US2017174671A1PendingUtilityA1
Heterocyclic compounds as immunomodulators
Est. expiryDec 17, 2035(~9.4 yrs left)· nominal 20-yr term from priority
C07D 405/14C07D 401/06C07D 401/12C07D 213/81C07D 213/84C07D 405/12C07D 401/14A61P 31/00C07D 239/28A61P 37/04C07D 237/24C07D 413/12C07D 241/24A61P 31/12A61P 35/00
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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 N or CR 4 ;
wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N;
X 5 is N or CR 6a ;
X 6 is N or CR 6b ;
ring B is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
R 1 , R 2 , R 3 , R 4 and R 7 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 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 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R b substituents;
R 5 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 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 , and 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 5 are each optionally substituted with 1, 2 or 3 R b substituents; wherein R 5 is other than F when ring B is C 3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl;
each R 11 is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 R b substituents;
R 6a , R 6b and R 6c 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 3-10 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-, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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 6a , R 6b , R 6c and R 10 are each optionally substituted with 1, 2 or 3 independently selected R d substituents;
or two adjacent R 7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents, provided
is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1, 2 or 3 independently selected R b substituents;
or two R 7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C 3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 1 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 2 and X 1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 2 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 3 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 3 and X 4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
or R 4 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 a are each optionally substituted with 1, 2, 3, 4, or 5 R d 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 b substituent is independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 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 , 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 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 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 c is independently selected from H, C 1-6 alkyl, C 1-4 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 c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 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 , 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 1-4 alkyl, C 1-4 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, 3, 4, or 5 R n substituents independently selected from C 1-4 alkyl, 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-, (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, halo, CN, R o , 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)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 1-4 alkyl, 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-, (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 1-4 haloalkyl of R n are each optionally substituted with 1, 2 or 3 R q substituents;
each R g is independently selected from H, C 1-6 alkyl, C 1-4 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 1-6 haloalkoxy, 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 1-6 haloalkoxy, 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 are each 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 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-, (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkyl, C 1-6 haloalkoxy, 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 , 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 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 further optionally substituted by 1, 2, or 3 R j substituents independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, 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, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-6 alkynyl, 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; and
each R e , R i , R k , R o or R r is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, 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, and C 2-4 alkynyl of R e , 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 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 8 , NR 8 R 8 , and C 1-4 haloalkoxy, 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, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl and each R 8 is independently C 1-6 alkyl;
is a single bond or a double bond, wherein ring A includes at least one double bond;
the subscript n is an integer of 1, 2, 3, 4 or 5; and
with the proviso (i) when
is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
(ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
(iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
(iv) when
is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
(v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R 2 is other than t-butyl;
(vi) when
is 3,5-dimethylphenyl, R 5 is other than 4-amino-1-piperidinyl; and
(vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
2 . The compound of claim 1 , 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 N or CR 4 ; wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N; X 5 is N or CR 6a ; X 6 is N or CR 6b ; ring B is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl; R 1 , R 2 , R 3 , R 4 and R 7 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 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 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R b substituents; R 5 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 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , 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 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 , and 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 5 are each optionally substituted with 1, 2 or 3 R b substituents; wherein R 5 is other than F when ring B is C 3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl; each R 11 is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 R b substituents; R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 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 H or C 1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C 1-4 alkoxy, and wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl and C 2-4 alkynyl of R 6a , R 6b , and R 6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C 1-4 alkyl and C 1-4 alkoxy; or two adjacent R 7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents, provided
is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1 or 2 independently selected R b substituents;
or two R 7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C 3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C 3-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 1 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 2 and X 1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 2 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 3 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 3 and X 4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 4 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 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 , 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 1-4 alkyl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl of R d are each further optionally substituted with 1-3 independently selected R f substituents;
each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 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 , 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 1-4 alkyl, C 1-4 haloalkyl, C 1-4 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 c is independently selected from H, C 1-6 alkyl, C 1-4 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 c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 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 , 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 1-4 alkyl, C 1-4 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, 3, 4, or 5 R n substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, R o , 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)NR o R o , NR o C(═NR)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 ;
each R g is independently selected from H, C 1-6 alkyl, C 1-4 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 independently selected R p 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 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 1-6 haloalkyl, 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 (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 , 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 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-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl- of R h are each further optionally substituted by 1, 2, or 3 R j substituents independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, 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 ; 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; and
each R e , R i , R k , R o or R p is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 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 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R e , R i , R k , R o or R p 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 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 8 , NR 8 R 8 , and C 1-4 haloalkoxy, 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 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R 8 is independently C 1-6 alkyl;
is a single bond or a double bond, wherein ring A includes at least one double bond;
the subscript n is an integer of 1, 2, 3, 4 or 5; and
with the proviso (i) when
is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
(ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
(iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
(iv) when
is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
(v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R 2 is other than t-butyl;
(vi) when
is 3,5-dimethylphenyl, R 5 is other than 4-amino-1-piperidinyl; and
(vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
3 . The compound of claim 1 or 2 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 N or CR 4 ;
wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N;
R 1 , R 2 , R 3 , R 4 and R 7 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 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 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R b substituents;
R 5 is C 1-4 alkyl, halo, CN, OH, cyclopropyl, C 2-4 alkynyl, 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 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 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 , and S(O) 2 NR 11 R 11 , wherein each R 11 is independently selected from H and C 1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH 3 ;
each R 6 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 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 H or C 1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C 1-4 alkoxy, and wherein the C 1-4 alkyl, C 3-4 cycloalkyl, C 2-4 alkenyl and C 2-4 alkynyl of R 6 are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C 1-4 alkyl and C 1-4 alkoxy;
or two adjacent R 7 substituents, taken together with the carbon atoms to which they are attached, form a fused phenyl ring, a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 5-6 cycloalkyl ring, wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R q substituents;
or R 1 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 2 and X 1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 2 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 3 and X 2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 3 and X 4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
or R 4 and X 3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 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 , 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 1-4 alkyl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl of R d are each further optionally substituted with 1-3 independently selected R q substituents;
each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 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 , 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 1-4 alkyl, C 1-4 haloalkyl, C 1-4 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 c is independently selected from H, C 1-6 alkyl, C 1-4 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 c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 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 , 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 1-4 alkyl, C 1-4 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, 3, 4, or 5 R n substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, R o , 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)NR o R o , NR o C(═NR)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 ;
each R g is independently selected from H, C 1-6 alkyl, C 1-4 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 independently selected R p 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 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 1-6 haloalkyl, 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 , 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 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-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl- of R h are each further optionally substituted by 1, 2, or 3 R j substituents independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, 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 ; 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; and
each R e , R i , R k , R o or R p is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 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 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R e , R i , R k , R o or R p 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 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, NHR 8 , NR 8 R 8 , and C 1-4 haloalkoxy, wherein the C 1-4 alkyl, phenyl and 5-6 membered heteroaryl of R q are each optionally substituted with OH, CN, —COOH, NH 2 , C 1-4 alkoxy, C 3-10 cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each R 8 is independently C 1-6 alkyl;
the subscript n is an integer of 1, 2, 3, 4 or 5;
the subscript m is an integer of 1, 2 or 3; and
is a single bond or a double bond, wherein ring A includes at least one double bond;
with the proviso that the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide.
4 . The compound of any one of claims 1 - 3 , wherein ring A is aromatic.
5 . The compound of any one of claims 1 - 4 , having Formula (II):
wherein R 2 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 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 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 2 are each optionally substituted with 1, 2, 3, or 4 R b substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
6 . The compound of any one of claims 1 - 5 , having Formula (III):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
7 . The compound of any one of claims 1 - 6 , having Formula (IV):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
8 . The compound of any one of claims 1 - 5 , having Formula (V):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
9 . The compound of any one of claims 1 - 5 and 8 , having Formula (VI):
or a pharmaceutically acceptable salt or a stereoisomer thereof.
10 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the moiety
is selected from:
11 . The compound of any one of claims 1 - 4 , having Formula (VII):
wherein R 3 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 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 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 1 are each optionally substituted with 1, 2, 3, or 4 R b substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
12 . The compound of any one of claims 1 - 4 and 11 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the moiety
is selected from:
13 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X 1 is CR 1 , X 3 is CR 3 and X 4 is CR 4 .
14 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X 1 is CR 1 , X 3 is N and X 4 is CR 4 .
15 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X 1 is N, X 3 is CR 3 and X 4 is CR 4 .
16 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X 1 is CR 1 , X 3 is CR 3 and X 4 is N.
17 . The compound of any one of claims 1 - 10 and 13 - 16 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 , R 3 and R 4 , when applicable, are each independently selected from H, C 1-6 alkyl and halo.
18 . The compound of claim 11 or 12 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 , R 2 and R 4 , when applicable, are each independently selected from H, C 1-6 alkyl and halo.
19 . The compound of any one of claims 1 - 10 and 13 - 17 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is —CH 2 —R b .
20 . The compound of claim 19 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R b is —NR c R c .
21 . The compound of any of claims 11 , 12 and 18 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is —CH 2 —R b .
22 . The compound of claim 21 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R b is —NR c R c .
23 . The compound of any of claims 1 - 10 , and 13 - 16 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
24 . The compound of any of claims 1 , 2 , 11 , and 12 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
25 . 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 N or CR 4 ;
wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N;
X 5 is N or CR 6a ;
X 6 is CR 6b ;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, OR a , NHR a , and 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 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R b substituents;
R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or CN, 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 5 are each optionally substituted with 1, 2 or 3 R b substituents;
R 6a , R 6b and R 6c 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, NH 2 , —NH—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl of R 6a , R 6b , and R 6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C 1-4 alkyl and C 1-4 alkoxy;
or two adjacent R 7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH 2 , 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 , and NR e C(O)R e , and S(O) 2 NR e R e , wherein the C 1-4 alkyl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl of R d are each further optionally substituted with 1-3 independently selected R f substituents;
each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 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 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R b 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 1-4 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 c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 , and NR g C(O)R g ;
each R g is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
each R e is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl;
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
26 . 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 N or CR 4 ;
wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N;
X 5 is N or CR 6a ;
X 6 is CR 6b ;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a , NHR a , and NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R b substituents;
R 5 is C 1-6 alkyl or CN;
R 6a , R 6b and R 6c 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 ;
or two adjacent R 7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, and NH 2 ;
each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OH, NH 2 , C(O)OR c , NHR c , and NR c R c ;
each R c is independently selected from H, C 1-6 alkyl, C 1-4 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 c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 ;
each R g is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
27 . 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 N or CR 4 ;
wherein no more than two of X 1 , X 2 , X 3 and X 4 are simultaneously N;
X 5 is N or CR 6a ;
X 6 is CR 6b ;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a , NHR a , and NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1 or 2, R b substituents;
R 5 is C 1-6 alkyl or CN;
R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl and halo;
or two adjacent R 7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
each R a is independently selected from H, CN, 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-, 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 a are each optionally substituted with 1 or 2 R d substituents;
each R d is independently selected from C 1-4 alkyl, halo, CN, and NH 2 ;
each R b substituent is independently selected from halo, C 1-4 alkyl, CN, OH, NH 2 , C(O)OR c , NHR c , and NR c R c ;
each R c is independently selected from H, C 1-6 alkyl, 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 c are each optionally substituted with 1, 2 or R f substituents independently selected from C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, and OR g ;
each R g is independently selected from H and C 1-6 alkyl;
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
28 . The compound of claim 1 , wherein the compound is selected from:
(2S)-1-[(6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; (2S)-1-[(5-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrimidin-5-yl)methyl]piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide; (2S)-1-[(6-{[(2-cyanobiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; N-(2-cyanobiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; (2S)-1-{[6-({[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]amino}carbonyl)pyridin-3-yl]methyl}piperidine-2-carboxylic acid; N-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-5-((2-hydroxyethylamino)methyl)picolinamide; 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide; 6-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide; (2S)-1-[(2-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; (2S)-1-[(5-chloro-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; 3-chloro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; 3-fluoro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; 4-[(3-cyanobenzyl)oxy]-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide; 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide; 3-(dimethylamino)-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid; 4-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; N-(2-methylbiphenyl-3-yl)-6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide; 4-cyano-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide; N-(2-methylbiphenyl-3-yl)pyrimidine-4-carboxamide; N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide; N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide; and N-(2-methylbiphenyl-3-yl)-2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide; or a pharmaceutically acceptable salt or a stereoisomer thereof.
29 . The compound of claim 1 , wherein the compound is selected from:
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide; (2S)-1-[(4-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; 4-(cyclopropylmethoxy)-5-((2-hydroxyethylamino)methyl)-N-(2-methylbiphenyl-3-yl)picolinamide; 5-{[(2-hydroxyethyl)amino]methyl}-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; (2S)-1-[(5-methyl-2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid; 4-{[(2-hydroxyethyl)amino]methyl}-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide; N-(2-cyano-3-cyclohex-1-en-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; N-(2-cyano-3-piperidin-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; tert-butyl 5-(2-cyano-3-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)carbonyl]amino}phenyl)-3,6-dihydropyridine-1 (2H)-carboxylate; N-(2-cyano-3-cyclohexylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; (S)-1-((6-(3-methyl-2-phenylpyridin-4-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid; 5-{[(2-hydroxyethyl)amino]methyl}-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide; N-[2-cyano-3-(3,4-dihydro-2H-pyran-5-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-fluoro-2-methylphenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; N-[2-cyano-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; N-[2-cyano-3-(2,3-dihydro-1-benzofuran-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; N-[2-cyano-3-(2-methyl-2H-indazol-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; and N-[2-cyano-3-(1-methyl-1H-indazol-4-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; or a pharmaceutically acceptable salt or a stereoisomer thereof.
30 . A pharmaceutical composition comprising a compound of any one of claims 1 - 29 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
31 . A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of any one of claims 1 - 29 or a pharmaceutically acceptable salt or a stereoisomer thereof.
32 . A method of treating a disease or disorder associated with PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 - 29 , or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition of claim 30 .
33 . The method of claim 32 , wherein the disease or disorder is a viral infection or cancer.
34 . A method of enhancing, stimulating, modulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any of claims 1 - 29 , or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a composition of claim 30 .
35 . A method of inhibiting growth, proliferation, or metastasis of cancer cells in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any of claims 1 - 29 , or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a composition of claim 30 .Join the waitlist — get patent alerts
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