Heterocyclic compounds as immunomodulators

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 R6 substituents;
• L is a bond, —C(O)NR13—, or —NR13C(O);
• R3 is methyl, halo, or CN;
• R5 is C1-4 alkyl, C1-4 alkoxy, CN, halo, or OH;
• each R6 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, and NRaC(O)Ra, wherein the C1-6 alkyl, C2 alkenyl, and C2-6 alkynyl of R6 are each optionally substituted with 1 or 2 Rb substituents;
• R7 is C1-4 alkyl, C1-4 alkoxy, CN, halo, OH, or —COOH, wherein the C1-4 alkyl and C1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo or —C(O)NH2;
• R8 and R9 are each independently selected from H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy of R8 or R9 are each optionally substituted with 1 or 2 independently selected Rq substituents;
• R10 and R11 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl of R10 or R11 are each optionally substituted with 1 or 2 independently selected Rf substituents;
• each R13 is independently H, C1-6 haloalkyl or C1-6 alkyl optionally substituted with a substituent selected from C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, and OH;
• each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRcC(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, and NRcC(O)Rc;
• each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1 or 2 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, and NRgC(O)Rg;
• each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rq is independently selected from halo, OH, CN, —COOH, NH2, —NH—C1-6 alkyl, —N(C1-6 alky)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• and
• the subscript p is an integer of 1, 2, 3 or 4.

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 R6 substituents;
• L is a bond, —C(O)NR13—, or —NR13C(O)—;
• R3 is methyl, halo, or CN;
• R5 is C1-4 alkyl, C1-4 alkoxy, CN, halo, or OH;
• each R6 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 haloalkyl, C1-6 haloalkoxy, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, and NRaC(O)Ra, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R6 are each optionally substituted with 1 or 2 Rb substituents;
• R7 is C1-4 alkyl, C1-4 alkoxy, CN, halo, OH, or —COOH, wherein the C1-4 alkyl and C1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo or —C(O)NH2;
• R8 and R9 are each independently selected from H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy of R8 or R9 are each optionally substituted with 1 or 2 independently selected Rq substituents;
• R10 and R11 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl of R10 or R11 are each optionally substituted with 1 or 2 independently selected Rf substituents;
• each R13 is independently H, C1-6 haloalkyl or C1-6 alkyl optionally substituted with a substituent selected from C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, and OH;
• each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, and NRcC(O)Rc;
• each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1 or 2 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, and NRgC(O)Rg;
• each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rq is independently selected from halo, OH, CN, —COH, NH2, —NH—C1-6 alkyl, —N(C1-6 alky), C1-6 alkyl C1-6alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• and
• the subscript p is an integer of 1, 2, 3 or 4.

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 R6 substituents;
• L is a bond, —C(O)NR13—, or —NR13C(O;
• R3 is methyl, halo, or CN;
• R5 is C1-4 alkyl, C1-4 alkoxy, CN, halo, or OH;
• each R6 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)RaOC(O)NRaRa, NRa, NRaRa, and NRaC(O)Ra, wherein the C6 alkyl, C2 alkenyl, and C2-6 alkynyl of R6 are each optionally substituted with 1 or 2 Rb substituents;
• R7 is C1-4 alkyl, C1-4 alkoxy, CN, halo, OH, or —COOH, wherein the C1-4 alkyl and C1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo or —C(O)NH2;
• R8 and R9 are each independently selected from H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy of R8 or R9 are each optionally substituted with 1 or 2 independently selected Rq substituents;
• R10 and R11 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl of R10 or R11 are each optionally substituted with 1 or 2 independently selected Rf substituents;
• each R13 is independently H, C1-6 haloalkyl or C1-6 alkyl optionally substituted with a substituent selected from C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, and OH;
• each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, and NRcC(O)Rc;
• each Rc is independently selected from H, C1-6 alkyl C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1 or 2 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, and NRgC(O)Rg;
• each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rq is independently selected from halo, OH, CN, —COOH, NH2, —NH—C1-6 alkyl, —N(C1-6 alky), C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• and
• the subscript p is an integer of 1, 2, 3 or 4.