Heterocyclic compounds as immunomodulators

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

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 ; 
 X 5  is N or CR 5 ; 
 Cy is C 6-10  aryl, C 3-10  cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R 6  substituents; 
 R 1 , R 2  and R 3  are each independently selected from H, C 1-4  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-4  alkyl-, C 2-4  alkenyl, C 2-4  alkynyl, halo, CN, OH, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, NH 2 , —NH—C 1-4  alkyl, —N(C 1-4  alkyl) 2 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 OC(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 and 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, C 2-4  alkynyl and C 1-4  alkoxy of R 1 , R 2  and R 3  are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN and C 1-4  alkoxy; 
 R 4 , R 5  and R 6  are each independently selected from H, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 6-10  aryl, C 3-10  cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-14 membered heteroaryl)-C 1-4  alkyl-, (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR a )R a , C(═NR a )NR a R a , NR a C(═NR a )NR a R a , NR a C(═NOH)NR a R a , NR a C(═NCN)NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-14 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R 4 , R 5  and R 6  are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b  substituents; 
 or two adjacent R 6  substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6  cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6  cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b  substituents; 
 R 7  and R 8  are each independently 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 , —N(R 11 ) 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 C(═NOH)NR 11 R 11 , NR 11 C(═NCN)NR 11 R 11 , NR 11 S(O)R 11 , NR 11 S(O) 2 R 11 , NR 11 S(O) 2 NR 11 R 11 , S(O)R 11 , S(O)NR 11 R 11 , S(O) 2 R 11 , or S(O) 2 NR 11 R 11 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 6-10  aryl, C 3-10  cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-14 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R 7  and R 8  are each optionally substituted with 1, 2 or 3 independently selected R b  substituents; 
 R 9  is 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, OR 12 , SR 12 , C(O)R 12 , C(O)NR 12 R 12 , C(O)OR 12 , OC(O)R 12 , OC(O)NR 12 R 12 , C(═NR 12 )R 12 , C(═NR 12 )NR 12 R 12 , S(O)R 12 , S(O)NR 12 R 12 , S(O) 2 R 12 , or S(O) 2 NR 12 R 12 , 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 9  are each optionally substituted with 1, 2 or 3 independently selected R b  substituents; 
 R 11  and R 12  are each independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R 11  and R 12  are each optionally substituted with 1, 2 or 3 independently selected R b  substituents; 
 each R a  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R a  are each optionally substituted with 1, 2 or 3 independently selected R d  substituents; 
 each R b  substituent is independently selected from halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c  and S(O) 2 NR c R c ; wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R b  are each further optionally substituted with 1-3 independently selected R d  substituents; 
 each R c  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R c  are each optionally substituted with 1, 2 or 3 R f  substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , NR g C(O)OR g , C(═NR g )NR g R g , NR g C(═NR g )NR g R g , NR g C(═NOH)NR g R g , NR g C(═NCN)NR g R g , S(O)R g , S(O)NR g R g , S(O) 2 R g , NR g S(O) 2 R g , NR g S(O) 2 NR g R g , and S(O) 2 NR g R g ; wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R f  are each optionally substituted with 1, 2 or 3 R n  substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, CN, phenyl, C 3-6  cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR o , OR o , SR o , C(O)R o , C(O)NR o R o , C(O)OR o , OC(O)R o , OC(O)NR o R o , NHR o , NR o R o , NR o C(O)R o , NR o C(O)NR o R o , NR o C(O)OR o , C(═NR o )NR o R o , NR o C(═NR o )NR o R o , S(O)R o , S(O)NR o R o , S(O) 2 R o , NR o S(O) 2 R o , NR o S(O) 2 NR o R o , and S(O) 2 NR o R o , wherein the C 1-6  alkyl, C 1-6  haloalkyl, phenyl, C 3-6  cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R n  is optionally substituted with 1, 2 or 3 R q  substituents; 
 each R d  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, C 6-10  aryl, 5-10 membered heteroaryl, C 3-10  cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e R e , NR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , C(═NR e )NR e R e )NR e C(═NR e )NR e R e NR e C(═NOH)NR e R e , NR e C(═NCN)NR e R e , S(O)R e , S(O)NR e R e , S(O) 2 R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , and S(O) 2 NR e R e , wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, C 3-10  cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R d  are each optionally substituted with 1-3 independently selected R f  substituents; 
 each R e  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R e  are each optionally substituted with 1, 2 or 3 independently selected R f  substituents; 
 each R g  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R g  are each optionally substituted with 1-3 R p  substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl-, (4-10 membered heterocycloalkyl)-C 1-4  alkyl-, halo, CN, NHOR r , OR r , SR r , C(O)R r , C(O)NR r R r , C(O)OR r , OC(O)R r , OC(O)NR r R r , NHR r , NR r , NR r (O)R r , NR r (O)NR r R r , NR r C(O)OR r , C(═NR r )NR r R r , NR r C(═NR r )R r R r , NR r C(═NOH)NR r R r  NR r C(═NCN)NR r R r , S(O)R r , S(O)NR r R r , S(O) 2 R r , NR r S(O) 2 R r , NR r S(O) 2 NR r R r  and S(O) 2 NR r R r , wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-10  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-4  alkyl-, C 3-10  cycloalkyl-C 1-4  alkyl-, (5-10 membered heteroaryl)-C 1-4  alkyl- and (4-10 membered heterocycloalkyl)-C 1-4  alkyl- of R p  is optionally substituted with 1, 2 or 3 R q  substituents; 
 or any two R a  substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 R h  substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 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 , NR i C(═NOH)NR i R i , NR i C(═NCN)NR i R i , S(O)R i , S(O)NR i R i , S(O) 2 R i , NR i S(O) 2 R i , NR i S(O) 2 NR i R i , and S(O) 2 NR i R i , wherein the C 1-6  alkyl, C 1-6  haloalkyl, C 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- of R h  are each optionally substituted by 1, 2, or 3 R j  substituents independently selected from C 1-4  alkyl, C 3-6  cycloalkyl, C 6-10  aryl, 5- or 6-membered heteroaryl, C 2-4  alkenyl, C 2-4  alkynyl, halo, C 1-4  haloalkyl, C 1-4  haloalkoxy, CN, NHOR k , OR k , SR k , C(O)R k , C(O)NR k R k , C(O)OR k , OC(O)R k , OC(O)NR k R k , NHR k , NR k R k , NR k C(O)R k , NR k C(O)NR k R k , NR k C(O)OR k , C(═NR k )NR k R k , NR k C(═NR k )NR k R k , S(O)R k , S(O)NR k R k , S(O) 2 R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , and S(O) 2 NR k R k ; 
 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; and 
 or any two R r  substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h  substituents; 
 each R i , R k , R o  or R r  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, C 6-10  aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 1 -4 haloalkyl, C 2-4  alkenyl, and C 2-4  alkynyl, wherein the C 1-4  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, C 6-10  aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 2-4  alkenyl, and C 2-4  alkynyl of R i , R k , R o  or R r  are each optionally substituted with 1, 2 or 3 R q  substituents; and 
 each R q  is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6  haloalkyl, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6  cycloalkyl, NHR 13  and NR 13 R 13 , wherein the C 1-6  alkyl, phenyl, C 3-6  cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, phenyl, C 3-10  cycloalkyl and 4-6 membered heterocycloalkyl and each R 13  is independently C 1-6  alkyl. 
 
     
     
         2 .- 29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         31 . 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. 
     
     
         32 . 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. 
     
     
         33 . A method of enhancing, stimulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof.