U.S. patent application number 15/850660 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 Liangxing Wu, Wenqing Yao, Zhiyong Yu, Fenglei Zhang.
Application Number | 20180179179 15/850660 |
Document ID | / |
Family ID | 61148470 |
Filed Date | 2018-06-28 |
United States Patent
Application |
20180179179 |
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) ; Yu; Zhiyong; (Wilmington, DE) ; Zhang;
Fenglei; (Berwyn, PA) ; Yao; Wenqing; (Chadds
Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
61148470 |
Appl. No.: |
15/850660 |
Filed: |
December 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62438020 |
Dec 22, 2016 |
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62487356 |
Apr 19, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/00 20180101;
C07D 513/04 20130101; C07D 413/14 20130101; C07D 213/81 20130101;
C07D 471/04 20130101; C07D 498/04 20130101; C07D 401/12 20130101;
C07D 401/14 20130101 |
International
Class: |
C07D 401/12 20060101
C07D401/12; C07D 401/14 20060101 C07D401/14; C07D 513/04 20060101
C07D513/04; C07D 498/04 20060101 C07D498/04; C07D 471/04 20060101
C07D471/04; C07D 213/81 20060101 C07D213/81 |
Claims
1. A compound of Formula (I): ##STR00083## 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, B, P, 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)--, --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-- or
--NR.sup.13C(O)NR.sup.13--; 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 and R.sup.17 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.3-14 cycloalkyl, 5-14 membered
heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-14 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, 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,
C(O)NR.sup.aS(O).sub.2R.sup.a, NR.sup.aC(.dbd.NR.sup.a)R.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.3-14 cycloalkyl,
5-14 membered heteroaryl, 4-14 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14 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.6 and R.sup.17
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, C(O)NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eC(.dbd.NR.sup.e)R.sup.e, S(O).sub.2NR.sup.eC(O)R.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, 5-10
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.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,
C(O)NR.sup.cS(O).sub.2R.sup.c, NR.sup.cC(.dbd.NR.sup.c)R.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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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, C(O)NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gC(.dbd.NR.sup.g)R.sup.g, S(O).sub.2NR.sup.gC(O)R.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 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)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, C(O)NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oC(.dbd.NR)R.sup.o, S(O).sub.2NR.sup.oC(O)R.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 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, C(O)NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rC(.dbd.NR.sup.r)R.sup.r, S(O).sub.2NR.sup.rC(O)R.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 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, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.6-10 aryl-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-, 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, C(O)NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iC(.dbd.NR.sup.i)R.sup.i, S(O).sub.2NR.sup.iC(O)R.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, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.6-10 aryl-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- of
R.sup.h are each further optionally substituted by 1, 2, or 3 R
substituents each R.sup.j is independently selected from C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10
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, C(O)NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kC(.dbd.NR.sup.k)R.sup.k, S(O).sub.2NR.sup.kC(O)R.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- to
10-membered heteroaryl, 4-10 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-, 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-, 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-, 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-, 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 nitrogen atom to which they are
attached form a 4-, 5-, 6-, 7-, 8-, 9-, 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 nitrogen atom to which they are
attached form a 4-, 5-, 6-, 7-, 8-, 9-, 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-, 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 alky).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, 3 or 4.
2. The compound of claim 1, having Formula (I): ##STR00084## 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--O--, --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--; 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 and R.sup.17 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.3-14 cycloalkyl, 5-14 membered
heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-14 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, 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.3-14 cycloalkyl,
5-14 membered heteroaryl, 4-14 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14 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.6 and R.sup.17
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.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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR)NR.sup.oR.sup.o, S(O)R.sup.o,
S(O)NR.sup.oR.sup.o, S(O).sub.2R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and S(O).sub.2NR.sup.oR.sup.o,
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, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.6-10 aryl-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-, 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.1, 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.i
C(.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, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.6-10 aryl-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- 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, 5-10 membered heteroaryl, 4-10 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- to 10-membered heteroaryl, 4-10 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-, 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-, 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-, 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-, 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-, 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-, 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-, 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 alky).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, 3 or 4.
3. The compound of claim 1, having Formula (I): ##STR00085## 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--; 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 and R.sup.17 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 and R.sup.17
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.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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR)NR.sup.oR.sup.o, S(O)R.sup.o,
S(O)NR.sup.oR.sup.o, S(O).sub.2R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and S(O).sub.2NR.sup.oR.sup.o,
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.1, 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 alky).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,
3 or 4.
4. 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.
5. 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 2-benzoxazolyl; (3) when L is --NH--, ring
A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or
(4) when L is a bond, ring A is not
[1,2,4]triazolo[1,5-a]pyridin-2-yl.
6. The compound of claim 1, having Formula (Ia): ##STR00086## or a
pharmaceutically acceptable salt or a stereoisomer thereof,
wherein: 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, 11-membered heterocycloalkyl, wherein the 4-11 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.
7. The compound of claim 6, having Formula (II): ##STR00087## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
8. The compound of claim 6, having Formula (IIa): ##STR00088## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
9. The compound of claim 6, having Formula (IIb): ##STR00089## or a
pharmaceutically acceptable salt or a stereoisomer thereof.
10. The compound of claim 6, having Formula (III): ##STR00090## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
11. The compound of claim 6, having Formula (IIIa): ##STR00091## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
12. The compound of claim 6, having Formula (IIIb): ##STR00092## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
13. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein ring A is selected from:
##STR00093## 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.
14. 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.
15. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the subscript m is 0.
16. 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.
17. The compound of claim 1, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.3 is methyl, CN or Cl.
18. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.12 is H.
19. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.7 is H, 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.
20. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.2 is H, halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy.
21. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.1 is H, halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy.
22. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein the subscript p is 1.
23. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.8 and R.sup.9 are each
H.
24. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein R.sup.10 is H.
25. The compound of claim 6, 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.
26. The compound of claim 6, or a pharmaceutically acceptable salt
or a stereoisomer thereof, wherein --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 2-carboxy-1-piperidinyl,
3-hydroxypyrrolidin-1-yl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino or
[2-(dimethylamino)-2-oxo-ethyl]amino.
27. 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.
28. The compound of claim 1 selected from:
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-((2-hydroxyethylamino)me-
thyl)picolinamide);
(2S,2'S)-1,1'-(6,6'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(azanediyl)b-
is(oxomethylene)bis(pyridine-6,3-diyl))bis(methylene)dipiperidine-2-carbox-
ylic acid;
N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-yl)m-
ethyl)picolinamido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinam-
ide;
(R)--N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-yl)me-
thyl)picolinamido)biphenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picol-
inamide;
N-(2-chloro-2'-methyl-3'-(5-((2-oxooxazolidin-3-yl)methyl)picolin-
amido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide;
(R)--N-(2-chloro-2'-methyl-3'-(5-((2-oxooxazolidin-3-yl)methyl)picolinami-
do)biphenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide;
(S)-1-((6-(2'-chloro-3'-(5-((2-hydroxyethylamino)methyl)picolinamido)-2-m-
ethylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic
acid;
(S)-1-((6-(2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pi-
colinamido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)pyrrolidine-
-3-carboxylic acid;
(R)-1-((6-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido-
)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-4-carboxyl-
ic acid;
(R)-1-((6-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)pico-
linamido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)azetidine-3-c-
arboxylic acid;
(S)-1-((6-((2-chloro-2'-fluoro-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)pipe-
ridine-2-carboxylic acid;
(S)-1-((6-((2'-chloro-2-methyl-3'-(5-(pyrrolidin-1-ylmethyl)picolinamido)-
-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2--
carboxylic acid; and
(S)-1-((6-((2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-biphenyl]-
-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carboxylic
acid; or a pharmaceutically acceptable salt or a stereoisomer
thereof.
29. The compound of claim 6, 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)--, or --NR.sup.13; 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, or 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,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, halo, or OH; 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, 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, and 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 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, 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; 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; 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, and 4-10 membered heterocycloalkyl, 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 and 4-10 membered
heterocycloalkyl of R.sup.10 or R.sup.11 are each optionally
substituted with 1, 2, or 3 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, or halo; 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, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl of R.sup.a are each optionally substituted with 1
or 2 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, wherein the C.sub.1-6 alkyl, and C.sub.1-6
haloalkyl 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, 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, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-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,
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.1-6 alkyl, 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- 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; 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, 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, halo, CN, OR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.g,
C(O)OR.sup.g, NHR.sup.g, NR.sup.gR.sup.g, and NR.sup.g(O)R.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, NHR.sup.i, NR.sup.iR.sup.i, and NR.sup.iC(O)R.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, 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.
30. The compound of claim 6, 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, 2, or 3 R.sup.6 substituents; L is --C(O)NR.sup.13-- or
--NR.sup.13C(O)--; 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, halo, or
CN; R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, or halo;
R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, or halo; each
R.sup.6 is independently selected from H, halo, C.sub.1-6 alkyl,
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-, and OR.sup.a, wherein the
C.sub.1-6 alkyl, 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 or 2 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.a is independently
selected from H and C.sub.1-6 alkyl; each R.sup.d is independently
selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, OR.sup.e,
C(O)R.sup.e, C(O)NR.sup.eR.sup.e, and C(O)OR.sup.e; each R.sup.e is
independently selected from H and C.sub.1-6 alkyl; each R.sup.b
substituent is independently selected from halo, C.sub.1-6 alkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10
membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C(O)OR.sup.c, NHR.sup.c, and
NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.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 and
C.sub.1-6 alkyl optionally substituted with 1 or 2 R.sup.f
substituents; each R.sup.f is independently selected from C.sub.1-4
alkyl, halo, and 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.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, NHR.sup.i,
NR.sup.iR.sup.i, and NR.sup.iC(O)R.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.
31. 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.
32. 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.
33. 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.
34. 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, PNAS2002, 99(19):12293-7; Blank et al,
Cancer Res 2004, 64(3):1140-5). In fact, tumor PD-L1 expression
status has been shown to be prognostic in multiple tumor types
(Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015;
Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2
expression, in contrast, is more restricted and is expressed mainly
by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73).
Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells
delivers a signal that inhibits IL-2 and IFN-.gamma. production, as
well as cell proliferation induced upon T cell receptor activation
(Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J
Exp Med 2000, 192(7): 1027-34). The mechanism involves recruitment
of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling
such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol
2007, 8, 239-245).
[0005] 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).
[0006] 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
[0007] The present disclosure provides, inter alia, a compound of
Formula (I):
##STR00002##
[0008] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein constituent variables are defined herein.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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
[0013] The present disclosure provides, inter alia, a compound of
Formula (I):
##STR00003##
[0014] or a pharmaceutically acceptable salt or a stereoisomer
thereof, wherein:
[0015] 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, B, P, 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;
[0016] 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-- or
--NR.sup.13C(O)NR.sup.13--;
[0017] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0018] 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;
[0019] 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;
[0020] R.sup.6 and R.sup.17 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.3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14
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,
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,
C(O)NR.sup.aS(O).sub.2R.sup.a, NR.sup.aC(.dbd.NR.sup.a)R.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.3-14 cycloalkyl,
5-14 membered heteroaryl, 4-14 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14 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.6 and R.sup.17
are each optionally substituted with 1, 2, 3, 4 or 5 R.sup.b
substituents;
[0021] 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;
[0022] 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;
[0023] 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;
[0024] 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;
[0025] each R.sup.a is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents;
[0026] each R.sup.d is independently selected from C.sub.1-6 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, C(O)NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eC(.dbd.NR.sup.e)R.sup.e, S(O).sub.2NR.sup.eC(O)R.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, 5-10
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;
[0027] 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;
[0028] 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,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-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,
C(O)NR.sup.cS(O).sub.2R.sup.c, NR.sup.cC(.dbd.NR.sup.c)R.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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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;
[0029] 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, C(O)NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gC(.dbd.NR.sup.g)R.sup.g, S(O).sub.2NR.sup.gC(O)R.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 R.sup.n substituents;
[0030] 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)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, C(O)NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oC(.dbd.NR)R.sup.o, S(O).sub.2NR.sup.oC(O)R.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;
[0031] 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;
[0032] 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, C(O)NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rC(.dbd.NR.sup.r)R.sup.r, S(O).sub.2NR.sup.rC(O)R.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 R.sup.q substituents;
[0033] or any two R.sup.a substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 R.sup.h substituents;
[0034] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.6-10 aryl-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-, 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, C(O)NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iC(.dbd.NR.sup.1)R.sup.i, S(O).sub.2NR.sup.iC(O)R.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, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.6-10 aryl-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- of
R.sup.h are each further optionally substituted by 1, 2, or 3
R.sup.j substituents
[0035] each R.sup.j is independently selected from C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10
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, C(O)NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kC(.dbd.NR.sup.k)R.sup.k, S(O).sub.2NR.sup.kC(O)R.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- to
10-membered heteroaryl, 4-10 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;
[0036] 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;
[0037] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0038] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0039] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0040] 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-,
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;
[0041] 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-,
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;
[0042] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0043] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0044] 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;
[0045] 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 alky).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;
[0046] the subscript m is an integer of 0, 1, 2 or 3;
[0047] the subscript n is an integer of 0, 1, 2 or 3;
[0048] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0049] the subscript s is an integer of 1, 2, 3 or 4.
[0050] In some embodiments, presented herein is a compound of
Formula (I), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0051] 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;
[0052] 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.qNR.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--;
[0053] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0054] 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;
[0055] 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;
[0056] R.sup.6 and R.sup.17 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.3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14
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,
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.3-14 cycloalkyl,
5-14 membered heteroaryl, 4-14 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-14 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.6 and R.sup.17
are each optionally substituted with 1, 2, 3, 4 or 5 R.sup.b
substituents;
[0057] 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;
[0058] 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;
[0059] 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;
[0060] 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;
[0061] 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;
[0062] 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;
[0063] 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;
[0064] 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,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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;
[0065] 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;
[0066] 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;
[0067] 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)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;
[0068] 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;
[0069] 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;
[0070] 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;
[0071] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.6-10 aryl-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-, 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.1C(O)R.sup.i, NR.sup.1C(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.1S(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, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.6-10 aryl-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- of R.sup.h are each further
optionally substituted by 1, 2, or 3 R.sup.j substituents
[0072] each R.sup.j is independently selected from C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10
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- to 10-membered heteroaryl, 4-10 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;
[0073] 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;
[0074] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0075] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0076] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0077] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0078] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0079] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0080] 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-,
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 independently selected R.sup.h substituents;
[0081] 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;
[0082] 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 alky).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;
[0083] the subscript m is an integer of 0, 1, 2 or 3;
[0084] the subscript n is an integer of 0, 1, 2 or 3;
[0085] each subscript q is independently an integer of 1, 2, 3 or
4; and the subscript s is an integer of 1, 2, 3 or 4.
[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 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;
[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.13C(O)O-- or --NR.sup.13C(O)NR.sup.13--;
[0089] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0090] 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;
[0091] 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;
[0092] R.sup.6 and R.sup.17 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 and R.sup.17
are each optionally substituted with 1, 2, 3, 4 or 5 R.sup.b
substituents;
[0093] 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;
[0094] 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;
[0095] 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;
[0096] 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;
[0097] 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;
[0098] 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;
[0099] 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;
[0100] 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,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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;
[0101] 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;
[0102] 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;
[0103] 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)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;
[0104] 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;
[0105] 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;
[0106] 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;
[0107] 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 substituents
[0108] 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;
[0109] 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;
[0110] 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;
[0111] 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;
[0112] 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;
[0113] 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;
[0114] 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;
[0115] 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;
[0116] 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;
[0117] 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;
[0118] 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 alky).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;
[0119] the subscript m is an integer of 0, 1, 2 or 3;
[0120] the subscript n is an integer of 0, 1, 2 or 3;
[0121] each subscript q is independently an integer of 1, 2, 3 or
4; and
[0122] the subscript s is an integer of 1, 2, 3 or 4.
[0123] In some embodiments, the present disclosure provides a
compound of Formula (I): or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0124] 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;
[0125] 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--;
[0126] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0127] 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;
[0128] 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;
[0129] R.sup.6 and R.sup.17 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;
[0130] 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;
[0131] 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;
[0132] 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;
[0133] 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;
[0134] 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;
[0135] 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;
[0136] 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;
[0137] 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,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-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.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-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;
[0138] 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;
[0139] 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;
[0140] 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)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;
[0141] 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;
[0142] 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;
[0143] 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;
[0144] 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.1, 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
[0145] 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;
[0146] 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;
[0147] 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;
[0148] 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;
[0149] 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;
[0150] 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;
[0151] 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;
[0152] 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;
[0153] 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;
[0154] 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;
[0155] 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 alky).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;
[0156] the subscript m is an integer of 0, 1, 2 or 3;
[0157] the subscript n is an integer of 0, 1, 2 or 3;
[0158] the subscript p is an integer of 1, 2, 3 or 4;
[0159] each subscript q is independently an integer of 1, 2, 3 or
4; and the subscript s is an integer of 1, 2, 3 or 4.
[0160] 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;
[0161] 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.
[0162] In some embodiments, (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 2-benzoxazolyl; (3) when L is --NH--, ring A is
not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; and (4)
when L is a bond, ring A is not
[1,2,4]triazolo[1,5-a]pyridin-2-yl.
[0163] In some embodiments, (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 2-benzoxazolyl; (3) when L is --NH--, ring A is
not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or (4)
when L is a bond, ring A is not
[1,2,4]triazolo[1,5-a]pyridin-2-yl.
[0164] In some embodiments, provided herein is a compound having
Formula (Ia):
##STR00004##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
[0165] 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;
[0166] 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;
[0167] 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;
[0168] 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;
[0169] 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;
[0170] 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;
[0171] 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,
11-membered heterocycloalkyl, wherein the 4-11 membered
heterocycloalkyl is each optionally substituted with 1, 2 or 3
R.sup.f substituents;
[0172] 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.
[0173] In some embodiments, provided herein is a compound having
Formula (II):
##STR00005##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0174] In some embodiments, provided herein is a compound having
Formula (IIa):
##STR00006##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0175] In some embodiments, provided herein is a compound having
Formula (IIb):
##STR00007##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0176] In some embodiments, provided herein is a compound having
Formula (III):
##STR00008##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0177] In some embodiments, provided herein is a compound having
Formula (IIIa):
##STR00009##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0178] In some embodiments, provided herein is a compound having
Formula (IIIb):
##STR00010##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0179] In some embodiments, provided herein are compounds having
Formula (IV):
##STR00011##
or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein the subscript r is 1, 2, 3, 4 or 5. 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.
[0180] In some embodiments, provided herein are compounds having
Formula (V):
##STR00012##
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.
[0181] In some embodiments, provided herein are compounds having
Formula (VI):
##STR00013##
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.
[0182] In some embodiments, provided herein are compounds having
Formula (VIIa) or (VIIb):
##STR00014##
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.
[0183] In some embodiments, provided herein are compounds having
Formula (VIIIa) or (VIIIb):
##STR00015##
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.
[0184] In some embodiments, ring A is selected from:
##STR00016##
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.
[0185] In some embodiments, ring A is selected from:
##STR00017##
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.
[0186] In some embodiments, ring A is selected from:
##STR00018##
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.
[0187] In some embodiments, ring A is selected from:
##STR00019##
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.
[0188] In some embodiments, ring A is
##STR00020##
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.
[0189] In some embodiments, ring A is selected from:
##STR00021##
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.
[0190] In some embodiments, ring A is selected from:
##STR00022##
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.
[0191] In some embodiments, ring A is
##STR00023##
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.
[0192] In some embodiments, ring A is
##STR00024##
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. In some
embodiments, ring A is 2-pyridyl, optionally substituted with 1, 2,
3, or 4 independently selected R.sup.6 substituents.
[0193] In some embodiments, L is a bond, --C(O)NR.sup.13--,
--NR.sup.13C(O)--, --CH.dbd.CH-- or --NR.sup.13--. In some
embodiments, L is a --C(O)NR.sup.13-- or --NR.sup.13C(O)--. 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 --C(O)NH--, wherein the
carbonyl group in the --C(O)NH-- linkage is attached to ring A.
[0194] 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.
[0195] In some embodiments, L is a bond.
[0196] In some embodiment, L is --NR.sup.13--. In certain
instances, R.sup.13 is H or C.sub.1-4 alkyl.
[0197] In some embodiment, L is --CH.sub.2O-- or --OCH.sub.2--.
[0198] In some embodiment, 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.
[0199] In some embodiments, the subscript m is 0 or 1. In some
embodiments, the subscript m is 0.
[0200] 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, CN, halo, or OH.
In some embodiments, the subscript n is 1 or 2. In some
embodiments, the subscript n is 1. 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 Cl or methyl.
[0201] In some embodiments, R.sup.3 is methyl, halo, or CN. In some
embodiments, R.sup.3 is methyl, CN or Cl. 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.
[0202] 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, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CN, halo, or OH. In some embodiments, R.sup.12 is
H or C.sub.1-4 alkyl. In some embodiments, R.sup.12 is H.
[0203] 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, 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 or C.sub.1-4 alkyl. In some embodiments,
R.sup.7 is H.
[0204] 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, or halo, 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, or C.sub.1-4 alkoxy, 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, 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, or C.sub.1-4 alkoxy.
[0205] In some embodiments, R.sup.2 is H, halo, C.sub.1-4 alkyl or
C.sub.1-4 alkoxy. In some embodiments, R.sup.2 is halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy.
[0206] In some embodiments, R.sup.1 is H, halo, C.sub.1-4 alkyl or
C.sub.1-4 alkoxy. In some embodiments, R.sup.1 is halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy.
[0207] In some embodiments, the subscript p is 1, 2, or 3. In some
embodiments, the subscript p is 1 or 2. In some embodiments, the
subscript p is 1.
[0208] 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. In
some embodiments, R.sup.8 and R.sup.9 are each independently
selected from H, halo, CN, OH, C.sub.1-4 alkyl, and C.sub.1-4
alkoxy. In some embodiments, R.sup.8 and R.sup.9 are each
independently selected from H and C.sub.1-4 alkyl. In some
embodiments, R.sup.8 and R.sup.9 are each H. In some embodiments,
R.sup.8 is H. In some embodiments, R.sup.9 is H.
[0209] 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;
[0210] 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.
[0211] 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;
[0212] 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 or 2 R.sup.h
substituents.
[0213] 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 embodiment, 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 or 2
R.sup.h substituents.
[0214] In some embodiments, R.sup.10 is H.
[0215] In some embodiments, R.sup.11 is 2-hydroxyethyl,
[1-(hydroxymethyl)cyclopropyl]methyl,
[1-(hydroxymethyl)cyclobutyl]methyl or
2-(dimethylamino)-2-oxo-ethyl.
[0216] In some embodiments, --NR.sup.10R.sup.11 is
(2-hydroxyethyl)amino, 2-carboxy-1-piperidinyl,
3-hydroxypyrrolidin-1-yl, 2-oxooxazolidin-3-yl,
[1-(hydroxymethyl)cyclopropyl]methylamino,
[1-(hydroxymethyl)cyclobutyl]methylamino or
[2-(dimethylamino)-2-oxo-ethyl]amino.
[0217] In some embodiments, provided herein is a compound of
Formula (I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0218] 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;
[0219] L is a bond, --C(O)NR.sup.13--, --NR.sup.13C(O)--, or
--NR.sup.13;
[0220] 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, or
OH;
[0221] R.sup.3 is methyl, halo, CN or C.sub.1-4 haloalkyl;
[0222] 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, or OH;
[0223] 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;
[0224] 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, 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, and
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 are each optionally
substituted with 1, 2, or 3 R.sup.b substituents;
[0225] 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;
[0226] 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;
[0227] 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, and 4-10 membered
heterocycloalkyl, 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 and
4-10 membered heterocycloalkyl of R.sup.10 or R.sup.11 are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.f substituents;
[0228] 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;
[0229] 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, or halo;
[0230] each R.sup.13 is independently H, C.sub.1-6 haloalkyl or
C.sub.1-6 alkyl;
[0231] 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, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl of R.sup.a are each optionally substituted with 1
or 2 R.sup.d substituents;
[0232] 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, and C.sub.1-6
haloalkyl of R.sup.d are each optionally substituted with 1, 2, or
3 independently selected R.sup.f substituents;
[0233] 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;
[0234] 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,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-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, 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.1-6 alkyl, 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.14 alkyl-, C.sub.3-10 cycloalkyl-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;
[0235] 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, 2, 3, 4, or 5 R.sup.f substituents;
[0236] 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,
NHR.sup.g, NR.sup.gR.sup.g, and NR.sup.gC(O)R.sup.g;
[0237] 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;
[0238] 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, NHR.sup.i, NR.sup.iR.sup.i, and
NR.sup.iC(O)R.sup.i;
[0239] 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;
[0240] each R.sup.i is independently selected from H and C.sub.1-4
alkyl;
[0241] the subscript m is an integer of 0, 1, or 2;
[0242] the subscript n is an integer of 0, 1, or 2; and the
subscript p is an integer of 1, 2, or 3.
[0243] In some embodiments, provided herein is a compound of
Formula (I) or (Ia), or a pharmaceutically acceptable salt or a
stereoisomer thereof, wherein:
[0244] 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, 2, or 3 R.sup.6
substituents;
[0245] L is --C(O)NR.sup.13-- or --NR.sup.13C(O)--;
[0246] 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;
[0247] R.sup.3 is methyl, halo, or CN;
[0248] R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, or
halo;
[0249] R.sup.5 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, or
halo;
[0250] each R.sup.6 is independently selected from H, halo,
C.sub.1-6 alkyl, 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-, and OR.sup.a,
wherein the C.sub.1-6 alkyl, 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 or 2 R.sup.b
substituents;
[0251] R.sup.7 is H or C.sub.1-4 alkyl;
[0252] R.sup.8 and R.sup.9 are each independently selected from H
and C.sub.1-4 alkyl;
[0253] 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;
[0254] 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;
[0255] R.sup.12 is H or C.sub.1-4 alkyl;
[0256] each R.sup.13 is independently H or C.sub.1-6 alkyl;
[0257] each R.sup.a is independently selected from H and C.sub.1-6
alkyl;
[0258] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, OR.sup.e, C(O)R.sup.e,
C(O)NR.sup.eR.sup.e, and C(O)OR.sup.e;
[0259] each R.sup.e is independently selected from H and C.sub.1-6
alkyl;
[0260] each R.sup.b substituent is independently selected from
halo, C.sub.1-6 alkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-,
(4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, C(O)OR.sup.c,
NHR.sup.c, and NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.b are each further
optionally substituted with 1 or 2 independently selected R.sup.d
substituents;
[0261] each R.sup.c is independently selected from H and C.sub.1-6
alkyl optionally substituted with 1 or 2 R.sup.f substituents;
[0262] each R.sup.f is independently selected from C.sub.1-4 alkyl,
halo, and OR.sup.g;
[0263] each R.sup.g is independently selected from H and C.sub.1-6
alkyl;
[0264] 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, NHR.sup.i, NR.sup.iR.sup.i, and
NR.sup.iC(O)R.sup.i;
[0265] 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;
[0266] each R.sup.i is independently selected from H and C.sub.1-4
alkyl;
[0267] the subscript m is an integer of 0 or 1;
[0268] the subscript n is an integer of 0 or 1; and
[0269] the subscript p is an integer of 1 or 2.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] 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.
[0280] 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.
[0281] The term "amino," employed alone or in combination with
other terms, refers to a group of formula --NH.sub.2.
[0282] The term "carbamyl," employed alone or in combination with
other terms, refers to a group of formula --C(O)NH.sub.2.
[0283] 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).
[0284] The term "cyano" or "nitrile," employed alone or in
combination with other terms, refers to a group of formula
--C.ident.N, which also may be written as --CN.
[0285] 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.
[0286] The term "haloalkyl," employed alone or in combination with
other terms, as used herein refers to an alkyl group in which one
or more of the hydrogen atoms has been replaced by a halogen atom.
The term "C.sub.n-mhaloalkyl" refers to a C.sub.n-malkyl 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.
[0287] 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.
[0288] 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.
[0289] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0290] The term "aromatic" refers to a carbocycle or heterocycle
having one or more polyunsaturated rings having aromatic character
(i.e., having (4n+2) delocalized 71 (pi) electrons where n is an
integer).
[0291] 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.
[0292] The term "heteroaryl" or "heteroaromatic," employed alone or
in combination with other terms, refers to a monocyclic or
polycyclic aromatic heterocycle having at least one heteroatom ring
member selected from sulfur, oxygen and nitrogen. In some
embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring
members independently selected from nitrogen, sulfur and oxygen. In
some embodiments, any ring-forming N in a heteroaryl moiety can be
an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms
including carbon atoms and 1, 2, 3 or 4 heteroatom ring members
independently selected from nitrogen, sulfur and oxygen. In some
embodiments, the heteroaryl has 5-14, 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,
tetrahydrothiazolopyridinyl (e.g.,
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine) and the like.
[0293] 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.
[0294] 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.
[0295] 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.
[0296] The term "heterocycloalkyl," employed alone or in
combination with other terms, refers to a non-aromatic ring or ring
system, which may optionally contain one or more alkenylene groups
as part of the ring structure, which has at least one heteroatom
ring member independently selected from nitrogen, sulfur oxygen and
phosphorus, and which has 4-14 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, oxoimidazolidinyl (e.g.,
3-methyl-2-oxoimidazolidin-1-yl), oxooxazolidinyl (e.g.,
2-oxooxazolidin-3-yl), and thiomorpholino.
[0297] 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.
[0298] 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.
[0299] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. One method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are,
e.g., optically active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,
malic acid, lactic acid or the various optically active
camphorsulfonic acids such as .beta.-camphorsulfonic acid. Other
resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of .alpha.-methylbenzylamine
(e.g., S and R forms, or diastereomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,
cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
[0300] 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.
[0301] 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.
[0302] 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.
[0303] 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.
[0304] 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.
[0305] 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.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] 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
[0310] 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.
[0311] 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.
[0312] 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).
[0313] 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).
[0314] 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.
[0315] Compound of Formula I can be synthesized using a process
shown in Scheme 1. In Scheme 1, a suitable halo
(W.sub.1)-substituted aromatic amine 1-1 was reacted with a
suitable coupling reagent 1-2 (where M is, e.g., --B(OH).sub.2) to
produce compound 1-3 under standard metal catalyzed cross-coupling
reaction conditions (such as Suzuki coupling reaction, e.g., in the
presence of a palladium catalyst (e.g.,
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a
base (e.g., a bicarbonate or a carbonate base)). Then the aromatic
amine 1-3 reacted with an acid of formula 1-4 under suitable
conditions forming an amide bond to provide the product of formula
I using coupling reagents such as, but not limited to, HATU and
DIPEA.
##STR00025##
[0316] Compound of formula II can be synthesized using a process
shown in Scheme 2. The aromatic amine 2-1 reacted with an acid of
formula 2-2 under suitable conditions forming an amide bond to
provide the product 2-3, using coupling reagents such as, but not
limited to, HATU and DIPEA. The compound of formula 2-4 can be
synthesized by coupling the halo group (W.sub.2) of 2-3 with a
vinyl reagent (e.g., vinyl boronic acid pinacol ester) under
standard coupling reaction conditions (such as Suzuki coupling
reaction, e.g., in the presence of a palladium catalyst (e.g.,
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a
base (e.g., a bicarbonate or a carbonate base)). The vinyl group in
compound 2-4 was oxidatively cleaved to afford an aldehyde of
formula 2-5 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 was obtained by a reductive amination between the compound of
formula 2-5 and a suitable amine 2-6 in a proper solvent such as
THF or DCM using a reducing reagent 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.
##STR00026##
[0317] Compound of formula III can be synthesized using a process
shown in Scheme 3. The aromatic amine 3-1 reacted with an ester of
formula 3-2 in the presence of a suitable base such as, but not
limited to, potassium tert-butoxide forming an amide bond to
provide the product of formula 3-3. The compound of formula 3-5 was
obtained by coupling the halo (W.sub.1)-substituted 3-3 with a
suitable coupling reagent 3-4 (where M is, e.g., --B(OH).sub.2)
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 aromatic amine
3-5 reacted with an acid of formula 3-6 under suitable conditions
forming an amide bond to provide the product 3-7, using coupling
reagents such as, but not limited to, HATU and DIPEA. Subsequent
removal of the acetal group in the compound of formula 3-7 gave an
aldehyde of formula 3-8 in a proper solvent such as DCM using a
suitable acid such as, but not limited to, TFA. Then the compound
of formula III was obtained by a reductive amination between an
aldehyde of formula 3-8 and a suitable amine 3-9 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.
##STR00027##
[0318] Compound of formula IV can be synthesized using a process
shown in Scheme 4. A suitable halo (W.sub.1)-substituted aromatic
amine 4-1 was reacted with a suitable coupling reagent aromatic
amine 4-2 (where M is, e.g., --B(OH).sub.2) to produce compound 4-3
under standard metal catalyzed cross-coupling reaction conditions
(such as Suzuki coupling reaction, e.g., in the presence of a
palladium catalyst (e.g.,
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a
base (e.g., a bicarbonate or a carbonate base)). The aromatic amine
4-3 reacted with an ester of formula 4-4 in the presence of a
suitable base such as, but not limited to, potassium tert-butoxide
forming an amide bond to provide the product of formula 4-5.
Subsequent removal of the acetal groups in the compound of formula
4-5 gave an aldehyde of formula 4-6 in a proper solvent such as DCM
using a suitable acid such as, but not limited to, TFA. Then the
compound of formula IV was obtained by a reductive amination
between the compound of formula 4-6 and a suitable amine 4-7 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.
##STR00028##
III. Uses of the Compounds
[0319] Compounds of the present disclosure can inhibit the activity
of PD-1/PD-L1 protein/protein interaction and, thus, are useful in
treating diseases and disorders associated with activity of PD-1
and the diseases and disorders associated with PD-L1 including its
interaction with other proteins such as PD-1 and B7-1 (CD80). In
certain embodiments, the compounds of the present disclosure, or
pharmaceutically acceptable salts or stereoisomers thereof, are
useful for therapeutic administration to enhance stimulate and/or
increase immunity in cancer, 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.
[0320] 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.
[0321] 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.
[0322] In some embodiments, the present disclosure provides a
method of enhancing, stimulating and/or increasing the immune
response in a patient. The method includes administering to the
patient in need thereof a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein,
a compound or composition as recited in any of the claims and
described herein, or a salt thereof.
[0323] Examples of cancers that are treatable using the compounds
or combinations of the present disclosure include, but are not
limited to, ewing sarcoma, cholangiocarcinoma, bone cancer,
pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular malignant melanoma, uterine cancer,
ovarian cancer, rectal cancer, cancer of the anal region, stomach
cancer, testicular cancer, uterine cancer, carcinoma of the
fallopian tubes, carcinoma of the endometrium, endometrial cancer,
carcinoma of the cervix, carcinoma of the vagina, carcinoma of the
vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the
esophagus, cancer of the small intestine, cancer of the endocrine
system, cancer of the thyroid gland, cancer of the parathyroid
gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer
of the urethra, cancer of the penis, chronic or acute leukemias
including acute myeloid leukemia, chronic myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors
of childhood, lymphocytic lymphoma, cancer of the bladder, cancer
of the kidney or urethra, carcinoma of the renal pelvis, neoplasm
of the central nervous system (CNS), primary CNS lymphoma, tumor
angiogenesis, spinal axis tumor, brain stem glioma, pituitary
adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,
T-cell lymphoma, environmentally induced cancers including those
induced by asbestos, and combinations of said cancers. The
compounds of the present disclosure are also useful for the
treatment of metastatic cancers, especially metastatic cancers that
express PD-L1.
[0324] In some embodiments, cancers treatable with compounds or
combinations 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.
[0325] In some embodiments, cancers that are treatable using the
compounds or combinations 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.
[0326] 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.
[0327] In some embodiments, the compounds of the present disclosure
can be used to treat sickle cell disease and sickle cell
anemia.
[0328] 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.
[0329] 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.
[0330] 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.
[0331] The present disclosure provides a method for treating
parasite infections. The method includes administering to a patient
in need thereof, a therapeutically effective amount of a compound
of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or a
salt thereof. Non-limiting examples of pathogenic parasites causing
infections treatable by methods of the disclosure include Entamoeba
histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0332] 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.
[0333] 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.
[0334] 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.
[0335] 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.
[0336] 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
[0337] 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.
[0338] 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, PDGFatR,
PDGF(3R, 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, and 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, a CSF1R inhibitor,
a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), a 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, and an
adenosine receptor antagonist or combinations thereof.
[0339] 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.
[0340] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0341] 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.
[0342] 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.
[0343] 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.
[0344] 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.
[0345] 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.
[0346] 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.
[0347] 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.
[0348] 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).
[0349] 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.
[0350] 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.
[0351] 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).
[0352] Compounds of the present disclosure can be used in
combination with one or more immune checkpoint inhibitors for the
treatment of diseases, such as cancer or infections. 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.
[0353] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0354] 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.
[0355] 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.
[0356] 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.
[0357] 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.
[0358] 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.
[0359] 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.
[0360] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0361] 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.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] 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.
[0366] Viruses causing infections treatable by methods of the
present disclosure include, but are not limit to human
papillomavirus, influenza, hepatitis A, B, C or D viruses,
adenovirus, poxvirus, herpes simplex viruses, human
cytomegalovirus, severe acute respiratory syndrome virus, ebola
virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6,
HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus,
rhinovirus, coxsackie virus, comovirus, respiratory syncytial
virus, mumpsvirus, rotavirus, measles virus, rubella virus,
parvovirus, vaccinia virus, HTLV virus, dengue virus,
papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus
and arboviral encephalitis virus.
[0367] 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.
[0368] 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.
[0369] Pathogenic parasites causing infections treatable by methods
of the disclosure include, but are not limited to, Entamoeba
histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp.,
Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma
cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus
brasiliensis.
[0370] 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
[0371] 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.
[0372] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, the compound of the
present disclosure or a pharmaceutically acceptable salt thereof,
in combination with one or more pharmaceutically acceptable
carriers or excipients. In some embodiments, the composition is
suitable for topical administration. In making the compositions of
the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, e.g., a capsule, sachet, paper, or other
container. When the excipient serves as a diluent, it can be a
solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing,
e.g., up to 10% by weight of the active compound, soft and hard
gelatin capsules, suppositories, sterile injectable solutions and
sterile packaged powders.
[0373] 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.
[0374] 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.
[0375] 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.
[0376] 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.
[0377] In some embodiments, the composition is a sustained release
composition comprising at least one compound described herein, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier or excipient. In some
embodiments, the composition comprises at least one compound
described herein, or a pharmaceutically acceptable salt thereof,
and at least one component selected from microcrystalline
cellulose, lactose monohydrate, hydroxypropyl methylcellulose and
polyethylene oxide. In some embodiments, the composition comprises
at least one compound described herein, or a pharmaceutically
acceptable salt thereof, and microcrystalline cellulose, lactose
monohydrate and hydroxypropyl methylcellulose. In some embodiments,
the composition comprises at least one compound described herein,
or a pharmaceutically acceptable salt thereof, and microcrystalline
cellulose, lactose monohydrate and polyethylene oxide. In some
embodiments, the composition further comprises magnesium stearate
or silicon dioxide. In some embodiments, the microcrystalline
cellulose is Avicel PH102.TM.. In some embodiments, the lactose
monohydrate is Fast-flo 316.TM.. In some embodiments, the
hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208
K4M (e.g., Methocel K4 M Premier.TM.) and/or hydroxypropyl
methylcellulose 2208 K100LV (e.g., Methocel KOOLV.TM.). In some
embodiments, the polyethylene oxide is polyethylene oxide WSR 1105
(e.g., Polyox WSR 1105.TM.).
[0378] 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.
[0379] 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.
[0380] 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.
[0381] 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.
[0382] 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.
[0383] 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.
[0384] 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.
[0385] 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.
[0386] 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.
[0387] 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.
[0388] 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.
[0389] 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.
[0390] 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 rig/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
[0391] 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.
[0392] The present invention further includes
isotopically-substituted compounds of the disclosure. An
"isotopically-substituted" compound is a compound of the invention
where one or more atoms are replaced or substituted by an atom
having an atomic mass or mass number different from the atomic mass
or mass number typically found in nature (i.e., naturally
occurring). It is to be understood that a "radio-labeled" compound
is a compound that has incorporated at least one isotope that is
radioactive (e.g., radionuclide). Suitable radionuclides that may
be incorporated in compounds of the present invention include but
are not limited to .sup.3H (also written as T for tritium),
.sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O,
.sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br,
.sup.75Br, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I
and .sup.131I. The radionuclide that is incorporated in the instant
radio-labeled compounds will depend on the specific application of
that radio-labeled compound. For example, for in vitro PD-L1
protein labeling and competition assays, compounds that incorporate
.sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I, .sup.35S or
will generally be most useful. For radio-imaging applications C,
.sup.18F, .sup.125I, .sup.123I, .sup.124I, .sup.131I, .sup.75Br,
.sup.76Br or .sup.77Br will generally be most useful. In some
embodiments the radionuclide is selected from the group consisting
of .sup.3H, .sup.14C, .sup.125I, .sup.35S and .sup.82Br. Synthetic
methods for incorporating radio-isotopes into organic compounds are
known in the art.
[0393] Specifically, a labeled compound of the invention can be
used in a screening assay to identify and/or evaluate compounds.
For example, a newly synthesized or identified compound (i.e., test
compound) which is labeled can be evaluated for its ability to bind
a PD-L1 protein by monitoring its concentration variation when
contacting with the PD-L1 protein, through tracking of the
labeling. For example, a test compound (labeled) can be evaluated
for its ability to reduce binding of another compound which is
known to bind to a PD-L1 protein (i.e., standard compound).
Accordingly, the ability of a test compound to compete with the
standard compound for binding to the PD-L1 protein directly
correlates to its binding affinity. Conversely, in some other
screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the
labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound,
and the relative binding affinity of the test compound is thus
ascertained.
VI. Kits
[0394] 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.
[0395] 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
[0396] 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:
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-((2-hydroxyeth-
ylamino)methyl)picolinamide)
##STR00029##
[0397] Step 1: 2-chloro-2'-methylbiphenyl-3,3'-diamine
##STR00030##
[0399] (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
(28.2 mg, 0.039 mmol) was added to a mixture of
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127; 90 mg, 0.386 mmol),
3-bromo-2-chloroaniline (Astatech, cat#CL9068; 80 mg, 0.386 mmol),
sodium carbonate (82 mg, 0.772 mmol) in 1,4-dioxane (1072 .mu.l)
and water (214 .mu.l). The mixture was purged with N.sub.2 and
heated at 90.degree. C. for 2 h. The mixture was concentrated and
purified by silica gel column eluting with 0 to 20% EtOAc in DCM.
LC-MS calculated for C.sub.13H.sub.14ClN.sub.2 (M+H)+: m/z=233.1;
found 233.1.
Step 2:
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(dimethoxymethyl)-
picolinamide)
##STR00031##
[0401] Potassium tert-butoxide in THF (851 .mu.l, 0.851 mmol) was
added to a dry THF (773 l) solution of methyl
5-(dimethoxymethyl)picolinate (Combi-Blocks, cat# QY-1318; 163 mg,
0.773 mmol) and 2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diamine
(90. mg, 0.387 mmol) under N.sub.2 at room temperature. After 2 h,
the mixture was quenched with water and extracted with EtOAc. The
organic layers were combined and dried over Na.sub.2SO.sub.4 and
concentrated to afford desired product which was used in next step
without further purification. LC-MS calculated for
C.sub.31H.sub.32ClN.sub.4O.sub.6(M+H)+: m/z=591.2; found 591.1.
Step 3:
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(dimethoxymethyl)-
picolinamide)
##STR00032##
[0403] TFA (0.029 ml, 0.380 mmol) was added to a DCM (0.760 ml)
solution of
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(dimethoxymet-
hyl)picolinamide) (0.225 g, 0.38 mmol) at room temperature. The
mixture was concentrated under reduced pressure after 2 h. The
residue was diluted with DCM and the organic layer was washed with
saturated aqueous NaHCO.sub.3. The organic layers were combined and
dried over Na.sub.2SO.sub.4 and concentrated to afford desired
product which was used in next step without further purification.
LC-MS calculated for C.sub.27H.sub.20ClN.sub.4O.sub.4(M+H)+:
m/z=499.1; found 499.1.
Step 4:
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-((2-hydroxyethyla-
mino)methyl) picolinamide)
##STR00033##
[0405] Sodium triacetoxyborohydride (0.042 g, 0.200 mmol) was added
to a mixture of
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-formylpicolinami-
de) (0.040 g, 0.08 mmol) and ethanolamine (0.019 ml, 0.320 mmol) in
DCM (0.400 ml) at room temperature. After stirring at rt for 2 h,
the mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for
C.sub.31H.sub.34ClN.sub.6O.sub.4(M+H).sup.+: m/z=589.2; found
589.2. .sup.1H NMR (500 MHz, DMSO) .delta. 10.73 (s, 1H), 10.41 (s,
1H), 9.07 (s, 2H), 8.84 (d, J=6.6 Hz, 2H), 8.44 (dd, J=8.2, 1.4 Hz,
1H), 8.31 (d, J=8.2 Hz, 1H), 8.26 (d, J=8.1 Hz, 2H), 8.22 (dd,
J=8.1, 2.0 Hz, 1H), 7.84 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H),
7.37 (t, J=7.8 Hz, 1H), 7.16 (dd, J=7.6, 1.5 Hz, 1H), 7.09 (d,
J=6.8 Hz, 1H), 4.43-4.25 (m, 4H), 3.75-3.61 (m, 4H), 3.12-2.97 (m,
4H), 2.06 (s, 3H).
Example 2:
(2S,2'S)-1,1'-(6,6'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(a-
zanediyl)bis(oxomethylene)bis(pyridine-6,3-diyl))bis(methylene)dipiperidin-
e-2-carboxylic acid
##STR00034##
[0407] A mixture of
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-formylpicolinami-
de) (Example 1, Step 4; 0.040 g, 0.08 mmol) and
(S)-piperidine-2-carboxylic acid (0.041 g, 0.320 mmol) in DCM
(0.400 ml) and Hunig's base (0.1 mL) was heated at 40.degree. C.
overnight. After cooling to room temperature, sodium
triacetoxyborohydride (0.042 g, 0.200 mmol) was added to the
mixture. After 2 h, it was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt, and it was further purified by prep-HPLC (pH=10,
acetonitrile/water+NH.sub.4OH) to give the desired product. LC-MS
calculated for C.sub.39H.sub.42ClN.sub.6O.sub.6(M+H).sup.+:
m/z=725.3; found 725.4.
Example 3:
N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-yl)m-
ethyl)picolinamido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinam-
ide
##STR00035##
[0408] Step 1: 5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinic
acid
##STR00036##
[0410] Sodium hydride (7.82 mg, 0.326 mmol) was added to a THF
(1087 .mu.l) solution of 1-methylimidazolidin-2-one (Astatech,
cat#81682; 43.5 mg, 0.435 mmol) at rt. After 1 h, methyl
5-(bromomethyl)picolinate (Ark Pharm, cat# AK153186; 50 mg, 0.217
mmol) was added in one portion at room temperature. The mixture was
allowed to stir at rt for 1 h and it was concentrated and used in
next step without further purification. LC-MS calculated for
C.sub.11H.sub.14N.sub.3O.sub.3 (M+H).sup.+: m/z=236.1; found:
236.2.
Step 2:
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)-N-(2-methyl-3-(4,4,5,5-
-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide
##STR00037##
[0412] Hunig's base (54.2 .mu.l, 0.311 mmol) was added to a DMF
(414 .mu.l) solution of
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinic acid (48.7 mg,
0.207 mmol) and
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127; 48 mg, 0.207 mmol) and HATU (118 mg,
0.311 mmol). After stirring for 4 h, the mixture was diluted with
MeOH and purified by pH=10 LCMS. LC-MS calculated for
C.sub.24H.sub.32BN.sub.4O.sub.4(M+H).sup.+: m/z=451.2; found:
451.2.
Step 3:
N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide
##STR00038##
[0414] Potassium tert-butoxide (16.95 ml, 16.95 mmol) in THF was
added to a dry THF (33.9 ml) solution of methyl
5-(dimethoxymethyl)picolinate (Combi-Blocks, cat# QY-1318; 3.58 g,
16.95 mmol) and 3-bromo-2-chloroaniline (Astatech, cat#CL9068; 3.5
g, 16.95 mmol) under N.sub.2. After stirring for 2 h, the mixture
was quenched with water and concentrated. The resulting solid was
filtered and rinsed with water to afford titled compound as light
yellow solid. LC-MS calculated for
C.sub.15H.sub.15BrClN.sub.2O.sub.3 (M+H).sup.+: m/z=387.0; found:
387.0.
Step 4: N-(3-bromo-2-chlorophenyl)-5-formylpicolinamide
##STR00039##
[0416] TFA (0.999 ml, 12.97 mmol) was added to a DCM (2.59 ml)
suspension of
N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide (0.5 g,
1.297 mmol). The mixture was allowed to stir at rt for 2 h. The
mixture was concentrated under reduced pressure and diluted with
DCM and washed with saturated NaHCO.sub.3 aq. The organic layer was
dried and concentrated to afford desired product as white solid,
which was used in next step without further purification. LC-MS
calculated for C.sub.13H.sub.9BrClN.sub.2O.sub.2(M+H).sup.+:
m/z=340.9; found: 341.0.
Step 5:
N-(3-bromo-2-chlorophenyl)-5-((2-hydroxyethylamino)methyl)picolina-
mide
##STR00040##
[0418] This compound was prepared using a similar procedure as
describe for example 1, Step 4 with
N-(3-bromo-2-chlorophenyl)-5-formylpicolinamide replacing
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(dimethoxymethyl)picolin-
amide). The reaction mixture was purified by silica gel column
eluting with 0 to 17% MeOH in DCM. LC-MS calculated for
C.sub.15H.sub.16BrClN.sub.3O.sub.2(M+H).sup.+: m/z=384.0; found:
384.0.
Step 6:
N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-yl)meth-
yl)picolinamido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide
##STR00041##
[0420] (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
(1.902 mg, 2.60 .mu.mol) was added to a mixture of
N-(3-bromo-2-chlorophenyl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
(10 mg, 0.026 mmol),
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)-N-(2-methyl-3-(4,4,5,5-tetram-
ethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide (11.71 mg, 0.026
mmol), sodium carbonate (5.51 mg, 0.052 mmol) in 1,4-dioxane (217
.mu.l) and water (43.3 .mu.l). The mixture was purged with N.sub.2
and heated at 90.degree. C. for 2 h. The reaction mixture was
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as its TFA salt. LC-MS calculated for
C.sub.33H.sub.35ClN.sub.7O.sub.4(M+H).sup.+: m/z=628.2; found:
628.2.
Example 4:
(R)--N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-
-yl)methyl)picolinamido)biphenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl-
)picolinamide
##STR00042##
[0421] Step 1:
(R)--N-(3-bromo-2-chlorophenyl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picol-
inamide
##STR00043##
[0423] This compound was prepared using a similar procedure as
described for Example 1, Step 4 with
N-(3-bromo-2-chlorophenyl)-5-formylpicolinamide (Example 3, Step 4)
and (R)-pyrrolidin-3-ol replacing
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(dimethoxymethyl)picolin-
amide) and 2-aminoethanol. The reaction mixture was purified by
silica gel column eluting with 0 to 17% MeOH in DCM. LC-MS
calculated for C.sub.17H.sub.18BrClN.sub.3O.sub.2 (M+H).sup.+:
m/z=410.0; found: 410.0.
Step 2:
(R)--N-(2-chloro-2'-methyl-3'-(5-((3-methyl-2-oxoimidazolidin-1-yl-
)methyl)picolinamido
biphenyl-3-yl-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamide
##STR00044##
[0425] This compound was prepared using a similar procedure as
described for Example 3, Step 6 with
(R)--N-(3-bromo-2-chlorophenyl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picol-
inamide replacing
N-(3-bromo-2-chlorophenyl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide.
The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for
C.sub.35H.sub.37ClN.sub.7O.sub.4(M+H).sup.+: m/z=654.3; found:
654.4.
Example 5:
N-(2-chloro-2'-methyl-3'-(5-((2-oxooxazolidin-3-yl)methyl)picol-
inamido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide
##STR00045##
[0426] Step 1: 5-((2-oxooxazolidin-3-yl)methyl)picolinic acid
##STR00046##
[0428] This compound was prepared using a similar procedure as
described for Example 3, Step 1 with oxazolidin-2-one (Aldrich,
cat#09409) replacing 1-methylimidazolidin-2-one. LC-MS calculated
for C.sub.10H.sub.11N.sub.2O.sub.4 (M+H).sup.+: m/z=223.1; found:
223.2.
Step 2:
N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
-5-((2-oxooxazolidin-3-yl)methyl)picolinamide
##STR00047##
[0430] This compound was prepared using a similar procedure as
described for Example 3, Step 2 with
5-((2-oxooxazolidin-3-yl)methyl)picolinic acid replacing
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinic acid. LC-MS
calculated for C.sub.23H.sub.29BN.sub.3O.sub.5(M+H).sup.+:
m/z=438.2; found: 438.3.
Step 3:
N-(2-chloro-2'-methyl-3'-(5-((2-oxooxazolidin-3-yl)methyl)picolina-
mido)biphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide
##STR00048##
[0432] This compound was prepared using a similar procedure as
described for Example 3, Step 6 with
N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-((2--
oxooxazolidin-3-yl)methyl)picolinamide replacing
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)-N-(2-methyl-3-(4,4,5,5-tetram-
ethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide. The reaction
mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to
give the desired product as its TFA salt. LC-MS calculated for
C.sub.32H.sub.32ClN.sub.6O.sub.5(M+H).sup.+: m/z=615.2; found:
615.2.
Example 6:
(R)--N-(2-chloro-2'-methyl-3'-(5-((2-oxooxazolidin-3-yl)methyl)-
picolinamido)biphenyl-3-yl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picolinami-
de
##STR00049##
[0434] This compound was prepared using a similar procedure as
described for Example 4, Step 6 with
N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-((2--
oxooxazolidin-3-yl)methyl)picolinamide (Example 5, Step 2) and
(R)--N-(3-bromo-2-chlorophenyl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picol-
inamide (Example 4, Step 1) replacing
5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)-N-(2-methyl-3-(4,4,5,5-tetram-
ethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide and
N-(3-bromo-2-chlorophenyl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide.
The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for
C.sub.34H.sub.34ClN.sub.6O.sub.5(M+H).sup.+: m/z=641.2; found:
641.2. .sup.1H NMR (600 MHz, DMSO) .delta. 10.75 (s, 1H), 10.40 (s,
1H), 8.90 (d, J=17.8 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 8.43 (dd,
J=8.2, 1.4 Hz, 1H), 8.38-8.26 (m, 2H), 8.19 (d, J=8.3 Hz, 1H), 8.01
(dd, J=8.0, 2.1 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.54 (t, J=7.9 Hz,
1H), 7.37 (t, J=7.8 Hz, 1H), 7.17 (dd, J=7.6, 1.5 Hz, 1H),
7.10-7.01 (m, 1H), 5.54 (m, 1H), 4.69-4.56 (m, 1H), 4.53 (s, 2H),
4.50-4.43 (m, 1H), 4.36-4.24 (m, 1H), 3.67-3.57 (m, 2H), 3.56-3.44
(m, 2H), 3.41-3.35 (m, 1H), 3.33-3.17 (m, 2H), 2.35-2.25 (m, 1H),
2.06 (s, 3H), 2.02-1.94 (m, 1H), 1.88-1.81 (m, 1H).
Example 7:
(S)-1-((6-(2'-chloro-3'-(5-((2-hydroxyethylamino)methyl)picolin-
amido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-car-
boxylicacid
##STR00050##
[0435] Step 1:
N-(3'-amino-2-chloro-2'-methylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinam-
ide
##STR00051##
[0437] (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
(133 mg, 0.182 mmol) was added to a mixture of
N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide (Example
3, Step 3; 700 mg, 1.815 mmol),
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127; 465 mg, 1.997 mmol), sodium carbonate
(385 mg, 3.63 mmol) in 1,4-dioxane (5042 .mu.l) and water (1008
.mu.l). The mixture was purged with N.sub.2 and heated at
90.degree. C. for 20 h. The mixture was purified by silica gel
column eluting with 0 to 50% EtOAc in Hex. LC-MS calculated for
C.sub.22H.sub.23ClN.sub.3O.sub.3(M+H).sup.+: m/z=412.1; found:
412.2.
Step 2:
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methylbiphenyl-
-3-yl)-5-(hydroxymethyl)picolinamide
##STR00052##
[0439] Hunig's base (172 .mu.l, 0.983 mmol) was added to a DMF
(1311 .mu.l) solution of 5-(hydroxymethyl)picolinic acid (Ark
Pharm, cat#AK127091; 151 mg, 0.983 mmol),
N-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)p-
icolinamide (270 mg, 0.656 mmol) and HATU (274 mg, 0.721 mmol).
After 4 h, the mixture was diluted with water and then extracted
with EtOAc.times.3, the organic layer was dried and concentrated to
afford desired product. It was used in next step w/o further
purification. LC-MS calculated for
C.sub.29H.sub.28ClN.sub.4O.sub.5(M+H).sup.+: m/z=547.2; found:
547.1.
Step 3:
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methylbiphenyl-
-3-yl)-5-formylpicolinamide
##STR00053##
[0441] Dess-Martin periodinane (0.388 g, 0.915 mmol) was added to a
mixture of
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-(hydroxymethyl)picolinamide (0.334 g, 0.61 mmol), sodium
bicarbonate (0.154 g, 1.830 mmol) in DCM (1.220 ml). After 1 h, the
mixture was concentrated and purified by silica gel column eluting
with 0 to 30% EtOAc in DCM. LC-MS calculated for
C.sub.29H.sub.26ClN.sub.4O.sub.5(M+H).sup.+: m/z=545.2; found:
545.1.
Step 4:
(S)-1-((6-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-
biphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic
acid
##STR00054##
[0443] A mixture of
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formylpicolinamide (90 mg, 0.165 mmol) and
(S)-piperidine-2-carboxylic acid (85 mg, 0.661 mmol) in DCM (826
.mu.l) and Hunig's base (115 .mu.l, 0.661 mmol) was allowed to stir
at rt 1 h. Then sodium triacetoxyborohydride (105 mg, 0.495 mmol)
was added to the mixture and allowed to stir at rt overnight. The
mixture was diluted with DCM and saturated NaHCO.sub.3 solution,
and it was extracted with DCM/iPrOH. The combined organic layers
were dried over Na.sub.2SO.sub.4 and concentrated to afford desired
product, which was used in next step without further purification.
LC-MS calculated for C.sub.35H.sub.37ClN.sub.5O.sub.6(M+H).sup.+:
m/z=658.2; found: 658.2.
Step 5:
(S)-1-((6-(2'-chloro-3'-(5-formylpicolinamido)-2-methylbiphenyl-3--
ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
##STR00055##
[0445] This compound was prepared using similar procedure in
Example 1, Step 3 with
(S)-1-((6-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methylbipheny-
l-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
replacing
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(dimethoxymethyl-
)picolinamide). LC-MS calculated for
C.sub.33H.sub.31ClN.sub.5O.sub.5(M+H).sup.+: m/z=612.1; found:
612.2.
Step 6:
(S)-1-((6-(2'-chloro-3'-(5-((2-hydroxyethylamino)methyl)picolinami-
do)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carbox-
ylic acid
##STR00056##
[0447] This compound was prepared using a similar procedure as
described for Example 1, Step 4 with
(S)-1-((6-(2'-chloro-3'-(5-formylpicolinamido)-2-methylbiphenyl-3-ylcarba-
moyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid replacing
N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(dimethoxymethyl)picolin-
amide). The reaction mixture was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for
C.sub.35H.sub.38ClN.sub.6O.sub.5(M+H).sup.+: m/z=657.3; found:
657.2.
Example 8:
(S)-1-((6-(2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methy-
l)picolinamido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)pyrroli-
dine-3-carboxylic acid
##STR00057##
[0448] Step 1:
5-(dimethoxymethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)picolinamide
##STR00058##
[0450] This compound was prepared using a similar procedure in
Example 3, Step 3 with
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127) replacing 3-bromo-2-chloroaniline.
LC-MS calculated for C.sub.22H.sub.30BN.sub.2O.sub.5 (M+H).sup.+:
m/z=413.2; found: 413.2.
Step 2:
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolina-
mido)-2-methylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinamide
##STR00059##
[0452] This compound was prepared using a similar procedure as
described for Example 1, Step 1 with
5-(dimethoxymethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)picolinamide and
(R)--N-(3-bromo-2-chlorophenyl)-5-((3-hydroxypyrrolidin-1-yl)methyl)picol-
inamide (Example 4, Step 1) replacing
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and
3-bromo-2-chloroaniline. LC-MS calculated for
C.sub.33H.sub.35ClN.sub.5O.sub.5 (M+H).sup.+: m/z=616.2; found:
616.3.
Step 3:
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolina-
mido)-2-methylbiphenyl-3-yl)-5-formylpicolinamide
##STR00060##
[0454] This compound was prepared using a similar procedure as
described for Example 1, Step 3 with
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-
-methylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinamide replacing
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(dimethoxymethyl-
)picolinamide). LC-MS calculated for
C.sub.31H.sub.29ClN.sub.5O.sub.4(M+H).sup.+: m/z=570.2; found:
570.1.
Step 4:
(S)-1-((6-(2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)p-
icolinamido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)pyrrolidin-
e-3-carboxylic acid
##STR00061##
[0456] This compound was prepared using a similar procedure as
described for Example 7, Step 4 with (S)-pyrrolidine-3-carboxylic
acid (Combi-Blocks, cat#ST-1381) and
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-
-methylbiphenyl-3-yl)-5-formylpicolinamide replacing
(S)-piperidine-2-carboxylic acid and
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formylpicolinamide. The mixture was purified by prep-HPLC
(pH=2, acetonitrile/water+TFA) to give the desired product as its
TFA salt. LC-MS calculated for C.sub.36H.sub.38ClN.sub.6O.sub.5
(M+H).sup.+: m/z=669.3; found: 669.2.
Example 9:
(R)-1-((6-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)pi-
colinamido)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)piperidine--
4-carboxylic acid
##STR00062##
[0458] This compound was prepared using a similar procedure as
described for Example 7, Step 4 with piperidine-4-carboxylic acid
(Aldrich, cat#I18008) and
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-
-methylbiphenyl-3-yl)-5-formylpicolinamide replacing
(S)-piperidine-2-carboxylic acid and
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formylpicolinamide. The mixture was purified by prep-HPLC
(pH=10, acetonitrile/water+NH.sub.4OH) to give the desired product.
LC-MS calculated for C.sub.37H.sub.40ClN.sub.6O.sub.5(M+H).sup.+:
m/z=683.3; found: 683.2.
Example 10:
(R)-1-((6-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido-
)-2-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)azetidine-3-carboxyli-
c acid
##STR00063##
[0460] This compound was prepared using a similar procedure as
described for Example 7, Step 4 with azetidine-3-carboxylic acid
(Aldrich, cat#391131) and
(R)--N-(2'-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-
-methylbiphenyl-3-yl)-5-formylpicolinamide replacing
(S)-piperidine-2-carboxylic acid and
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formylpicolinamide. The 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.36ClN.sub.6O.sub.5(M+H).sup.+:
m/z=655.2; found: 655.2.
Example 11:
(S)-1-((6-((2-chloro-2'-fluoro-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)pipe-
ridine-2-carboxylic acid
##STR00064##
[0461] Step 1:
N-(3'-amino-2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)p-
icolinamide
##STR00065##
[0463] A mixture of (3-amino-2-fluorophenyl)boronic acid (Astatech,
cat#90470; 177 mg, 1.141 mmol),
N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide (Example
3, Step 3; 220.0 mg, 0.570 mmol), sodium carbonate (0.137 mL, 1.426
mmol) in dioxane (10 mL) and water (1 mL) was degassed with
nitrogen, then stirred and heated at 95.degree. C. for overnight.
After the reaction mixture was cooled to r.t., it was filtered and
the filtrate was concentrated. The residue was purified by flash
chromatograph on a silica gel column eluting with 25% AcOEt in
Hexanes to afford the desired compound. LC-MS calculated for
C.sub.21H.sub.20ClFN.sub.3O.sub.3(M+H).sup.+: m/z=416.1; found:
416.1.
Step 2: tert-butyl
2-((2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-fluoro-[1,1'-bipheny-
l]-3-yl)carbamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00066##
[0465] This compound was prepared using similar procedure in
Example 3, Step 3 with
N-(3'-amino-2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-5-(dimethoxymethyl)p-
icolinamide and 5-(tert-butyl) 2-ethyl
6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (Ark
Pharm, cat#Ak-27573) replacing methyl 5-(dimethoxymethyl)picolinate
and 3-bromo-2-chloroaniline. It was purified by flash chromatograph
on a silica gel column using 25% AcOEt in Hexanes as eluent to
afford the desired compound. LC-MS calculated for
C.sub.33H.sub.34ClFN.sub.5O.sub.6S (M+H).sup.+: m/z=682.2; found:
682.2.
Step 3: tert-butyl
2-((2'-chloro-2-fluoro-3'-(5-formylpicolinamido)-[1,1'-biphenyl]-3-yl)car-
bamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00067##
[0467] To the solution of tert-butyl
2-((2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-fluoro-[1,1'-bipheny-
l]-3-yl)carbamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5
(4H)-carboxylate (85 mg, 0.125 mmol) in dioxane (2 ml) was added 1N
HCl in water (1.246 ml, 1.246 mmol) at r.t., the mixture was
stirred at r.t. overnight. The suspension was diluted with
NaHCO.sub.3 solution and extracted with DCM.times.3. The combined
organic layers were dried over MgSO.sub.4, and concentrated to
afford the desired compound and used in next step without further
purification. LC-MS calculated for
C.sub.31H.sub.27ClFN.sub.5NaO.sub.5S (M+Na).sup.+: m/z=658.1;
found: 658.1.
Step 4:
(S)-1-((6-((2-chloro-2'-fluoro-3'-(4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)meth-
yl)piperidine-2-carboxylic acid
##STR00068##
[0469] To a solution of tert-butyl
2-((2'-chloro-2-fluoro-3'-(5-formylpicolinamido)-[1,1'-biphenyl]-3-yl)car-
bamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (82
mg, 0.129 mmol) in DCM (4 ml) was added (S)-piperidine-2-carboxylic
acid (83 mg, 0.645 mmol) and DIEA (0.180 ml, 1.031 mmol), the
mixture was allowed to stir at r.t. 60 min. Then sodium
triacetoxyborohydride (82 mg, 0.387 mmol) was added and allowed to
stir at r.t. overnight. 0.5 mL TFA was added to the reaction
mixture, then continued to stir for 1 hour. The reaction mixture
was concentrated and it was diluted with MeOH, and purified by
prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired
product as its TFA salt. LC-MS calculated for
C.sub.32H.sub.31ClFN.sub.6O.sub.4S (M+H).sup.+: m/z=649.2; found:
649.1.
Example 12:
(S)-1-((6-((2'-chloro-2-methyl-3'-(5-(pyrrolidin-1-ylmethyl)picolinamido)-
-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2--
carboxylic acid
##STR00069##
[0470] Step 1:
5-bromo-N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'--
biphenyl]-3-yl)-4-methylpicolinamide
##STR00070##
[0472] This compound was prepared using similar procedure in
Example 3, Step 3 with
N-(3'-amino-2-chloro-2'-methylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinam-
ide (Example 7, Step 1) and methyl 5-bromo-4-methylpicolinate (Ark
Pharm, cat#AK-36736) replacing methyl 5-(dimethoxymethyl)picolinate
and 3-bromo-2-chloroaniline. LC-MS calculated for
C.sub.29H.sub.27BrClN.sub.4O.sub.4(M+H).sup.+: m/z=609.1; found:
609.1.
Step 2:
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-b-
iphenyl]-3-yl)-5-formyl-4-methylpicolinamide
##STR00071##
[0474] To the THF (20 ml) solution of
5-bromo-N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'--
biphenyl]-3-yl)-4-methylpicolinamide (410 mg, 0.672 mmol) was added
3.0 M methyl magnesium chloride in THF (0.784 ml, 2.353 mmol) at
-78.degree. C., the mixture was stirred 20 min, then 2.5 M
n-butyllithium in hexane (0.672 ml, 1.681 mmol) was added. The
reaction mixture was stirred at -78.degree. C. for another 30 min,
followed by addition of morpholine-4-carbaldehyde (0.343 ml, 3.43
mmol). The reaction mixture was continued to stir at -78.degree. C.
for 20 min, and it was allowed to warm up to r.t. and stir for 3
hours. Water was added to quench the reaction. The mixture was
extracted with AcOEt, and the organic layer was washed with
NaHCO.sub.3 aqueous solution, brine, dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatograph eluting with 25% AcOEt in Hexanes to afford the
desired compound. LC-MS calculated for
C.sub.30H.sub.28ClN.sub.4O.sub.5(M+H).sup.+: m/z=559.2; found:
559.2.
Step 3:
(S)-1-((6-((2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methy-
l-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-
-carboxylic acid
##STR00072##
[0476] To a solution of
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formyl-4-methylpicolinamide (95 mg, 0.170 mmol) in DCM (5
ml) was added (S)-piperidine-2-carboxylic acid (114 mg, 0.884 mmol)
and DIEA (0.237 ml, 1.360 mmol), the mixture and stir at r.t. for
60 min, followed by addition of sodium triacetoxyborohydride (108
mg, 0.510 mmol). Then the reaction mixture was stirred at r.t.
overnight. The mixture was diluted with NaHCO.sub.3 solution and
extracted with DCM/IPA. The organic layers were combined and dried
over MgSO.sub.4, and concentrated to afford the desired compound
and used in next step without further purification. LC-MS
calculated for C.sub.36H.sub.39ClN.sub.5O.sub.6(M+H).sup.+:
m/z=672.3; found: 672.2.
Step 4:
(S)-1-((6-((2'-chloro-3'-(5-formylpicolinamido)-2-methyl-[1,1'-bip-
henyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carboxylic
acid
##STR00073##
[0478] This compound was prepared using similar procedure in
Example 1, Step 3 with
(S)-1-((6-((2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-
-biphenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carbox-
ylic acid replacing
N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(dimethoxymethyl-
)picolinamide). LC-MS calculated for
C.sub.34H.sub.33ClN.sub.5O.sub.5(M+H).sup.+: m/z=626.2; found:
626.2.
Step 6:
(S)-1-((6-((2'-chloro-2-methyl-3'-(5-(pyrrolidin-1-ylmethyl)picoli-
namido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperi-
dine-2-carboxylic acid
##STR00074##
[0480] To a solution of
(S)-1-((6-((2'-chloro-3'-(5-formylpicolinamido)-2-methyl-[1,1'-biphenyl]--
3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carboxylic
acid (30 mg, 0.048 mmol) in DCM (2 ml) was added pyrrolidine (6.82
mg, 0.096 mmol), the mixture was allowed to stir at r.t. for 60
min, then sodium triacetoxyborohydride (30.5 mg, 0.144 mmol) was
added and it was allowed to stir at r.t. overnight. The reaction
mixture was concentrated, the residue was diluted with MeOH, and
purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the
desired product as its TFA salt. LC-MS calculated for
C.sub.38H.sub.42ClN.sub.6O.sub.4(M+H).sup.+: m/z=681.3; found:
681.2.
Example 13:
(S)-1-((6-((2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-biphenyl]-
-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carboxylic
acid
##STR00075##
[0481] Step 1: methyl
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
##STR00076##
[0483] To the solution of
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(Combi-Blocks, cat#PN-9127, 1.0 g, 4.29 mmol) in DCM (10 ml) was
added methyl carbonochloridate (0.365 ml, 4.72 mmol) and DIEA
(1.124 ml, 6.43 mmol) at 0.degree. C., the mixture was stirred at
0.degree. C. for 3 hours. The reaction mixture was diluted with DCM
and washed with 1N HCl aqueous solution, NaHCO.sub.3 aqueous
solution, brine, and the organic layer was dried over MgSO.sub.4.
It was concentrated to afford the desired compound and used in next
step without further purification. LC-MS calculated for
C.sub.15H.sub.23BNO.sub.4 (M+H).sup.+: m/z=292.2; found: 292.1.
Step 2: methyl
(3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamate
##STR00077##
[0485] This compound was prepared using similar procedure in
Example 1, Step 1 with methyl
(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
replacing
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline- .
LC-MS calculated for C.sub.15H.sub.16ClN.sub.2O.sub.2(M+H).sup.+:
m/z=291.0; found: 291.1.
Step 3: methyl
(3'-(5-bromo-4-methylpicolinamido)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-y-
l)carbamate
##STR00078##
[0487] This compound was prepared using similar procedure in
Example 3, Step 3 with methyl
(3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamate and
methyl 5-bromo-4-methylpicolinate replacing methyl
5-(dimethoxymethyl)picolinate and 3-bromo-2-chloroaniline. LC-MS
calculated for C.sub.22H.sub.20BrClN.sub.3O.sub.3(M+H).sup.+:
m/z=488.0; found: 488.1.
Step 4:
N-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-bromo-4-met-
hylpicolinamide
##STR00079##
[0489] Iodotrimethylsilane (1.619 mL, 11.38 mmol) was added to a
solution of methyl
(3'-(5-bromo-4-methylpicolinamido)-2'-chloro-2-methyl-[1,1'-bip-
henyl]-3-yl)carbamate (1.39 g, 2.84 mmol) in acetonitrile (30.0 mL)
and the reaction mixture was allowed to stir at r.t. overnight. The
reaction mixture was concentrated and the resulting mixture was
dissolved in DCM, washed with NaHCO.sub.3 aqueous solution, brine,
and the organic layer was dried over MgSO.sub.4, filtered and
concentrated. The residue was washed with 50% Hexanes in Et.sub.2O,
then filtered to afford desired compound as solid. LC-MS calculated
for C.sub.20H.sub.18BrClN.sub.3O (M+H).sup.+: m/z=430.0; found:
430.1.
Step 5:
5-bromo-N-(2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-bip-
henyl]-3-yl)-4-methylpicolinamide
##STR00080##
[0491] This compound was prepared using similar procedure in
Example 3, Step 3 with
N-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-bromo-4-methylpico-
linamide and methyl 4-methoxypicolinate replacing methyl
5-(dimethoxymethyl)picolinate and 3-bromo-2-chloroaniline. LC-MS
calculated for C.sub.27H.sub.23BrClN.sub.4O.sub.3(M+H).sup.+:
m/z=565.1; found: 565.2.
Step 6:
N-(2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-biphenyl]-3-
-yl)-5-formyl-4-methylpicolinamide
##STR00081##
[0493] To a THF (4 ml) solution of
5-bromo-N-(2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-biphenyl]--
3-yl)-4-methylpicolinamide (47 mg, 0.083 mmol) was added 3.0 M
methyl magnesium chloride in THF (0.097 ml, 0.291 mmol) at
-78.degree. C., the mixture was stirred 20 min, then 2.5 M
n-butyllithium in hexane (0.083 ml, 0.208 mmol) was added to the
reaction. After 30 min at -78.degree. C., morpholine-4-carbaldehyde
(0.083 ml, 0.831 mmol) was added to the mixture. The reaction
mixture was stirred at -78.degree. C. for 20 min, then allowed to
warm up to r.t. and stirred at r.t. for 3 hours, followed by
addition of water to quench the reaction. Then the reaction mixture
was extracted with AcOEt.times.3, and the combined organic layers
was washed with NaHCO.sub.3 aqueous solution, brine, and dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
flash chromatograph on a silica gel column eluting with 25% AcOEt
in Hexanes to afford the desired compound. LC-MS calculated for
C.sub.28H.sub.24ClN.sub.4O.sub.4(M+H).sup.+: m/z=515.1; found:
515.2.
Step 7:
(S)-1-((6-((2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-bi-
phenyl]-3-yl)carbamoyl)-4-methylpyridin-3-yl)methyl)piperidine-2-carboxyli-
c acid
##STR00082##
[0495] This compound was prepared using similar procedure in
Example 12, Step 3 with
N-(2-chloro-3'-(4-methoxypicolinamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-5--
formyl-4-methylpicolinamide replacing
N-(2'-chloro-3'-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1'-biphenyl-
]-3-yl)-5-formylpicolinamide. It was purified by prep-HPLC (pH=2,
acetonitrile/water+TFA) to give the desired product as its TFA
salt. LC-MS calculated for
C.sub.34H.sub.35ClN.sub.5O.sub.5(M+H).sup.+: m/z=628.2; found:
628.1.
Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)
Binding Assay
[0496] 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 .about.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.
[0497] 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; ++++=IC.sub.50>1000 nM
Data obtained for the Example compounds using the PD-1/PD-L1
homogenous time-resolved fluorescence (HTRF) binding assay
described in Example A is provided in Table 1.
TABLE-US-00001 TABLE 1 PD-1/PD-L1 HTRF Example IC.sub.50 (nM) 1 + 2
+ 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 +
[0498] 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.
* * * * *