Granted Patent B2

US 12,466,822 · App. 17/483,959 · Granted Nov 11, 2025

Inventors: Liangxing Wu (Wilmington, DE); Neil Lajkiewicz (Bedford, MA); Chunhong He (Boothwyn, PA); Kaijiong Xiao (Clark, NJ); Wenyu Zhu (Media, PA); Zhenwu Li (Wilmington, DE); Chao Qi (Newark, DE); Leah C. Konkol (Newark, DE); Wenqing Yao (Chadds Ford, PA)

Assignee: Incyte Corporation

C07D471/04A61P37/00A61P37/02C07D401/04C07D519/00

Abstract

Claims (189)

1 . A compound of Formula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is selected from:

wherein each subscript r is an integer of 1, 2, or 3;

L is —C(O)NR 13 —, wherein the carbonyl group is attached to ring A;

X is N or CR 17 ;

R 2 is H, 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 or —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl and C 1-4 alkoxy of R 2 is optionally substituted with 1 or 2 substituents independently selected from C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, —C(O)NH 2 , NH 2 , —NHC 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;

R 3 is methyl, halo, CN or C 1-4 haloalkyl;

R 4 is 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 or —N(C 1-4 alkyl) 2 ;

R 5 is 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 or —N(C 1-4 alkyl) 2 ;

R 6 is 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 6 is optionally substituted with 1, 2, 3, 4 or 5 R b substituents;

R 7 is H, halo, CN, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy of R 7 are each optionally substituted with CN;

or two R 6 substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f substituents;

R 8 and R 9 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 8 or R 9 are each optionally substituted with 1, 2 or 3 independently selected R 9 substituents;

or R 8 and R 9 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or 7-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 R q substituents;

or R 8 and R 10 taken together with the atoms to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to one additional heteroatoms as ring members selected from O, N or S, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R 8 and R 10 are each optionally substituted with 1 or 2 R q substituents;

R 10 and R 11 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, —C(O)R g , —C(O)OR g , —C(O)NR g R g , —SO 2 R g and —SO 2 NR g R g , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 10 or R 11 are each optionally substituted with 1, 2, or 3 independently selected R d substituents;

or R 10 and R 11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is each optionally substituted with 1, 2 or 3 R f substituents;

R 12 is H, 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 or —N(C 1-4 alkyl) 2 ;

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 R q substituents;

R 17 is H, 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 or —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl and C 1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo and —C(O)NH 2 ;

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, 2, or 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 b substituent is independently selected from 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, 5-10 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 1-6 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 b are each further optionally substituted with 1, 2, or 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;

each R f is 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;

each R n is 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 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 1-4 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 n are each optionally substituted with 1, 2 or 3 independently selected 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, 2, or 3 R p substituents;

each R p is 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;

each R h is 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 , NRiS(O) 2 R i , NRiS(O) 2 NR i R i , and S(O) 2 NR i R i , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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- of R h are each further optionally substituted by 1, 2, or 3 R i substituents;

each R j is 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, 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 2-4 alkynyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R i 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 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 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 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, 4-7 membered heterocycloalkyl, 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 halo, OH, CN, —COOH, NH 2 , —NH—C 1-6 alkyl, —N(C 1-6 alky) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C 3-6 cycloalkyl, 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 1, 2, or 3 substituents selected from 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;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript p is an integer of 1, 2, 3 or 4.

2 . The compound of claim 1 , having Formula (IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 6 is H, C 1-6 alkyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl, (2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl, 2-(3-carboxyazetidin-1-yl)ethanoyl, (R)-2-(3-carboxyazetidin-1-yl)ethanoyl, (S)-2-(3-carboxyazetidin-1-yl)ethanoyl, 2-(2-carboxypiperidin-1-yl)ethanoyl, (R)-2-(2-carboxypiperidin-1-yl)ethanoyl, (S)-2-(2-carboxypiperidin-1-yl)ethanoyl, 2-(3-carboxypyrrolidin-1-yl)ethanoyl, (S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (5-cyanopyridin-3-yl) methoxy, halo or CN.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 6 is (4-carboxycyclohexyl)methyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, 1-carboxy-2-propyl, (R)-1-carboxy-2-propyl, (S)-1-carboxy-2-propyl, (4-carboxy-4-methylcyclohexyl)methyl, 2-pyrrolidinyl, 2-(3-hydroxypyrrolidin-1-yl)acetyl, 2-((R)-3-hydroxypyrrolidin-1-yl)acetyl, 2-((S)-3-hydroxypyrrolidin-1-yl)acetyl, 2-(3-hydroxyazetidin-1-yl)acetyl, 2-((2-hydroxyethyl)(methyl)amino)acetyl, (4-carboxycyclohexyl)ethyl, 4-carboxycyclohexyl, 4-carboxy-4-methylcyclohexyl, dimethylglycyl, or N-ethyl-N-methylglycyl.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein L is —C(O)NH—, wherein the carbonyl group in the —C(O)NH— linkage is attached to ring A.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript m is 0.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript n is 1 and R 5 is halo or C 1-4 alkyl.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is methyl, CN or C 1 .

9 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 12 is H, halo, CN, C 1-4 alkyl or C 1-4 alkoxy.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is H.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript p is 1.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 8 and R 9 are each H.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 10 is H.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 11 is 2-hydroxyethyl, [1-(hydroxymethyl)cyclopropyl]methyl, [1-(hydroxymethyl)cyclobutyl]methyl or 2-(dimethylamino)-2-oxo-ethyl.

15 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein —NR 10 R 11 is (2-hydroxyethyl)amino, 3-hydroxypyrrolidin-1-yl, 3-carboxypyrrolidin-1-yl, 3-carboxyazetidin-1-yl, (S)-3-carboxyazetidin-1-yl, (R)-3-carboxyazetidin-1-yl, 2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl, [1-(hydroxymethyl)cyclopropyl]methylamino, [1-(hydroxymethyl)cyclobutyl]methylamino or [2-(dimethylamino)-2-oxo-ethyl]amino.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring A is 2-pyridyl, optionally substituted with 1, 2, 3, or 4 independently selected R 6 substituents.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is N or CH.

18 . The compound of claim 1 selected from:

1-(((6-(2-fluoro-3′-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)pyridin-3-yl)methyl)amino)cyclobutanecarboxylic acid;

(S)-1-((6-((2-fluoro-3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl) carbamoyl)pyridin-3-yl)methyl) piperidine-2-carboxylic acid;

N-(2-fluoro-3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;

N-(2-chloro-3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;

N-(2-chloro-3′-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamide;

(R)-1-((8-((2′-chloro-3′-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid; and

(R)-1-((8-((2′-chloro-3′-(5-((3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

19 . The compound of claim 1 selected from:

1-((8-(2-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid;

(R)-1-((5-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;

(R)-1-((8-(2,2′-dichloro-3′-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido) biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid;

1-((8-(2,2′-dichloro-3′-(5-((2-hydroxyethylamino)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido) biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid;

1-((8-(2,2′-dichloro-3′-(5-((2-hydroxy-2-methylpropylamino)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido) biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)azetidine-3-carboxylic acid;

(R)-1-((8-(3′-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;

(R)-1-((8-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;

(S)-N-(2-chloro-3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; and

(R)-1-((8-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 1 selected from:

(R)-1-((8-(2′-Chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido) biphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid;

(R)-1-((8-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;

trans-4-((2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

cis-4-((2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

cis-4-((2-(2-chloro-2′-methyl-3′-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino) biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

trans-4-((2-(2-chloro-3′-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

trans-4-((2-(2-chloro-3′-(3-(((1S,2S)-2-hydroxycyclopentylamino)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

trans 4-(2-(2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

cis 4-(2-(2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

3-(2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)butanoic acid;

cis 4-((2-(2-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

cis 4-((2-(2-chloro-3′-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

(R)-4-(2-(2-chloro-3′-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid;

(S)-4-(2-(2-chloro-3′-(3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid;

trans 4-(2-(2-(2-chloro-3′-(3-(((R)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

trans 4-(2-(2-(2-chloro-3′-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

trans-4-(2-(2-(2-chloro-3′-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

(R)-4-(2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic acid;

trans-4-(2-(2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

(R)-4-(2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cyclohexanecarboxylic acid;

Trans-4-(2-(2-(2,2′-dichloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino) biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c] pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

trans 4-(2-(2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylic acid;

(R)-1-((4-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

(R)-4-(2-(2-chloro-3′-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic acid;

trans 4-((2-(2-chloro-3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid; and

Cis-4-((2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

X is N or CR 17 , wherein R 17 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, or OH, wherein the C 1-4 alkyl and C 1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo and —C(O)NH 2 ;

R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, or OH, wherein the C 1-4 alkyl and C 1-4 alkoxy of R 1 or R 2 is optionally substituted with 1 or 2 substituents independently selected from C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, and OH;

R 4 is C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 haloalkyl;

R 5 is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, or OH;

each R 6 is 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, 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, NO 2 , OR 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 , or NR a C(O)OR 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 6 are each optionally substituted with 1, 2, or 3 R b substituents;

R 7 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, halo, or OH;

R 8 and R 9 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 , and C 1-4 haloalkyl;

R 10 and R 11 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, —C(O)R 8 , —C(O)OR 8 , and —C(O)NR 8 R 8 , wherein the C 1-6 alkyl and C 1-6 haloalkyl of R 10 or R 11 are each optionally substituted with 1 or 2 independently selected R f substituents;

or R 10 and R 11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R h substituents;

R 12 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, or OH;

each R 13 is independently H, C 1-6 haloalkyl or C 1-6 alkyl;

each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, NH 2 , OR 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 ;

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 b substituent is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , NO 2 , OR 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 , 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 or 2 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, C 6-10 aryl-C 1-4 alkyl-, and C 3-10 cycloalkyl-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, C 6-10 aryl-C 1-4 alkyl-, and C 3-10 cycloalkyl-C 1-4 alkyl- of R c are each optionally substituted with 1, 2, or 3 R f substituents;

each R f is 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 , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , and NR g C(O)OR 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 h is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR 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 , and NR i C(O)OR i , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R h are each further optionally substituted by 1, 2, or 3 R i substituents;

each R j is independently selected from C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, and CN;

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;

each R i is independently selected from H, C 1-4 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-4 alkenyl, and C 2-4 alkynyl;

the subscript m is an integer of 0, 1, or 2;

the subscript n is an integer of 0, 1, or 2; and

the subscript p is an integer of 1, 2, or 3.

22 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

X is CR 17 , wherein R 17 is H or C 1-4 alkyl;

one of R 1 and R 2 is —(CR 8 R 9 ) p —NR 10 R 11 and the other is H, C 1-4 alkyl, or C 1-4 alkoxy;

R 3 is methyl or halo;

R 4 is C 1-4 alkyl or C 1-4 alkoxy;

R 5 is C 1-4 alkyl, C 1-4 alkoxy, or halo;

each R 6 is 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-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, 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 6 are each optionally substituted with 1, 2, or 3 R b substituents;

R 7 is H or C 1-4 alkyl;

R 8 and R 9 are each independently selected from H and C 1-4 alkyl;

R 10 and R 11 are each independently selected from H and C 1-6 alkyl optionally substituted with 1 or 2 independently selected R f substituents;

or R 10 and R 11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R h substituents;

R 12 is H or C 1-4 alkyl;

each R 13 is independently H or C 1-6 alkyl;

each R b substituent is independently selected from halo, C 1-6 alkyl, 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, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 3-10 cycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 3-10 cycloalkyl-C 1-4 alkyl- of R c are each optionally substituted with 1 or 2 R f substituents;

each R f is independently selected from C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, OR g , and C(O)OR g ;

each R g is independently selected from H and C 1-6 alkyl;

each R h is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i , and C(O)OR i ,

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;

each R i is independently selected from H and C 1-4 alkyl;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1 or 2.

23 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

X is CR 17 , wherein R 17 is H;

one of R 1 and R 2 is —(CR 8 R 9 ) p —NR 10 R 11 and the other is H;

R 3 is methyl or halo;

R 4 is C 1-4 alkyl or C 1-4 alkoxy;

R 5 is C 1-4 alkyl or halo;

each R 6 is independently selected from H, C 1-6 alkyl, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 6 are each optionally substituted with 1 or 2 R b substituents;

R 7 is H;

R 8 and R 9 are each independently selected from H and C 1-4 alkyl;

R 10 and R 11 are each independently selected from H and C 1-6 alkyl optionally substituted with 1 or 2 independently selected R f substituents;

or R 10 and R 11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R h substituents;

R 12 is H;

R 13 is H;

each R b substituent is independently selected from OH, C(O)OR c , NHR c , and NR c R c ;

each R c is independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl, wherein the C 1-6 alkyl, and C 3-10 cycloalkyl of R c are each optionally substituted with 1 or 2 R f substituents;

each R f is independently selected from OR g , and C(O)OR g ;

R g is H;

each R h is independently selected from OR i and C(O)OR i ;

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;

R i is H;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1 or 2.

24 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable excipient or carrier.

25 . 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.

26 . 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, wherein the disease or disorder is cancer.

27 . The method according to claim 26 , wherein the cancer is selected from urothelial cancer, cancers with high microsatellite instability (MSI high ), genitourinary tract cancers, liver cancers, nervous system cancers, gynecological cancers, acute promyelocytic leukemia (APL), myeloproliferative diseases, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), osteosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, cancers of the small bowel, leiomyoma, hemangioma, cancers of the large bowel, tubular adenoma, villous adenoma, hamartoma, colorectal cancer, Wilm's tumor [nephroblastoma], transitional cell carcinoma, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatoblastoma, hepatocellular adenoma, malignant fibrous histiocytoma, malignant lymphoma, reticulum cell sarcoma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, cancers of the skull, osteoma, granuloma, xanthoma, osteitis deformans, cancers of the meninges, meningioma, meningiosarcoma, gliomatosis, meduoblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancers of the spinal cord, Lhermitte-Duclos disease, endometrial carcinoma, cancers of the cervix, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, cancers of the vulva, intraepithelial carcinoma, cancers of the vagina, botryoid sarcoma, embryonal rhabdomyosarcoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, and urothelial carcinoma.

28 . The method according to claim 26 , wherein the cancer is selected from a metastatic cancer that expresses PD-L1, lung cancer, non-small cell lung cancer, kidney cancer, hepatic cancer, melanoma, cancer of the bladder, cancer of the urethra, renal cancer, and renal cell carcinoma.

Assignments (1)

Continuity (10)

References Cited (400)