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 .- 32 . (canceled) 
     
     
         33 . A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to an individual a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 X 1  is O, S, N, NR 1  or CR 1 ; 
 X 2  is N or C; 
 X 3  is O, S, N, NR 3  or CR 3 ; 
 X 4  is N or CR 4 ; 
 X 5  is N or CR 5 ; 
 X 6  is N or CR 6 ; 
 Y is C or N; 
 at least one of X 1 , X 2 , X 3  and Y is a heteroatom selected from N, O and S, wherein N is optionally substituted by R 1  or R 3 ; 
 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 7  substituents; 
 R 1 , R 3 , R 4 , R 5  and R 6  are each independently selected from H, C 1-4  alkyl, C 3-4 cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo, CN, OH, C 1-4  alkoxy, C 1-4  haloalkyl, C 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)R 10 , NR 10 S(O) 2 NR 10 R 10 , S(O)R 10 , S(O)NR 10 R 10 , S(O)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 3-4  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 1 , R 3 , R 4 , R 5  and R 6  are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN and C 1-4  alkoxy; 
 R 9  is C 1-4  alkyl, halo, CN, OH, cyclopropyl, C 2-4  alkenyl, 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 C 1-4  alkyl, cyclopropyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 9  are each optionally substituted with 1 or 2 substituents selected from halo, OH, CN and OCH 3  and 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  substituents; 
 R 7 , R 13  and R 14  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 N 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 7 , R 13  and R 14  are each optionally substituted with 1, 2, 3, or 4 R b  substituents; 
 or two adjacent R 7  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; 
 or two R 13  substituents attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a C 3-6  cycloalkyl ring or 4-, 5-, 6- or 7-membered heterocycloalkyl ring, wherein the C 3-6  cycloalkyl ring and 4-, 5-, 6- or 7-membered heterocycloalkyl 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-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(ON)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)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)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-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, 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 ; 
 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-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)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-, (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)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 
 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  haloalkoxy, C 1-6  alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6  cycloalkyl, NHR 12 , NR 12 R 12 , 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 12  is independently C 1-6  alkyl; 
    is a single bond or a double bond to maintain ring A being aromatic; 
 the subscript n is an integer of 1, 2, 3, 4, 5 or 6; and 
 when R 9  is OH, Cy is other than 6-carbamimidoyl-1H-benzo[d]imidazol-2-yl. 
 
     
     
         34 . 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 Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 X 1  is O, S, N, NR 1  or CR 1 ; 
 X 2  is N or C; 
 X 3  is O, S, N, NR 3  or CR 3 ; 
 X 4  is N or CR 4 ; 
 X 5  is N or CR 5 ; 
 X 6  is N or CR 6 ; 
 Y is C or N; 
 at least one of X 1 , X 2 , X 3  and Y is a heteroatom selected from N, O and S, wherein N is optionally substituted by R 1  or R 3 ; 
 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 7  substituents; 
 R 1 , R 3 , R 4 , R 5  and R 6  are each independently selected from H, C 1-4  alkyl, C 3-4  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 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 3-4  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 1 , R 3 , R 4 , R 5  and R 6  are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN and C 1-4  alkoxy; 
 R 9  is C 1-4  alkyl, halo, CN, OH, cyclopropyl, C 2-4  alkenyl, 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)R 11 , and S(O) 2 NR 11 R 11 , wherein C 1-4  alkyl, cyclopropyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 9  are each optionally substituted with 1 or 2 substituents selected from halo, OH, CN and OCH 3  and 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  substituents; 
 R 7 , R 13  and R 14  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)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 7 , R 13  and R 14  are each optionally substituted with 1, 2, 3, or 4 R b  substituents; 
 or two adjacent R 7  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; 
 or two R 13  substituents attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a C 3-6  cycloalkyl ring or 4-, 5-, 6- or 7-membered heterocycloalkyl ring, wherein the C 3-6  cycloalkyl ring and 4-, 5-, 6- or 7-membered heterocycloalkyl 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 1-4  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)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, 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, 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)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-, (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(═N 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)NR k R k , and S(O)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 
 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 2-6  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  haloalkoxy, C 1-6  alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6  cycloalkyl, NHR 12 , NR 12 R 12 , 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 12  is independently C 1-6  alkyl 
 
         is a single bond or a double bond to maintain ring A being aromatic;
 the subscript n is an integer of 1, 2, 3, 4, 5 or 6; and   when R 9  is OH, Cy is other than 6-carbamimidoyl-1H-benzo[d]imidazol-2-yl.   
     
     
         35 . The method of  claim 34 , wherein the disease or disorder is a viral infection or cancer. 
     
     
         36 . 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 Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 X 1  is O, S, N, NR 1  or CR 1 ; 
 X 2  is N or C; 
 X 3  is O, S, N, NR 3  or CR 3 ; 
 X 4  is N or CR 4 ; 
 X 5  is N or CR 5 ; 
 X 6  is N or CR 6 ; 
 Y is C or N; 
 at least one of X 1 , X 2 , X 3  and Y is a heteroatom selected from N, O and S, wherein N is optionally substituted by R 1  or R 3 ; 
 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 7  substituents; 
 R 1 , R 3 , R 4 , R 5  and R 6  are each independently selected from H, C 1-4  alkyl, C 3-4  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)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 3-4  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 1 , R 3 , R 4 , R 5  and R 6  are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN and C 1-4  alkoxy; 
 R 9  is C 1-4  alkyl, halo, CN, OH, cyclopropyl, C 2-4  alkenyl, 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)R 11 , and S(O) 2 NR 11 R 11 , wherein C 1-4  alkyl, cyclopropyl, C 2-4  alkenyl, C 2-4  alkynyl and C 1-4  alkoxy of R 9  are each optionally substituted with 1 or 2 substituents selected from halo, OH, CN and OCH 3  and 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  substituents; 
 R 7 , R 13  and R 14  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 N 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 7 , R 13  and R 14  are each optionally substituted with 1, 2, 3, or 4 R b  substituents; 
 or two adjacent R 7  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; 
 or two R 13  substituents attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a C 3-6  cycloalkyl ring or 4-, 5-, 6- or 7-membered heterocycloalkyl ring, wherein the C 3-6  cycloalkyl ring and 4-, 5-, 6- or 7-membered heterocycloalkyl 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-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-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)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)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-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, 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 ; 
 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-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, (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)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 
 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 2-6  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  haloalkoxy, C 1-6  alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6  cycloalkyl, NHR 12 , NR 12 R 12 , 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 12  is independently C 1-6  alkyl; 
    is a single bond or a double bond to maintain ring A being aromatic; 
 the subscript n is an integer of 1, 2, 3, 4, 5 or 6; and 
 when R 9  is OH, Cy is other than 6-carbamimidoyl-1H-benzo[d]imidazol-2-yl.