IP Library › Granted Patent US 12,247,038
Granted Patent B2
US 12,247,038 · App. 17/850,505 · Granted Mar 11, 2025

Pyrido[3,2-d]pyrimidine compounds as immunomodulators

Inventors: Jingwei Li (Westfield, NJ); Liangxing Wu (Wilmington, DE); Wenqing Yao (Chadds Ford, PA)
Assignee: Incyte Corporation
C07D519/00
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Quick Facts
Patent No.
US 12,247,038
App. No.
17/850,505
Granted
Mar 11, 2025
Kind
B2
Abstract

The present disclosure is directed to compounds of Formula (I): which modulate PD-1/PD-L1 protein/protein interaction, compositions, and methods of treating various diseases, including infectious diseases and cancer.

Claims (42)

1. A compound selected from:

(S)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

(S)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

(R)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

(R)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(pyrrolidin-1-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

(R)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,l′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,l′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,l′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxyazetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

(S)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid; and

(S)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is(S)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is(S)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is (R)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is (R)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(pyrrolidin-1-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is (R)-4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-(((2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxyazetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is 4-(2-(2-((2-chloro-3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is(S)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,l′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is(S)-4-(2-(2-((3′-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

16. A pharmaceutical composition comprising a compound of 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

17. A pharmaceutical composition comprising a compound of 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

18. A pharmaceutical composition comprising a compound of 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

19. A pharmaceutical composition comprising a compound of 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

20. A pharmaceutical composition comprising a compound of 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

21. A pharmaceutical composition comprising a compound of 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

22. A pharmaceutical composition comprising a compound of 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

23. A pharmaceutical composition comprising a compound of 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

24. A pharmaceutical composition comprising a compound of 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

25. A pharmaceutical composition comprising a compound of 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

26. A pharmaceutical composition comprising a compound of 12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

27. A pharmaceutical composition comprising a compound of 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

28. A pharmaceutical composition comprising a compound of 14 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2022
From: LI, JINGWEI; WU, LIANGXING; YAO, WENQING
To: INCYTE CORPORATION
Reel/Frame 060505/0603 →
Continuity (3)
Continuation 17036234 · Sep 29, 2020
Provisional Application 62908317 · Sep 30, 2019
Related Publication 20220340600A1 · Oct 27, 2022
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