US2018057486A1PendingUtilityA1
Heterocyclic compounds as immunomodulators
Est. expiryAug 29, 2036(~10.1 yrs left)· nominal 20-yr term from priority
C07D 417/14C07D 231/14C07D 277/56C07D 401/06C07D 403/06C07D 405/12C07D 263/34C07D 403/12C07D 233/90C07D 417/06
60
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is N or CR 1 ;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is O, S, N, NR 4 or CR 4 ;
X 5 is O, S, N, NR 5 or CR 5 ;
Cy is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents;
R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OR 10 , C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NHR 10 , —NR 10 R 10 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C(═NR 10 )R 10 , C(═NR 10 )NR 10 R 10 , NR 10 C(═NR 10 )NR 10 R 10 , NR 10 S(O)R 10 , NR 10 S(O) 2 R 10 , NR 10 S(O) 2 NR 10 R 10 , S(O)R 10 , S(O)NR 10 R 10 , S(O) 2 R 10 , —P(O)R 10 R 10 , —P(O)(OR 10 )(OR 10 ), —B(OH) 2 , —B(OR 10 ) 2 and S(O) 2 NR 10 R 10 , wherein each R 10 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 and R 10 are each optionally substituted with 1 or 2 independently selected R d substituents;
R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR a )R a , C(═NR a )NR a R a , NR a C(═NR a )NR a R a , NR a C(═NOH)NR a R a , NR a C(═NCN)NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , —P(O)R a R a , —P(O)(OR a )(OR a ), —B(OH) 2 , —B(OR a ) 2 , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 4 , R 5 and R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents;
or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from B, P, N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 11 , —NR 11 R 11 , NHOR 11 , C(O)R 1 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C(═NR 11 )R 11 , C(═NR 11 )NR 11 R 11 , NR 11 C(═NR 11 )NR 11 R 11 , NR 11 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , —P(O)R 11 R 11 , —P(O)(OR 11 )(OR 11 ), —B(OH) 2 , —B(OR 11 ) 2 , or S(O) 2 NR 11 R 11 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 7 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 8 is halo, ethyl, propyl, isopropyl, butyl, 2-butyl, 2-methylpropyl, C 5-6 alkyl, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, C 7 -10 aryl, cyclopropyl substituted with 1-3 independently selected R b substituents, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 9 , —NR 9 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C(═NR 11 )R 11 , C(═NR 11 )NR 11 R 11 , NR 11 C(═NR 11 )NR 11 R 11 , NR 11 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , —P(O)R 11 R 11 , —P(O)(OR 11 )(OR 11 ), —B(OH) 2 , —B(OR 11 ) 2 , or S(O) 2 NR 11 R 11 , wherein the butyl, 2-butyl, 2-methylpropyl, C 5-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 7-10 aryl, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 9 is methyl, ethyl, propyl, isopropyl, C 5-6 alkyl, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- or (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 5-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 9 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 11 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R a are each optionally substituted with 1, 2 or 3 independently selected R d substituents;
each R b substituent is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c , —P(O)R c R c , —P(O)(OR c )(OR c ), —B(OH) 2 , —B(OR c ) 2 and S(O) 2 NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each further optionally substituted with 1-3 independently selected R d substituents;
each R b1 is independently selected from Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c , —P(O)R c R c , —P(O)(OR c )(OR c ), —B(OH) 2 , —B(OR c ) 2 and S(O) 2 NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b1 are each further optionally substituted with 1-3 independently selected R d substituents.
each R b2 is independently selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c , —P(O)R c R c , —P(O)(OR c )(OR c ), —B(OH) 2 , —B(OR c ) 2 and S(O) 2 NR c R c ; wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b2 are each further optionally substituted with 1-3 independently selected R d substituents.
each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R c are each optionally substituted with 1, 2 or 3 R f substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , NR g C(O)OR g , C(═NR g )NR g R g , NR g C(═NR g )NR g R g , NR g C(═NOH)NR g R g , NR g C(═NCN)NR g R g , S(O)R g , S(O)NR g R g , S(O) 2 R g , NR g S(O) 2 R g , NR g S(O) 2 NR g R g , —P(O)R g R g , —P(O)(OR g )(OR g ), —B(OH) 2 , —B(OR g ) 2 and S(O) 2 NR g R g ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f are each optionally substituted with 1, 2 or 3 R n substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR o , OR o , SR o , C(O)R o , C(O)NR o R o , C(O)OR o , OC(O)R o , OC(O)NR o R o , NHR o , NR o R o , NR o C(O)R o , NR o C(O)NR o R o , NR o C(O)OR o , C(═NR o )NR o R o , NR o C(═NR o )NR o R o , S(O)R o , S(O)NR o R o , S(O) 2 R o , NR o S(O) 2 R o , NR o S(O) 2 NR o R o , —P(O)R o R o , —P(O)(OR o )(OR o ), —B(OH) 2 , —B(OR o ) 2 and S(O) 2 NR o R o , wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R n is optionally substituted with 1, 2 or 3 R q substituents;
each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , C(═NR e )NR e R e , NR e C(═NR e )NR e R e , NR e C(═NOH)NR e R e , NR e C(═NCN)NR e R e , S(O)R e , S(O)NR e R e , S(O) 2 R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , —P(O)R e R e , —P(O)(OR e )(OR e ), —B(OH) 2 , —B(OR e ) 2 and S(O) 2 NR e R e , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1-3 independently selected R f substituents;
each R e is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e are each optionally substituted with 1, 2 or 3 independently selected R f substituents;
each R g is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g are each optionally substituted with 1-3 R p substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-(5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r , OR r , SR r , C(O)R r , C(O)NR r R r , C(O)OR r , OC(O)R r , OC(O)NR r R r , NHR r , NR r R r , NR r C(O)R r , NR r C(O)NR r R r , NR r C(O)OR r , C(═NR r )NR r R r , NR r C(═NR r )NR r R r , NR r C(═NOH)NR r R r , NR r C(═NCN)NR r R r , S(O)R r , S(O)NR r R r , S(O) 2 R r , NR r S(O) 2 R r , NR r S(O) 2 NR r R r , —P(O)R r R r , —P(O)(OR r )(OR r ), —B(OH) 2 , —B(OR r ) 2 and S(O) 2 NR r R r , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p is optionally substituted with 1, 2 or 3 R q substituents;
or any two R a substituents together with the nitrogen, phosphorus or boron 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 h substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, C 6-10 aryl-C 1-4 alkyl-, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i , SR i , NHOR i , C(O)R i , C(O)NR i R i , C(O)OR i , OC(O)R i , OC(O)NR i R i , NHR i , NR i R i , NR i C(O)R i , NR i C(O)NR i R i , NR i C(O)OR i , C(═NR i )NR i R i , NR i C(═NR i )NR i R i , NR i C(═NOH)NR i R i , NR i C(═NCN)NR i R i , S(O)R i , S(O)NR i R i , S(O) 2 R i , NR i S(O) 2 R i , NR i S(O) 2 NR i R i , —P(O)R i R i , —P(O)(OR)(OR), —B(OH) 2 , —B(OR i ) 2 and S(O) 2 NR i R i , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl- of R h are each optionally substituted by 1, 2, or 3 R j substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NHOR k , OR k , SR k , C(O)R k , C(O)NR k R k , C(O)OR k , OC(O)R k , OC(O)NR k R k , NHR k , NR k R k , NR k C(O)R k , NR k C(O)NR k R k , NR k C(O)OR k , C(═NR k )NR k R k , NR k C(═NR k )NR k R k , S(O)R k , S(O)NR k R k , S(O) 2 R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , —P(O)R k R k , —P(O)(OR k )(OR k ), —B(OH) 2 , —B(OR k ) 2 and S(O) 2 NR k R k , wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 2-4 alkenyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j are each optionally substituted with 1, 2 or 3 independently selected R q substituents;
or two R 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 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 c substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R e substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R g substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R i substituents together with the nitrogen, phosphorus or boron 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 h substituents, or 1, 2, or 3 independently selected R q substituents;
or any two R k substituents together with the nitrogen, phosphorus or boron 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 h substituents, or 1, 2, or 3 independently selected R q substituents;
or any two R o substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R r substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R 10 substituents together with the nitrogen, phosphorus or boron 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 h substituents;
or any two R 11 substituents together with the nitrogen, phosphorus or boron 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 h substituents;
each R i , R k , R o or R r is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R i , R k , R o or R r are each optionally substituted with 1, 2 or 3 R q substituents;
each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 12 and NR 12 R 12 , wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R 12 is independently C 1-6 alkyl; and
is a single bond or a double bond to maintain ring A being aromatic.
2 . The compound of claim 1 , having Formula (I):
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is N or CR 1 ;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is O, S, N, NR 4 or CR 4 ;
X 5 is O, S, N, NR 5 or CR 5 ;
Cy is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents;
R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OR 10 , C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NHR 10 , —NR 10 R 10 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C(═NR 10 )R 10 , C(═NR 10 )NR 10 R 10 , NR 10 C(═NR 10 )NR 10 R 10 , NR 10 S(O)R 10 , NR 10 S(O) 2 R 10 , NR 10 S(O) 2 NR 10 R 10 , S(O)R 10 , S(O)NR 10 R 10 , S(O) 2 R 10 , and S(O) 2 NR 10 R 10 , wherein each R 10 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3 -10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 and R 10 are each optionally substituted with 1 or 2 independently selected R d substituents;
R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR a )R a , C(═NR a )NR a R a , NR a C(═NR a )NR a R a , NR a C(═NOH)NR a R a , NR a C(═NCN)NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 4 , R 5 and R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents;
or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 11 , —NR 11 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C(═NR 11 )R 11 , C(═NR 11 )NR 11 R 11 , NR 11 C(═NR 11 )NR 11 R 11 , NR 11 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , or S(O) 2 NR 11 R 11 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3 -10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 7 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 8 is halo, ethyl, propyl, isopropyl, butyl, 2-butyl, 2-methylpropyl, C 5-6 alkyl, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, C 7-10 aryl, cyclopropyl substituted with 1-3 independently selected R b substituents, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 9 , —NR 9 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C(═NR 11 )R 11 , C(═NR 11 )NR 11 R 11 , NR 11 C(═NR 11 )NR 11 R 11 , NR 11 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , or S(O) 2 NR 11 R 11 , wherein the butyl, 2-butyl, 2-methylpropyl, C 5-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 7-10 aryl, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
R 9 is methyl, ethyl, propyl, isopropyl, C 5-6 alkyl, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- or (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 5-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 9 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 11 are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R a are each optionally substituted with 1, 2 or 3 independently selected R d substituents;
each R b substituent is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c and S(O) 2 NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each further optionally substituted with 1-3 independently selected R d substituents;
each R b1 is independently selected from Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c and S(O) 2 NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b1 are each further optionally substituted with 1-3 independently selected R d substituents.
each R b2 is independently selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c and S(O) 2 NR c R c ; wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b2 are each further optionally substituted with 1-3 independently selected R d substituents.
each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R c are each optionally substituted with 1, 2 or 3 R f substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , NR g C(O)OR g , C(═NR g )NR g R g , NR g C(═NR g )NR g R g , NR g C(═NOH)NR g R g , NR g C(═NCN)NR g R g , S(O)R g , S(O)NR g R g , S(O) 2 R g , NR g S(O) 2 R g , NR g S(O) 2 NR g R g , and S(O) 2 NR g R g ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f are each optionally substituted with 1, 2 or 3 R n substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR o , OR o , SR o , C(O)R o , C(O)NR o R o , C(O)OR o , OC(O)R o , OC(O)NR o R o , NHR o , NR o R o , NR o C(O)R o , NR o C(O)NR o R o , NR o C(O)OR o , C(═NR o )NR o R o , NR o C(═NR o )NR o R o , S(O)R o , S(O)NR o R o , S(O) 2 R o , NR o S(O) 2 R o , NR o S(O) 2 NR o R o , and S(O) 2 NR o R o , wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R n is optionally substituted with 1, 2 or 3 R q substituents;
each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , C(═NR e )NR e R e , NR e C(═NR e )NR e R e , NR e C(═NOH)NR e R e , NR e C(═NCN)NR e R e , S(O)R e , S(O)NR e R e , S(O) 2 R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , and S(O) 2 NR e R e , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1-3 independently selected R f substituents;
each R e is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e are each optionally substituted with 1, 2 or 3 independently selected R f substituents;
each R g is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g are each optionally substituted with 1-3 R p substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r , OR r , SR r , C(O)R r , C(O)NR r R r , C(O)OR r , OC(O)R r , OC(O)NR r R r , NHR r , NR r R r , NR r C(O)R r , NR r C(O)NR r R r , NR r C(O)OR r , C(═NR r )NR r R r , NR r C(═NR r )NR r R r , NR r C(═NOH)NR r R r , NR r C(═NCN)NR r R r , S(O)R r , S(O)NR r R r , S(O) 2 R r , NR r S(O) 2 R r , NR r S(O) 2 NR r R r and S(O) 2 NR r R r , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p is optionally substituted with 1, 2 or 3 R q substituents;
or any two R 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 h substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, C 6-10 aryl-C 1-4 alkyl-, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i , SR i , NHOR i , C(O)R i , C(O)NR i R i , C(O)OR i , OC(O)R i , OC(O)NR i R i , NHR i , NR i R i , NR i C(O)R i , NR i C(O)NR i R i , NR i C(O)OR i , C(═NR i )NR i R i , NR i C(═NR i )NR i R i , NR i C(═NOH)NR i R i , NR i C(═NCN)NR i R i , S(O)R i , S(O)NR i R i , S(O) 2 R i , NR i S(O) 2 R i , NR i S(O) 2 NR i R i , and S(O) 2 NR i R i , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3 -10 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl- of R h are each optionally substituted by 1, 2, or 3 R j substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NHOR k , OR k , SR k , C(O)R k , C(O)NR k R k , C(O)OR k , OC(O)R k , OC(O)NR k R k , NHR k , NR k R k , NR k C(O)R k , NR k C(O)NR k R k , NR k C(O)OR k , C(═NR k )NR k R k , NR k C(═NR k )NR k R k , S(O)R k , S(O)NR k R k , S(O) 2 R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , and S(O) 2 NR k R k , wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 2-4 alkenyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j are each optionally substituted with 1, 2 or 3 independently selected R q substituents;
or two R 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 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 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 h substituents;
or any two R 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 h substituents;
or any two R 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 h substituents;
or any two R 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 h substituents;
or any two R 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 h substituents;
or any two R 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 h substituents;
or any two R 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 h substituents;
each R i , R k , R o or R r is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R i , R k , R o or R r are each optionally substituted with 1, 2 or 3 R q substituents;
each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 12 and NR 12 R 12 , wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R 12 is independently C 1-6 alkyl; and
is a single bond or a double bond to maintain ring A being aromatic.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
any two R 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 q substituents; or any two R 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 q .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 8 is halo, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, C 7-10 aryl, cyclopropyl substituted with 1-3 independently selected R b substituents, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 9 , —NR 9 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C(═NR 11 )R 11 , C(═NR 11 )NR 11 R 11 , NR 11 C(═NR 11 )NR 11 R 11 , NR 11 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , or S(O) 2 NR 11 R 11 , wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 7 -10 aryl, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; and R 9 is C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- or (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 9 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R b1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c and S(O) 2 NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b1 are each further optionally substituted with 1-3 independently selected R d substituents.
5 . The compound of claim 1 , having Formula (II):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein (i) X 1 is N, X 2 is CR 2 and X 3 is CR 3 ; (ii) X 1 is CR 1 , X 2 is N and X 3 is CR 3 ; (iii) X 1 is CR 1 , X 2 is CR 2 and X 3 is N; (iv) X 1 is N, X 2 is CR 2 and X 3 is N; (v) X 1 is N, X 2 is N and X 3 is CR 3 ; or (vi) X 1 is CR 1 , X 2 is N and X 3 is N.
7 . The compound of claim 1 , having Formula (III):
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
L is a bond, —C(O)NR 13 —, —NR 13 C(O)—, O, —(CR 14 R 15 ) q —, —(CR 14 R 15 ) q —O—, —O(CR 14 R 15 ) q —, —NR 13 —, —(CR 14 R 15 ) q —NR 13 —, —NR 13 —(CR 14 R 15 ) q —, —CH═CH—, —C≡C—, —SO 2 NR 13 —, —NR 13 SO 2 —, —NR 13 SO 2 NR 13 —, —NR 13 C(O)O—, —OC(O)NR 13 or —NR 13 C(O)NR 13 —;
each R 13 is independently H, C 1-6 haloalkyl or C 1-6 alkyl optionally substituted with a substituent selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl and —N(C 1-4 alkyl) 2 ;
R 14 and R 15 are each independently selected from H, halo, CN, OH, —COOH, C 1-4 alkyl, C 1-4 alkoxy, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R 14 or R 15 are each optionally substituted with 1, 2, or 3 independently selected R q substituents;
or R 14 and R 15 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 independently selected R q substituents;
ring B is C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 independently selected R d substituents; and
the subscript n is an integer of 1, 2, 3 or 4.
8 . The compound of claim 1 , having Formula (IIIa):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
9 . The compound of claim 1 , having Formula (IIIa-1):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
10 . The compound of claim 1 , having Formula (IIIa-2):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
11 . The compound of claim 7 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R d is C 1-6 alkyl, phenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, OR e , C(O)R e , halo or CN, wherein the C 1-6 alkyl, phenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1, 2 or 3 independently selected R f substituents.
12 . The compound of claim 7 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R d is (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl, (2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl, 2-(3-carboxyazetidin-1-yl)ethanoyl, (R)-2-(3-carboxyazetidin-1-yl)ethanoyl, (S)-2-(3-carboxyazetidin-1-yl)ethanoyl, 2-(2-carboxypiperidin-1-yl)ethanoyl, (R)-2-(2-carboxypiperidin-1-yl)ethanoyl, (S)-2-(2-carboxypiperidin-1-yl)ethanoyl, 2-(3-carboxypyrrolidin-1-yl)ethanoyl, (S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (5-cyanopyridin-3-yl)methoxy, (2-hydroxyethylamino)methyl, 2-carboxy-1-piperidinylmethyl, (S)-2-carboxy-1-piperidinylmethyl, (R)-2-carboxy-1-piperidinylmethyl, halo or CN.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the moiety
is selected from:
14 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein (i) X 4 is S and X 5 is CR 5 ; (ii) X 4 is O and X 5 is CR 5 ; (iii) X 4 is NR 4 and X 5 is CR 5 ; or (iv) X 4 is CR 4 and X 5 is NR 5 .
15 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3,6-dihydro-2H-pyran-4-yl, cyclohexyl, cyclohexenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzodioxin-5-yl, 2-methylindazol-6-yl or 1-methylindazol-4-yl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl optionally substituted with 1 to 5 independently selected R 6 substituents.
18 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 2-fluorophenyl, 2-fluoro-3-methoxyphenyl, or 1-methyl-1H-indazol-4-yl.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C(═NR 10 )R 10 , C(═NR 10 )NR 10 R 10 , NR 10 C(═NR 10 )NR 10 R 10 , NR 10 S(O)R 10 , NR 10 S(O) 2 R 10 , NR 10 S(O) 2 NR 10 R 10 , S(O)R 10 , S(O)NR 10 R 10 , S(O) 2 R 10 , and S(O) 2 NR 10 R 10 wherein each R 10 is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 and R 10 are each optionally substituted with 1 or 2 groups-independently selected from halo, OH, CN and C 1-4 alkoxy.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 4 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 1-6 halo alkoxy.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 5 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 1-6 halo alkoxy.
22 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 6 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a , C(O)NR a R a , or NR a C(O)R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents.
23 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 6 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, or OR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents.
24 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are each optionally substituted with 1, 2 or 3 independently selected R q substituents.
25 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 is C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents or (4-10 membered heterocycloalkyl)-C 1-4 alkyl- optionally substituted with 1, 2 or 3 independently selected R b substituents.
26 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 is C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents.
27 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 is —CH 2 NHR c or —CH 2 NR c R c .
28 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 is (2-hydroxyethylamino)methyl, 2-carboxy-1-piperidinylmethyl, (S)-2-carboxy-1-piperidinylmethyl, (R)-2-carboxy-1-piperidinylmethyl, or 3-hydroxypyrrolidin-1-ylmethyl.
29 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 is (2-hydroxyethylamino)methyl, 2-carboxy-1-piperidinylmethyl, (S)-2-carboxy-1-piperidinylmethyl, or (R)-2-carboxy-1-piperidinylmethyl.
30 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is O, S, N NR 4 or CR 4 ; X 5 is O, S, N, NR 5 or CR 5 ; Cy is phenyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused 5-, 6- or 7-membered heterocycloalkyl ring, or a fused 5- or 6-membered heteroaryl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, COOH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyclopropyl, cyclopropylmethyl, phenyl, phenyl-C 1-4 alkyl-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C 1-4 alkyl-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C 1 -4 alkyl-, NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(O)R 10 , —O(CO)R 10 , —C(O)OR 10 , —O(CO)NHR 10 , —NHC(O)OR 10 , —NHC(O)NHR 10 , —C(O)NHR 10 , —NHC(O)R 1′ , —SO 2 R 10 , —NHSO 2 R 10 and —SO 2 NHR 10 , wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, cyclopropyl, cyclopropylmethyl, phenyl, phenyl-C 1-4 alkyl-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C 1-4 alkyl-, 4-6 membered heterocycloalkyl and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 or R 3 are each optionally substituted with halo, OH, CN or C 1-4 alkoxy; R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- or (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, COOH, NO 2 , OR a , C(O)OR a , NH 2 , —NHR a , —N(R a ) 2 , —C(O)R a , —O(CO)R a , —C(O)OR a , —O(CO)NR a R a , —NHC(O)OR a , —NHC(O)NR a R a , —C(O)NR a R a , —NHC(O)R a , —SO 2 R a , —NHSO 2 R a and —SO 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R 4 , R 5 and R 6 are each optionally substituted with 1 or 2 R b substituents; R 7 is halo, C 1-6 alkyl, CN, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-4 alkyl-, (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-4 alkyl-, (4-6 membered heterocycloalkyl)-C 1-4 alkyl- and (5-6 membered heteroaryl)-C 1-4 alkyl of R 7 are each optionally substituted with 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , COOH, —OC 1-6 alkyl, —SC 1-6 alkyl, C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)NH(C 1-6 alkyl) 2 , —C(O)OC 1-6 alkyl, —OC(O)NHC 1-6 alkyl, —OC(O)NH 2 , —OC(O)NH(C 1-6 alkyl) 2 , —NHC(O)C 1-6 alkyl, —NHC(O)H, —N(C 1-6 alkyl)C(O)C 1-6 alkyl, —NHC(O)OC 1-6 alkyl, —N(C 1-6 alkyl)C(O)OC 1-6 alkyl, —NHC(O)NH(C 1-6 alkyl), —NHC(O)N(C 1-6 alkyl) 2 , —NHC(O)NH 2 , —N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), —N(C 1-6 alkyl)C(O)N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl)C(O)NH 2 , —NHS(O) 2 (C 1-6 alkyl), —N(C 1-6 alkyl)S(O) 2 (C 1-6 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-6 alkyl), —NHS(O) 2 N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl)S(O) 2 NH 2 , —N(C 1-6 alkyl)S(O) 2 NH(C 1-6 alkyl), —N(C 1-6 alkyl)S(O) 2 N(C 1-6 alkyl) 2 , —S(O) 2 (C 1-6 alkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1-6 alkyl) and —S(O) 2 N(C 1-6 alkyl) 2 ; R 8 is halo, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, C 7 -10 aryl, cyclopropyl substituted with 1-3 independently selected R b substituents, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, OR 11 , NH 2 , —NHR 9 , —NR 9 R 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O) 2 R 11 , or S(O) 2 NR 11 R 11 , wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 7-10 aryl, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; and R 9 is C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- or (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R 9 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R 11 are each optionally substituted with 1 or 2 R b substituents; each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-4 alkyl-; each R b is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NHR c , N(R c ) 2 , OR c , C(O)NR c R c , C(O)OR c , COOH, NR c C(O)R c , OC(O)NR c R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O) 2 R c and S(O) 2 NR c R c , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1 -4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each optionally substituted with 1 or 2 R d substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C 1-4 alkyl-, CN, OH, COOH, OR e , C(O)OR e , NH 2 , —NHR e , —N(R e ) 2 , —C(O)NR e R e , —NR e C(O)R e , OC(O)NR e R e , NR e C(O)OR e , NR e C(O)NR e R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , S(O) 2 R e and S(O) 2 NR e R e , wherein R e is H or C 1-6 alkyl; each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl- and (4-6 membered heterocycloalkyl)-C 1-4 alkyl- of R c are each optionally substituted with 1 or 2 R f substituents; or two R 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 or 2 independently selected R h substituents; each R f is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, CN, OH, COOH, OR g , C(O)OR g , NH 2 , —NHR g , —N(R g ) 2 , —C(O)NR g R g , —NR g C(O)R g , OC(O)NR g R g , NR g C(O)OR g , NR g C(O)NR g R g , NR g S(O) 2 R g , NR g S(O) 2 NR g R g , S(O) 2 R g and S(O) 2 NR g R g , wherein each R g is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and each R h is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , NHR i , N(R i ) 2 , OR i , C(O)NR i R i , NR i C(O)R i and C(O)OR i , wherein R i is H or C 1-6 alkyl.
31 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is O, S, N, NR 4 or CR 4 ; X 5 is O, S, N, NR 5 or CR 5 ; Cy is C 6-10 aryl, C 3 -10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents; R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NHR 10 , —NR 10 R 10 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , and NR 10 C(O)OR 10 , wherein each R 10 is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R 1 , R 2 , R 3 and R 10 are each optionally substituted with 1 or 2 independently selected R d substituents; R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , NR a C(O)R a , and NR a C(O)OR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl of R 4 , R 5 and R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 11 , —NR 11 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , and NR 11 C(O)OR 11 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl of R 7 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 8 is halo, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, C 7-10 aryl, cyclopropyl substituted with 1-3 independently selected R b substituents, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 9 , —NR 9 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , or NR 11 C(O)OR 11 , wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 7-10 aryl, C 4-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 9 is methyl, ethyl, propyl, isopropyl, C 5-6 alkyl, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein the C 5-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R 9 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R 11 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R a are each optionally substituted with 1, 2 or 3 independently selected R d substituents; each R b substituent is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , and OC(O)NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R b are each further optionally substituted with 1-3 independently selected R d substituents; each R b1 is independently selected from Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , and NR c C(O)NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R b1 are each further optionally substituted with 1-3 independently selected R d substituents. each R b2 is independently selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , NR c C(O)R c , and NR c C(O)OR c ; wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R b2 are each further optionally substituted with 1-3 independently selected R d substituents; each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R c are each optionally substituted with 1, 2 or 3 R f substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , and NR g C(O)OR g ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f are each optionally substituted with 1, 2 or 3 R n substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR o , OR o , SR o , C(O)R o , C(O)NR o R o , C(O)OR o , OC(O)R o , OC(O)NR o R o , NHR o , NR o R o , NR o C(O)R o , NR o C(O)NR o R o , and NR o C(O)OR o , wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R n is optionally substituted with 1, 2 or 3 R q substituents; each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , and NR e C(O)OR e , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1-3 independently selected R f substituents; each R e is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R g is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (5-10 membered heteroaryl)-C 1-4 alkyl-; wherein the C 1-6 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl- of R g are each optionally substituted with 1-3 R p substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR r , C(O)R r , C(O)NR r R r , C(O)OR r , OC(O)R r , OC(O)NR r R r , NHR r , NR r R r , and NR r C(O)R r ; each R o is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl; each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 12 and NR 12 R 12 and each R 12 is independently C 1-6 alkyl; and is a single bond or a double bond to maintain ring A being aromatic.
32 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is O, S, NR 4 or CR 4 ; X 5 is NR 5 or CR 5 ; Cy is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents; R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl and C 1-4 alkoxy of R 1 , R 2 and R 3 are each optionally substituted with 1 or 2 independently selected R d substituents; R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , NHR a , NR a R a , and NR a C(O)R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 4 , R 5 and R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 11 , —NR 11 R 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , NR 11 C(O)R 11 , and NR 11 C(O)OR 11 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy of R 7 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 8 is halo, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl substituted with 1-3 independently selected R b1 substituents, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 11 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-10 membered heteroaryl of R a are each optionally substituted with 1, 2 or 3 independently selected R d substituents; each R b substituent is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , NHOR c , OR c , C(O)R c , C(O)NR c R c , and C(O)OR c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy of R b are each further optionally substituted with 1-3 independently selected R d substituents; each R b1 is independently selected from Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , OR c , C(O)R c , C(O)NR c R c , C(O)OR c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , and NR c C(O)NR c R c ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy of R b1 are each further optionally substituted with 1-3 independently selected R d substituents; each R b2 is independently selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , NR c C(O)R c , and NR c C(O)OR c ; wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R b2 are each further optionally substituted with 1-3 independently selected R d substituents; each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 6-10 aryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 6-10 aryl of R c are each optionally substituted with 1, 2 or 3 R f substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, OR g , C(O)R g , C(O)NR g R g , C(O)OR g , NHR g , NR g R g , and NR g C(O)R g ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f are each optionally substituted with 1, 2 or 3 R n substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, phenyl, OR o , C(O)R o , C(O)NR o R o , C(O)OR o , NHR o , NR o R o , and NR o C(O)R o ; each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , C(O)R e , C(O)NR e R e , C(O)OR e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , and NR e C(O)OR e , wherein the C 1-6 alkyl and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1-3 independently selected R f substituents; each R e is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R g is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (5-10 membered heteroaryl)-C 1-4 alkyl-; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (5-10 membered heteroaryl)-C 1-4 alkyl- of R g are each optionally substituted with 1-3 R p substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR r , C(O)R r , C(O)NR r R r , and C(O)OR r ; each R o is independently selected from H and C 1-6 alkyl; and is a single bond or a double bond to maintain ring A being aromatic.
33 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is O, S, NR 4 or CR 4 ; X 5 is NR 5 or CR 5 ; Cy is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6 substituents; R 1 , R 2 and R 3 are each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, NH 2 , —NH—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 ; R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a , C(O)NR a R a , and NR a C(O)R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 4 , R 5 and R 6 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents; or two adjacent R 6 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or CN, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 7 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; R 8 is halo, C 1-6 alkyl substituted with 1-3 independently selected R b2 substituents, C 2-6 alkenyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 2-6 alkenyl and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 8 are each optionally substituted with 1, 2 or 3 independently selected R b substituents; each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 5-10 membered heteroaryl of R a are each optionally substituted with 1, 2 or 3 independently selected R d substituents; each R b substituent is independently selected from halo, C 1-6 alkyl, and OR c ; each R b2 is independently selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, NHR c , NR c R c , and NR c C(O)R c ; wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R b2 are each further optionally substituted with 1-3 independently selected R d substituents; each R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 6-10 aryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 6-10 aryl of R c are each optionally substituted with 1, 2 or 3 R f substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, OR g , C(O)R g , C(O)NR g R g , NHR g , and NR g R g ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f are each optionally substituted with 1, 2 or 3 R n substituents independently selected from C 1-6 alkyl, halo, CN, OR o , and C(O)OR o ; each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , OR e , C(O)R e , C(O)NR e R e , C(O)OR e , NHR e , NR e R e , and NR e C(O)R e ; wherein the C 1-6 alkyl and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d are each optionally substituted with 1-3 independently selected R f substituents; each R e is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R g is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (5-10 membered heteroaryl)-C 1-4 alkyl-; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and (5-10 membered heteroaryl)-C 1-4 alkyl- of R g are each optionally substituted with 1-3 R p substituents independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, and CN; each R o is independently selected from H and C 1-6 alkyl; and is a single bond or a double bond to maintain ring A being aromatic.
34 . The compound of claim 1 , selected from:
(2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}-1,3-thiazol-5-yl)methyl]piperidine-2-carboxylic acid, 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-1,3-thiazole-2-carboxamide, 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-1,3-oxazole-2-carboxamide, (2S)-1-[(1-methyl-2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}-1H-imidazol-5-yl)methyl]piperidine-2-carboxylic acid, 5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-N-(2-methylbiphenyl-3-yl)-1H-imidazole-2-carboxamide, (2S)-1-[(1-methyl-3-{[(2-methylbiphenyl-3-yl)amino]carbonyl}-1H-pyrazol-5-yl)methyl]piperidine-2-carboxylic acid, 5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-N-(2-methylbiphenyl-3-yl)-1H-pyrazole-3-carboxamide, 4-chloro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-1,3-thiazole-2-carboxamide, 5-{[(2-hydroxyethyl)amino]methyl}-4-methyl-N-(2-methylbiphenyl-3-yl)-1,3-thiazole-2-carboxamide, N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-pyrazole-3-carboxamide, N-(2-cyano-2′-fluorobiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-pyrazole-3-carboxamide N-(2-cyano-2′-fluoro-3′-methoxybiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-pyrazole-3-carboxamide, N-[2-cyano-3-(1-methyl-1H-indazol-4-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-pyrazole-3-carboxamide, N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-imidazole-2-carboxamide, N-(2-cyano-2′-fluoro-3′-methoxybiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-imidazole-2-carboxamide, and N-[2-cyano-3-(1-methyl-1H-indazol-4-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}-1-methyl-1H-imidazole-2-carboxamide or a pharmaceutically acceptable salt or a stereoisomer thereof.
35 . The compound of claim 1 , selected from:
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamido)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid; (S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazole-2-carboxamido)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid; and 5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-N-(3′-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-carboxamido)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)thiazole-2-carboxamide; or a pharmaceutically acceptable salt or a stereoisomer thereof.
36 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
37 . 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.
38 . 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.
39 . 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.Join the waitlist — get patent alerts
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