438 mmol) was
added in portions. The reaction was stirred at rt for 2 h, then
quenched with a saturated aqueous solution of sodium bicarbonate.
The mixture was then extracted with a 3:1 mixture of
chloroform/isopropanol. The combined organic layers were dried over
sodium sulfate, and concentrated in vacuo. The crude residue was
purified by silica gel chromatography (0.fwdarw.30% methanol/DCM)
to give the desired product. LC-MS calculated for
C.sub.20H.sub.22BrN.sub.4O (M+H).sup.+: m/z=413.1; found 413.1.
Step 4:
(R)-1-((8-(3'-amino-2'-chloro-2-methylbiphenyl-3-ylamino)-1,7-naph-
thyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00095##
[0866] To a vial was added
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Step 1: 0.101 g, 0.399 mmol),
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (0.165 g, 0.399 mmol), sodium carbonate (0.047 g,
0.439 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.029
g, 0.040 mmol), 1,4-dioxane (3.52 ml), and water (0.470 ml). The
mixture was degassed, sealed, and heated to 90.degree. C. whilst
stirring for 18 h. The mixture was cooled, diluted with water and
methylene chloride, and the layers were separated. The aqueous
layer was further extracted with methylene chloride, and the
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (15% MeOH/DCM) to provide the desired product. LC-MS
calculated for C.sub.26H.sub.27ClN.sub.5O (M+H).sup.+: m/z=460.2;
found 460.3.
Step 5: methyl
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate
##STR00096##
[0868] Methyl iodide (1.713 ml, 27.5 mmol) was added to a mixture
of 5-bromo-2-hydroxynicotinic acid (Combi-Blocks, cat# CA-4087: 2.0
g, 9.17 mmol), and potassium carbonate (1.811 ml, 20.18 mmol) in
methanol (45.9 mL), which was stirred at 70.degree. C. overnight.
The solvent was removed, and the crude mixture was extracted with
DCM/water. The organic extracts were dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The crude
product was used directly in the next step without further
purification. LC-MS calculated for C.sub.8H.sub.9BrNO.sub.3
(M+H).sup.+: m/z=246.0; found 246.0.
Step 6: 1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic
acid
##STR00097##
[0870] A mixture of methyl
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (745 mg,
3.03 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (565
.mu.l, 3.33 mmol), tetrakis(triphenylphosphine)palladium(O) (175.0
mg, 0.151 mmol), 2.0 M sodium carbonate in water (4543 .mu.l, 9.09
mmol) and 1,4-dioxane (6058 .mu.l) was sparged with nitrogen and
then heated at 100.degree. C. for 30 min. The mixture was
partitioned between EtOAc and water and the layers separated. The
organic layer was 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.9H.sub.10NO.sub.3 (M+H).sup.+:
m/z=180.1; found 180.1.
Step 7:
(R)--N-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-ylamino)-2'-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dih-
ydropyridine-3-carboxamide
##STR00098##
[0872] A mixture of
1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
(0.0550 g, 0.307 mmol),
(R)-1-((8-((3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-n-
aphthyridin-3-yl)methyl)pyrrolidin-3-ol (Step 4: 0.141 g, 0.307
mmol),
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide (0.140 g, 0.368 mmol),
and N,N-diisopropylethylamine (0.107 ml, 0.614 mmol) in
1,2-dichloroethane (4.39 ml) was stirred at rt for 2 h. The mixture
was concentrated under reduced pressure. The residue was diluted
with ethyl acetate, and washed with water followed by brine. The
organic layer was dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. The crude residue was purified by silica
gel chromatography (MeOH/DCM) to provide the desired compound.
LC-MS calculated for C.sub.35H.sub.34ClN.sub.6O.sub.3 (M+H).sup.+:
m/z=621.2; found 621.4.
Step 8:
(R)--N-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-ylamino)-2'-methylbiphenyl-3-yl)-5-formyl-1-methyl-2-oxo-,
2-dihydropyridine-3-carboxamide
##STR00099##
[0874] A flask was charged with
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-5-vinyl-1,2--
dihydropyridine-3-carboxamide (0.131 g, 0.211 mmol), 1,4-dioxane
(40 mL) and water (40 mL). A 4% osmium tetroxide solution in water
(0.094 ml, 0.015 mmol) was added to the reaction mixture. After 5
min, sodium periodate (0.361 g, 1.687 mmol) was added. The mixture
was stirred overnight at rt. The mixture was diluted with water (2
mL) and 3:1 chloroform/isopropanol (5 mL), and the layers were
separated. The organic extract was dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude aldehyde was
purified by silica gel chromatography (20% MeOH/DCM). LC-MS
calculated for C.sub.34H.sub.32ClN.sub.6O.sub.4 (M+H).sup.+:
m/z=623.2; found 623.4.
Step 9:
(R)-1-((5-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-
-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
[0875] To a vial was added
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-1-methyl-2-oxo-1,2-
-dihydropyridine-3-carboxamide (0.022 g, 0.035 mmol),
(R)-pyrrolidine-3-carboxylic acid (Combi-Blocks, cat#ST-7698: 0.012
g, 0.106 mmol), dichloromethane (0.579 ml) and triethylamine (0.016
ml, 0.115 mmol). The reaction was stirred at rt for 2 h, then
sodium triacetoxyborohydride (0.037 g, 0.177 mmol) and acetic acid
(6.06 .mu.l, 0.106 mmol) were added. The reaction was stirred for 2
h, then the mixture was diluted with methanol and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide the desired compound
as its TFA salt. LC-MS calculated for
C.sub.39H.sub.41ClN.sub.7O.sub.5 (M+H).sup.+: m/z=722.3; found
722.2.
Example 16
(R)-1-((8-(2,2'-dichloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-
-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyri-
din-3-yl)methyl)azetidine-3-carboxylic acid
##STR00100##
[0876] Step 1: methyl
1-((8-(3'-amino-2,2'-dichlorobiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)me-
thyl)azetidine-3-carboxylate
##STR00101##
[0878] To a vial was added
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Example 15, Step 1: 0.137 g, 0.539 mmol), methyl
1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)azetid-
ine-3-carboxylate (Example 14, Step 7: 0.166 g, 0.360 mmol), sodium
carbonate (0.057 g, 0.539 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.026
g, 0.036 mmol), 1,4-dioxane (3.17 ml), and water (0.423 ml). The
mixture was degassed, sealed, and heated to 90.degree. C. whilst
stirring for 1 h. The mixture was cooled, diluted with water and
3:1 chloroform/isopropanol, and the layers were separated. The
aqueous layer was further extracted with 3:1
chloroform/isopropanol, and the combined organic extracts were
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
desired compound was purified by silica gel chromatography (20%
MeOH/DCM). LC-MS calculated for
C.sub.26H.sub.24Cl.sub.2N.sub.5O.sub.2 (M+H).sup.+: m/z=508.1;
found 508.2.
Step 2: methyl
1-((8-(2,2'-dichloro-3'-(1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-car-
boxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carb-
oxylate
##STR00102##
[0880] In a vial,
1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
(Example 15, Step 6: 0.051 g, 0.285 mmol) HATU (0.130 g, 0.342
mmol) and N,N-diisopropylethylamine (0.099 ml, 0.569 mmol) were
dissolved in DMF (2.85 ml). After stirring for 5 min, methyl
1-((8-(3'-amino-2,2'-dichlorobiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)me-
thyl)azetidine-3-carboxylate (0.285 mmol) was added, and the
resulting mixture was stirred at 40.degree. C. for 24 h. Excess DMF
was concentrated, and the resulting oil was diluted with EtOAc and
water. The layers were separated and the water layer was further
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and
concentrated in vacuo. After concentrating, the crude residue was
triturated with DCM and filtered to provide the desired product.
The filtrate was purified by silica gel chromatography (20%
MeOH/DCM) to provide additional desired product. LC-MS calculated
for C.sub.35H.sub.31Cl.sub.2N.sub.6O.sub.4 (M+H).sup.+: m/z=669.2;
found 669.1.
Step 3: methyl
1-((8-(2,2'-dichloro-3'-(5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3-ca-
rboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-car-
boxylate
##STR00103##
[0882] This compound was prepared using similar procedures as
described for Example 14 with methyl
1-((8-(2,2'-dichloro-3'-(1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-car-
boxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carb-
oxylate replacing
N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine in Step
6. The crude product was purified by silica gel chromatography (20%
MeOH/DCM) to provide the desired product. LC-MS calculated for
C.sub.34H.sub.29Cl.sub.2N.sub.6O.sub.5 (M+H).sup.+: m/z=671.2;
found 671.4.
Step 4: (R)-methyl
1-((8-(2,2'-dichloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2--
oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-
-3-yl)methyl)azetidine-3-carboxylate
##STR00104##
[0884] This compound was prepared using similar procedures as
described for Example 15 with methyl
1-((8-(2,2'-dichloro-3'-(5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3-ca-
rboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-car-
boxylate replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 3. The crude product was purified by silica gel
chromatography (MeOH/DCM) to provide the desired product. LC-MS
calculated for C.sub.38H.sub.38Cl.sub.2N.sub.7O.sub.5 (M+H).sup.+:
m/z=742.2; found 742.4.
Step 5:
(R)-1-((8-(2,2'-dichloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)--
1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-n-
aphthyridin-3-yl)methyl)azetidine-3-carboxylic acid
[0885] This compound was prepared using similar procedures as
described for Example 14 with (R)-methyl
1-((8-(2,2'-dichloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2--
oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-
-3-yl)methyl)azetidine-3-carboxylate replacing methyl
1-((8-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyr-
idine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)azetidine-3-carboxylate in Step 11. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.37H.sub.36Cl.sub.2N.sub.7O.sub.5
(M+H).sup.+: m/z=728.2; found 728.1.
Example 17
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxyethylamino)methyl)-1-methyl-2-oxo-1,-
2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)-
methyl)azetidine-3-carboxylic acid
##STR00105##
[0886] Step 1: methyl
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxyethylamino)methyl)-1-methyl-2-oxo-1-
,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl-
)methyl)azetidine-3-carboxylate
##STR00106##
[0888] A mixture of methyl
1-((8-((2,2'-dichloro-3'-(5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3-c-
arboxamido)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)azeti-
dine-3-carboxylate (Example 16, Step 3: 0.020 g, 0.030 mmol) and
ethanolamine (Aldrich, cat#411000: 0.089 mmol) in methylene
chloride (0.596 ml) and N,N-diisopropylethylamine (0.026 ml, 0.149
mmol) was stirred at rt for 1 h. Sodium triacetoxyborohydride
(0.019 g, 0.089 mmol) was carefully added. The reaction was stirred
at rt for 2 h and sodium tetrahydroborate (2.384 .mu.l, 0.060 mmol)
and methanol (6 mL) were carefully added. The mixture was stirred
overnight, and the reaction was quenched with a saturated solution
of sodium bicarbonate. The mixture was then extracted with a 3:1
mixture of chloroform/isopropanol. The combined organic layers were
washed with brine, dried over sodium sulfate, and then concentrated
in vacuo. The crude residue was purified by column chromatography
(0.fwdarw.50% methanol/DCM). LC-MS calculated for
C.sub.36H.sub.36Cl.sub.2N.sub.7O.sub.5 (M+H).sup.+: m/z=716.2;
found 716.3.
Step 2:
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxyethylamino)methyl)-1-methyl--
2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyrid-
in-3-yl)methyl)azetidine-3-carboxylic acid
[0889] This compound was prepared using similar procedures as
described for Example 14 with methyl
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxyethylamino)methyl)-1-methyl-2-oxo-1-
,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl-
)methyl)azetidine-3-carboxylate replacing methyl
1-((8-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyr-
idine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)azetidine-3-carboxylate in Step 11. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.35H.sub.34Cl.sub.2N.sub.7O.sub.5
(M+H).sup.+: m/z=702.2; found 702.2.
Example 18
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxy-2-methylpropylamino)methyl)-1-methy-
l-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthyr-
idin-3-yl)methyl)azetidine-3-carboxylic acid
##STR00107##
[0890] Step 1: methyl
1l-((8-(2,2'-dichloro-3'-(5-((2-hydroxy-2-methylpropylamino)methyl)-1-met-
hyl-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphth-
yridin-3-yl)methyl)azetidine-3-carboxylate
##STR00108##
[0892] This compound was prepared using similar procedures as
described for Example 17 with 1-amino-2-methyl-2-propanol (Aldrich,
cat#777625) replacing ethanolamine in Step 1.
[0893] The crude residue was purified by column chromatography
(0.fwdarw.50% methanol/DCM). LC-MS calculated for
C.sub.38H.sub.40Cl.sub.2N.sub.7O.sub.5 (M+H).sup.+: m/z=744.2;
found 744.4.
Step 2:
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxy-2-methylpropylamino)methyl)-
-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7--
naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid
[0894] This compound was prepared using similar procedures as
described for Example 14 with methyl
1-((8-(2,2'-dichloro-3'-(5-((2-hydroxy-2-methylpropylamino)methyl)-1-meth-
yl-2-oxo-1,2-dihydropyridine-3-carboxamido)biphenyl-3-ylamino)-1,7-naphthy-
ridin-3-yl)methyl)azetidine-3-carboxylate replacing methyl
1-((8-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyr-
idine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)azetidine-3-carboxylate in Step 11. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.37H.sub.38Cl.sub.2N.sub.7O.sub.5
(M+H).sup.+: m/z=730.2; found 730.2.
Example 19
2,2'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(1,7-n-
aphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol)
##STR00109##
[0895] Step 1:
2-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)amino)ethanol
##STR00110##
[0897] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 15, Step 2: 0.100 g, 0.292 mmol) and ethanolamine
(Aldrich, cat#411000: 0.292 mmol) in 1,2-dichloroethane (1.46 ml)
and N,N-diisopropylethylamine (0.051 ml, 0.292 mmol) was stirred at
rt for 1 h. Sodium triacetoxyborohydride (0.093 g, 0.438 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h, then methanol (1 mL) and sodium borohydride (0.584 mmol) were
added. The reaction was quenched with a saturated aqueous solution
of sodium bicarbonate. The mixture was then extracted with a 3:1
mixture of chloroform/isopropanol. The combined organic layers were
dried over sodium sulfate, then concentrated in vacuo. The crude
residue was purified by silica gel chromatography (0.fwdarw.50%
methanol/DCM) to give the desired product. LC-MS calculated for
C.sub.18H.sub.20BrN.sub.4O (M+H).sup.+: m/z=387.1; found 387.2.
Step 2:
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methanol
##STR00111##
[0899] A mixture of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, cat#ARI-0169: 0.300 g, 0.872 mmol),
bis(pinacolato)diboron (Aldrich, #473294: 0.266 g, 1.046 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.071 g, 0.087 mmol) and potassium acetate
(0.214 g, 2.179 mmol) was charged with nitrogen and stirred at
110.degree. C. for 2 h. The crude was diluted with DCM, and then
filtered through Celite.RTM.. The filtrate was concentrated, and
the resulting residue was used directly in the next step without
further purification. LC-MS calculated for
C.sub.22H.sub.27BN.sub.3O.sub.3 (M+H).sup.+: m/z=392.2; found
392.3.
Step 3:
2-((8-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dime-
thylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)amino)ethanol
##STR00112##
[0901] To a vial was added
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (0.064 g, 0.165 mmol),
2-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methylamino)eth-
anol (Step 1: 0.058 g, 0.150 mmol), 1 M aqueous sodium carbonate
(0.300 mmol),
(1,1'-bis(di-cyclohexylphosphino)ferrocene)-dichloropalladium(II)
(10.96 mg, 0.015 mmol), and 1,4-dioxane (1.321 ml). The mixture was
degassed, sealed, and heated to 90.degree. C. whilst stirring for 4
h. The mixture was cooled, diluted with EtOAc and filtered through
Celite.RTM.. The filtrate was concentrated and the crude residue
was purified using silica gel chromatography (MeOH/DCM). LC-MS
calculated for C.sub.34H.sub.34N.sub.7O.sub.2 (M+H).sup.+:
m/z=572.3; found 572.4.
Step 4:
8-(3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-
-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridine-3-carbaldehyde
##STR00113##
[0903] This compound was prepared using similar procedures as
described for Example 9 with
2-((8-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbip-
henyl-3-ylamino)-1,7-naphthyridin-3-yl)amino)ethanol replacing
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol in Step 5. LC-MS calculated for C.sub.34H.sub.32N.sub.7O.sub.2
(M+H).sup.+: m/z=570.3; found 570.4.
Step 5:
2,2'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))b-
is(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-o-
l)
[0904] To a vial was added
8-(3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-d-
imethylbiphenyl-3-ylamino)-1,7-naphthyridine-3-carbaldehyde (0.034
g, 0.065 mmol), ethanolamine (Aldrich, cat#411000: 0.024 mL, 0.194
mmol), dichloromethane (0.997 ml) and N,N-diisopropylethylamine
(0.027 ml, 0.194 mmol). The reaction was stirred at rt for 2 h,
then sodium triacetoxyborohydride (0.041 g, 0.194 mmol) and acetic
acid (0.011 ml, 0.194 mmol) were added. After 2 h, sodium
borohydride (0.130 mmol) and methanol (0.350 mL) were carefully
added. The mixture was stirred overnight, then the mixture was
diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.36H.sub.39N.sub.8O.sub.2
(M+H).sup.+: m/z=615.3; found 615.3.
Example 20
(3R,3'R)-1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))b-
is(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol)
##STR00114##
[0905] Step 1:
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
##STR00115##
[0907] A suspension of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, cat#ARI-0169: 300.0 mg, 0.872 mmol)
and manganese dioxide (1515 mg, 17.43 mmol) in DCM (8716 .mu.l) was
stirred at 45.degree. C. for 1 h. The reaction was filtered through
Celite.RTM. and the filtrate was concentrated to yield a crude
residue, which was used directly in the next step without further
purification. LC-MS calculated for C.sub.16H.sub.13BrN.sub.3O
(M+H).sup.+: m/z=342.0; found 342.0.
Step 2:
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol
##STR00116##
[0909] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(0.100 g, 0.292 mmol) and (R)-3-hydroxypyrrolidine (Combi-Blocks,
cat#AM-2005: 0.025 g, 0.292 mmol) in 1,2-dichloroethane (1.46 ml)
and N,N-diisopropylethylamine (0.051 ml, 0.292 mmol) was stirred at
rt for 1 h. Sodium triacetoxyborohydride (0.093 g, 0.438 mmol) was
carefully added in portions. The reaction was stirred at rt for 2
h, then quenched with a saturated aqueous solution of sodium
bicarbonate. The mixture was then extracted with a 3:1 mixture of
chloroform/isopropanol. The combined organic layers were dried over
sodium sulfate, then concentrated in vacuo. The crude residue was
purified by silica gel chromatography (0.fwdarw.30% methanol/DCM)
to give the desired product. LC-MS calculated for
C.sub.20H22BrN.sub.4O (M+H).sup.+: m/z=413.1; found 413.1.
Step 3:
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methanol
##STR00117##
[0911] A mixture of
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, cat#ARI-0169: 0.300 g, 0.872 mmol),
bis(pinacolato)diboron (Aldrich, cat#473294: 0.266 g, 1.046 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.071 g, 0.087 mmol) and potassium acetate
(0.214 g, 2.179 mmol) was charged with nitrogen and stirred at
110.degree. C. for 2 h. The crude was diluted with DCM, and then
filtered through Celite.RTM.. The filtrate was concentrated, and
the resulting residue was used directly in the next step without
further purification. LC-MS calculated for
C.sub.22H.sub.27BN.sub.3O.sub.3 (M+H).sup.+: m/z=392.2; found
392.3.
Step 4:
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,-
2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol
##STR00118##
[0913] To a vial was added
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (0.162 g, 0.414 mmol),
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (0.163 g, 0.394 mmol), 1 M aqueous sodium carbonate
(0.789 mmol),
[1,1'-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium (II)
(0.029 g, 0.039 mmol), and 1,4-dioxane (3.48 ml). The mixture was
purged with nitrogen, sealed, and heated to 90.degree. C. whilst
stirring for 2 h. The mixture was cooled, diluted with EtOAc and
filtered through Celite.RTM.. The filtrate was concentrated and
purified using silica gel chromatography (20% MeOH/DCM) to provide
the desired compound as an orange solid. LC-MS calculated for
C.sub.36H.sub.36N.sub.7O.sub.2 (M+H).sup.+: m/z=598.3; found
598.4.
Step 5:
(R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-
-carbaldehyde
##STR00119##
[0915] To a solution of
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol (0.0715 g, 0.12 mmol) in DCM (1.20 ml) was added manganese
dioxide (0.208 g, 2.392 mmol). The resulting mixture was heated at
45.degree. C. for 30 min. After cooling, the mixture was filtered
through Celite.RTM. and the filtrate was concentrated. The crude
orange solid was used directly in the next step. LC-MS calculated
for C.sub.36H.sub.34N.sub.7O.sub.2 (M+H).sup.+: m/z=596.3; found
596.5.
Step 6:
(3R,3'R)-1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azan-
ediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol)
[0916] To a vial was added
(R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbal-
dehyde (0.0085 g, 0.014 mmol), (R)-pyrrolidin-3-ol (Combi-Blocks,
cat#AM-2005: 4 mg, 0.043 mmol), dichloromethane (0.357 ml) and
triethylamine (5.97 .mu.l, 0.043 mmol). The reaction was stirred at
rt for 2 h, then sodium triacetoxyborohydride (0.015 g, 0.071 mmol)
and acetic acid (2.451 .mu.l, 0.043 mmol) were added. The reaction
was stirred for 2 h, then the mixture was diluted with methanol and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as its TFA salt. LC-MS calculated for
C.sub.40H.sub.43N.sub.8O.sub.2 (M+H).sup.+: m/z=667.3; found 667.3.
.sup.1H NMR (600 MHz, DMSO) .delta. 10.68 (s, 2H), 9.09 (s, 2H),
8.53 (s, 2H), 7.96 (m, 4H), 7.41 (s, 2H), 7.24 (s, 2H), 7.10 (s,
2H), 5.62 (br s, 2H), 4.70 (m, 4H), 4.46 (m, 2H), 3.70-3.10 (ovrlp
m, 8H), 2.31 (s, 2H), 2.07 (s, 6H), 1.93 (m, 2H).
Example 21
(R)-1-((8-(3'-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-
-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin--
3-ol
##STR00120##
[0918] This compound was prepared using similar procedures as
described for Example 20 with ethanolamine (Aldrich, cat#411000)
replacing (R)-pyrrolidin-3-ol in Step 6. The reaction mixture was
diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.38H.sub.41N.sub.8O.sub.2
(M+H).sup.+: m/z=641.3; found 641.3.
Example 22
(3R,3'R)-1,1'-((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))b-
is(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol)
##STR00121##
[0919] Step 1: 8-chloro-3-vinyl-1,7-naphthyridine
##STR00122##
[0921] 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, 61.8 mmol) and water (6 mL, 300 mmol) 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.10HsClN.sub.2 (M+H).sup.+:
m/z=191.0; found 191.0.
Step 2: 8-chloro-1,7-naphthyridine-3-carbaldehyde
##STR00123##
[0923] A flask was charged with 8-chloro-3-vinyl-1,7-naphthyridine
(391. mg, 2.05 mmol), 1,4-dioxane (40. mL), a stir bar and water
(40. mL). To this suspension was added a 4% w/w mixture of osmium
tetraoxide in water (0.84 mL, 0.132 mmol). The reaction was stirred
for 5 min then sodium periodate (3.23 g, 15.11 mmol) was added and
stirred for 3 h. The mixture was diluted with water (20 mL) and
EtOAc (20 mL). The layers were separated and the aqueous layer was
further extracted with EtOAc (2.times.20 mL). The combined organic
extracts were washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude aldehyde was
purified by silica gel chromatography (0.fwdarw.60% EtOAc/hexanes).
LC-MS calculated for C.sub.9H6ClN.sub.2O (M+H).sup.+: m/z=193.0;
found 192.9.
Step 3:
(R)-1-((8-chloro-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00124##
[0925] This compound was prepared using similar procedures as
described for Example 20 with
8-chloro-1,7-naphthyridine-3-carbaldehyde replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 2. The crude amine was purified by silica gel
chromatography (0.fwdarw.25% MeOH/DCM). LC-MS calculated for
C.sub.13H.sub.15ClN.sub.3O (M+H).sup.+: m/z=264.1; found 264.1.
Step 4:
(R)-1-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)meth-
yl)pyrrolidin-3-ol
##STR00125##
[0927] In a vial, 3-bromo-2-chloroaniline (Enamine,
cat#EN300-105778: 0.063 g, 0.303 mmol) and
(R)-1-((8-chloro-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(0.080 g, 0.303 mmol) were suspended in isopropanol (1.517 ml).
Sulfuric acid (0.016 ml, 0.303 mmol) was added to the reaction
mixture. The resulting mixture was heated to 100.degree. C. for 1
h. The mixture was cooled, quenched with aqueous saturated sodium
bicarbonate, and diluted with 3:1 chloroform/isopropanol. The
layers were separated and the water layer was further extracted
with 3:1 chloroform/isopropanol. The combined organic layers were
dried over magnesium sulfate, filtered and concentrated in vacuo.
The crude solid was purified by column chromatography (0.fwdarw.25%
Methanol/DCM). LC-MS calculated for C.sub.19H.sub.19BrClN.sub.4O
(M+H).sup.+: m/z=433.0; found 433.0.
Step 5:
(R)-1-((8-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00126##
[0929] This compound was prepared using similar procedures as
described for Example 20 with
(R)-1-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)pyrr-
olidin-3-ol replacing
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
in Step 3. The crude boronic ester was used directly in the next
step without further purification. LC-MS calculated for
C.sub.25H.sub.31BClN.sub.4O.sub.3 (M+H).sup.+: m/z=481.2; found
481.2.
Step 6:
(3R,3'R)-1,1'-((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(azan-
ediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(pyrrolidin-3-ol)
[0930] To a vial was added
(R)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (0.010 g, 0.023 mmol),
(R)-1-((8-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (0.011 g,
0.023 mmol), 1 M aqueous sodium carbonate (0.046 mmol), dioxane
(0.231 ml),
(1,1'-bis(di-cyclohexylphosphino)ferrocene)-dichloropalladium(II)
(1.687 mg, 2.306 .mu.mol), and a stir bar. The mixture was sparged
with nitrogen and heated at 90.degree. C. for 2 h. The mixture was
diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.38H.sub.37Cl.sub.2N.sub.8O.sub.2
(M+H).sup.+: m/z=707.2; found 707.3.
Example 23
(R)-1-((4-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)meth-
yl)pyrrolidin-3-ol
##STR00127##
[0931] Step 1:
(R)-1-((8-(3'-amino-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-y-
l)methyl)pyrrolidin-3-ol
##STR00128##
[0933] To a vial was added
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127: 0.108 g, 0.465 mmol),
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 15, Step 3: 0.192 g, 0.465 mmol), 1 M
aqueous sodium carbonate (0.929 mmol),
(1,1'-bis(di-cyclohexylphosphino)ferrocene)-dichloropalladium(II)
(0.034 g, 0.046 mmol), and 1,4-dioxane (3.10 mL). The mixture was
degassed, sealed, and heated to 90.degree. C. whilst stirring for 4
h. The mixture was cooled, diluted with EtOAc and filtered through
celite. The filtrate was concentrated and the crude solid was
purified by column chromatography (0.fwdarw.25% Methanol/DCM).
LC-MS calculated for C.sub.27H.sub.30N.sub.5O (M+H).sup.+:
m/z=440.2; found 440.3.
Step 2:
(R)-1-((8-(3'-(7-bromopyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimet-
hylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00129##
[0935] To a vial was added 7-bromo-4-chloropyrido[3,2-d]pyrimidine
(Synthonix, cat#B0473: 0.187 g, 0.765 mmol),
(R)-1-((8-((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphth-
yridin-3-yl)methyl)pyrrolidin-3-ol (0.336 g, 0.765 mmol),
2-propanol (3.82 ml), a stir bar and sulfuric acid (0.041 ml, 0.765
mmol). The mixture was heated to 100.degree. C. for 2 h. After
cooling to rt, the mixture was diluted with 3:1
CHCl.sub.3/isopropanol and aqueous saturated sodium bicarbonate.
The layers were separated, and the aqueous phase was further
extracted. The combined organic layers were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The crude solid was washed
with ether to provide the desired product as a yellow solid. LC-MS
calculated for C.sub.34H.sub.32BrN.sub.8O (M+H).sup.+: m/z=647.2;
found 647.3.
Step 3:
(R)-1-((8-(2,2'-dimethyl-3'-(7-vinylpyrido[3,2-d]pyrimidin-4-ylami-
no)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00130##
[0937] A mixture of
(R)-1-((8-((3'-((7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(0.248 g, 0.383 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.130 ml, 0.766
mmol), sodium carbonate (0.074 ml, 0.766 mmol) and
(1,1'-bis(di-cyclohexylphosphino)ferrocene)-dichloropalladium(II)
(0.015 g, 0.019 mmol) in 1,4-dioxane (1.915 mL) and water (0.479
mL) was degassed and sealed. It was stirred at 90.degree. C. for
1.5 h. The mixture was cooled to rt, and water and 3:1
chloroform/isopropanol were added. The layers were separated and
the aqueous layer was further extracted with 3:1
chloroform/isopropanol. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
solid was then washed with ether to provide the desired compound as
a yellow solid. LC-MS calculated for C.sub.36H.sub.35N.sub.8O
(M+H).sup.+: m/z=595.3; found 595.3.
Step 4:
(R)-4-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidine-7-carbal-
dehyde
##STR00131##
[0939] To a flask was added
(R)-1-((8-((2,2'-dimethyl-3'-((7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(0.128 g, 0.215 mmol), THF (3.8 mL), water (1 mL), sodium periodate
(0.655 g, 3.06 mmol), and 4% osmium tetroxide solution in water
(0.170 ml, 0.027 mmol). The resulting mixture was stirred for 1 h
at rt. The mixture was diluted with water and 3:1
CHCl.sub.3/isopropanol and the layers were separated. The aqueous
layer was further extracted with CHCl.sub.3/isopropanol (3:1). The
combined organic layers were washed dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The resulting solid was washed
with ether to provide the desired product as a brown solid. LC-MS
calculated for C.sub.35H.sub.33N.sub.8O.sub.2 (M+H).sup.+:
m/z=597.3; found 597.5.
Step 5:
(R)-1-((4-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-
-yl)methyl)pyrrolidin-3-ol
[0940] To a vial was added
(R)-4-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)pyrido[3,2-d]pyrimidine-7-c-
arbaldehyde (0.064 g, 0.107 mmol), (R)-pyrrolidin-3-ol
(Combi-Blocks, cat#AM-2005: 0.037 g, 0.322 mmol),
1,2-dichloroethane (1.073 ml) and triethylamine (0.045 ml, 0.322
mmol). The reaction was stirred at rt for 2 h, then sodium
triacetoxyborohydride (0.114 g, 0.536 mmol) and acetic acid (0.018
ml, 0.322 mmol) were added. The reaction was stirred for 2 h, then
the mixture was diluted with methanol and purified by prep HPLC
(pH=2, acetonitrile/water+TFA) to provide the desired compound as
its TFA salt. LC-MS calculated for C.sub.39H.sub.42N.sub.9O.sub.2
(M+H).sup.+: m/z=668.3; found 668.3.
Example 24
(R)-1-((8-(3'-(7-((2-hydroxyethylamino)methyl)pyrido[3,2-d]pyrimidin-4-yla-
mino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrol-
idin-3-ol
##STR00132##
[0942] This compound was prepared using similar procedures as
described for Example 23 with ethanolamine (Aldrich, cat#411000)
replacing (R)-pyrrolidin-3-ol in Step 5. The reaction mixture was
diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.37H.sub.40N.sub.9O.sub.2
(M+H).sup.+: m/z=642.3; found 642.3.
Example 25
(R)-1-((8-(3'-(7-(((2-hydroxyethyl)(methyl)amino)methyl)pyrido[3,2-d]pyrim-
idin-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)met-
hyl)pyrrolidin-3-ol
##STR00133##
[0944] This compound was prepared using similar procedures as
described for Example 23 with 2-(methylamino)ethanol (Aldrich,
cat#471445) replacing (R)-pyrrolidin-3-ol in Step 5. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.38H.sub.42N.sub.9O.sub.2
(M+H).sup.+: m/z=656.3; found 656.4.
Example 26
(R)-1-((8-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-N-
,N-dimethylpyrrolidine-3-carboxamide
##STR00134##
[0946] A mixture of
(R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)pyrrolidine-3-carboxylic acid (Example 9, Step 6: 0.007
g, 5.08 .mu.mol), 2.0 M dimethylamine in THF (0.102 mmol), HATU
(2.316 mg, 6.09 .mu.mol), and N,N-diisopropylethylamine (8.84
.mu.l, 0.051 mmol) in DMF (0.051 ml) was stirred at r.t. for 2 h.
The reaction mixture was diluted with methanol and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide the desired compound
as its TFA salt. LC-MS calculated for
C.sub.43H.sub.48N.sub.9O.sub.2 (M+H).sup.+: m/z=722.4; found
722.4.
Example 27
(R)-1-((8-(3'-(7-(((S)-2-hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin--
4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)p-
yrrolidin-3-ol
##STR00135##
[0948] This compound was prepared using similar procedures as
described for Example 23 with (S)-(+)-1-amino-2-propanol (Aldrich,
cat#238864) replacing (R)-pyrrolidin-3-ol in Step 5. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.38H.sub.42N.sub.9O.sub.2
(M+H).sup.+: m/z=656.3; found 656.3.
Example 28
(R)-1-((8-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-
-dihydropyridine-3-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-napht-
hyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00136##
[0949] Step 1:
N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-c-
arboxamide
##STR00137##
[0951] A mixture of
1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
(Example 15, Step 6: 1.3 g, 7.26 mmol), 3-bromo-2-methylaniline
(Aldrich, cat#530018: 0.894 ml, 7.26 mmol), HATU (3.31 g, 8.71
mmol), and N,N-diisopropylethylamine (2.53 ml, 14.51 mmol) in
1,2-dichloroethane (36.3 ml) was stirred at rt for 2 h. The mixture
was concentrated under reduced pressure. The residue was diluted
with ethyl acetate, and the resulting mixture was washed with water
and brine. The organic layer was 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.16H.sub.16BrN.sub.2O.sub.2 (M+H).sup.+:
m/z=347.0; found 347.0.
Step 2:
N-(3-bromo-2-methylphenyl)-5-formyl-1-methyl-2-oxo-1,2-dihydropyri-
dine-3-carboxamide
##STR00138##
[0953] This compound was prepared using similar procedures as
described for Example 23, Step 4 with
N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-c-
arboxamide replacing
(R)-1-((8-((2,2'-dimethyl-3'-((7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol.
The crude aldehyde was purified by silica gel chromatography (5%
MeOH/DCM). LC-MS calculated for C.sub.15H.sub.14BrN.sub.2O.sub.3
(M+H).sup.+: m/z=349.0; found 349.1.
Step 3:
(R)--N-(3-bromo-2-methylphenyl)-5-((3-hydroxypyrrolidin-1-yl)methy-
l)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00139##
[0955] This compound was prepared using similar procedures as
described for Example 20, Step 2 with
N-(3-bromo-2-methylphenyl)-5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3--
carboxamide replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde.
The crude amine was purified by silica gel chromatography (20%
MeOH/DCM). LC-MS calculated for C.sub.19H.sub.23BrN.sub.3O.sub.3
(M+H).sup.+: m/z=420.1; found 420.1.
Step 4:
(R)--N-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dim-
ethylbiphenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,-
2-dihydropyridine-3-carboxamide
##STR00140##
[0957] This compound was prepared using similar procedures as
described for Example 20, Step 4 with
(R)--N-(3-bromo-2-methylphenyl)-5-((3-hydroxypyrrolidin-1-yl)methyl)-1-me-
thyl-2-oxo-1,2-dihydropyridine-3-carboxamide replacing
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol. The crude amine was purified by silica gel
chromatography (20% MeOH/DCM). LC-MS calculated for
C.sub.35H.sub.37N.sub.6O.sub.4 (M+H).sup.+: m/z=605.3; found
605.3.
Step 5:
(R)--N-(3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiph-
enyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydro-
pyridine-3-carboxamide
##STR00141##
[0959] This compound was prepared using similar procedures as
described for Example 20, Step 5 with
(R)--N-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbi-
phenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihyd-
ropyridine-3-carboxamide replacing
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol. LC-MS calculated for C.sub.35H.sub.35N.sub.6O.sub.4
(M+H).sup.+: m/z=603.3; found 603.3.
Step 6:
(R)-1-((8-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-
-oxo-1,2-dihydropyridine-3-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1-
,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
[0960] To a vial was added
(R)--N-(3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3--
yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridin-
e-3-carboxamide (0.010 g, 0.017 mmol), (R)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, cat#ST-7698: 6 mg, 0.050 mmol),
1,2-dichloroethane (0.4 ml) and triethylamine (6.94 .mu.l, 0.050
mmol). The reaction was stirred at rt for 2 h, then sodium
triacetoxyborohydride (0.018 g, 0.083 mmol) and acetic acid (2.85
.mu.l, 0.050 mmol) were added. The reaction was stirred for 2 h,
then the mixture was diluted with methanol and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as
the TFA salt. LC-MS calculated for C.sub.40H.sub.44N.sub.7O.sub.5
(M+H).sup.+: m/z=702.3; found 702.3.
Example 29
(R)-1-((8-(3'-(7-(((R)-2-hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin--
4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)p-
yrrolidin-3-ol
##STR00142##
[0962] This compound was prepared using similar procedures as
described for Example 23 with (R)-(+)-1-amino-2-propanol (Aldrich,
cat#238856) replacing (R)-pyrrolidin-3-ol in Step 5. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.38H.sub.42N.sub.9O.sub.2
(M+H).sup.+: m/z=656.3; found 656.4.
Example 30
(R)-1-((8-(3'-(7-((2-hydroxy-2-methylpropylamino)methyl)pyrido[3,2-d]pyrim-
idin-4-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)met-
hyl)pyrrolidin-3-ol
##STR00143##
[0964] This compound was prepared using similar procedures as
described for Example 23 with 1-amino-2-methyl-2-propanol (Aldrich,
cat#777625) replacing (R)-pyrrolidin-3-ol in Step 5. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.39H.sub.44N.sub.9O.sub.2
(M+H).sup.+: m/z=670.3; found 670.4.
Example 31
(R)-1-((8-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-
pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)-
methyl)pyrrolidine-3-carboxylic acid
##STR00144##
[0965] Step 1: tert-butyl
1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
##STR00145##
[0967] A solution of
1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Accela,
cat#SY032476: 2.0 g, 14.58 mmol) and (Boc).sub.2O (3.38 mL, 14.58
mmol) in dichloromethane (60.0 mL) was stirred at room temperature
for 1 h. The reaction was quenched with saturated aqueous
NaHCO.sub.3 solution, and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was used for next step without further
purification. LC-MS calculated for C.sub.12H.sub.20N.sub.3O.sub.2
(M+H).sup.+: m/z=238.2; found 238.2.
Step 2: 5-tert-butyl 2-methyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate
##STR00146##
[0969] n-Butyllithium in hexanes (2.5 M, 7.00 mL, 17.49 mmol) was
added to a cold (-78.degree. C.) solution of the crude product from
Step 1 in tetrahydrofuran (60.0 mL). The reaction mixture was
stirred at -78.degree. C. for 10 min prior to the addition of
methyl chloroformate (1.7 mL, 21.9 mmol). After being stirred at
-78.degree. C. for 15 min, the reaction was then quenched with
saturated aqueous NaHCO.sub.3 solution, and extracted with ethyl
acetate, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on a silica gel column eluting with 80% ethyl
acetate in hexanes to afford the desired product ( ). LC-MS
calculated for C.sub.14H.sub.22N.sub.3O.sub.4 (M+H).sup.+:
m/z=296.2; found 296.3.
Step 3: tert-butyl
2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imid-
azo[4,5-c]pyridine-5-carboxylate
##STR00147##
[0971] Potassium tert-butoxide in tetrahydrofuran (1.0 M, 3.39 mL,
3.39 mmol) was added to a solution of 5-tert-butyl 2-methyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate
(Step 2: 500 mg, 1.69 mmol) and 3-bromo-2-chloroaniline (348 mg,
1.69 mmol) in tetrahydrofuran (12.0 mL). After being stirred at
room temperature for 1 h, the reaction mixture was quenched with
water, and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on a silica gel column eluting
with 50% ethyl acetate in hexanes to afford the desired product.
LC-MS calculated for C.sub.19H.sub.23BrClN.sub.4O.sub.3
(M+H).sup.+: m/z=469.1/471.1; found 469.1/471.1.
Step 4:
N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imid-
azo[4,5-c]pyridine-2-carboxamide
##STR00148##
[0973] A solution of tert-butyl
2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imid-
azo[4,5-c]pyridine-5-carboxylate (Step 3: 300 mg, 0.64 mmol) in
trifluoroacetic acid (0.2 mL) and dichloromethane (0.4 mL) was
stirred at room temperature for 1 h. The solvent was evaporated,
and the residue was dissolved in tetrahydrofuran (1.0 mL). 37%
formaldehyde in water (0.48 mL, 6.39 mmol) and sodium
triacetoxyborohydride (406 mg, 1.92 mmol) were successively added.
After being stirred at room temperature for 1 h, the mixture was
quenched with sat. aq. NaHCO.sub.3 solution and was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography
on a silica gel column eluting with 10% methanol in dichloromethane
to afford the desired product. LC-MS calculated for
C.sub.15H.sub.17BrClN.sub.4O (M+H).sup.+: m/z=383.0/385.0; found
383.0/385.0.
Step 5:
N-(2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-
-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4-
,5-c]pyridine-2-carboxamide
##STR00149##
[0975] A mixture of
N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-
-c]pyridine-2-carboxamide (Step 4: 60 mg, 0.156 mmol),
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (Example 9, Step 3: 73.4 mg, 0.188
mmol), sodium carbonate (66.3 mg, 0.626 mmol) and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(11.8 mg, 0.016 mmol) in 1,4-dioxane (0.8 mL) and water (0.8 mL)
was charged with nitrogen and stirred at 100.degree. C. for 2 h.
The reaction mixture was diluted with water and extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on a silica gel column eluting with 10% methanol in dichloromethane
to afford the desired product. LC-MS calculated for
C.sub.31H.sub.31ClN.sub.7O.sub.2 (M+H).sup.+: m/z=568.2; found
568.3.
Step 6:
N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[-
1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyri-
dine-2-carboxamide
##STR00150##
[0977] A suspension of
N-(2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-
-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]py-
ridine-2-carboxamide (Step 5: 40 mg, 0.070 mmol) and manganese
dioxide (92 mg, 1.056 mmol) in dichloromethane (0.5 mL) was stirred
at 45.degree. C. for 30 min. The reaction was filtered through a
short pad of Celite.RTM. and then concentrated to yield a crude
residue, which was used directly without further purification.
LC-MS calculated for C.sub.31H.sub.29ClN.sub.7O.sub.2 (M+H).sup.+:
m/z=566.2; found 566.2.
Step 7:
(R)-1-((8-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidaz-
o[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyrid-
in-3-yl)methyl)pyrrolidine-3-carboxylic acid
[0978] A mixture of
N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-bi-
phenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2--
carboxamide (Step 6: 39.9 mg, 0.070 mmol) and
(R)-pyrrolidine-3-carboxylic acid (24.3 mg, 0.211 mmol) in
dichloromethane (0.5 mL) was stirred at room temperature for 1 h.
Then sodium triacetoxyborohydride (14.92 mg, 0.070 mmol) and acetic
acid (4.03 .mu.l, 0.070 mmol) was added. After being stirred at
room temperature for 1 h, the reaction was diluted with MeOH and
then purified by prep-HPLC (pH=10, acetonitrile/water+NH.sub.4OH)
to give the desired product. LC-MS calculated for
C.sub.36H.sub.38ClN.sub.8O.sub.3 (M+H).sup.+: m/z=665.3; found
665.4.
Example 32
(S)--N-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-
-8-ylamino)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imi-
dazo[4,5-c]pyridine-2-carboxamide
##STR00151##
[0980] This compound was prepared using similar procedures as
described for Example 31, Step 7 with (S)-pyrrolidin-3-ol
(Combi-Blocks, cat#SS-7948) replacing (R)-pyrrolidine-3-carboxylic
acid. The reaction mixture was purified by prep-HPLC (pH=10,
acetonitrile/water+NH.sub.4OH) to give the desired product. LC-MS
calculated for C.sub.35H.sub.38ClN.sub.8O.sub.2 (M+H).sup.+:
m/z=637.3; found 637.4.
Example 33
(R)-1-((8-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-
pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)-
methyl)-3-methylpyrrolidine-3-carboxylic acid
##STR00152##
[0982] This compound was prepared using similar procedures as
described for Example 31, Step 7 with
(R)-3-methylpyrrolidine-3-carboxylic acid (Ark Pharm, cat#AK601708)
replacing (R)-pyrrolidine-3-carboxylic acid. The reaction mixture
was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give
the desired product. LC-MS calculated for
C.sub.37H.sub.40ClN.sub.8O.sub.3 (M+H).sup.+: m/z=679.3; found
679.2.
Example 34
(R)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-y-
l)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3--
carboxylic acid
##STR00153##
[0983] Step 1: tert-butyl
2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00154##
[0985] This compound was prepared using similar procedures as
described for Example 1, Step 7 with
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, #ARI-0169) replacing
2-(((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino-
)ethan-1-ol. After 5 h, saturated aqueous NaHCO.sub.3 (5 mL)
solution was added to the reaction mixture followed by extraction
with dichloromethane (5 mL.times.3). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was used for next step without further purification.
LC-MS calculated for C.sub.34H.sub.36N.sub.5O.sub.3S (M+H).sup.+:
m/z=594.2; found 594.3.
Step 2: tert-butyl
2-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00155##
[0987] To a solution of tert-butyl
2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
(130 mg, 0.22 mmol) in DCM (2 mL) was added Dess-Martin periodinane
(186 mg, 0.44 mmol). After 1 h, saturated NaHCO.sub.3 (5 mL) was
added to the reaction mixture followed by extraction with
dichloromethane (5 mL.times.3). The combined organic layers were
dried Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was used for next step without further purification. LC-MS
calculated for C.sub.34H.sub.34N.sub.5O.sub.3S (M+H).sup.+:
m/z=592.2; found 592.3.
Step 3:
(R)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idin-2-yl)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrol-
idine-3-carboxylic acid
[0988] To a solution of tert-butyl
2-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (10
mg, 0.017 mmol) and DIPEA (5 uL) in DCM (0.5 mL) was added
(R)-pyrrolidine-3-carboxylic acid (5.8 mg, 0.05 mmol). After 1 h,
sodium triacetoxyborohydride (6.6 mg, 0.033 mmol) was added to the
reaction mixture. After 2 h, TFA (0.5 mL) was added to the reaction
mixture. After another 1 h, the reaction mixture was concentrated,
then dissolved in MeOH and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the compound as the TFA salt.
LC-MS calculated for C.sub.34H.sub.35N.sub.6O.sub.2S (M+H).sup.+:
m/z=591.2; found 591.3.
Example 35
(R)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-y-
l)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-o-
l
##STR00156##
[0990] This compound was prepared using similar procedures as
described for Example 34 with (R)-3-hydroxypyrrolidine replacing
(R)-pyrrolidine-3-carboxylic acid in Step 3. The reaction mixture
was diluted with MeOH then purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.33H.sub.35N60S (M+H).sup.+:
m/z=563.3; found 563.3.
Example 36
(S)-1-((8-((2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-y-
l)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-o-
l
##STR00157##
[0992] This compound was prepared using similar procedures as
described for Example 34 with (S)-3-hydroxypyrrolidine replacing
(R)-pyrrolidine-3-carboxylic acid in Step 3. The reaction mixture
was diluted with MeOH then purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as the TFA
salt. LC-MS calculated for C.sub.33H.sub.35N60S (M+H).sup.+:
m/z=563.3; found 563.3.
Example 37
(R)-2-(dimethylamino)-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7--
naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5-
H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one
##STR00158##
[0993] Step 1: Benzyl 6-oxa-3-azabicyclo[3.1.
O]hexane-3-carboxylate
##STR00159##
[0995] To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate
(12.4 g, 61.0 mmol) in DCM (200 ml) was added m-CPBA (16.20 g, 61.0
mmol). The resulting mixture was stirred at room temperature for 3
h. The reaction was quenched with saturated aqueous NaHCO.sub.3
solution, the organic layer was separated, and the aqueous layer
was extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified using flash chromatography (eluting with 0-50% ethyl
acetate in hexanes) to give the desired product as clear oil (13 g,
97%). LC-MS calculated for C.sub.12H.sub.14NO.sub.3 (M+H).sup.+:
m/z=220.1; found 220.1.
Step 2: Benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate
##STR00160##
[0997] To a flask was charged with benzyl
6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (13.0 g, 59.3 mmol)
and ammonium hydroxide (115 ml, 2.96 mol). The reaction mixture was
heated at 90.degree. C. overnight. The solvent was removed. The
residue was used in the next step without further purification.
LC-MS calculated for C.sub.12H.sub.17N.sub.2O.sub.3 (M+H).sup.+:
m/z=237.1; found 237.1.
Step 3: Benzyl
3-(3-bromo-2-methylbenzamido)-4-hydroxypyrrolidine-1-carboxylate
##STR00161##
[0999] A solution of 3-bromo-2-methylbenzoic acid (9.70 g, 45.1
mmol) in N,N-dimethylformamide (226 ml) was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (18.87 g, 49.6 mmol). After stirring for 5 min,
benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (10.66 g, 45.1
mmol) and N,N-diisopropylethylamine (23.57 ml, 135 mmol) were
added. The reaction mixture was stirred at room temperature for 2
h. The reaction was diluted with water, and the aqueous layer was
extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified with flash chromatography (eluting with 0-60% ethyl
acetate in hexanes) to give the desired product (11.5 g, 59%).
LC-MS calculated for C.sub.20H.sub.22BrN.sub.2O.sub.4 (M+H).sup.+:
m/z=433.1, 435.1; found 433.1, 435.1.
Step 4: benzyl
3-(3-bromo-2-methylbenzamido)-4-oxopyrrolidine-1-carboxylate
##STR00162##
[1001] To a solution of benzyl
3-(3-bromo-2-methylbenzamido)-4-hydroxypyrrolidine-1-carboxylate
(16.50 g, 38.1 mmol) in DCM (200 ml) was added Dess-Martin
periodinane (19.38 g, 45.7 mmol). The resulting mixture was stirred
at room temperature for 2 h. The reaction mixture was diluted with
Et.sub.2O and 1 M NaOH solution. After stirring for 1 h, the
organic layer was separated and dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified with flash
chromatography (eluting with 0-50% ethyl acetate in hexanes) to
give the desired product (9.2 g, 56%). LC-MS calculated for
C.sub.20H.sub.20BrN.sub.2O.sub.4 (M+H).sup.+: m/z=431.1, 433.1;
found 431.1, 433.1.
Step 5: benzyl
2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxy-
late
##STR00163##
[1003] To a solution of benzyl
3-(3-bromo-2-methylbenzamido)-4-oxopyrrolidine-1-carboxylate (9.23
g, 21.40 mmol) in 1,4-dioxane (100 ml) was added POCl.sub.3 (1.995
ml, 21.40 mmol). The resulting mixture was stirred at 110.degree.
C. for 3 h. After cooling to room temperature, the reaction mixture
was diluted with saturated NaHCO.sub.3 solution and ethyl acetate.
The aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The precipitate was collected via
filtration and washed with ethyl acetate and hexanes to give the
desired product as an off white solid (4.85 g, 55%). LC-MS
calculated for C.sub.20H.sub.18BrN.sub.2O.sub.3 (M+H).sup.+:
m/z=413.0, 415.0; found 413.0, 415.0.
Step 6.
2-(3-Bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole
##STR00164##
[1005] To solution of benzyl
2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxy-
late (3.70 g, 8.95 mmol) in DCM (60 ml) was added 1 M BBr.sub.3 in
DCM solution (17.91 ml, 17.91 mmol) at 0.degree. C. After stirring
at same temperature for 1 h, the reaction mixture was diluted DCM
and saturated NaHCO.sub.3 solution. The resultant precipitate was
collected vial filtration and dried under vacuum to give the
desired product as white solid (2.0 g, 80%). LC-MS calculated for
C.sub.12H.sub.12BrN.sub.2O (M+H).sup.+: m/z=279.0, 281.0; found
279.0, 281.0.
Step 7.
1-(2-(3-Bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-(dimethylamino)ethan-1-one
##STR00165##
[1007] A solution of dimethylglycine (20.5 mg, 0.199 mmol) in
N,N-dimethylformamide (1 ml) was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (104 mg, 0.274 mmol). After stirring for 5 min,
2-(3-bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole
(55.5 mg, 0.199 mmol) and N,N-diisopropylethylamine (104 .mu.l,
0.596 mmol) were added. The reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with water,
and the aqueous layer was extracted with DCM. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified with silica gel column (eluting with 0-30%
MeOH in DCM) to give the desired product (35 mg, 49%). LC-MS
calculated for C.sub.16H.sub.19BrN.sub.3O.sub.2 (M+H).sup.+:
m/z=364.1, 366.1; found 364.1, 366.1.
Step 8.
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol
##STR00166##
[1009] To a mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 9, Step 1: 340 mg, 0.994 mmol), (R)-pyrrolidin-3-ol (104
mg, 1.192 mmol) in DCM (1.0 ml) was added sodium
triacetoxyborohydride (316 mg, 1.490 mmol). After stirring for 2 h
at room temperature, the mixture was purified with flash
chromatography (0-100% ethyl acetate in hexanes, then 0-35%
methanol in DCM). LC-MS calculated for C.sub.20H.sub.22BrN.sub.4O
(M+H).sup.+: m/z=413.1, 415.1; found 413.1, 415.1.
Step 9:
(R)-1-((8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00167##
[1011] A mixture of
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (281 mg, 0.680 mmol), bis(pinacolato)diboron (207 mg,
0.816 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (55.5 mg, 0.068 mmol), 1,4-dioxane (3.4 mL)
and potassium acetate (167 mg, 1.700 mmol) was stirred at
90.degree. C. under N.sub.2 atmosphere for 3 h. The crude was
diluted with DCM, and then filtered through a pad of Celite.RTM..
The filtrate was concentrated and purified with flash
chromatography (eluting with ethyl acetate in hexane 0-100%, then
methanol/DCM 0-25%) (210 mg, 67%). LC-MS calculated for
C.sub.26H.sub.34BN.sub.4O.sub.3 (M+H).sup.+: m/z=461.3; found
461.2.
Step 10:
(R)-2-(dimethylamino)-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)met-
hyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6--
dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one
[1012] A microwave vial charged with
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one (9.49 mg, 0.026 mmol),
(R)-1-((8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (12 mg, 0.026
mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphen-
yl-2-yl)(chloro)palladium (1:1) (2.051 mg, 2.61 .mu.mol) and
tripotassium phosphate hydrate (13.21 mg, 0.057 mmol) was evacuated
under high vacuum and refilled with nitrogen (repeated three
times). 1,4-Dioxane (0.6 mL) and water (0.2 mL) was added and
resulting mixture was stirred at 80.degree. C. for 1 h. The
reaction mixture was diluted with methanol and 1 N HCl solution and
purified with prep-LC-MS (pH=2, acetonitrile/water+TFA) to give the
desired product as white solid. LC-MS calculated for
C.sub.36H.sub.40N.sub.7O.sub.3 (M+H).sup.+: m/z=618.3; found
618.3.
Example 38
(S)-2-(dimethylamino)-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7--
naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5-
H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one
##STR00168##
[1014] This compound was prepared using similar procedures as
described for Example 37 with (S)-pyrrolidin-3-ol (Combi-Blocks,
cat#SS-7948) replacing (R)-pyrrolidin-3-ol in Step 8. LC-MS
calculated for C.sub.36H.sub.40N.sub.7O.sub.3 (M+H).sup.+:
m/z=618.3; found 618.3.
Example 39
(R)-1-(2-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8--
yl)amino)-2,2'-dimethyl-[1,1''-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4--
d]oxazol-5-yl)-2-oxoethyl)azetidine-3-carboxylic acid
##STR00169##
[1015] Step 1:
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-chloroethan-1-one
##STR00170##
[1017] A solution of
2-(3-bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole
(Example 37, Step 6: 1.04 g, 3.73 mmol) in CH.sub.2Cl.sub.2 (18 ml)
was added 2-chloroacetyl chloride (0.421 g, 3.73 mmol) and
N,N-diisopropylethylamine (1.947 ml, 11.18 mmol) at 0.degree. C.
The reaction mixture was stirred at room temperature for 2 h. The
reaction was diluted with water, and the aqueous layer was
extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified with flash chromatography (eluting with 0-60% ethyl
acetate in hexanes) to give the desired product as white solid
(0.65 g, 49%). LC-MS calculated for
C.sub.14H.sub.13BrClN.sub.2O.sub.2 (M+H).sup.+: m/z=355.0, 357.0;
found 355.0, 357.0.
Step 2:
1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxaz-
ol-5-yl)-2-oxoethyl)azetidine-3-carboxylic acid
##STR00171##
[1019] The mixture of
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-chloroethan-1-one (15 mg, 0.042 mmol), azetidine-3-carboxylic acid
(Aldrich, cat#391131: 4.26 mg, 0.042 mmol), TEA (0.018 ml, 0.127
mmol) and N,N-dimethylformamide (1.0 ml) was heated at 60.degree.
C. for 2 h. The reaction mixture was diluted with methanol and 1 N
HCl, then purified with prep-LC-MS (pH 2) to give the desired
product C (12 mg, 67%). LC-MS calculated for
C.sub.18H.sub.19BrN.sub.3O.sub.4 (M+H).sup.+: m/z=420.1; found
420.1.
Step 3:
(R)-1-(2-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthy-
ridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrro-
lo[3,4-d]oxazol-5-yl)-2-oxoethyl)azetidine-3-carboxylic acid
[1020] This compound was prepared using similar procedures as
described for Example 37, Step 10 with
1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl-
)-2-oxoethyl)azetidine-3-carboxylic acid replacing
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one. LC-MS calculated for
C.sub.38H.sub.40N.sub.7O.sub.5 (M+H).sup.+: m/z=674.3; found
674.3.
Example 40
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1''-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[-
3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid
##STR00172##
[1021] Step 1:
(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid
##STR00173##
[1023] This compound was prepared using similar procedures as
described for Example 39, Step 2 with (S)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, #ST-1381) replacing azetidine-3-carboxylic
acid. LC-MS calculated for C.sub.19H.sub.21BrN.sub.3O.sub.4
(M+H).sup.+: m/z=434.1, 436.1; found 434.1, 436.1.
Step 2:
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxy)pyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H--
pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic
acid
[1024] This compound was prepared using similar procedures as
described for Example 37, Step 10 with
(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid replacing
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one. LC-MS calculated for
C.sub.39H.sub.42N.sub.7O.sub.5 (M+H).sup.+: m/z=688.3; found
688.3.
Example 41
(R)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3-
,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid
##STR00174##
[1025] Step 1:
(R)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid
##STR00175##
[1027] This compound was prepared using similar procedures as
described for Example 39, Step 2 with (R)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, cat#ST-7698) replacing azetidine-3-carboxylic
acid. LC-MS calculated for C.sub.19H.sub.21BrN.sub.3O.sub.4
(M+H).sup.+: m/z=434.1, 436.1; found 434.1, 436.1.
Step 2:
(R)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-nap-
hthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-p-
yrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic
acid
[1028] This compound was prepared using similar procedures as
described for Example 37, Step 10 with
(R)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)pyrrolidine-3-carboxylic acid replacing
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one. LC-MS calculated for
C.sub.39H.sub.42N.sub.7O.sub.5 (M+H).sup.+: m/z=688.3; found
688.3.
Example 42
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-yl)amino)-2,2'-dimethyl-[1,1''-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[-
3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylic acid
##STR00176##
[1029] Step 1:
(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)piperidine-2-carboxylic acid
##STR00177##
[1031] This compound was prepared using similar procedures as
described for Example 39, Step 2 with (S)-piperidine-2-carboxylic
acid (Alfa Aesar, cat#L15373) replacing azetidine-3-carboxylic
acid. LC-MS calculated for C.sub.20H.sub.23BrN.sub.3O.sub.4
(M+H).sup.+: m/z=448.1, 450.1; found 448.1, 450.1.
Step 2:
(S)-1-(2-(2-(3'-((3-(((R)-3-hydroxy)pyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H--
pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylic
acid
[1032] This compound was prepared using similar procedures as
described for Example 37, Step 10 with
(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol--
5-yl)-2-oxoethyl)piperidine-2-carboxylic acid replacing
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one. LC-MS calculated for
C.sub.40H.sub.44N.sub.7O.sub.5 (M+H).sup.+: m/z=702.3; found
702.3.
Example 43
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((3-(((R)-3-hydrox-
ypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'--
biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
##STR00178##
[1033] Step 1:
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde
##STR00179##
[1035] To a mixture of (3-bromo-2-methylphenyl)methanol (Ark Pharm,
cat#AK162869: 2.330 g, 11.59 mmol),
5-chloro-2,4-dihydroxybenzaldehyde (Ark Pharm, cat#AK199510: 2.0 g,
11.59 mmol) and triphenylphosphine (3.65 g, 13.91 mmol) in THF (10
ml) at 0.degree. C. was added DIAD (2.93 ml, 15.07 mmol). The
mixture was stirred at room temperature overnight. The mixture was
concentrated and diluted with EtOAc. The solid was collected by
filtration to give
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (2.0
g, 5.62 mmol, 48.5% yield). LC-MS calculated for
C.sub.15H.sub.13BrClO.sub.3 (M+H).sup.+: m/z=355.0; found
355.2.
Step 2:
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methy-
l)nicotinonitrile
##STR00180##
[1037] A mixture of
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (2.0
g, 5.62 mmol), 5-(chloromethyl)nicotinonitrile (0.927 g, 6.07 mmol)
and cesium carbonate (2.75 g, 8.44 mmol) in DMF (12 ml) was stirred
at 70.degree. C. for 3 hours. The mixture was poured into water.
The solid was collected by filtration and air dried to give
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicot-
inonitrile (2.2 g, 4.66 mmol, 83% yield). LC-MS calculated for
C.sub.22H.sub.17BrClN.sub.2O.sub.3 (M+H).sup.+: m/z=471.0; found
471.2.
Step 3:
(R)-5-((4-chloro-2-formyl-5-((3'-((3-((3-hydroxypyrrolidin-1-yl)me-
thyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)meth-
oxy)phenoxy)methyl)nicotinonitrile
##STR00181##
[1039] A mixture of
5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicot-
inonitrile (78 mg, 0.165 mmol),
(R)-1-((8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (Example 37,
Step 9: 91 mg, 0.198 mmol), potassium carbonate (45.7 mg, 0.331
mmol) and
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (12.1
mg, 0.017 mmol) in 1,4-dioxane (3 mL) and water (0.600 mL) was
purged with nitrogen, and heated at 95.degree. C. for 2 hours. The
mixture was purified on prep-HPLC (pH=2, acetonitrile/water+TFA) to
give
(R)-5-((4-chloro-2-formyl-5-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phe-
noxy)methyl)nicotinonitrile (60 mg, 0.083 mmol, 50.0% yield). LC-MS
calculated for C.sub.42H.sub.38ClN.sub.6O.sub.4 (M+H).sup.+:
m/z=725.3; found 725.2.
Step 4:
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((3-(((R)--
3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethy-
l-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic
acid
[1040] Sodium triacetoxyborohydride (2.192 mg, 10.34 .mu.mol) was
added to a mixture of
(R)-5-((4-chloro-2-formyl-5-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phe-
noxy)methyl)nicotinonitrile (5 mg, 6.89 .mu.mol),
(S)-piperidine-2-carboxylic acid (1.4 mg, 10.34 .mu.mol) and
triethylamine (1.922 .mu.L, 0.014 mmol) in DCM (1.0 mL) after
stirring for 2 hours at room temperature. After stirring at room
temperature overnight, the mixture was purified using prep-HPLC
(pH=2, acetonitrile/water+TFA) to give the desired product as its
TFA salt. LC-MS calculated for C.sub.48H.sub.49ClN.sub.7O.sub.5
(M+H).sup.+: m/z=838.3; found 838.2.
Example 44
(R)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-((3-(((R)-3-hydrox-
ypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'--
biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-3-carboxylic acid
##STR00182##
[1042] Sodium triacetoxyborohydride (2.192 mg, 10.34 .mu.mol) was
added to a mixture of
(R)-5-((4-chloro-2-formyl-5-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phe-
noxy)methyl)nicotinonitrile (Example 43, Step 3: 5 mg, 6.9
.mu.mol), (R)-pyrrolidine-3-carboxylic acid (Combi-Blocks,
cat#ST-7698: 1.2 mg, 10.34 .mu.mol) and triethylamine (1.9 .mu.l,
0.014 mmol) in DCM (1.0 mL) after stirring for 2 h at room
temperature. After stirring at room temperature for 2 h, the
mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA)
to give the desired product as its TFA salt. LC-MS calculated for
C.sub.47H.sub.47ClN.sub.7O.sub.5 (M+H).sup.+: m/z=824.3; found
824.2.
Example 45
(R)-1-((8-(2'-Chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4-
,5-c]pyridine-2-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)meth-
yl)-3-methylpyrrolidine-3-carboxylic acid
##STR00183##
[1043] Step 1:
8-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)-1-
,7-naphthyridine-3-carbaldehyde
##STR00184##
[1045] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 9, Step 1: 0.684 g, 2.0 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.660
g, 2.60 mmol), potassium acetate (0.393 g, 4.00 mmol), and
PdCl.sub.2(dppf) (0.146 g, 0.200 mmol) in dioxane (10.0 mL) was
vacuumed and refilled with nitrogen 3 times and then the reaction
mixture was stirred at 110.degree. C. for 7 h. The mixture was
diluted with EtOAc, filtered through Celite.RTM. and concentrated
under reduced pressure. The residue was purified by column
chromatography eluting with CH.sub.2Cl.sub.2 to give the desired
product. LC-MS calculated for C.sub.22H.sub.25BN.sub.3O.sub.3
(M+H).sup.+: m/z=390.2; found 390.3.
Step 2: tert-butyl
2-(2-chloro-3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3--
ylcarbamoyl)-l-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxyl-
ate
##STR00185##
[1047] A mixture of tert-butyl
2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imid-
azo[4,5-c]pyridine-5-carboxylate (Example 31, Step 3: 0.12 g, 0.255
mmol),
8-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)-1-
,7-naphthyridine-3-carbaldehyde (0.10 g, 0.26 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.019 g, 0.023 mmol) and sodium carbonate
(0.049 g, 0.464 mmol) in dioxane (2.4 mL)/water (0.6 mL) was
evacuated and backfilled with N.sub.2 3 times. The reaction mixture
was stirred at 110.degree. C. for 24 h. The mixture was diluted
with ethyl acetate and washed with water, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product
was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (7:3). LC-MS calculated for
C.sub.35H.sub.35ClN.sub.7O.sub.4 (M+H).sup.+: m/z=652.2; found
652.2.
Step 3:
(R)-1-((8-(3'-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-chloro-2-methylbiphenyl-3-yla-
mino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic
acid
##STR00186##
[1049] (R)-3-methylpyrrolidine-3-carboxylic acid (J&W PharmLab,
cat#75R0495: 0.071 g, 0.552 mmol) was added to a suspension of
tert-butyl
2-((2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-b-
iphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyri-
dine-5-carboxylate (0.12 g, 0.184 mmol) in CH.sub.2Cl.sub.2 (1.0
mL) followed by triethylamine (0.205 mL, 1.472 mmol). The mixture
was stirred at rt for 1 h. At this time sodium
triacetoxyborohydride (0.117 g, 0.552 mmol) was added and then
stirred at rt for 2 h. The reaction was quenched with water,
extracted with CH.sub.2Cl.sub.2/iPrOH, and the organic phase was
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was used directly in the next step
without further purification. LC-MS calculated for
C.sub.41H.sub.46ClN.sub.8O.sub.5 (M+H).sup.+: m/z=765.3; found
765.2.
Step 4:
(R)-1-((8-(2'-chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylamino)-1,7-naphthyridin-3-
-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid
[1050] TFA (2.0 mL) was added to a mixture of
(R)-1-((8-((3'-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-im-
idazo[4,5-c]pyridine-2-carboxamido)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-y-
l)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic
acid (0.15 g) in CH.sub.2Cl.sub.2 (2.0 mL) and then stirred at rt
for 30 min. The solvent was concentrated and the mixture was
diluted with acetonitrile/water and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.36H.sub.38ClN.sub.8O.sub.3
(M+H).sup.+: m/z=665.3; found 665.2.
Example 46
(R)-1-((8-(3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-
-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methy-
l)pyrrolidine-3-carboxylic acid
##STR00187##
[1051] Step 1: tert-butyl
2-(3-bromo-2-methylphenylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c-
]pyridine-5(4H)-carboxylate
##STR00188##
[1053] Potassium tert-butoxide (1.0 M THF solution, 17.61 mL, 17.61
mmol) was added to a solution of 5-tert-butyl 2-methyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate
(Example 14, Step 2: 2.6 g, 8.80 mmol) and 3-bromo-2-methylaniline
(Aldrich, cat#530018: 1.802 g, 9.68 mmol) in THF (45 mL) at
0.degree. C. After being stirred at rt for 2 h, the reaction
mixture was quenched with water, and extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude was stirred with 3:1 hexanes/EtOAc (40 mL) for 30 min and
then filtered and dried to provide the desired product. LC-MS
calculated for C.sub.20H.sub.26BrN.sub.4O.sub.3 (M+H).sup.+:
m/z=449.1; found 449.1.
Step 2: tert-butyl
2-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbipheny-
l-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carb-
oxylate
##STR00189##
[1055] A mixture of tert-butyl
2-((3-bromo-2-methylphenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imid-
azo[4,5-c]pyridine-5-carboxylate (0.12 g, 0.267 mmol),
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (Example 9, Step 3: 0.095 g, 0.243
mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.020 g, 0.024 mmol) and sodium carbonate
(0.051 g, 0.486 mmol) in dioxane (2.4 mL)/water (0.6 mL) was
evacuated and backfilled with N.sub.2. The evacuation/backfill
sequence was repeated two additional times, and the reaction was
stirred at 110.degree. C. for 24 h. The mixture was diluted with
ethyl acetate and washed with water, dried over Na.sub.2SO.sub.4,
and concentrated under reduced pressure. The crude product was
purified by column chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (1:1). LC-MS calculated for
C.sub.36H.sub.40N.sub.7O.sub.4 (M+H).sup.+: m/z=634.3; found
634.5.
Step 3:
N-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethyl-
biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-car-
boxamide
##STR00190##
[1057] 4 N HCl in dioxane (1.0 mL) was added to a mixture of
tert-butyl
2-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,-
1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-
pyridine-5-carboxylate (0.10 g, 0.158 mmol) in CH.sub.2Cl.sub.2
(1.0 mL), and the reaction was stirred at rt for 2 h. The solvent
was removed and the crude residue was used directly in the next
step without further purification. LC-MS calculated for
C.sub.31H.sub.32N.sub.7O.sub.2 (M+H).sup.+: m/z=534.3; found
534.3.
Step 4:
N-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethyl-
biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-
-carboxamide
##STR00191##
[1059] Formaldehyde (36% H.sub.2O solution, 6.3 .mu.L, 0.075 mmol)
was added to a mixture of
N-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2--
carboxamide (20.0 mg, 0.037 mmol) in CH.sub.2Cl.sub.2 (1.0 mL)
followed by the addition of triethylamine (0.026 mL, 0.187 mmol).
The mixture was stirred at rt for 10 min. At this time sodium
triacetoxyborohydride (23.8 mg, 0.11 mmol) was added and then the
mixture was stirred at rt for 30 min. The reaction mixture was
quenched with water and then extracted with CH.sub.2Cl.sub.2. The
combined organic phase was concentrated under reduced pressure and
the crude product was used directly in the next step without
further purification. LC-MS calculated for
C.sub.32H.sub.34N.sub.7O.sub.2 (M+H).sup.+: m/z=548.3; found
548.4.
Step 5:
N-(3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl--
3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxam-
ide
##STR00192##
[1061] Manganese dioxide (0.143 g, 1.643 mmol) was added to a
solution of
N-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-
e-2-carboxamide (0.060 g, 0.110 mmol) in CH.sub.2Cl.sub.2 (2.0 mL)
and then the mixture was stirred at 40.degree. C. overnight. The
mixture was diluted with CH.sub.2Cl.sub.2, filtered through
Celite.RTM. and then concentrated under reduced pressure to provide
the desired product which was used directly in the next step. LC-MS
calculated for C.sub.32H.sub.32N.sub.7O.sub.2 (M+H).sup.+:
m/z=546.3; found 546.2.
Step 6:
(R)-1-((8-(3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]py-
ridine-2-carboxamido)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
[1062] To a mixture of
N-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carbo-
xamide (0.010 g, 0.018 mmol) and (R)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, cat#ST-7698: 6.3 mg, 0.055 mmol) in CH.sub.2Cl.sub.2
(1.0 mL) was added triethylamine (6.3 .mu.L, 0.11 mmol). After
stirring for 10 min sodium triacetoxyborohydride (0.012 g, 0.055
mmol) was added, and the reaction was further stirred at rt for 2
h. The reaction was concentrated and the mixture was diluted with
acetonitrile/water and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.37H.sub.41N.sub.8O.sub.3
(M+H).sup.+: m/z=645.3; found 645.4.
Example 47
trans-4-((2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-nap-
hthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-
-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00193##
[1063] Step 1: tert-butyl
2-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoy-
l)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
##STR00194##
[1065] Potassium tert-butoxide (1.0 M in THF, 2.20 mL, 2.20 mmol)
was added to a solution of 5-tert-butyl 2-methyl
1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate
(Example 14, Step 2: 0.295 g, 1.0 mmol) and
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Example 5, Step 1: 0.304 g, 1.200 mmol) in THF (4.0 mL). After
being stirred at rt for 2 h, the reaction mixture was quenched with
water, and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na.sub.2SO.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 (0-50%) to afford the desired
product. LC-MS calculated for C.sub.25H.sub.35BClN.sub.4O.sub.5
(M+H).sup.+: m/z=517.2; found 517.3.
Step 2: tert-butyl
2-(2-chloro-3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3--
ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxyl-
ate
##STR00195##
[1067] A mixture of tert-butyl
2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbam-
oyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(0.35 g, 0.677 mmol),
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 9, Step 1: 0.255 g, 0.745 mmol),
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]-palladium(II)
(0.051 g, 0.068 mmol) and cesium fluoride (0.514 g, 3.39 mmol) in
t-BuOH (3.00 mL)/water (1.2 mL) was evacuated and backfilled with
N.sub.2 3 times. The reaction was stirred at 105.degree. C. for 2
h. The mixture was cooled to rt, diluted with ethyl acetate, and
washed with water. The organic layers were washed with brine, dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (7:3). LC-MS calculated for
C.sub.35H.sub.35ClN.sub.7O.sub.4 (M+H).sup.+: m/z=652.2; found
652.4.
Step 3: (R)-tert-butyl
2-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-y-
lamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4-
,5-c]pyridine-5(4H)-carboxylate
##STR00196##
[1069] (R)-pyrrolidin-3-ol (Combi-Blocks, cat#AM-2005: 0.072 g,
0.828 mmol) was added to a solution of tert-butyl
2-((2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-b-
iphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyri-
dine-5-carboxylate (0.180 g, 0.276 mmol) in CH.sub.2Cl.sub.2 (1.0
mL). Triethylamine (0.308 mL, 2.208 mmol) was then added and the
mixture was stirred at rt for 1 h. At this time sodium
triacetoxyborohydride (0.175 g, 0.828 mmol) was added and then
stirred at rt for 2 h. The reaction was quenched with water,
extracted with CH.sub.2Cl.sub.2, and the organic phase was dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.39H.sub.44ClN.sub.8O.sub.4 (M+H).sup.+: m/z=723.3; found
723.5.
Step 4:
(R)--N-(2-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph-
thyridin-8-ylamino)-2'-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-
-imidazo[4,5-c]pyridine-2-carboxamide
##STR00197##
[1071] 4 N HCl in dioxane (2.0 mL) was added to a mixture of
tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (0.18 g, 0.249
mmol) in CH.sub.2Cl.sub.2 (1.0 mL)/MeOH (1.0 mL) and the reaction
was stirred at rt for 2 h. The solvent was removed and the crude
HCl salt was used directly in the next step. LC-MS calculated for
C.sub.34H.sub.36ClN.sub.8O.sub.2 (M+H).sup.+: m/z=623.3; found
623.3.
Step 5:
trans-4-((2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-
-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-
-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
[1072] To a mixture of
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.025 g, 0.040 mmol) and
methyl trans-4-formylcyclohexane-1-carboxylate (Ark Pharm,
cat#AK-50935: 0.014 g, 0.080 mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was
added triethylamine (0.011 mL, 0.201 mmol) and the resulting
mixture was stirred for 10 min. Sodium triacetoxyborohydride (0.026
g, 0.120 mmol) was added and the reaction was stirred at rt for 2
h. The solvent was removed and the crude residue was redissolved in
methanol/THF/water (0.5/0.5/0.2 mL) and LiOH monohydrate (20 mg)
was added. The mixture was then stirred at rt for 3 h. The mixture
was diluted with acetonitrile/water, acidified to pH=2, and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as its TFA salt. LC-MS calculated for
C.sub.42H.sub.48ClN.sub.8O.sub.4 (M+H).sup.+: m/z=763.3; found
763.3.
Example 48
cis-4-((2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00198##
[1074] To a mixture of
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamide (Example 47, Step 4: 85.0
mg, 0.136 mmol) in DMF (2.0 mL) was added methyl
cis-4-(((methylsulfonyl)oxy)methyl)cyclohexane-1-carboxylate
(Aldlab Chemicals, cat#JPM2-11253: 102 mg, 0.409 mmol), potassium
carbonate (56.6 mg, 0.409 mmol), potassium iodide (22.64 mg, 0.136
mmol) and benzyltriethylammonium chloride (31.1 mg, 0.136 mmol).
The mixture was then stirred at 75.degree. C. overnight. The
solvent was removed and the crude residue was redissolved in
methanol/THF/water (0.5/0.5/0.2 mL). LiOH hydrate (20 mg) was added
and the mixture was stirred at rt for 5 h. The mixture was diluted
with acetonitrile/water, acidified to pH=2 and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide the desired compound
as its TFA salt. LC-MS calculated for
C.sub.42H.sub.48ClN.sub.8O.sub.4 (M+H).sup.+: m/z=763.3; found
763.4.
Example 49
cis-4-((2-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyrid-
in-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c-
]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid
##STR00199##
[1075] Step 1:
N-(3-bromo-2-methylphenyl)-3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-a-
mine
##STR00200##
[1077] A mixture of
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 9, Step 1: 0.342 g, 1.0 mmol) and pyrrolidine (0.107 g,
1.500 mmol) in CH.sub.2Cl.sub.2 (8.0 mL) was stirred at rt for 10
min. Sodium triacetoxyborohydride (0.424 g, 2.000 mmol) was then
added and the mixture was stirred at rt for 2 h. The mixture was
diluted with CH.sub.2Cl.sub.2, washed with 1 N NaOH, water, brine,
and the organic phase was separated and dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.20H.sub.22BrN.sub.4 (M+H).sup.+: m/z=397.1; found 397.2.
Step 2: tert-butyl
2-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-yl-
amino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridi-
ne-5(4H)-carboxylate
##STR00201##
[1079] A mixture of tert-butyl
2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbam-
oyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(Example 47, Step 1: 1.0 g, 1.935 mmol),
N-(3-bromo-2-methylphenyl)-3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-a-
mine (0.846 g, 2.128 mmol),
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II)
(0.146 g, 0.193 mmol) and cesium fluoride (1.470 g, 9.67 mmol) in
t-BuOH (3.00 mL)/water (1.2 mL) was evacuated and backfilled with
N.sub.2 3 times. The reaction mixture was stirred at 105.degree. C.
for 2 h. The mixture was diluted with ethyl acetate and washed with
water, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The product was purified by column
chromatography eluting with CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS
calculated for C.sub.39H.sub.44ClN.sub.8O.sub.3 (M+H).sup.+:
m/z=707.3; found 707.5.
Step 3:
N-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyrid-
in-8-ylamino)biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]p-
yridine-2-carboxamide
##STR00202##
[1081] This compound was prepared using a similar procedure as
described for Example 47, Step 4 with tert-butyl
2-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-yl-
amino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridi-
ne-5(4H)-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate. LC-MS
calculated for C.sub.34H.sub.36ClN.sub.8O (M+H).sup.+: m/z=607.3;
found 607.4.
Step 4:
cis-4-((2-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-na-
phthyridin-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imida-
zo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid
[1082] This compound was prepared using a similar procedure as
described for Example 48 with
N-(2-chloro-2'-methyl-3'-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-yl-
amino)biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-
-2-carboxamide replacing
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamide. LC-MS calculated for
C.sub.42H.sub.48ClN.sub.8O.sub.3 (M+H).sup.+: m/z=747.4; found
747.5.
Example 50
trans-4-((2-(2-chloro-3'-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-na-
phthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydr-
o-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00203##
[1083] Step 1: tert-butyl
2-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-methylbi-
phenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-
-carboxylate
##STR00204##
[1085] A mixture of tert-butyl
2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbam-
oyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(Example 47, Step 1: 1.0 g, 1.935 mmol),
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
(Affinity Research Chemicals, #ARI-0169: 0.733 g, 2.128 mmol),
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II)
(0.146 g, 0.193 mmol) and cesium fluoride (1.470 g, 9.67 mmol) in
t-BuOH (3.00 mL)/water (1.2 mL) was evacuated and backfilled with
N.sub.2 3 times. The reaction was stirred at 105.degree. C. for 2
h. The mixture was diluted with ethyl acetate and washed with
water, brine, dried over Na.sub.2SO.sub.4, and concentrated under
reduced pressure. The product was purified by column chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (1:1). LC-MS calculated for
C.sub.35H.sub.37ClN.sub.7O.sub.4 (M+H).sup.+: m/z=654.2; found
654.2.
Step 2:
N-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-m-
ethylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine--
2-carboxamide
##STR00205##
[1087] This compound was prepared using a similar procedure as
described for Example 47, Step 4 with tert-butyl
2-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-methylbi-
phenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-
-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate. LC-MS
calculated for C.sub.30H.sub.29ClN.sub.7O.sub.2 (M+H).sup.+:
m/z=554.2; found 554.2.
Step 3: trans-methyl
4-((2-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-meth-
ylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(-
4H)-yl)methyl)cyclohexanecarboxylate
##STR00206##
[1089] To a mixture of
N-(2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-
-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridi-
ne-2-carboxamide (0.075 g, 0.135 mmol) and methyl
trans-4-formylcyclohexane-1-carboxylate (Ark Pharm, cat#AK-50935:
0.046 g, 0.271 mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was added
triethylamine (0.039 mL, 0.677 mmol), and the resulting mixture was
stirred at 40.degree. C. for 30 min. Sodium triacetoxyborohydride
(0.086 g, 0.406 mmol) was added and stirred at rt for 4 h. The
mixture was diluted with CH.sub.2Cl.sub.2 and washed with 1 N NaOH,
water, and brine. The organic phase was concentrated under reduced
pressure and the crude product was purified by column
chromatography eluting with CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS
calculated for C.sub.39H.sub.43ClN.sub.7O.sub.4 (M+H).sup.+:
m/z=708.3; found 708.4.
Step 4: trans-methyl
4-((2-(2-chloro-3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2'-methylbipheny-
l-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)me-
thyl)cyclohexanecarboxylate
##STR00207##
[1091] Manganese dioxide (0.313 g, 3.60 mmol) was added to a
solution of methyl trans
4-((2-((2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-m-
ethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imida-
zo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylate (0.17 g,
0.240 mmol) in CH.sub.2Cl.sub.2 (5.0 mL) and the mixture was
stirred at 45.degree. C. for 5 h. The mixture was diluted with
CH.sub.2Cl.sub.2, filtered through Celite.RTM. and then
concentrated under reduced pressure. The crude product which was
purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.39H.sub.41ClN.sub.7O.sub.4 (M+H).sup.+: m/z=706.3; found
706.4.
Step 5:
trans-4-((2-(2-chloro-3'-(3-(((S)-1-hydroxypropan-2-ylamino)methyl-
)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,-
7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
[1092] A mixture of methyl trans
4-((2-((2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,-
1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-
pyridin-5-yl)methyl)cyclohexane-1-carboxylate (0.010 g, 0.014 mmol)
and (S)-2-aminopropan-1-ol (Aldrich, cat#A76206: 5.32 mg, 0.071
mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was stirred for 30 min at rt.
Sodium triacetoxyborohydride (9.0 mg, 0.042 mmol) was added and the
mixture was stirred at rt overnight. The solvent was removed and
the crude material was redissolved in methanol/THF/water
(0.5/0.5/0.2 mL). LiOH monohydrate (40 mg) was added and the
mixture was stirred at rt for 5 h. The mixture was diluted with
acetonitrile/water, acidified to pH=2 and purified by prep HPLC
(pH=2, acetonitrile/water+TFA) to provide the desired compound as
its TFA salt. LC-MS calculated for C.sub.41H.sub.48ClN.sub.8O.sub.4
(M+H).sup.+: m/z=751.3; found 751.4.
Example 51
trans-4-((2-(2-chloro-3'-(3-(((1S,2S)-2-hydroxycyclopentylamino)methyl)-1,-
7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-di-
hydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00208##
[1094] This compound was prepared using a similar procedure as
described for Example 50 with (1S,2S)-2-aminocyclopentan-1-ol (Ark
Pharm, cat#AK-88109) replacing (S)-2-aminopropan-1-ol in Step 5.
LC-MS calculated for C.sub.43H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=777.4; found 777.4.
Example 52
trans
4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00209##
[1096] This compound was prepared using a similar procedure as
described for Example 47 with methyl
4-(2-oxoethyl)cyclohexane-1-carboxylate (Enamine, cat#EN300-198655)
replacing methyl trans-4-formylcyclohexane-1-carboxylate in Step 5
as a mixture of diastereomers. The diastereomers were separated
using prep HPLC (pH=2, acetonitrile/water+TFA), with the trans
isomer eluting first in the column, peak 1: retention time on
analytical LCMS (pH=2, acetonitrile/water+TFA) t.sub.r=0.80 min;
LC-MS calculated for C.sub.43H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=777.4; found 777.4.
Example 53
cis
4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-nap-
hthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-
-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00210##
[1098] This compound was prepared using a similar procedure as
described for Example 52 The diastereomers were separated using
prep HPLC (pH=2, acetonitrile/water+TFA), with the minor cis isomer
eluting later in the column, peak 2: retention time on analytical
LCMS (pH=2, acetonitrile/water+TFA) t.sub.r=0.82 min; LC-MS
calculated for C.sub.43H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=777.4; found 777.4.
Example 54
3-(2-(2-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imi-
dazo[4,5-c]pyridin-5(4H)-yl)butanoic acid
##STR00211##
[1100] This compound was prepared using a similar procedure as
described for Example 47 with methyl 3-oxobutanoate (Aldrich,
cat#537365) replacing methyl
trans-4-formylcyclohexane-1-carboxylate in Step 5. LC-MS calculated
for C.sub.38H.sub.42ClN.sub.8O.sub.4 (M+H).sup.+: m/z=709.3; found
709.2.
Example 55
cis
4-((2-(2-chloro-3'-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00212##
[1101] Step 1:
N-(2-chloro-3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3--
yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide
##STR00213##
[1103] TFA (2.0 mL, 26.0 mmol) was added to a solution of
tert-butyl
2-((2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-b-
iphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyri-
dine-5-carboxylate (Example 45, Step 2: 0.20 g, 0.307 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL) at rt and the reaction was stirred for 30
min. The solvent was removed under vacuum and the crude TFA salt
was used directly in the next step without further purification.
LC-MS calculated for C.sub.30H.sub.27ClN.sub.7O.sub.2 (M+H).sup.+:
m/z=552.2; found 552.1.
Step 2: cis-methyl
4-((2-(2-chloro-3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2'-methylbipheny-
l-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)me-
thyl)cyclohexanecarboxylate
##STR00214##
[1105] To a mixture of
N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-bi-
phenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carb-
oxamide (150.0 mg, 0.272 mmol) in DMF (2.0 mL) was added methyl
cis-4-(((methylsulfonyl)oxy)methyl)cyclohexane-1-carboxylate
(Aldlab Chemicals, cat#JPM2-11253: 136 mg, 0.543 mmol), potassium
carbonate (113 mg, 0.815 mmol), potassium iodide (45.1 mg, 0.272
mmol), and benzyltriethylammonium chloride (61.9 mg, 0.272 mmol).
The resulting mixture was then stirred at 75.degree. C. overnight.
The mixture was diluted with CH.sub.2Cl.sub.2 and then washed with
water and brine. The organic phase was dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The product was
purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.39H.sub.41ClN.sub.7O.sub.4 (M+H).sup.+: m/z=706.3; found
706.4.
Step 3:
cis-4-((2-(2-chloro-3'-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-
,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-d-
ihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
[1106] A mixture of methyl
cis-4-((2-((2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methyl-
-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,-
5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylate (0.010 g, 0.014
mmol) and (S)-pyrrolidin-3-ol (Combi-Blocks, cat#SS-7948, 1.234 mg,
0.014 mmol) in CH.sub.2C.sub.2(1.0 mL) was stirred for 30 min and
then sodium triacetoxyborohydride (9.00 mg, 0.042 mmol) was added
and stirred at rt overnight. The solvent was removed and the crude
was redissolved in methanol/THF/water (0.5/0.5/0.2 mL). LiOH
monohydrate (40 mg) was added and the mixture was stirred at rt for
5 h. The mixture was diluted with acetonitrile/water, acidified to
pH=2 and purified by prep HPLC (pH=2, acetonitrile/water+TFA) to
provide the desired compound as its TFA salt. LC-MS calculated for
C.sub.42H.sub.48ClN.sub.8O.sub.4 (M+H).sup.+: m/z=763.3; found
763.5.
Example 56
cis
4-((2-(2-chloro-3'-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)--
1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7--
dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00215##
[1108] This compound was prepared using a similar procedure as
described for Example 55 with (R)-3-methylpyrrolidin-3-ol (Ark
Pharm, cat#AK100499) replacing (S)-pyrrolidin-3-ol in Step 3. LC-MS
calculated for C.sub.43H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=777.3; found 777.3.
Example 57
(R)-4-(2-(2-chloro-3'-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid
##STR00216##
[1109] Step 1: tert-butyl
4-(2-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-methy-
lbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4-
H)-yl)cyclohexanecarboxylate
##STR00217##
[1111] To a mixture of
N-(2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-
-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridi-
ne-2-carboxamide (Example 50, Step 2: 0.275 g, 0.496 mmol) and
tert-butyl 4-oxocyclohexane-1-carboxylate (Ark Pharm, cat#AK-40114:
0.197 g, 0.993 mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was added
triethylamine (0.142 mL, 2.482 mmol). The resulting mixture was
stirred at 40.degree. C. for 30 min and then sodium
triacetoxyborohydride (0.316 g, 1.489 mmol) was added and stirred
at rt overnight. The mixture was diluted with CH.sub.2Cl.sub.2 and
washed with 1 N NaOH, water, and brine. The solvent was removed and
the product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.41H.sub.47ClN.sub.7O.sub.4 (M+H).sup.+: m/z=736.3; found
736.3.
Step 2: tert-butyl
4-(2-(2-chloro-2'-methyl-3'-(3-((methylsulfonyloxy)methyl)-1,7-naphthyrid-
in-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c-
]pyridin-5(4H)-yl)cyclohexanecarboxylate
##STR00218##
[1113] Methanesulfonyl chloride (0.023 g, 0.204 mmol) was added to
a solution of tert-butyl
4-(2-((2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-me-
thyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidaz-
o[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylate (0.10 g, 0.136 mmol)
and triethylamine (0.057 mL, 0.407 mmol) in CH.sub.2Cl.sub.2 (2.0
mL) at 0.degree. C. and then the reaction was stirred at this
temperature for 30 min. The mixture was quenched by adding aqueous
saturated NaHCO.sub.3, and the aqueous phase was extracted with
methylene chloride. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure, and the crude product was used directly in the next step.
LC-MS calculated for C.sub.42H.sub.49ClN.sub.7O.sub.6S (M+H).sup.+:
m/z=814.3; found 814.3.
Step 3:
(R)-4-(2-(2-chloro-3'-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methy-
l)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-
,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic
acid
[1114] (R)-3-methylpyrrolidin-3-ol (Ark Pharm, cat#AK100499: 2.484
mg, 0.025 mmol) was added to a solution of tert-butyl
4-(2-((2-chloro-2'-methyl-3'-((3-(((methylsulfonyl)oxy)methyl)-1,7-naphth-
yridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrah-
ydro-5H-imidazo[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylate (0.020
g, 0.025 mmol) and triethylamine (0.021 mL, 0.147 mmol) in
CH.sub.2Cl.sub.2 (0.8 mL) at rt. The reaction was stirred at
30.degree. C. for 1 h. The solvent was removed and the residue was
treated with 4 N HCl in dioxane (1.0 mL) for 2 h. The mixture was
diluted with acetonitrile/water, acidified to pH=2 and purified by
prep HPLC (pH=2, acetonitrile/water+TFA) to provide the desired
compound as its TFA salt. LC-MS calculated for
C.sub.42H.sub.48ClN.sub.8O.sub.4 (M+H).sup.+: m/z=763.3; found
763.3.
Example 58
(S)-4-(2-(2-chloro-3'-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid
##STR00219##
[1116] This compound was prepared using a similar procedure as
described for Example 57 with (S)-3-methylpyrrolidin-3-ol (J&W
Pharma, cat#75R0496) replacing (R)-3-methylpyrrolidin-3-ol in Step
3. LC-MS calculated for C.sub.42H.sub.48ClN.sub.8O.sub.4
(M+H).sup.+: m/z=763.3; found 763.3.
Example 59
trans
4-(2-(2-(2-chloro-3'-(3-(((R)-1-hydroxypropan-2-ylamino)methyl)-1,7--
naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihy-
dro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00220##
[1117] Step 1: trans methyl
4-(2-(2-(2-chloro-3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2'-me-
thylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin--
5(4H)-yl)ethyl)cyclohexanecarboxylate
##STR00221##
[1119] To a mixture of
N-(2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-
-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridi-
ne-2-carboxamide (Example 50, Step 2: 0.075 g, 0.135 mmol) and
methyl trans 4-(2-oxoethyl)cyclohexane-1-carboxylate (Enamine,
cat#EN300-198655: 0.050 g, 0.271 mmol) in CH.sub.2Cl.sub.2 (1.0 mL)
was added triethylamine (0.039 mL, 0.677 mmol) and the resulting
mixture was stirred at 40.degree. C. for 30 min. Sodium
triacetoxyborohydride (0.086 g, 0.406 mmol) was added and stirred
at rt for 4 h. The mixture was diluted with CH.sub.2Cl.sub.2 and
washed with 1 N NaOH, water, and brine. The solvent was removed and
the product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.40H.sub.45ClN.sub.7O.sub.4 (M+H).sup.+: m/z=722.3; found
722.4.
Step 2: trans methyl
4-(2-(2-(2-chloro-2'-methyl-3'-(3-((methylsulfonyloxy)methyl)-1,7-naphthy-
ridin-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,-
5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylate
##STR00222##
[1121] Methanesulfonyl chloride (0.024 g, 0.208 mmol) was added to
a solution of trans methyl
4-(2-(2-((2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2'-
-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imi-
dazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylate (0.10 g,
0.138 mmol) and triethylamine (0.058 mL, 0.415 mmol) in
CH.sub.2Cl.sub.2 (2.0 mL) at 0.degree. C. and then the reaction was
stirred at this temperature for 30 min. The mixture was quenched by
adding aqueous saturated NaHCO.sub.3, and the reaction was
extracted with methylene chloride. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The crude product was used directly in the next
step. LC-MS calculated for C.sub.41H.sub.47ClN.sub.7O.sub.6S
(M+H).sup.+: m/z=800.3; found 800.3.
Step 3:
trans-4-(2-(2-(2-chloro-3'-(3-(((R)-1-hydroxypropan-2-ylamino)meth-
yl)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl--
6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
[1122] (R)-2-aminopropan-1-ol (Aldrich, cat#297682: 1.9 mg, 0.025
mmol) was added to a solution of trans methyl
4-(2-(2-((2-chloro-2'-methyl-3'-((3-(((methylsulfonyl)oxy)methyl)-1,7-nap-
hthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tet-
rahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylate
(20 mg, 0.025 mmol) and triethylamine (0.021 mL, 0.147 mmol) in
CH.sub.2Cl.sub.2 (0.8 mL) at rt. The reaction was stirred at
30.degree. C. for 1 h. The solvent was removed and the residue was
dissolved in MeOH/THF/water (0.4/0.4/0.2 mL). LiOH monohydrate (40
mg) was added and stirred at rt for 4 h. The mixture was diluted
with acetonitrile/water, acidified to pH=2 and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide the desired compound
as its TFA salt. LC-MS calculated for
C.sub.42H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+: m/z=765.4; found
765.5.
Example 60
trans
4-(2-(2-(2-chloro-3'-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7--
naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihy-
dro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00223##
[1124] This compound was prepared using a similar procedure as
described for Example 59 with (S)-2-aminopropan-1-ol (Aldrich,
cat#A76206) replacing (R)-2-aminopropan-1-ol in Step 3. LC-MS
calculated for C.sub.42H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=765.4; found 765.5.
Example 61
trans-4-(2-(2-(2-chloro-3'-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)meth-
yl)-1,7-naphthyridin-8-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl--
6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00224##
[1126] This compound was prepared using a similar procedure as
described for Example 59 with (R)-3-methylpyrrolidin-3-ol (Ark
Pharm, cat#AK100499) replacing (R)-2-aminopropan-1-ol in Step 3.
LC-MS calculated for C.sub.44H.sub.52ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=791.4; found 791.4.
Example 62
(R)-4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylam-
ino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[-
4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic acid
##STR00225##
[1127] Step 1: (R)-tert-butyl
2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-
,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]-
pyridine-5(4H)-carboxylate
##STR00226##
[1129] A mixture of tert-butyl
1-methyl-2-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)carbamoyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(Example 14, Step 3: 0.25 g, 0.504 mmol),
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 9, Step 2: 0.229 g, 0.554 mmol),
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II),
(0.038 g, 0.050 mmol), and cesium fluoride (0.383 g, 2.52 mmol) in
t-BuOH (8.00 mL)/water (3.0 mL) was evacuated and backfilled with
N.sub.2. The evacuation/backfill sequence was repeated two more
times, and then the reaction was stirred at 105.degree. C. for 2 h.
The mixture was diluted with ethyl acetate and washed with water
and brine. The organic phase was dried over MgSO.sub.4, filtered,
and concentrated. The product was purified by column chromatography
eluting with CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.40H.sub.47N.sub.8O.sub.4 (M+H).sup.+: m/z=703.4; found
703.6.
Step 2:
(R)--N-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin--
8-ylamino)-2,2'-dimethylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imid-
azo[4,5-c]pyridine-2-carboxamide
##STR00227##
[1131] This compound was prepared using a similar procedure as
described for Example 47, Step 4 with (R)-tert-butyl
2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-
,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]-
pyridine-5(4H)-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate. LC-MS
calculated for C.sub.35H.sub.39N.sub.8O.sub.2 (M+H).sup.+:
m/z=603.3; found 603.3.
Step 3:
(R)-4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-ylamino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H--
imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic
acid
[1132] To a mixture of
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide (0.025 g, 0.041 mmol) and
1-methyl-4-oxocyclohexane-1-carboxylic acid (Aurum Pharmatech,
cat#U31985: 6.48 mg, 0.041 mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was
added triethylamine (0.012 mL, 0.207 mmol), and the reaction was
stirred for 30 min at 40.degree. C. Sodium triacetoxyborohydride
(0.026 g, 0.124 mmol) was added and stirred at 40.degree. C. for 4
h. The mixture was diluted with acetonitrile/water, acidified to
pH=2 and purified by prep HPLC (pH=2, acetonitrile/water+TFA) to
provide the two desired compounds as TFA salts.
[1133] Peak 1:
[1134] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA) t.sub.r=0.686 min; LC-MS calculated for
C.sub.43H.sub.51N.sub.8O.sub.4 (M+H).sup.+: m/z=743.4; found
743.4.
[1135] Peak 2:
[1136] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA) t.sub.r=0.700 min; LC-MS calculated for
C.sub.43H.sub.51N.sub.8O.sub.4 (M+H).sup.+: m/z=743.4; found
743.4.
Example 63
trans-4-(2-(2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-ylamino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00228##
[1138] To a mixture of
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide (Example 62, Step 2: 0.025 g,
0.041 mmol) and methyl trans
4-(2-oxoethyl)cyclohexane-1-carboxylate (Enamine, cat#EN300-198655:
0.015 g, 0.083 mmol) in CH.sub.2Cl.sub.2 (1.0 mL) was added
triethylamine (0.012 mL, 0.207 mmol). The resulting mixture was
stirred for 10 min and then sodium triacetoxyborohydride (0.026 g,
0.124 mmol) was added and stirred at rt overnight. The solvent was
removed and the crude was redissolved in methanol/THF/water
(0.5/0.5/0.2 mL). LiOH monohydrate (20 mg) was added and the
mixture was stirred at rt for 3 h. The mixture was diluted with
acetonitrile/water, acidified to pH=2, and purified by prep HPLC
(pH=2, acetonitrile/water+TFA) to provide the desired compound as
its TFA salt. LC-MS calculated for C.sub.44H.sub.53N.sub.8O.sub.4
(M+H).sup.+: m/z=757.4; found 757.6.
Example 64
(R)-4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylam-
ino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[-
4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid
##STR00229##
[1140] To a mixture of
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide (Example 62, Step 2: 0.275 g,
0.456 mmol) and tert-butyl 4-oxocyclohexane-1-carboxylate (Ark
Pharm, cat#AK-40114: 0.181 g, 0.912 mmol) in CH.sub.2Cl.sub.2 (1.0
mL) was added triethylamine (0.131 mL, 2.281 mmol). The mixture was
stirred at 40.degree. C. for 30 min and then sodium
triacetoxyborohydride (0.290 g, 1.369 mmol) was added and stirred
at rt overnight to provide (R)-tert-butyl
4-(2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino-
)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-
-c]pyridin-5(4H)-yl)cyclohexanecarboxylate as a mixture of cis
& trans isomers which were separated by prep-HPLC (pH=10,
acetonitrile/water+NH.sub.4OH):
[1141] Peak 1:
[1142] retention time on analytical LCMS (pH=10,
acetonitrile/water+NH.sub.4OH), t.sub.r=1.78 min; LC-MS calculated
for C.sub.46H.sub.57N.sub.8O.sub.4 (M+H).sup.+: m/z=785.4; found
785.4. Peak 2: retention time on analytical LCMS (pH=10,
acetonitrile/water+NH.sub.4OH), t.sub.r=1.82 min; LC-MS calculated
for C.sub.46H.sub.57N.sub.8O.sub.4 (M+H).sup.+: m/z=785.4; found
785.4.
[1143] The fractions of each peak were combined, concentrated under
reduced pressure, and the resulting residues were then treated with
4 N HCl (in dioxane) for 4 h. The respective mixtures were diluted
with acetonitrile/water, acidified to pH=2 and purified by prep
HPLC (pH=2, acetonitrile/water+TFA) to provide each isomer as its
TFA salt.
[1144] Peak 1:
[1145] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA), t.sub.r=0.656 min; LC-MS calculated for
C.sub.42H.sub.49N.sub.8O.sub.4 (M+H).sup.+: m/z=729.4; found
729.4.
[1146] Peak 2:
[1147] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA), t.sub.r=0.663 min; LC-MS calculated for
C.sub.42H.sub.49N.sub.8O.sub.4 (M+H).sup.+: m/z=729.4; found
729.4.
Example 65
Trans-4-(2-(2-(2,2'-dichloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)--
1,7-naphthyridin-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00230##
[1148] Step 1: (R)-tert-butyl
2-(2,2'-dichloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]-
pyridine-5(4H)-carboxylate
##STR00231##
[1150] A mixture of tert-butyl
2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbam-
oyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
(Example 47, Step 1: 0.050 g, 0.097 mmol),
(R)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 22, Step 4: 0.046 g, 0.106 mmol),
dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II)
(7.31 mg, 9.67 .mu.mol) and cesium fluoride (0.073 g, 0.484 mmol)
in t-BuOH (8.00 mL)/water (3.0 mL) was evacuated and flushed with
N.sub.2 3 times. The reaction was stirred at 105.degree. C. for 2
h. The mixture was diluted with ethyl acetate and washed with water
and brine. The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The product was purified by column chromatography eluting
with CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.38H.sub.41Cl.sub.2N.sub.8O.sub.4 (M+H).sup.+: m/z=743.3;
found 743.3.
Step 2:
(R)--N-(2,2'-dichloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-
-naphthyridin-8-ylamino)biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imid-
azo[4,5-c]pyridine-2-carboxamide
##STR00232##
[1152] This compound was prepared using a similar procedure as
described for Example 47, Step 4 with (R)-tert-butyl
2-(2,2'-dichloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridi-
n-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]-
pyridine-5(4H)-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate. LC-MS
calculated for C.sub.33H.sub.33Cl.sub.2N.sub.8O.sub.2 (M+H).sup.+:
m/z=643.2; found 643.2.
Step 3: Trans
4-(2-(2-(2,2'-dichloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-ylamino)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imid-
azo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid
[1153] This compound was prepared using a similar procedure as
described for Example 63 with
(R)--N-(2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide replacing
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide. LC-MS calculated for
C.sub.42H.sub.47Cl.sub.2N.sub.8O.sub.4 (M+H).sup.+: m/z=797.3;
found 797.2.
Example 66
trans
4-(2-(2-(2'-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7--
naphthyridin-8-ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihyd-
ro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
##STR00233##
[1154] Step 1: (R)-tert-butyl
2-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8--
ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4-
,5-c]pyridine-5(4H)-carboxylate
##STR00234##
[1156] This compound was prepared using a similar procedure as
described for Example 65 with tert-butyl
1-methyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
lcarbamoyl)-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
(Example 14, Step 3) replacing tert-butyl
2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbam-
oyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate
in Step 1. LC-MS calculated for C.sub.39H.sub.44ClN.sub.8O.sub.4
(M+H).sup.+: m/z=723.3; found 723.3.
Step 2:
(R)--N-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-nap-
hthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-
-imidazo[4,5-c]pyridine-2-carboxamide
##STR00235##
[1158] This compound was prepared using a similar procedure as
described for Example 47 with (R)-tert-butyl
2-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8--
ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4-
,5-c]pyridine-5(4H)-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate in Step 4. LC-MS
calculated for C.sub.34H.sub.36ClN.sub.8O.sub.2 (M+H).sup.+:
m/z=623.3; found 623.3.
Step 3: trans
4-(2-(2-(2'-chloro-3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-
-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic
acid
[1159] This compound was prepared using a similar procedure as
described for Example 63 with
(R)--N-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-ylamino)-2-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidaz-
o[4,5-c]pyridine-2-carboxamide replacing
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide. LC-MS calculated for
C.sub.43H.sub.50ClN.sub.8O.sub.4 (M+H).sup.+: m/z=777.4; found
777.4.
Example 67
(R)-1-((4-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-
pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin--
7-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid
##STR00236##
[1160] Step 1: tert-butyl
2-(3'-amino-2-chloro-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydr-
o-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
##STR00237##
[1162] A mixture of tert-butyl
2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imid-
azo[4,5-c]pyridine-5-carboxylate (Example 31, Step 3: 0.470 g, 1.0
mmol),
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127: 0.233 g, 1.000 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.082 g, 0.100 mmol) and sodium carbonate
(0.212 g, 2.000 mmol) in dioxane (6 mL)/water (2 mL) was evacuated
under vacuum and flushed with N.sub.2 3 times. The reaction was
stirred at 110.degree. C. overnight. The mixture was diluted with
ethyl acetate and washed with saturated NaHCO.sub.3, water, and
brine. The organic phase was separated and dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The product was purified by silica gel chromatography
using CH.sub.2Cl.sub.2/EtOAc (1:1). LC-MS calculated for
C.sub.26H.sub.31ClN.sub.5O.sub.3 (M+H).sup.+: m/z=496.2; found
496.1.
Step 2: tert-butyl
2-(3'-(7-bromopyrido[3,2-d]pyrimidin-4-ylamino)-2-chloro-2'-methylbipheny-
l-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carb-
oxylate
##STR00238##
[1164] 7-Bromo-4-chloropyrido[3,2-d]pyrimidine (Synthonix,
cat#B0473: 0.217 g, 0.887 mmol) was added to a mixture of
tert-butyl
2-((3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl--
1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (0.40 g,
0.806 mmol) and triethylamine (0.225 mL, 1.613 mmol) in 2-propanol
(5.0 mL) at rt. The reaction was stirred at 100.degree. C. for 2 h.
Diethyl ether (5.0 mL) was added to the reaction mixture and the
resulting precipitate was filtered and dried to provide the crude
product which was used directly in the next step without further
purification. LC-MS calculated for
C.sub.33H.sub.33BrClN.sub.8O.sub.3 (M+H).sup.+: m/z=703.2; found
703.3.
Step 3: tert-butyl
2-(2-chloro-2'-methyl-3'-(7-vinylpyrido[3,2-d]pyrimidin-4-ylamino)bipheny-
l-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carb-
oxylate
##STR00239##
[1166] A mixture of tert-butyl
2-((3'-((7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)-2-chloro-2'-methyl-[1,-
1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-
pyridine-5-carboxylate (0.35 g, 0.497 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
cat#663348: 0.115 g, 0.746 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium (II)
dichloromethane adduct (0.041 g, 0.050 mmol) and sodium carbonate
(0.105 g, 0.994 mmol) in dioxane (6 mL)/water (2 mL) was evacuated
under vacuum and flushed with N.sub.2 3 times. The reaction was
stirred at 110.degree. C. for 2 h. The mixture was diluted with
ethyl acetate and washed with saturated NaHCO.sub.3, water, and
brine. The organic phase was separated, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
product was purified by column chromatography using
CH.sub.2Cl.sub.2/EtOAc (7:3). LC-MS calculated for
C.sub.35H.sub.36ClN.sub.8O.sub.3 (M+H).sup.+: m/z=651.3; found
651.2.
Step 4: tert-butyl
2-(2-chloro-3'-(7-formylpyrido[3,2-d]pyrimidin-4-ylamino)-2'-methylbiphen-
yl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-car-
boxylate
##STR00240##
[1168] A vial was charged with tert-butyl
2-((2-chloro-2'-methyl-3'-((7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,-
1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-
pyridine-5-carboxylate (10.0 mg, 0.015 mmol), a stir bar, THF (2.0
mL) and water (0.8 mL). To this suspension was added a 4% w/w
mixture of osmium tetroxide in water (12.0 .mu.L, 1.529 .mu.mol).
The reaction was stirred for 5 min then sodium periodate (16.42 mg,
0.077 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 washed with
brine, 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.34H.sub.34ClN.sub.8O.sub.4 (M+H).sup.+:
m/z=653.2; found 653.2.
Step 5:
(R)-1-((4-(2'-chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylamino)pyrido[3,2-d]pyrimi-
din-7-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid
##STR00241##
[1170] (R)-3-methylpyrrolidine-3-carboxylic acid (J&W PharmLab,
cat#75R0495: 0.015 g, 0.115 mmol) was added to a suspension of
tert-butyl
2-((2-chloro-3'-((7-formylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'-methyl-[1-
,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c-
]pyridine-5-carboxylate (0.025 g, 0.038 mmol) in CH.sub.2Cl.sub.2
(1.0 mL). Triethylamine (0.043 mL, 0.306 mmol) was added and the
mixture was stirred at rt for 1 h. At this time sodium
triacetoxyborohydride (0.024 g, 0.115 mmol) was added and then
stirred at rt for 2 h. The reaction was quenched with water,
extracted with CH.sub.2Cl.sub.2/iPrOH, and the layers were
separated. The organic phase was dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The resulting
crude residue was redissolved in CH.sub.2Cl.sub.2 (0.2 mL) and then
TFA (0.5 mL) was added and the reaction was stirred at rt for 30
min. The solvent was removed and the crude product was used
directly in the next step. LC-MS calculated for
C.sub.35H.sub.37ClN.sub.9O.sub.3 (M+H).sup.+: m/z=666.3; found
666.5.
Step 6:
(R)-1-((4-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidaz-
o[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)pyrido[3,2-d]py-
rimidin-7-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid
[1171] Formaldehyde (4.5 mg, 0.15 mmol) was added to a mixture of
(R)-1-((4-(2'-chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[-
4,5-c]pyridine-2-carboxamido)biphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-y-
l)methyl)-3-methylpyrrolidine-3-carboxylic acid (20. mg, 0.03 mmol)
in CH.sub.2Cl.sub.2 (1.0 mL) followed by the addition of
triethylamine (0.021 mL, 0.15 mmol). The mixture was stirred at rt
for 10 min. At this time sodium triacetoxyborohydride (19 mg, 0.09
mmol) was added and then stirred at rt for 30 min. The mixture was
diluted with acetonitrile/water, acidified to pH=2 and purified by
prep HPLC (pH=2, acetonitrile/water+TFA) to provide the desired
compound as its TFA salt. LC-MS calculated for
C.sub.36H.sub.39ClN.sub.9O.sub.3 (M+H).sup.+: m/z=680.3; found
680.4.
Example 68
(R)-4-(2-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]py-
rimidin-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1-
H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic
acid
##STR00242##
[1172] Step 1: (R)-tert-butyl
2-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidi-
n-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imid-
azo[4,5-c]pyridine-5(4H)-carboxylate
##STR00243##
[1174] A mixture of tert-butyl
2-((2-chloro-3'-((7-formylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'-methyl-[1-
,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c-
]pyridine-5-carboxylate (Example 67, Step 4: 0.10 g, 0.153 mmol)
and (R)-pyrrolidin-3-ol (Combi-Blocks, cat#AM-2005: 0.027 g, 0.306
mmol) in CH.sub.2Cl.sub.2 (8.0 mL) was stirred at rt for 10 min.
Sodium triacetoxyborohydride (0.097 g, 0.459 mmol) was then added
and the mixture was stirred at rt for 2 h. The mixture was diluted
with CH.sub.2Cl.sub.2, washed with 1 N NaOH, water, and brine. The
organic phase was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The product was purified by silica gel chromatography
eluting with CH.sub.2Cl.sub.2/MeOH (9:1). LC-MS calculated for
C.sub.38H.sub.43ClN.sub.9O.sub.4 (M+H).sup.+: m/z=724.3; found
724.5.
Step 2:
(R)--N-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,-
2-d]pyrimidin-4-ylamino)-2'-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahyd-
ro-1H-imidazo[4,5-c]pyridine-2-carboxamide
##STR00244##
[1176] This compound was prepared using a similar procedure as
described for Example 47 with (R)-tert-butyl
2-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidi-
n-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imid-
azo[4,5-c]pyridine-5(4H)-carboxylate replacing tert-butyl
(R)-2-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7--
tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate in Step 4. LC-MS
calculated for C.sub.33H.sub.35ClN.sub.9O.sub.2 (M+H).sup.+:
m/z=624.3; found 624.2.
Step 3:
(R)-4-(2-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[-
3,2-d]pyrimidin-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-d-
ihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic
acid
[1177] This compound was prepared using a similar procedure as
described for Example 62 with
(R)--N-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyr-
imidin-4-ylamino)-2'-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide replacing
(R)--N-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a-
mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide in Step 3.
[1178] Peak 1:
[1179] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA) t.sub.r=0.796 min; LC-MS calculated for
C.sub.41H.sub.47ClN.sub.9O.sub.4 (M+H).sup.+: m/z=764.3; found
764.4.
[1180] Peak 2:
[1181] retention time on analytical LCMS (pH=2,
acetonitrile/water+TFA) t.sub.r=0.805 min; LC-MS calculated for
C.sub.41H.sub.47ClN.sub.9O.sub.4 (M+H).sup.+: m/z=764.3; found
764.4.
Example 69
trans
4-((2-(2-chloro-3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3-
,2-d]pyrimidin-4-ylamino)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-di-
hydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic
acid
##STR00245##
[1183] This compound was prepared using a similar procedure as
described for Example 47 with
(R)--N-(2-chloro-3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyr-
imidin-4-ylamino)-2'-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-i-
midazo[4,5-c]pyridine-2-carboxamide (Example 68, Step 2) replacing
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamide in Step 5. LC-MS
calculated for C.sub.41H.sub.47ClN.sub.9O.sub.4 (M+H).sup.+:
m/z=764.3; found 764.5.
Example 70
(R)-1-((5-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[4,3-b]pyrazin-2-yl)methyl-
)pyrrolidine-3-carboxylic acid
##STR00246##
[1184] Step 1:
5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazin-2(H)-one
##STR00247##
[1186] In a vial was combined 3-chloro-2-methylaniline (Aldrich,
cat#101621: 351 mg, 2.478 mmol),
5-chloropyrido[3,4-b]pyrazin-2(1H)-one (Ark Pharm, cat#AK329687:
500 mg, 2.75 mmol), isopropanol (5.0 mL), and sulfuric acid (0.147
mL, 2.75 mmol). The vial was sealed, then the reaction was heated
to 100.degree. C. for 1 hour. The mixture was cooled to rt,
quenched with sat. NaHCO.sub.3, diluted with ethyl acetate and the
layers were separated. The aqueous layer was further extracted with
ethyl acetate, and the combined organic layers were washed with
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated in vacuo and the crude residue was purified by silica
gel chromatography (50% EtOAc/hexanes) to provide the desired
compound as a yellow oil. LC-MS calculated for
C.sub.14H.sub.12ClN.sub.4O (M+H).sup.+: m/z=287.1; found 287.1.
Step 2:
2-bromo-N-(3-chloro-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine
##STR00248##
[1188] In a vial, a mixture of
5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazin-2(1H)-one (200
mg, 0.698 mmol), phosphorus (V) oxybromide (1000 mg, 3.49 mmol),
and MeCN (6.0 mL) was stirred at 80.degree. C. for 4 hours. The
mixture was cooled to rt, quenched with sat. NaHCO.sub.3, diluted
with ethyl acetate and the layers were separated. The aqueous layer
was further extracted with ethyl acetate, and the combined organic
layers were washed with brine, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated in vacuo and the crude residue was
purified by silica gel chromatography (20% EtOAc/hexanes) to
provide the desired compound as a brown oil. LC-MS calculated for
C.sub.14H.sub.11ClBrN.sub.4 (M+H).sup.+: m/z=349.0; found
349.0.
Step 3:
N-(3-chloro-2-methylphenyl)-2-vinylpyrido[4,3-b]pyrazin-5-amine
##STR00249##
[1190] In a vial, a mixture of
2-bromo-N-(3-chloro-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine (30
mg, 0.086 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane
(Aldrich, cat#663348: 29.1 .mu.L, 0.172 mmol), sodium carbonate
(27.3 mg, 0.257 mmol), palladiumtetrakis (9.92 mg, 8.58 .mu.mol)
and 1,4-dioxane (2.0 mL) was stirred at 90.degree. C. for 2 hours.
The mixture was cooled to rt, diluted with ethyl acetate and washed
with water and brine, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated in vacuo and the crude residue was
purified by silica gel chromatography (20% EtOAc/hexanes) to
provide the desired compound as a brown oil. LC-MS calculated for
C.sub.16H.sub.14ClN.sub.4 (M+H).sup.+: m/z=297.1; found 297.1.
Step 4:
5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazine-2-carbaldehy-
de
##STR00250##
[1192] A 10 mL vial was charged with
N-(3-chloro-2-methylphenyl)-2-vinylpyrido[4,3-b]pyrazin-5-amine
(25.6 mg, 0.086 mmol) 1,4-dioxane (2 mL) and water (2 mL). A 4%
osmium tetroxide solution in water (38.2 .mu.L, 6.01 .mu.mol) was
added to the reaction mixture. After 5 min, sodium periodate (147
mg, 0.686 mmol) was added. The reaction was stirred at rt for 2
hours before being quenched with sat. NaHCO.sub.3. The resulting
mixture was extracted with DCM, and the combined organic layers
were washed with water and brine, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated in vacuo and the crude
residue was used directly in next step without further
purification. LC-MS calculated for C.sub.15H.sub.12ClN.sub.4O
(M+H).sup.+: m/z=299.1; found 299.1.
Step 5:
(R)-1-((5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazin-2-yl)-
methyl)pyrrolidine-3-carboxylic acid
##STR00251##
[1194] A 10 mL vial was charged with
5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazine-2-carbaldehyde
(10.0 mg, 0.033 mmol), (R)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, cat#ST-7698: 5.8 mg, 0.050 mmol) and DCM (1 mL).
Triethylamine (9.3 .mu.l, 0.067 mmol) and sodium
triacetoxyborohydride (14.2 mg, 0.067 mmol) were added
subsequently. The resulting reaction mixture was stirred at rt
overnight before being quenched with sat. NaHCO.sub.3. The
resulting mixture was extracted with a 3:1 DCM/IPA mixture, and the
combined organic layers were washed with water and brine, dried
over MgSO.sub.4, and filtered. The filtrate was concentrated in
vacuo and the crude residue was used directly in next step without
further purification. LC-MS calculated for
C.sub.20H.sub.21ClN.sub.5O.sub.2 (M+H).sup.+: m/z=398.1; found
398.1.
Step 6:
(R)-1-((5-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-ylamino)-2,2'-dimethylbiphenyl-3-ylamino)pyrido[4,3-b]pyrazin-2-y-
l)methyl)pyrrolidine-3-carboxylic acid
[1195] A mixture of
(R)-1-((5-(3-chloro-2-methylphenylamino)pyrido[4,3-b]pyrazin-2-yl)methyl)-
pyrrolidine-3-carboxylic acid (10.0 mg, 0.025 mmol),
(R)-1-((8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (Example 37,
step 9: 23.14 mg, 0.050 mmol), XPhos Pd G2 (2.0 mg, 2.51 .mu.mol),
and sodium carbonate (5.3 mg, 0.050 mmol) in 1,4-dioxane (1 mL) and
water (0.2 mL) was degassed and sealed. It was stirred at
90.degree. C. overnight. The reaction mixture was cooled then
diluted with methanol, then purified with prep-LC-MS (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for C.sub.40H.sub.42N.sub.9O.sub.3
(M+H).sup.+: m/z=696.3; found 696.3.
Example 71
(3R)-1-((8-(2,2'-dimethyl-3'-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylami-
no)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxyl-
ic acid
##STR00252##
[1196] Step 1: tert-butyl
4-(8-chloro-1,7-naphthyridin-3-yl)-4-oxobutylcarbamate
##STR00253##
[1198] To a solution of 3-bromo-8-chloro-1,7-naphthyridine
(PharmaBlock, cat#PBLJ2743: 100.2 mg, 0.411 mmol) in THF (10 mL)
was added n-butyllithium (1.6 M, 0.26 mL, 0.411 mmol) dropwise at
-78.degree. C. After stirring at this temperature for 1 hour,
tert-butyl 2-oxopyrrolidine-1-carboxylate (0.14 mL, 0.821 mmol) was
added. The reaction was further stirred at -78.degree. C. for 2
hours. After completion, the reaction mixture was quenched by
adding sat. NH.sub.4Cl, which was then extracted with EtOAc. The
combined organic layers were washed with water and brine, dried
over MgSO.sub.4, and filtered. The filtrate was concentrated in
vacuo and the crude residue was purified by silica gel
chromatography (80% EtOAc/hexanes) to provide the desired compound
as a brown oil. LC-MS calculated for
C.sub.17H.sub.21ClN.sub.3O.sub.3 (M+H).sup.+: m/z=350.1; found
350.1.
Step 2: tert-butyl
2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-ca-
rboxylate
##STR00254##
[1200] In a vial was combined 3-bromo-2-methylaniline (Aldrich,
cat#530018: 51.1 mg, 0.274 mmol), tert-butyl
(4-(8-chloro-1,7-naphthyridin-3-yl)-4-oxobutyl)carbamate (80.0 mg,
0.229 mmol), isopropanol (2.0 mL), and sulfuric acid (13.4 .mu.l,
0.252 mmol). The vial was sealed, then the reaction was heated to
100.degree. C. for 1 hour. The mixture was cooled to rt, quenched
with solid NaHCO.sub.3, diluted with ethyl acetate and filtered.
The filtrate was concentrated in vacuo and the crude residue was
dissolved in DCM (2.0 mL). Triethylamine (63.8 .mu.l, 0.457 mmol)
and sodium triacetoxyborohydride (72.7 mg, 0.343 mmol) were added
to the above solution. The reaction was stirred at rt overnight
before being quenched with sat. NaHCO.sub.3. The resulting mixture
was extracted with 3:1 DCM/IPA mixture, and the combined organic
layers were washed with water and brine, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated in vacuo and the crude
residue was dissolved in dry DCM (4.0 mL) followed by addition of
triethylamine (0.064 mL, 0.458 mmol) and Boc-anhydride (0.10 g,
0.458 mmol). The reaction mixture was stirred at rt for 2 hours
before being quenched with sat. NaHCO.sub.3. The resulting mixture
was extracted with DCM, and the combined organic layers were washed
with water and brine, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated in vacuo and the residue was purified by
silica gel chromatography (50% EtOAc/hexanes) to provide the
desired compound as a yellow oil. LC-MS calculated for
C.sub.24H.sub.28BrN.sub.4O.sub.2 (M+H).sup.+: m/z=483.1; found
483.1.
Step 3: tert-butyl
2-(8-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiph-
enyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate
##STR00255##
[1202] A mixture of tert-butyl
2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-ca-
rboxylate (200 mg, 0.414 mmol),
(8-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)--
1,7-naphthyridin-3-yl)methanol (Example 20, step 3 23.1 mg, 0.050
mmol), tetrakis(triphenylphosphine)palladium(O) (47.8 mg, 0.041
mmol), and sodium carbonate (88 mg, 0.827 mmol) in 1,4-dioxane (10
mL) and water (2 mL) was degassed and sealed. It was stirred at
100.degree. C. overnight. The reaction mixture was cooled and then
diluted with EtOAc. The organic layer was washed with water and
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated in vacuo and the crude residue was purified by silica
gel chromatography (90% EtOAc/hexanes) to provide the desired
compound as a brown oil. LC-MS calculated for
C.sub.40H.sub.42N.sub.7O.sub.3 (M+H).sup.+: m/z=668.3; found
668.3.
Step 4: tert-butyl
2-(8-(3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl-
amino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate
##STR00256##
[1204] To a stirred solution of tert-butyl
2-(8-(3'-(3-(hydroxymethyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiph-
enyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate
(276 mg, 0.414 mmol) in DCM (10.0 mL) was added manganese dioxide
(719 mg, 8.27 mmol). The resulted mixture was stirred at 45.degree.
C. for 2 hours, then filtered. The filtrate was concentrated under
reduced pressure. The residue was used in the next step directly
without further purification. LC-MS calculated for
C.sub.40H.sub.40N.sub.7O.sub.3 (M+H).sup.+: m/z=666.3; found
666.3.
Step 5:
(3R)-1-((8-(2,2'-dimethyl-3'-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-
-8-ylamino)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3--
carboxylic acid
[1205] To a solution of tert-butyl
2-(8-(3'-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl-
amino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate (20 mg,
0.030 mmol) in DCM (1 mL) was added (R)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, cat#ST-7698: 3.5 mg, 0.030 mmol) and
triethylamine (8.4 .mu.l, 0.060 mmol). The mixture was stirred at
rt for 60 min, then sodium triacetoxyborohydride (9.6 mg, 0.045
mmol) was added. The resulting mixture was stirred at rt overnight
before 1 mL of TFA was added. The reaction mixture was further
stirred for 1 h. The reaction mixture was concentrated then
purified with prep-LC-MS (pH 2, acetonitrile/water+TFA) to give the
desired product as its TFA salt. LC-MS calculated for
C.sub.40H.sub.41N.sub.8O.sub.2 (M+H).sup.+: m/z=665.3; found
665.3.
Example 72
(R)-1-((8-(2,2'-dichloro-3'-(3-((2-hydroxyethylamino)methyl)imidazo[1,2-a]-
pyrazin-8-ylamino)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrroli-
din-3-ol
##STR00257##
[1206] Step 1:
(R)-1-((8-(3'-amino-2,2'-dichlorobiphenyl-3-ylamino)-1,7-naphthyridin-3-y-
l)methyl)pyrrolidin-3-ol
##STR00258##
[1208] In a vial was combined
2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Example 5, step 1: 0.474 g, 1.870 mmol),
(R)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 22, step 4: 0.676 g, 1.559 mmol), sodium
carbonate (0.330 g, 3.12 mmol),
(1,1'-bis(di-cyclohexylphosphino)ferrocene)-dichloropalladium(II)
(Aldrich, cat#701998: 0.023 g, 0.031 mmol), 1,4-dioxane (2.92 mL)
and water (0.974 mL). The mixture was degassed, sealed, and heated
to 90.degree. C. whilst stirring for 2 h. The mixture was cooled,
diluted with EtOAc and filtered through celite. The filtrate was
concentrated and purified using flash chromatography (0.fwdarw.15%
MeOH/DCM). LC-MS calculated for C.sub.25H.sub.24Cl.sub.2N.sub.5O
(M+H).sup.+: m/z=480.1; found 480.2.
Step 2:
(R)-1-((8-(3'-(3-bromoimidazo[1,2-a]pyrazin-8-ylamino)-2,2'-dichlo-
robiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00259##
[1210] In a vial was combined
(R)-1-((8-((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)amino)-1,7-naphth-
yridin-3-yl)methyl)pyrrolidin-3-ol (497 mg, 1.035 mmol) and
3-bromo-8-chloroimidazo[1,2-a]pyrazine (Combi-Blocks, cat# QA-2223:
361 mg, 1.552 mmol). The reactants were diluted with 2-propanol
(5173 .mu.l). To this was then added sulfuric acid (83 .mu.l, 1.552
mmol) drop-wise. The reaction mixture was heated to 100.degree. C.
overnight. The solvent was removed under reduced pressure. The
crude residue was taken back up in a 3:1 chloroform/IPA mixture and
was neutralized with a saturated solution of sodium bicarbonate.
The aqueous layer was extracted once more with 3:1 chloroform/IPA.
The combined organic layers were washed with brine, dried over
magnesium sulfate and filtered. The filtrate was concentrated and
purified using flash chromatography (0.fwdarw.40% MeOH/DCM). LC-MS
calculated for C.sub.31H26BrCl.sub.2N.sub.8O (M+H).sup.+:
m/z=675.1; found 675.1.
Step 3:
(R)-1-((8-(2,2'-dichloro-3'-(3-vinylimidazo[1,2-a]pyrazin-8-ylamin-
o)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00260##
[1212] A mixture of
(R)-1-((8-((3'-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-2,2'-dichloro-[-
1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(458 mg, 0.677 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Sigma-Aldrich,
cat#633348: 126 .mu.l, 0.745 mmol), sodium carbonate (2.031 mmol)
and
[1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)
(Aldrich, cat#701998: 25.7 mg, 0.034 mmol) in 1,4-dioxane (3224
.mu.L) and water (1290 .mu.L) was degassed and sealed. It was
stirred at 90.degree. C. for 1.5 h. The crude reaction mixture was
diluted with water and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over magnesium sulfate
and filtered. The filtrate was concentrated under reduced pressure
and used without further purification. LC-MS calculated for
C.sub.33H.sub.29Cl.sub.2N.sub.8O (M+H).sup.+: m/z=623.2; found
623.4.
Step 4:
(R)-8-(2,2'-dichloro-3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7--
naphthyridin-8-ylamino)biphenyl-3-ylamino)imidazo[1,2-a]pyrazine-3-carbald-
ehyde
##STR00261##
[1214] In a vial was combined
(R)-1-((8-((2,2'-dichloro-3'-((3-vinylimidazo[1,2-a]pyrazin-8-yl)amino)-[-
1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(200 mg, 0.321 mmol) and THF (2053 .mu.l). The material was
sonicated until it was fully in solution. To this, in order, was
then added water (513 .mu.l), 2,6-lutidine (191 .mu.l, 1.636 mmol),
sodium periodate (343 mg, 1.604 mmol) and potassium osmate
dihydrate (17.73 mg, 0.048 mmol). The reaction was allowed to stir
at rt for 30 min. The reaction was diluted with water and was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over magnesium sulfate, and was filtered.
The filtrate was concentrated and purified using flash
chromatography (0.fwdarw.40% MeOH/DCM). LC-MS calculated for
C.sub.32H.sub.27Cl.sub.2N.sub.8O.sub.2 (M+H).sup.+: m/z=625.2;
found 625.2.
Step 5:
(R)-1-((8-(2,2'-dichloro-3'-(3-((2-hydroxyethylamino)methyl)imidaz-
o[1,2-a]pyrazin-8-ylamino)biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl-
)pyrrolidin-3-ol
[1215] In a vial
(R)-8-((2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)imidazo[1,2-a]pyrazine-3-ca-
rbaldehyde (10 mg, 0.016 mmol) was combined with ethanolamine (9.67
.mu.l, 0.160 mmol) and was diluted with methanol (160 .mu.l). To
this was then added acetic acid (13.73 .mu.l, 0.240 mmol) followed
by sodium cyanoborohydride (2.009 mg, 0.032 mmol) as a solution in
methanol (160 .mu.l). The reaction was allowed to stir at room
temperature for 15 minutes after which time the reaction mixture
was further diluted to a final volume of 5 mL with methanol and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as the TFA salt. LC-MS calculated for
C.sub.34H.sub.34Cl.sub.2N.sub.9O.sub.2 (M+H).sup.+: m/z=670.2;
found 670.5.
Example 73
(R)-1-((8-((2,2'-dimethyl-3'-((3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin--
8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol
##STR00262##
[1217] This compound was prepared using similar procedures as
described for Example 20 with pyrrolidine (Aldrich, cat#394238)
replacing (R)-pyrrolidin-3-ol in Step 6. The reaction mixture was
diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.40H.sub.43N.sub.8O (M+H).sup.+:
m/z=651.4; found 651.3.
Example 74
(S)-1-((8-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyrid-
in-3-yl)methyl)pyrrolidin-3-ol
##STR00263##
[1218] Step 1:
(R)-1-((8-((2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)--
2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrroli-
din-3-ol
##STR00264##
[1220] To a vial was added
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (Example 9, Step 3: 0.166 g, 0.424
mmol),
(R)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 22, Step 4: 0.184 g, 0.424 mmol), 1 M
aqueous sodium carbonate (0.848 mmol), tetrakis (0.049 g, 0.042
mmol), and 1,4-dioxane (3.74 mL). The mixture was degassed, sealed,
and heated to 110.degree. C. whilst stirring for 4 h. The mixture
was cooled, diluted with EtOAc and filtered through celite. The
filtrate was concentrated and purified by silica gel chromatography
(15% MeOH/DCM) to provide the desired product as a yellow solid.
LC-MS calculated for C.sub.35H.sub.33ClN.sub.7O.sub.2 (M+H).sup.+:
m/z=618.2; found 618.3.
Step 2:
(R)-8-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyrid-
ine-3-carbaldehyde
##STR00265##
[1222] This compound was prepared using similar procedures as
described for Example 9 with
(R)-1-((8-((2-chloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)--
2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrroli-
din-3-ol replacing
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol in Step 5. LC-MS calculated for
C.sub.35H.sub.31ClN.sub.7O.sub.2 (M+H).sup.+: m/z=616.2; found
616.3.
Step 3:
(S)-1-((8-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl-
)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-na-
phthyridin-3-yl)methyl)pyrrolidin-3-ol
[1223] To a vial was added
(R)-8-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyri-
din-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-c-
arbaldehyde (0.015 g, 0.024 mmol), (S)-pyrrolidin-3-ol
(Combi-Blocks, cat#SS-7948: 6.4 mg, 0.073 mmol), a stir bar, and
1,2-dichloroethane (0.122 mL). The mixture was stirred for 5 min,
then sodium triacetoxyborohydride (0.015 g, 0.073 mmol) and acetic
acid (0.011 mL, 0.195 mmol) were added. The mixture was stirred for
1 h, then was diluted with methanol and purified by prep HPLC
(pH=2, acetonitrile/water+TFA) to provide the desired compound as
its TFA salt. LC-MS calculated for C.sub.39H.sub.40ClN.sub.8O.sub.2
(M+H).sup.+: m/z=687.3; found 687.4.
Example 75
(R)-1-((8-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)azetidine-3-carboxylic acid
##STR00266##
[1225] This compound was prepared using similar procedures as
described for Example 74 with azetidine-3-carboxylic acid (Aldrich,
cat#391131) replacing (S)-pyrrolidin-3-ol in Step 3. The reaction
mixture was diluted with methanol and purified by prep HPLC (pH=2,
acetonitrile/water+TFA) to provide the desired compound as its TFA
salt. LC-MS calculated for C.sub.39H.sub.38ClN.sub.8O.sub.3
(M+H).sup.+: m/z=701.3; found 701.3.
Example 76
(R)-1-((8-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)-3-methylpyrrolidin-3-ol
##STR00267##
[1226] Step 1:
(8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methanol
##STR00268##
[1228] A flask was charged with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6: 0.586 g, 1.625 mmol), methanol (6.7 mL), and a
stir bar. The mixture was cooled to 0.degree. C., and sodium
borohydride (0.255 g, 6.74 mmol) was added portionwise over 1 h.
After the final addition, the mixture was warmed to rt and stirred
for 1 h. Another portion of sodium borohydride (0.050 g, 1.349
mmol) was added and stirred for 30 min. Saturated aqueous sodium
bicarbonate was added (5 mL), and the mixture was diluted with DCM
(10 mL). The layers were separated, and the aqueous layer was
further extracted with DCM (2.times.10 mL). The combined organic
extracts were dried over MgSO.sub.4, filtered, and concentrated in
vacuo. The crude product was purified by silica gel chromatography
(0.fwdarw.46% EtOAc/hexanes). LC-MS calculated for
C.sub.15H.sub.12BrClN.sub.3O (M+H).sup.+: m/z=364.0; found
364.0.
Step 2:
(8-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methanol
##STR00269##
[1230] This compound was prepared using similar procedures as
described for Example 9 with
(8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methanol
replacing
(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methan- ol
in Step 3. LC-MS calculated for C.sub.21H.sub.24BClN.sub.3O.sub.3
(M+H).sup.+: m/z=412.2; found 412.2.
Step 3:
(R)-1-((8-((2,2'-dichloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin--
8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol
##STR00270##
[1232] This compound was prepared using similar procedures as
described for Example 74 with
(8-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol replacing
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol in Step 1. LC-MS calculated for
C.sub.34H.sub.30Cl.sub.2N.sub.7O.sub.2 (M+H).sup.+: m/z=638.2;
found 638.2.
Step 4:
(R)-8-((2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-
-carbaldehyde
##STR00271##
[1234] This compound was prepared using similar procedures as
described for Example 9 with
(R)-1-((8-((2,2'-dichloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)am-
ino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol replacing
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol in Step 5. LC-MS calculated for
C.sub.34H.sub.28Cl.sub.2N.sub.7O.sub.2 (M+H).sup.+: m/z=636.2;
found 636.2.
Step 5:
(R)-1-((8-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)me-
thyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthy-
ridin-3-yl)methyl)-3-methylpyrrolidin-3-ol
[1235] To a vial was added
(R)-8-((2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbal-
dehyde (0.0150 g, 0.024 mmol), (R)-3-methylpyrrolidin-3-ol (Ark
Pharm, cat#AK100499: 7.15 mg, 0.071 mmol), a stir bar, and
1,2-dichloroethane (0.236 mL). The mixture was stirred for 5 min,
then sodium triacetoxyborohydride (0.015 g, 0.071 mmol) and acetic
acid (4.05 .mu.l, 0.071 mmol) were added. The reaction was stirred
for 1 h, and the mixture was diluted with methanol and purified by
prep HPLC (pH=2, acetonitrile/water+TFA) to provide the desired
compound as its TFA salt. LC-MS calculated for
C.sub.39H.sub.39Cl.sub.2N.sub.8O.sub.2 (M+H).sup.+: m/z=721.3;
found 721.3.
Example 77
(R)-1-((8-((2,2'-dichloro-3'-((3-(((2-hydroxyethyl)amino)methyl)-1,7-napht-
hyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)meth-
yl)pyrrolidin-3-ol
##STR00272##
[1237] This compound was prepared using similar procedures as
described for Example 76 with ethanolamine (Aldrich, cat#411000)
replacing (R)-3-methylpyrrolidin-3-ol in Step 5. LC-MS calculated
for C.sub.36H.sub.35Cl.sub.2N.sub.8O.sub.2 (M+H).sup.+: m/z=681.2;
found 681.2.
Example 78
(R)-1-((8-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00273##
[1239] This compound was prepared using similar procedures as
described for Example 76 with (R)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, cat#ST-7698) replacing (R)-3-methylpyrrolidin-3-ol
in Step 5. LC-MS calculated for
C.sub.39H.sub.37Cl.sub.2N.sub.8O.sub.3 (M+H).sup.+: m/z=735.2;
found 735.2.
Example 79
(R)-1-((8-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-nap-
hthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyrid-
in-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00274##
[1240] Step I:
(R)-1-((8-((2'-chloro-2-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
##STR00275##
[1242] To a vial was added
N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine
(Example 14, Step 5: 0.141 g, 0.391 mmol),
(R)-1-((8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (Example 37,
Step 9: 0.150 g, 0.326 mmol), sodium carbonate (0.069 g, 0.652
mmol), tetrakis (0.038 g, 0.033 mmol), 1,4-dioxane (2.444 mL), and
water (0.815 mL). The mixture was degassed, sealed, and heated to
110.degree. C. whilst stirring for 4 h. The mixture was cooled,
diluted with EtOAc and filtered through celite. The filtrate was
concentrated and purified using flash chromatography (0.fwdarw.15%
MeOH/DCM). LC-MS calculated for C.sub.36H.sub.33ClN.sub.7O
(M+H).sup.+: m/z=614.2; found 614.4.
Step 2:
(R)-8-((2-chloro-3'-((3-((3-hydroxy)pyrrolidin-1-yl)methyl)-1,7-na-
phthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyri-
dine-3-carbaldehyde
##STR00276##
[1244] To a vial was added
(R)-1-((8-((2'-chloro-2-methyl-3'-((3-vinyl-1,7-naphthyridin-8-yl)amino)--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol
(0.108 g, 0.176 mmol), tetrahydrofuran (1.125 mL), water (0.281
mL), 2,6-lutidine (0.107 mL, 0.914 mmol), sodium periodate (0.188
g, 0.879 mmol), then potassium osmate dihydrate (9.72 mg, 0.026
mmol). The mixture was stirred for 30 min at rt. The mixture was
diluted with 3:1 CHCl.sub.3/IPA (5 mL) and water (2 mL), and the
layers were separated. The aqueous layer was further extracted with
3:1 CHCl.sub.3/IPA, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The solid was slurried with
5:1 Et.sub.2O/DCM, and filtered to provide the desired product as a
beige solid. LC-MS calculated for C.sub.35H.sub.31ClN.sub.7O.sub.2
(M+H).sup.+: m/z=616.2; found 616.2.
Step 3:
(R)-1-((8-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-
-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-na-
phthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
[1245] To a vial was added
(R)-8-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-c-
arbaldehyde (0.0350 g, 0.057 mmol), (R)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, cat#ST-7698: 0.020 g, 0.170 mmol), a stir bar,
and 1,2-dichloroethane (0.568 mL). The mixture was stirred for 5
min, then sodium triacetoxyborohydride (0.036 g, 0.170 mmol) and
acetic acid (0.020 mL, 0.341 mmol) were added. The reaction was
stirred for 1 h, and the mixture was diluted with methanol and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as its TFA salt. LC-MS calculated for
C.sub.40H.sub.40ClN.sub.8O.sub.3 (M+H).sup.+: m/z=715.3; found
715.3.
Example 80
(R)-1-((8-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthy-
ridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-
-yl)methyl)azetidine-3-carboxylic acid
##STR00277##
[1247] This compound was prepared using similar procedures as
described for Example 79 with azetidine-3-carboxylic acid (Aldrich,
cat#391131) replacing (R)-pyrrolidine-3-carboxylic acid in Step 3.
LC-MS calculated for C.sub.39H.sub.38ClN.sub.8O.sub.3 (M+H).sup.+:
m/z=701.3; found 701.3.
Example 81
(R)-3-(((8-((2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphth-
yridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin--
3-yl)methyl)amino)propanoic acid
##STR00278##
[1249] This compound was prepared using similar procedures as
described for Example 79 with 3-alanine (Aldrich, cat#146064)
replacing (R)-pyrrolidine-3-carboxylic acid in Step 3. LC-MS
calculated for C.sub.38H.sub.38ClN.sub.8O.sub.3 (M+H).sup.+:
m/z=689.3; found 689.3.
Example 82
(R)-1-((8-((2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00279##
[1250] Step 1:
(S)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol
##STR00280##
[1252] To a vial was added
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6: 0.200 g, 0.552 mmol), (S)-3-hydroxypyrrolidine
(Combi-Blocks, cat#SS-7948: 0.144 g, 1.655 mmol), DCE (2.76 mL),
and a stir bar. The mixture was stirred at rt for 15 min, then
sodium cyanoborohydride (0.104 g, 1.655 mmol) and acetic acid
(0.120 mL, 2.096 mmol) were added. The mixture was stirred at rt
for 1 h, then the reaction was quenched with aqueous saturated
sodium bicarbonate (5 mL). 3:1 CHCl.sub.3/IPA was added (5 mL), and
the layers were separated. The aqueous layer was further extracted
with 3:1 CHCl.sub.3/IPA (2.times.5 mL), and the combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated under
reduced pressure. The resulting brown residue was purified by
silica gel chromatography (0.fwdarw.15% MeOH/DCM) to provide the
desired product as a brown solid. LC-MS calculated for
C.sub.19H.sub.19BrClN.sub.4O (M+H).sup.+: m/z=433.0; found
433.2.
Step 2:
(S)-1-((8-((2,2'-dichloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin--
8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrro-
lidin-3-ol
##STR00281##
[1254] To a vial was added
(8-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (Example 76, Step 2: 0.163 g,
0.396 mmol),
(S)-1-((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)me-
thyl)pyrrolidin-3-ol (0.172 g, 0.396 mmol), 1 M aqueous sodium
carbonate (0.792 mmol), tetrakis (0.046 g, 0.040 mmol), and
1,4-dioxane (2.97 mL). The mixture was degassed, sealed, and heated
to 110.degree. C. whilst stirring for 4 h. The mixture was cooled,
diluted with EtOAc and filtered through celite. The filtrate was
concentrated and purified by silica gel chromatography (15%
MeOH/DCM) to provide the desired product as a yellow solid. LC-MS
calculated for C.sub.34H.sub.30Cl.sub.2N.sub.7O.sub.2 (M+H).sup.+:
m/z=638.2; found 638.2.
Step 3:
(S)-8-((2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-
-carbaldehyde
##STR00282##
[1256] This compound was prepared using similar procedures as
described for Example 9 with
(S)-1-((8-((2,2'-dichloro-3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)am-
ino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol replacing
(R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dime-
thyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-
-ol in Step 5. LC-MS calculated for
C.sub.34H.sub.28Cl.sub.2N.sub.7O.sub.2 (M+H).sup.+: m/z=636.2;
found 636.2.
Step 4:
(R)-1-((8-((2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)me-
thyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthy-
ridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
[1257] To a vial was added
(S)-8-((2,2'-dichloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-napht-
hyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbal-
dehyde (0.009 g, 0.014 mmol), (R)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, cat#ST-7698: 4.88 mg, 0.042 mmol), a stir bar,
N,N-dimethylformamide (0.141 mL), and DIPEA (7.41 .mu.l, 0.042
mmol). The mixture was stirred for 5 min, then sodium
cyanoborohydride (2.67 mg, 0.042 mmol) and was added. The reaction
was stirred for 1 h, then the mixture was diluted with methanol and
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to provide the
desired compound as its TFA salt. LC-MS calculated for
C.sub.39H.sub.37Cl.sub.2N.sub.8O.sub.3 (M+H).sup.+: m/z=735.2;
found 735.2.
Example 83
(S)-1-((8-((2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,-
7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3--
yl)methyl)pyrrolidine-3-carboxylic acid
##STR00283##
[1259] This compound was prepared using similar procedures as
described for Example 82 with (S)-pyrrolidine-3-carboxylic acid
(Combi-Blocks, cat#ST-1381) replacing (R)-pyrrolidine-3-carboxylic
acid in Step 4. LC-MS calculated for
C.sub.39H.sub.37Cl.sub.2N.sub.8O.sub.3 (M+H).sup.+: m/z=735.2;
found 735.2.
Example 84
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrol[3,4-d]oxazol-2-yl-
)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)p-
yrrolidine-3-carboxylic acid
##STR00284##
[1260] Step 1:
2-(dimethylamino)-1-(2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amin-
o)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-
-5-yl)ethan-1-one
##STR00285##
[1262] A mixture of
1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-
-(dimethylamino)ethan-1-one (Example 37, Step 7:112 mg, 0.307
mmol),
(8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino-
)-1,7-naphthyridin-3-yl)methanol (Example 9, Step 3: 120 mg, 0.307
.mu.mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphen-
yl-2-yl)(chloro)palladium (1:1) (24.13 mg, 0.031 mmol) and
tripotassium phosphate hydrate (155 mg, 0.675 mmol) in 1,4-dioxane
(3 mL)/water (1 mL) was stirred at 80.degree. C. for 1 h. The
residue was dissolved in methanol and 1 N HCl and purified with
prep-LCMS (pH 2, acetonitrile/water+TFA) to give the desired
compound as light yellow solid. LC-MS calculated for
C.sub.32H.sub.33N.sub.6O.sub.3 (M+H).sup.+: m/z=549.3; found
549.3.
Step 2:
8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-y-
l)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbaldeh-
yde
##STR00286##
[1264] This compound was prepared using similar procedures as
described for Example 34, with
2-(dimethylamino)-1-(2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amin-
o)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-
-5-yl)ethan-1-one replacing tert-butyl
2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1-
'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
in Step 2. LC-MS calculated for C.sub.32H.sub.31N.sub.6O.sub.3
(M+H).sup.+: m/z=547.2; found 547.3.
Step 3.
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]ox-
azol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl-
)methyl)pyrrolidine-3-carboxylic acid
[1265] This compound was prepared using similar procedures as
described for Example 31 with
8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2'-
-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbaldehyde
replacing
N-(2-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2'-methy-
l-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]p-
yridine-2-carboxamide in Step 7. LC-MS calculated for
C.sub.37H.sub.40N.sub.7O.sub.4 (M+H).sup.+: m/z=646.3; found
646.3.
Example 85
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrol[3,4-d]thiazol-2-y-
l)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-
pyrrolidine-3-carboxylic acid
##STR00287##
[1266] Step 1: tert-butyl
2-bromo-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate
##STR00288##
[1268] To a stirred solution of
2-bromo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole, HBr salt (Aurum
Pharm, cat# MR22320: 220.0 mg, 0.769 mmol) and
N,N-diisopropylethylamine (0.269 mL, 1.539 mmol) in DCM (5.0 mL),
Boc-anhydride (201 mg, 0.923 mmol) was added at room temperature.
After 1 hour, the reaction mixture was diluted with EtOAc (100 mL),
and washed with water (3.times.15 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
to afford crude tert-butyl
2-bromo-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate (220 mg, 0.724
mmol, 93.6% yield), which was used directly in the next step
without further purification. LC-MS calculated for
C.sub.10H.sub.14BrN.sub.2O.sub.2S (M+H)+: m/z=305.0/307.0; found
305.0/307.0.
Step 2: tert-butyl
2-(3-chloro-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carbo-
xylate
##STR00289##
[1270] (3-Chloro-2-methylphenyl)boronic acid (344 mg, 2.02 mmol)
(Combi-blocks, cat#BB-2035), tert-butyl
2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (616
mg, 2.02 mmol), sodium carbonate (428 mg, 4.04 mmol) in 1,4-dioxane
(8 mL) and water (2 mL) was added palladiumtetrakis (233 mg, 0.202
mmol). The resulting mixture was purged with N.sub.2, then heated
at 100.degree. C. After 3 h, the reaction was concentrated, and
diluted with DCM. The crude product was added to a silica gel
column and was eluted with ethyl acetate/hexane from 0% to 40% to
give tert-butyl
2-(3-chloro-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carbo-
xylate (541 mg, 76% yield). LC-MS calculated for
C.sub.17H.sub.20ClN.sub.2O.sub.2S (M+H).sup.+: m/z=351.1; found
351.0.
Step 3: tert-butyl
2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,6-di-
hydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate
##STR00290##
[1272] A mixture of tert-butyl
2-(3-chloro-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carbo-
xylate (261 mg, 0.715 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(Aldrich, cat#473294: 545 mg, 2.14 mmol), palladium acetate (6.42
mg, 0.0286 mmol), K.sub.3PO.sub.4 (455 mg, 2.14 mmol) and
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (Strem
Chemicals, cat#15-1143: 29.4 mg, 0.0715 mmol) in 1,4-dioxane was
degassed and stirred at rt for 16 h. The mixture was diluted with
DCM, and washed with water. The organic layer was concentrated in
vacuo and purified by silica-gel chromatography (5% EtOAc/DCM).
LC-MS calculated for C.sub.23H.sub.32BN.sub.2O.sub.4S (M+H).sup.+:
m/z=443.2; found 443.3.
Step 4: tert-butyl
2-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate
##STR00291##
[1274] To a vial was added tert-butyl
2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,6-di-
hydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (0.013 g, 0.029
mmol),
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 15, Step 2: 7 mg, 0.020 mmol), sodium carbonate (6.24 mg,
0.059 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.436
mg, 1.962 .mu.mol), 1,4-dioxane (0.346 mL), and water (0.046 mL).
The mixture was degassed, sealed, and heated to 90.degree. C.
whilst stirring for 4 h. After cooling, the mixture was diluted
with DCM and water. The layers were separated and the aqueous layer
was further extracted. The combined organic layers were dried over
magnesium sulfate, filtered, concentrated in vacuo, and purified by
silica gel chromatography (MeOH/DCM). LC-MS calculated for
C.sub.33H.sub.32N.sub.5O.sub.3S (M+H).sup.+: m/z=578.2; found
578.4.
Step 5:
(R)-1-((8-((3'-(5-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[3,4-
-d]thiazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00292##
[1276] To a vial was added tert-butyl
2-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (9 mg,
0.02 mmol), (R)-pyrrolidine-3-carboxylic acid (Combi-Blocks,
cat#ST-7698: 0.017 g, 0.152 mmol), dichloromethane (0.829 mL) and
triethylamine (0.016 mL, 0.115 mmol). The reaction was stirred at
rt for 2 h, then sodium triacetoxyborohydride (0.054 g, 0.253 mmol)
and acetic acid (8.7 .mu.l, 0.15 mmol) were added. The reaction was
stirred at rt for 2 h, then quenched with a saturated aqueous
solution of sodium bicarbonate. The mixture was then extracted with
a 3:1 mixture of chloroform/isopropanol. The combined organic
layers were dried over sodium sulfate, then concentrated in vacuo
to provide the desired compound. LC-MS calculated for
C.sub.38H.sub.41N.sub.6O.sub.4S (M+H).sup.+: m/z=677.3; found
677.2.
Step 6:
(R)-1-((8-((3'-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2'-di-
methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-
e-3-carboxylic acid
##STR00293##
[1278] To a solution of
(R)-1-((8-((3'-(5-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thia-
zol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)-
methyl)pyrrolidine-3-carboxylic acid (7 mg, 0.02 mmol) in DCM (0.5
mL) was added TFA (0.2 mL). After 2 h, the reaction mixture was
concentrated, and then the crude product was used directly in the
next step. LC-MS calculated for C.sub.33H.sub.33N.sub.6O.sub.2S
(M+H).sup.+: m/z=577.2; found 577.3.
Step 7:
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]th-
iazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-y-
l)methyl)pyrrolidine-3-carboxylic acid
[1279] In a 1 dram vial
(R)-1-((8-((3'-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2'-dimethyl--
[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-car-
boxylic acid (6 mg, 0.02 mmol) and N,N-Dimethylglycine (6 mg, 0.06
mmol) were dissolved in DMF (0.2 mL). DIPEA (14 .mu.l, 0.08 mmol)
and HATU (18 mg, 0.05 mmol) were added to the reaction mixture in
one portion. After 5 h, the reaction mixture was diluted with MeOH
then purified by prep-HPLC (pH=10, acetonitrile/water+NH.sub.4OH)
to give the desired product. LC-MS calculated for
C.sub.37H.sub.40N.sub.7O.sub.3S (M+H).sup.+: m/z=662.3; found
662.2. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.30 (s, 1H),
8.85 (d, J=2.0 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.17 (d, J=1.7 Hz,
1H), 8.05 (d, J=5.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.42 (td,
J=7.6, 2.4 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H),
7.17 (d, J=5.8 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 5.06-4.96 (m, 1H),
4.88 (t, J=2.8 Hz, 1H), 4.77-4.68 (m, 1H), 4.63-4.54 (m, 1H), 3.81
(q, J=13.8 Hz, 2H), 3.16 (d, J=1.9 Hz, 2H), 2.97-2.85 (m, 1H), 2.75
(t, J=8.7 Hz, 1H), 2.66 (dd, J=9.1, 6.5 Hz, 1H), 2.61-2.52 (m, 2H),
2.25 (s, 6H), 2.21 (s, 3H), 2.08 (s, 3H), 1.96 (q, J=7.2 Hz,
2H).
Example 86
2-((R)-3-hydroxypyrrolidin-1-yl)-1-(2-(3'-((3-(((R)-3-hydroxypyrrolidin-1--
yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl-
)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one
##STR00294##
[1280] Step 1: tert-butyl
(R)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)am-
ino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thia-
zole-5-carboxylate
##STR00295##
[1282] This compound was prepared using a similar procedure as
described for Example 85, Step 4 with
(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)py-
rrolidin-3-ol (Example 20, Step 2) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde.
The crude compound was diluted with DCM and water. The layers were
separated and the aqueous layer was further extracted. The combined
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. LC-MS calculated for
C.sub.37H.sub.41N.sub.6O.sub.3S (M+H).sup.+: m/z=649.3; found
649.2.
Step 2:
(R)-1-((8-((3'-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2'-di-
methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-
-3-ol
##STR00296##
[1284] To a solution of tert-butyl
(R)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)am-
ino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thia-
zole-5-carboxylate (147 mg, 0.226 mmol) in DCM (3 mL) was added TFA
(1 mL). After 2 h, the reaction mixture was concentrated, and then
the crude product was used directly in the next step. LC-MS
calculated for C.sub.32H.sub.33N60S (M+H).sup.+: m/z=549.2; found
549.3.
Step 3:
(R)-2-chloro-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-n-
aphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-
-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one
##STR00297##
[1286] To a solution of the above crude product and DIPEA (118 uL,
0.678 mmol) in DCM (3 mL) was added chloroacetyl chloride (20 uL,
0.25 mmol) at -78.degree. C. After 15 min, the reaction mixture was
warmed to room temperature slowly. After 30 min, the reaction
mixture was concentrated and diluted with MeOH then purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for
C.sub.34H.sub.34ClN.sub.6O.sub.2S (M+H).sup.+: m/z=625.2; found
625.2.
Step 4:
2-((R)-3-hydroxypyrrolidin-1-yl)-1-(2-(3'-((3-(((R)-3-hydroxypyrro-
lidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphen-
yl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one
[1287] In a 1 dram vial
(R)-2-chloro-1-(2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyr-
idin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrol-
o[3,4-d]thiazol-5-yl)ethan-1-one (5 mg, 8.00 .mu.mol) was dissolved
in acetonitrile (400 .mu.L) to give a yellow solution.
(R)-pyrrolidin-3-ol (Combi-Blocks, cat#AM-2005: 5 mg) and DIPEA
(1.5 .mu.l, 8.0 .mu.mol) were added to the reaction mixture. The
reaction mixture was heated to 60.degree. C. After 12 h, the
reaction mixture was diluted with MeOH then purified by prep-HPLC
(pH=2, acetonitrile/water+TFA) to give the desired product as the
TFA salt. LC-MS calculated for C.sub.38H.sub.42N.sub.7O.sub.3S
(M+H).sup.+: m/z=676.3; found 676.3.
Example 87
(R)-1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2--
yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl-
)-3-methylpyrrolidine-3-carboxylic acid
##STR00298##
[1289] This compound was prepared using a similar procedure as
described for Example 85, Step 5 with
(R)-3-methylpyrrolidine-3-carboxylic acid (J&W PharmLab,
cat#75R0495) replacing (R)-pyrrolidine-3-carboxylic acid. LC-MS
calculated for C.sub.38H.sub.42N.sub.7O.sub.3S (M+H).sup.+:
m/z=676.3; found 676.3.
Example 88
1-((8-((3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)--
2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)aze-
tidine-3-carboxylic acid
##STR00299##
[1291] This compound was prepared using a similar procedure as
described for Example 85, Step 5 with azetidine-3-carboxylic acid
(Aldrich, cat#391131) replacing (R)-pyrrolidine-3-carboxylic acid.
LC-MS calculated for C.sub.36H.sub.38N.sub.7O.sub.3S (M+H).sup.+:
m/z=648.3; found 648.3.
Example 89
(R)-1-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]t-
hiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)m-
ethyl)pyrrolidine-3-carboxylic acid
##STR00300##
[1292] Step 1: tert-butyl
2-(2'-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-bi-
phenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate
##STR00301##
[1294] This compound was prepared using a similar procedure as
described for Example 85, Step 4 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde.
The crude compound was diluted with DCM and water. The layers were
separated and the aqueous layer was further extracted. The combined
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. LC-MS calculated for
C.sub.32H.sub.29ClN.sub.5O.sub.3S (M+H).sup.+: m/z=598.2; found
598.3.
Step 2:
(R)-1-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo-
[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)pyrrolidine-3-carboxylic acid
[1295] This compound was prepared using a similar procedure as
described for Example 85, Steps 5-7 with tert-butyl
2-(2'-chloro-3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-bi-
phenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate
replacing tert-butyl
2-(3'-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-bipheny-
l]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate. LC-MS
calculated for C.sub.36H.sub.37ClN.sub.7O.sub.3S (M+H).sup.+:
m/z=682.2; found 682.3.
Example 90
(R)-1-((8-((2-chloro-3'-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo-
[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridi-
n-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00302##
[1297] This compound was prepared using a similar procedure as
described for Example 85 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 4 and N-ethyl-N-methylglycine replacing N,N-dimethylglycine
in Step 7. LC-MS calculated for C.sub.37H.sub.39ClN.sub.7O.sub.3S
(M+H).sup.+: m/z=696.2; found 696.3.
Example 91
(R)-2-(1-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4--
d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-y-
l)methyl)pyrrolidin-3-yl)acetic acid
##STR00303##
[1299] This compound was prepared using a similar procedure as
described for Example 85 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 4 and (R)-2-(pyrrolidin-3-yl)acetic acid (Combi-Blocks,
cat#QE6116) replacing (R)-pyrrolidine-3-carboxylic acid in Step 5.
LC-MS calculated for C.sub.37H.sub.39ClN.sub.7O.sub.3S (M+H).sup.+:
m/z=696.2; found 696.3.
Example 92
2-((8-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiaz-
ol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methy-
l)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid
##STR00304##
[1301] This compound was prepared using a similar procedure as
described for Example 85 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 4 and 2-azabicyclo[2.2.1]heptane-5-carboxylic acid (Aurora
Fine Chemicals, cat#A30.309.242) replacing
(R)-pyrrolidine-3-carboxylic acid in Step 5. LC-MS calculated for
C.sub.38H.sub.39ClN.sub.7O.sub.3S (M+H).sup.+: m/z=708.2; found
708.3.
Example 93
(R)-2-(1-((8-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-
-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-
-3-yl)methyl)pyrrolidin-3-yl)acetic acid
##STR00305##
[1303] This compound was prepared using a similar procedure as
described for Example 85 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 4, (R)-2-(pyrrolidin-3-yl)acetic acid (Combi-Blocks,
cat#QE6116) replacing (R)-pyrrolidine-3-carboxylic acid in Step 5
and N-ethyl-N-methylglycine replacing N,N-dimethylglycine in Step
7. LC-MS calculated for C.sub.38H.sub.41ClN.sub.7O.sub.3S
(M+H).sup.+: m/z=710.3; found 710.3.
Example 94
2-((8-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrol-
o[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)m-
ethyl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid
##STR00306##
[1305] This compound was prepared using a similar procedure as
described for Example 85 with
8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde
(Example 14, Step 6) replacing
8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde
in Step 4,2-azabicyclo[2.2.1]heptane-5-carboxylic acid (Aurora Fine
Chemicals, cat#A30.309.242) replacing (R)-pyrrolidine-3-carboxylic
acid in Step 5 and N-ethyl-N-methylglycine replacing
N,N-dimethylglycine in Step 7. LC-MS calculated for
C.sub.39H.sub.41ClN.sub.7O.sub.3S (M+H).sup.+: m/z=722.3; found
722.3.
Example 95
(R)-1-((8-((2-chloro-3'-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-di-
hydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-
-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00307##
[1306] Step 1:
(R)-1-((8-((2-chloro-3'-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]-
thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)-
methyl)pyrrolidine-3-carboxylic acid
##STR00308##
[1308] This compound was prepared using a similar procedure as
described for Example 90 with chloracetyl acid replacing
N-ethyl-N-methylglycine. The reaction mixture was diluted with MeOH
then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give
the desired product as the TFA salt. LC-MS calculated for
C.sub.34H.sub.31Cl.sub.2N.sub.6O.sub.3S (M+H).sup.+: m/z=673.2;
found 673.3.
Step 2:
(R)-1-((8-((2-chloro-3'-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl-
)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-y-
l)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic
acid
[1309] In a 1 dram vial
(R)-1-((8-((2-chloro-3'-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]-
thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)-
methyl)pyrrolidine-3-carboxylic acid (5 mg, 8.00 .mu.mol) was
dissolved in acetonitrile (400 .mu.L) to give a yellow solution.
(R)-pyrrolidin-3-ol (Combi-Blocks, cat#AM-2005: 5 mg) and DIPEA
(1.5 .mu.l, 8.0 .mu.mol) were added to the reaction mixture. The
reaction mixture was heated to 60.degree. C. After 12 h, the
reaction mixture was diluted with MeOH then purified by prep-HPLC
(pH=2, acetonitrile/water+TFA) to give the desired product as the
TFA salt. LC-MS calculated for C.sub.38H.sub.39ClN.sub.7O.sub.4S
(M+H).sup.+: m/z=724.3; found 724.2.
Example 96
(R)-1-((8-((2-chloro-3'-(5-(N-(2-hydroxyethyl)-N-methylglycyl)-5,6-dihydro-
-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7--
naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00309##
[1311] This compound was prepared using a similar procedure as
described for Example 95 with N-(2-hydroxyethyl)-N-methylamine
replacing (R)-pyrrolidin-3-ol in Step 2. LC-MS calculated for
C.sub.37H.sub.39ClN.sub.7O.sub.4S (M+H).sup.+: m/z=712.3; found
712.3.
Example 97
(R)-1-((8-((2-chloro-3'-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-di-
hydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-
-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00310##
[1313] This compound was prepared using a similar procedure as
described for Example 95 with (S)-pyrrolidin-3-ol (Combi-Blocks,
cat#SS-7948) replacing (R)-pyrrolidin-3-ol in Step 2. LC-MS
calculated for C.sub.38H.sub.39ClN.sub.7O.sub.4S (M+H).sup.+:
m/z=724.3; found 724.3.
Example 98
(R)-1-((8-((2-chloro-3'-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro--
4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-n-
aphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid
##STR00311##
[1315] This compound was prepared using a similar procedure as
described for Example 95 with 3-hydroxyazetidine hydrochloride (Ark
Pharm, cat#AK-25536) replacing (R)-pyrrolidin-3-ol in Step 2. LC-MS
calculated for C.sub.37H.sub.37ClN.sub.7O.sub.4S (M+H).sup.+:
m/z=710.3; found 710.3.
Example 99
Cis-4-((2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-
-ylamino)-2,2'-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imi-
dazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid
##STR00312##
[1317] This compound was prepared using a similar procedure as
described for Example 48 with
(R)--N-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylami-
no)-2,2'-dimethylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-
-c]pyridine-2-carboxamide (Example 62, Step 2) replacing
(R)--N-(2-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyrid-
in-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-1-methyl-4,5,6,7-tetrahydro-
-1H-imidazo[4,5-c]pyridine-2-carboxamide. The reaction mixture was
purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the
desired compound as its TFA salt. LC-MS calculated for
C.sub.43H.sub.51N.sub.8O.sub.4 (M+H).sup.+: m/z=743.4; found
743.4.
Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)
Binding Assay
[1318] 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.
[1319] 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.
[1320] 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 Example PD-1/PD-L1 HTRF IC.sub.50 (nM) 1 + 2
+ 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 + 16 + 17
+ 18 + 19 + 20 + 21 + 22 + 23 + 24 + 25 + 26 + 27 + 28 + 29 + 30 +
31 + 32 + 33 + 34 + 35 + 36 + 37 + 38 + 39 + 40 + 41 + 42 + 43 + 44
+ 45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 + 53 + 54 + 55 + 56 + 57 +
58 + 59 + 60 + 61 + 62-peak1 + 62-peak2 + 63 + 64-peak1 + 64-peak2
+ 65 + 66 + 67 + 68-peak1 + 68-peak2 + 69 + 70 + 71 + 72 + 73 + 74
+ 75 + 76 + 77 + 78 + 79 + 80 + 81 + 82 + 83 + 84 + 85 + 86 + 87 +
88 + 89 + 90 + 91 + 92 + 93 ++ 94 + 95 + 96 + 97 + 98 + 99 +
[1321] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference,
including without limitation all patent, patent applications, and
publications, cited in the present application is incorporated
herein by reference in its entirety.
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