HETEROCYCLIC COMPOUNDS AS IMMUNOMODULATORS

• US 20170145025A1
• Filed: 11/18/2016
• Published: 05/25/2017
• Est. Priority Date: 11/19/2015
• Status: Abandoned Application

• Current Assignee: Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Li, Jingwei, Wu, Liangxing, Yao, Wenqing
• Application Number:
  US15/355,494
• Publication Number:
  US 20170145025A1
• Time in Patent Office: Days
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 263/57 Aryl or substituted aryl radicals
• CPC Class Codes: C07D 277/66 with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

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.

Claims

1. A compound of Formula (I′

);

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

one of X¹ and X² is O or S and the other of X¹ and X² is N, CR¹ or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

at least one of X¹, X², X³, X⁴, X⁵ and X⁶ is N;

Y¹ is N or CR^8a;

Y² is N or CR^8b;

Y³ is N or CR^8c;

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, 2, 3, 4 or 5 independently selected R⁷ substituents;

R¹, R², R^8a, R^8b and R^8c are each independently selected from H, C_1-4 alkyl, C_3-6 cycloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo, CN, OH, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, NH₂, —

NH—

C_1-4 alkyl, —

N(C_1-4 alkyl)₂, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═

NR¹⁰)R¹⁰, C(═

NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═

NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰, NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ is independently H or 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 and C_2-4 alkynyl of R¹, R², R^8a, R^8b, or R^8c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C_1-4 alkyl and C_1-4 alkoxy;

R⁹ is C_1-4 alkyl, Cl, Br, CN, cyclopropyl, C_2-4 alkynyl, C_1-4 haloalkyl, C_1-4 haloalkoxy, NH₂, —

NH—

C_1-4 alkyl, —

N(C_1-4 alkyl)₂, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, C(═

NR¹¹)R¹¹, C(═

NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹, wherein the C_1-4 alkyl, cyclopropyl, C_2-4 alkynyl and C_1-4 alkoxy of R⁹ are each optionally substituted with 1 or 2 halo, OH, CN or OCH₃ substituents and each R¹¹ is independently H or C_1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH₃;

R³, R⁴, R⁵, R⁶ and R⁷ 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, NO₂, OR^a, SR^a, NHOR^a, C(O)R^a, C(O)NR^aR^a, C(O)OR^a, OC(O)R^a, OC(O)NR^aR^a, NHR^a, NR^aR^a, NR^aC(O)R^a, NR^aC(O)OR^a, NR^aC(O)NR^aR^a, C(═

NR^a)R^a, C(═

NR^a)NR^aR^a, NR^aC(═

NR^a)NR^aR^a, NR^aS(O)R^a, NR^aS(O)₂R^a, NR^aS(O)₂NR^aR^a, S(O)R^a, S(O)NR^aR^a, S(O)₂R^a, and S(O)₂NR^aR^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 R³, R⁴, R⁵, R⁶ and R⁷ are each optionally substituted with 1, 2, 3, or 4 R^b substituents, with the proviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H;

or two adjacent R⁷ substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C_5-6 cycloalkyl ring, wherein the fused 5- to 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- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C_5-6 cycloalkyl ring are each optionally substituted with 1 or 2 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, NH₂, NHOR^e, OR^e, SR^e, C(O)R^e, C(O)NR^eR^e, C(O)OR^e, OC(O)R^e, OC(O)NR^eR^e, NHR^e, NR^eR^e, NR^eC(O)R^e, NR^eC(O)NR^eR^e, NR^eC(O)OR^e, C(═

NR^e)NR^eR^e, NR^eC(═

NR^e)NR^eR^e, S(O)R^e, S(O)NR^eR^e, S(O)₂R^e, NR^eS(O)₂R^e, NR^eS(O)₂NR^eR^e, and S(O)₂NR^eR^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, NH₂, NO₂, NHOR^c, SR^c, C(O)R^c, C(O)NR^cR^c, C(O)OR^c, OC(O)R^c, OC(O)NR^cR^c, C(═

NR^c)NR^cR^c, NR^cC(═

NR^c)NR^cR^c, NHR^c, NR^cR^c, NR^cC(O)R^c, NR^cC(O)OR^c, NR^cC(O)NR^cR^c, NR^cS(O)R^c, NR^cS(O)₂R^c, NR^cS(O)₂NR^cR^c, S(O)R^c, S(O)NR^cR^c, S(O)₂R^c and S(O)₂NR^cR^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^gR^g, C(O)OR^g, OC(O)R^g, OC(O)NR^gR^g, NHR^g, NR^gR^g, NR^gC(O)R^g, NR^gC(O)NR^gR^g, NR^gC(O)OR^g, C(═

NR^g)NR^gR^g, NR^gC(═

NR^g)NR^gR^g, S(O)R^g, S(O)NR^gR^g, S(O)₂R^g, NR^gS(O)₂R^g, NR^gS(O)₂NR^gR^g, and S(O)₂NR^gR^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 Rⁿ substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, halo, CN, R^o, NHOR^o, OR^o, SR^o, C(O)R^o, C(O)NR^oR^o, C(O)OR), OC(O)R^o, OC(O)NR^oR^o, NHR^o, NR^oR^o, NR^oC(O)R^o, NR^oC(O)NR^oR^o, NR^oC(O)OR^o, C(═

NR^o)NR^oR^o, NR^oC(═

NR^o)NR^oR^o, S(O)R^o, S(O)NR^oR^o, S(O)₂R^o, NR^oS(O)₂R^o, NR^oS(O)₂NR^oR^o, and S(O)₂NR^oR^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, ORⁱ, SRⁱ, NHORⁱ, C(O)Rⁱ, C(O)NRⁱRⁱ, C(O)ORⁱ, OC(O)Rⁱ, OC(O)NRⁱRⁱ, NHRⁱ, NRⁱRⁱ, NRⁱC(O)Rⁱ, NRⁱC(O)NRⁱRⁱ, NRⁱC(O)ORⁱ, C(═

NRⁱ)NRⁱRⁱ, NRⁱC(═

NRⁱ)NRⁱRⁱ, S(O)Rⁱ, S(O)NRⁱRⁱ, S(O)₂Rⁱ, NRⁱS(O)₂Rⁱ, NRⁱS(O)₂NRⁱRⁱ, and S(O)₂NRⁱRⁱ, 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-, and (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^kR^k, C(O)OR^k, OC(O)R^k, OC(O)NR^kR^k, NHR^k, NR^kR^k, NR^kC(O)R^k, NR^kC(O)NR^kR^k, NR^kC(O)OR^k, C(═

NR^k)NR^kR^k, NR^kC(═

NR^k)NR^kR^k, S(O)R^k, S(O)NR^kR^k, S(O)₂R^k, NR^kS(O)₂R^k, NR^kS(O)₂NR^kR^k, and S(O)₂NR^kR^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 attach form a C_3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N and 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 Rⁱ 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^k 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;

each R^e, Rⁱ, R^k, R^o or R^p is independently selected from H, C_1-4 alkyl, C_3-6 cycloalkyl, 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, Rⁱ, 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, NH₂, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C_3-6 cycloalkyl, NHR¹², NR¹²R¹², and C_1-4 haloalkoxy, wherein the C_1-4 alkyl, phenyl and 5-6 membered heteroaryl of R^q are each optionally substituted with OH, CN, —

COOH, NH₂, C_1-4 alkoxy, C_3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R¹² is independently C_1-6 alkyl;

is a single bond or a double bond to maintain ring A being aromatic; and

when the moiety

3. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents.

4. The compound of any one of claims 1-3, having Formula (I):

5. The compound of any one of claims 1-4, having Formula (II):

6. The compound of any one of claims 1-5, having Formula (III):

7. The compound of any one of claims 1-6, having Formula (IV):

8. The compound of any one of claims 1-5, having Formula (V):

9. The compound of any one of claims 1-5, having Formula (VI):

10. The compound of any one of claims 1-5, having Formula (VII):

11. The compound of any one of claims 1-5, having Formula (VIII):

12. The compound of any one of claims 1-5, having Formula (IX):

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the the moiety:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R¹, R², R³ and R⁵, when present, are each H.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R³ and R⁵ are each H.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R⁴ and R⁶ are each H.

17. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is CH, X² is O, X³ is N and X⁵ and X⁶ are each CH.

18. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is CH, X³ is N, X⁵ is CH and X⁶ is CR⁶.

19. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is CH, X³ is CH, X⁵ is N and X⁶ is CR⁶.

20. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is N, X³ is CH, X⁵ is CH and X⁶ is CR⁶.

21. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is CH, X³ is CH, X⁵ is CH and X⁶ is N.

22. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is S, X² is N, X³ is CH, X⁵ is CH and X⁶ is CR⁶.

23. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is N, X² is S, X³ is CH, X⁵ is CH and X⁶ is CR⁶.

24. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is CH, X³ is CH, X⁵ is CH and X⁶ is N.

25. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is N, X³ is CH and X⁶ is CR⁶.

26. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X² is O, X¹ is N, X³ is CH and X⁶ is CR⁶.

27. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O, X² is N, X³ is CH, X⁵ is N and X⁶ is CR⁶.

28. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹ is O or S and X² is N or CR².

29. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X² is O or S and X¹ is N or CR¹.

30. The compound of any one of claims 1-15 and 17-29, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁴ is —

CH₂—

R^h.

31. The compound of any one of claims 1-13, 16, and 25-29, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁵ is —

CH₂—

R^h.

32. The compound of claim 30 or 31, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R^h is —

NHR^c.

33. The compound of claim 32, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R^c is C_1-4 alkyl optionally substituted with a R^d substituent.

34. The compound of any one of claims 1-15 and 17-33, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁴ is 2-hydroxyethylaminomethyl.

35. The compound of claim 30 or 31, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R^b is —

NR^cR^c.

36. The compound of claim 35, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein 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.

37. The compound of claim 36, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein two R^c substituents together with the nitrogen atom to which they are attached form a 6-membered heterocycloalkyl substituted with 1 R^h substituent.

38. The compound of any one of claims 1-15 and 17-31, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁴ is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl or (R)-2-carboxypiperidin-1-ylmethyl.

39. The compound of any one of claims 1-13 and 25-29 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁴ and R⁵ are each independently selected from 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl, (3-cyanophenyl)methoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 2-morpholino-4-ylethoxy and pyridin-2-ylmethoxy.

40. The compound of any one of claims 1-4, wherein the compound is selected from:

2-({[2-(2-methylbiphenyl-3-yl)furo[2,3-b]pyridin-6-yl]methyl}amino)ethanol;

(2S)-1-{[2-(2-methylbiphenyl-3-yl)furo[2,3-b]pyridin-6-yl]methyl}piperidine-2-carboxylic acid;

2-({[7-methyl-2-(2-methylbiphenyl-3-yl)furo[3,2-b]pyridin-5-yl]methyl}amino)ethanol;

(2S)-1-{[7-methyl-2-(2-methylbiphenyl-3-yl)furo[3,2-b]pyridin-5-yl]methyl}piperidine-2-carboxylic acid;

2-({[7-methyl-2-(2-methylbiphenyl-3-yl)furo[2,3-c]pyridin-5-yl]methyl}amino)ethanol;

(2S)-1-{[7-methyl-2-(2-methylbiphenyl-3-yl)furo[2,3-c]pyridin-5-yl]methyl}piperidine-2-carboxylic acid;

(2S)-1-{[2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

2-({[2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}amino)ethanol;

(2S)-1-{[2-(2-methylbiphenyl-3-yl)furo[2,3-b]pyridin-5-yl]methyl}piperidine-2-carboxylic acid;

2-({[2-(2-methylbiphenyl-3-yl)furo[2,3-b]pyridin-5-yl]methyl}amino)ethanol;

(2S)-1-{[7-methyl-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

2-({[7-methyl-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}amino)ethanol;

(2S)-1-{[2-(2-cyanobiphenyl-3-yl)-7-methyl-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

3-(5-{[(2-hydroxyethyl)amino]methyl}-7-methyl-1,3-benzoxazol-2-yl)biphenyl-2-carbonitrile;

(2S)-1-({2-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-7-methyl-1,3-benzoxazol-5-yl}methyl)piperidine-2-carboxylic acid;

2-[({2-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-7-methyl-1,3-benzoxazol-5-yl}methyl)amino]ethanol;

(2S)-1-({2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-7-methyl-1,3-benzoxazol-5-yl}methyl)piperidine-2-carboxylic acid;

2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(5-{[(2-hydroxyethyl)amino]methyl}-7-methyl-1,3-benzoxazol-2-yl)benzonitrile;

(2S)-1-{[2-(2-methylbiphenyl-3-yl)-1,3-benzothiazol-5-yl]methyl}piperidine-2-carboxylic acid;

(2S)-1-{[2-(2-methylbiphenyl-3-yl)furo[3,2-b]pyridin-5-yl]methyl}piperidine-2-carboxylic acid;

2-({[2-(2-methylbiphenyl-3-yl)furo[3,2-b]pyridin-5-yl]methyl}amino)ethanol;

(2S)-1-{[4-methyl-2-(2-methylbiphenyl-3-yl)-1,3-benzothiazol-6-yl]methyl}piperidine-2-carboxylic acid;

2-({[4-methyl-2-(2-methylbiphenyl-3-yl)-1,3-benzothiazol-6-yl]methyl}amino)ethanol;

2-({[6-(2-methylbiphenyl-3-yl)furo[2,3-b]pyrazin-2-yl]methyl}amino)ethanol; and

(2 S)-1-{[6-(2-methylbiphenyl-3-yl)furo[2,3-b]pyrazin-2-yl]methyl}piperidine-2-carboxylic acid;

or

a pharmaceutically acceptable salt or a stereoisomer thereof.

41. The compound of any one of claims 1-4, wherein the compound is selected from:

(2S)-1-{[6-(cyanomethoxy)-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

{[5-1[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-6-yl]oxyl acetonitrile;

(2S)-1-{[6-(3-cyanopropoxy)-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

3-({[5-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-6-yl]oxy}methyl)benzonitrile;

2-({[2-(2-methylbiphenyl-3-yl)-6-(pyridin-2-ylmethoxy)-1,3-benzoxazol-5-yl]methyl}amino)ethanol;

2-({[6-methoxy-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-5-yl]methyl}amino)ethanol;

2-({[2-(2-methylbiphenyl-3-yl)-6-(2-morpholin-4-ylethoxy)-1,3-benzoxazol-5-yl]methyl}amino) ethanol;

2-({[2-(2-methylbiphenyl-3-yl)[1,3]oxazolo[5,4-c]pyridin-6-yl]methyl}amino) ethanol;

4-{[5-{[(2-hydroxyethyl)amino]methyl}-7-methyl-2-(2-methylbiphenyl-3-yl)-1,3-benzoxazol-6-yl]oxy}butanenitrile;

(2S)-1-({6-(cyanomethoxy)-2-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-2-yl]-1,3-benzoxazol-5-yl}methyl)piperidine-2-carboxylic acid;

(2S)-1-({6-(cyanomethoxy)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-1,3-benzoxazol-5-yl}methyl)piperidine-2-carboxylic acid;

(2S)-1-{[2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6-(cyanomethoxy)-1,3-benzoxazol-5-yl]methyl}piperidine-2-carboxylic acid;

(2S)-1-{[2(2-methylbiphenyl-3-yl)-1,3-benzoxazol-6-yl]methyl}piperidine-2-carboxylic acid;

[(2-(2′

-fluoro-2-methylbiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}-1,3-benzoxazol-6-yl)oxy]acetonitrile; and

[(2-(3-cyclohex-1-en-1-yl-2-methylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}-1,3-benzoxazol-6-yl)oxy]acetonitrile;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

42. A pharmaceutical composition comprising a compound of any of claims 1-41 or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

43. A method of inhibiting PD-1/PD-L1 interaction in an individual, said method comprising administering to the individual a compound of any of claims 1-41 or a pharmaceutically acceptable salt or a stereoisomer thereof.

44. 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 any of claims 1-41, or a pharmaceutically acceptable salt, or a stereoisomer thereof or a composition of claim 42.

45. The method of claim 44, wherein the disease or disorder is a viral infection or cancer.

46. 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 any of claims 1-41, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition of claim 42.