Heterocyclic compounds as immunomodulators
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:
R 1 is methyl, CN, F, Cl, or Br;
R 2 is methyl, CN, F, Cl, or Br; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl or 4- to 6-membered heterocycloalkyl-C 1-2 alkyl-, wherein the 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 alkyl- each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 alkyl- of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, OH, CON(CH 3 ) 2 , CH 3 , F, Cl, Br, CN, ethyl, and propyl.
2. A compound of Formula I:
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl, CN, F, Cl, or Br;
R 2 is methyl, CN, F, Cl, or Br; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl or 4- to 6-membered heterocycloalkyl-C 1-2 alkyl-, wherein the 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 alkyl- each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-2 alkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 alkyl- of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, and OH.
3. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is methyl, F, Cl, or Br.
4. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is methyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is F, Cl, or Br.
6. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is Cl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is methyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is CN.
9. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is F, Cl, or Br.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is Cl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is Cl and R 2 is Cl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is Cl and R 2 is methyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is methyl and R 2 is Cl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is Cl and R 2 is CN.
15. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is methyl and R 2 is methyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, OH, CON(CH 3 ) 2 , and CH 3 .
17. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, and OH.
18. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H.
19. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from COOH, OH, and CON(CH 3 ) 2 .
20. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from COOH and OH.
21. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl, 2-carboxy-2-methylpropyl, or 4-carboxybutyl.
22. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl or 2-carboxy-2-methylpropyl.
23. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 3-8 cycloalkyl, optionally substituted with 1 or 2 substituents independently selected from COOH, OH, and CH 3 .
24. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 3-8 cycloalkyl, optionally substituted with 1 or 2 substituents independently selected from COOH and OH.
25. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 3-8 cycloalkyl-C 1-2 alkyl-, optionally substituted with 1 or 2 substituents independently selected from COOH and OH.
26. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is C 6-10 aryl-C 1-2 alkyl, optionally substituted with 1 or 2 substituents independently selected from COOH and OH.
27. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, 4-carboxyphenethyl, (4-carboxycyclohexyl)ethyl, or 4-carboxy-4-methylcyclohexyl.
28. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, or 4-carboxyphenethyl.
29. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is 5- to 6-membered heteroaryl-C 1-2 alkyl, optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , and COOH.
30. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is 4- to 6-membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , and COOH.
31. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is (1H-pyrazol-3-yl)methyl, tetrahydro-2H-pyran-4-yl, 1-carbamoylpiperidin-4-yl, 1-sulfamoylpiperidin-4-yl, or (3-carboxy-1H-pyrazol-5-yl)methyl.
32. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H, methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl, 2-carboxy-2-methylpropyl, cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, 4-carboxyphenethyl, (1H-pyrazol-3-yl)methyl, tetrahydro-2H-pyran-4-yl, 1-carbamoylpiperidin-4-yl, 1-sulfamoylpiperidin-4-yl, (3-carboxy-1H-pyrazol-5-yl)methyl, 4-carboxybutyl, (4-carboxycyclohexyl)ethyl, or 4-carboxy-4-methylcyclohexyl.
33. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H, methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl, 2-carboxy-2-methylpropyl, cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, 4-carboxyphenethyl, (1H-pyrazol-3-yl)methyl, tetrahydro-2H-pyran-4-yl, 1-carbamoylpiperidin-4-yl, 1-sulfamoylpiperidin-4-yl, or (3-carboxy-1H-pyrazol-5-yl)methyl.
34. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl, CN, F, Cl, or Br;
R 2 is methyl, CN, F, Cl, or Br; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, OH, CON(CH 3 ) 2 , and CH 3 .
35. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl, CN, F, Cl, or Br;
R 2 is methyl, CN, F, Cl, or Br; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, and OH.
36. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl or Cl;
R 2 is methyl, CN, or Cl; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, OH, CON(CH 3 ) 2 , and CH 3 .
37. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl or Cl;
R 2 is methyl, CN, or Cl; and
R 3 is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl-C 1-2 alkyl and 4- to 6-membered heterocycloalkyl each has one or two heteroatoms as ring members selected from O, N and S, and wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl-, C 6-10 aryl-C 1-2 alkyl, 5- to 6-membered heteroaryl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl of R 3 are each optionally substituted with 1 or 2 substituents independently selected from CONH 2 , SO 2 NH 2 , COOH, and OH.
38. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl or Cl;
R 2 is methyl, CN, or Cl; and
R 3 is H, methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl, 2-carboxy-2-methylpropyl, cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, 4-carboxyphenethyl, (1H-pyrazol-3-yl)methyl, tetrahydro-2H-pyran-4-yl, 1-carbamoylpiperidin-4-yl, 1-sulfamoylpiperidin-4-yl, (3-carboxy-1H-pyrazol-5-yl)methyl, 4-carboxybutyl, (4-carboxycyclohexyl)ethyl, or 4-carboxy-4-methylcyclohexyl.
39. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R 1 is methyl or Cl;
R 2 is methyl, CN, or Cl; and
R 3 is H, methyl, ethyl, isopropyl, 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 3-carboxypropyl, 2-carboxy-2-methylpropyl, cyclobutyl, 4-hydroxycyclohexyl, (1-carboxycyclopropyl)methyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, (3-carboxybicyclo[1.1.1]pentan-1-yl)methyl, 4-carboxyphenethyl, (1H-pyrazol-3-yl)methyl, tetrahydro-2H-pyran-4-yl, 1-carbamoylpiperidin-4-yl, 1-sulfamoylpiperidin-4-yl, or (3-carboxy-1H-pyrazol-5-yl)methyl.
40. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.
41. A pharmaceutical composition comprising a compound of claim 20 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.