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 - 31 . (canceled) 
     
     
         32 . A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of Formula (IIb): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 ring A is 5- to 10-membered heteroaryl or 4- to 11-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1 or 2 R 6  substituents; 
 L is a bond, —C(O)NR 13 —, or —NR 13 C(O); 
 R 3  is methyl, halo, or CN; 
 R 5  is C 1-4  alkyl, C 1-4  alkoxy, 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, 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 , and NR a C(O)R a , wherein the C 1-6  alkyl, C 2  alkenyl, and C 2-6  alkynyl of R 6  are each optionally substituted with 1 or 2 R b  substituents; 
 R 7  is C 1-4  alkyl, C 1-4  alkoxy, CN, halo, OH, or —COOH, 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 or —C(O)NH 2 ; 
 R 8  and R 9  are each independently selected from H, halo, CN, OH, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy, wherein the C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy of R 8  or R 9  are each optionally substituted with 1 or 2 independently selected R q  substituents; 
 R 10  and R 11  are each independently selected from H, C 1-6  alkyl, and C 1-6  haloalkyl, 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; 
 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, and OH; 
 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 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 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , and NR c C(O)R c ; 
 each R c  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R c  are each optionally substituted with 1 or 2 R f  substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , and NR g C(O)R g ; 
 each R g  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 each R 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  haloalkyl, and C 1-6  haloalkoxy; and 
 the subscript p is an integer of 1, 2, 3 or 4. 
 
     
     
         33 . 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 (IIb): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 ring A is 5- to 10-membered heteroaryl or 4- to 11-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1 or 2 R 6  substituents; 
 L is a bond, —C(O)NR 13 —, or —NR 13 C(O)—; 
 R 3  is methyl, halo, or CN; 
 R 5  is C 1-4  alkyl, C 1-4  alkoxy, 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 2-6  haloalkyl, C 1-6  haloalkoxy, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , and NR a C(O)R a , wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R 6  are each optionally substituted with 1 or 2 R b  substituents; 
 R 7  is C 1-4  alkyl, C 1-4  alkoxy, CN, halo, OH, or —COOH, 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 or —C(O)NH 2 ; 
 R 8  and R 9  are each independently selected from H, halo, CN, OH, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy, wherein the C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy of R 8  or R 9  are each optionally substituted with 1 or 2 independently selected R q  substituents; 
 R 10  and R 11  are each independently selected from H, C 1-6  alkyl, and C 1-6  haloalkyl, 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; 
 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, and OH; 
 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 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 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , and NR c C(O)R c ; 
 each R c  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R c  are each optionally substituted with 1 or 2 R f  substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , and NR g C(O)R g ; 
 each R g  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 each R q  is independently selected from halo, OH, CN, —COH, NH 2 , —NH—C 1-6  alkyl, —N(C 1-6  alky), C 1-6  alkyl C 1-6 alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; and 
 the subscript p is an integer of 1, 2, 3 or 4. 
 
     
     
         34 . 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 (IIb): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
 ring A is 5- to 10-membered heteroaryl or 4- to 11-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1 or 2 R 6  substituents; 
 L is a bond, —C(O)NR 13 —, or —NR 13 C(O; 
 R 3  is methyl, halo, or CN; 
 R 5  is C 1-4  alkyl, C 1-4  alkoxy, 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, 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 , NR a , NR a R a , and NR a C(O)R a , wherein the C 6  alkyl, C 2  alkenyl, and C 2-6  alkynyl of R 6  are each optionally substituted with 1 or 2 R b  substituents; 
 R 7  is C 1-4  alkyl, C 1-4  alkoxy, CN, halo, OH, or —COOH, 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 or —C(O)NH 2 ; 
 R 8  and R 9  are each independently selected from H, halo, CN, OH, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy, wherein the C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy of R 8  or R 9  are each optionally substituted with 1 or 2 independently selected R q  substituents; 
 R 10  and R 11  are each independently selected from H, C 1-6  alkyl, and C 1-6  haloalkyl, 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; 
 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, and OH; 
 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 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 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , and NR c C(O)R c ; 
 each R c  is independently selected from H, C 1-6  alkyl C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R c  are each optionally substituted with 1 or 2 R f  substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , and NR g C(O)R g ; 
 each R g  is independently selected from H, C 1-6  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 each R q  is independently selected from halo, OH, CN, —COOH, NH 2 , —NH—C 1-6  alkyl, —N(C 1-6  alky), C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; and 
 the subscript p is an integer of 1, 2, 3 or 4.