IP Library › Granted Patent US 11,648,254
Granted Patent B2
US 11,648,254 · App. 17/685,370 · Granted May 16, 2023

Substituted pyrido[2,3-d]pyrimidines as inhibitors of Ras pathway signaling

Inventors: Baogen Wu (San Diego, CA); Xiangzhu Wang (San Diego, CA); Xiaoming Li (San Diego, CA); Zhiyong Chen (San Diego, CA); Pingda Ren (San Diego, CA); Yi Liu (San Diego, CA)
Assignee: Kumquat Biosciences Inc.
A61K31/519A61K31/506A61K31/5377A61K31/541A61K45/06A61P35/00C07D471/04C07D487/04
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Quick Facts
Patent No.
US 11,648,254
App. No.
17/685,370
Granted
May 16, 2023
Kind
B2
Abstract

The present disclosure provides compounds represented by Formula (I-1): and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.

Claims (60)

1. A compound of Formula (I-1):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

L 1 is a bond;

R 1 is 6- to 10-membered aryl, wherein the 6- to 10-membered aryl is optionally substituted with one or more independently selected R 10 substituents;

R 2 is halogen or OR 2a ;

R 2a is C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl is optionally substituted with one, two, or three independently selected R 20a substituents;

R 3 is halogen, C 1-6 alkyl, C 3-14 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl is optionally substituted with one, two, or three independently selected R 20b substituents;

R 4 is H, C 1-6 alkyl, or C 1-6 haloalkyl;

R 5 is H, C 1-6 alkyl, or C 1-6 haloalkyl;

R 6 is H, halogen, CN, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one, two, or three independently selected R 20c substituents;

each R 10 is independently halogen, CN, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein each C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three independently selected R 20d substituents;

each R 20a is independently halogen, CN, C 1-6 alkyl, CH 2 Cl 3-10 cycloalkyl, CH 2 Cl 2-9 heterocycloalkyl, CH 2 C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OCH 2 C(O)OR 22 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , S(O) 2 NR 22 R 23 , C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl;

wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ; and

wherein each C 3-10 cycloalkyl of CH 2 C 3-10 cycloalkyl, C 2-9 heterocycloalkyl of CH 2 C 2-9 heterocycloalkyl, C 6-10 aryl of CH 2 C 6-10 aryl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ;

each R 20e is independently halogen, CN, C 1-6 alkyl, CH 2 C 3-10 cycloalkyl, CH 2 C 2-9 heterocycloalkyl, CH 2 C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OCH 2 C(O)OR 22 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , S(O) 2 NR 22 R 23 , C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl;

wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ; and

wherein each C 3-10 cycloalkyl of CH 2 C 3-10 cycloalkyl, C 2-9 heterocycloalkyl of CH 2 C 2-9 heterocycloalkyl, C 6-10 aryl of CH 2 C 6-10 aryl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ;

each R 20e is independently halogen, CN, C 1-6 alkyl, CH 2 Cl 3-10 cycloalkyl, CH 2 Cl 2-9 heterocycloalkyl, CH 2 C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OCH 2 C(O)OR 22 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , S(O) 2 NR 22 R 23 , C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl;

wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ; and

wherein each C 3-10 cycloalkyl of CH 2 C 3-10 cycloalkyl, C 2-9 heterocycloalkyl of CH 2 C 2-9 heterocycloalkyl, C 6-10 aryl of CH 2 C 6-10 aryl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ;

each R 20d is independently halogen, CN, C 1-6 alkyl, CH 2 Cl 3-10 cycloalkyl, CH 2 Cl 2-9 heterocycloalkyl, CH 2 C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OCH 2 C(O)OR 22 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , S(O) 2 NR 22 R 23 , C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, Chao aryl, or C 1-9 heteroaryl;

wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ; and

wherein each C 3-10 cycloalkyl of CH 2 C 3-10 cycloalkyl, C 2-9 heterocycloalkyl of CH 2 C 2-9 heterocycloalkyl, C 6-10 aryl of CH 2 C 6-10 aryl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 25 , C(O)C(O)NR 22 R 23 , C(O)NR 22 R 23 , C(O)OR 22 , NR 22 R 23 , NR 24 C(O)R 25 , NR 24 C(O)NR 22 R 23 , NR 24 C(O)OR 25 , NR 24 S(O) 2 R 25 , ═NH, OR 21 , OC(O)R 25 , OC(O)NR 22 R 23 , ═O, SR 21 , S(O) 2 R 25 , and S(O) 2 NR 22 R 23 ;

each R 21 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein each C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C 1-6 alkyl;

each R 22 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein each C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C 1-6 alkyl;

each R 23 is independently H or C 1-6 alkyl;

each R 24 is independently H or C 1-6 alkyl; and

each R 25 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein each C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with one or more independently selected R 10 substituents.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 10 is independently halogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one, two, or three independently selected R 20d .

4. The compound of claim 3 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 20d is independently halogen or OH.

5. The compound of claim 3 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is:

6. The compound of claim 5 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 20d is C 1-5 alkyl, wherein the C 1-5 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of F and OH.

7. The compound of claim 6 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 20d is C 1-3 alkyl, wherein the C 1-3 alkyl is substituted with one OH substituent.

8. The compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is:

9. The compound of claim 1 , wherein the compound is of Formula (Ia-1):

or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one, two, or three independently selected R 20e substituents.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is C 1-6 alkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is CH 3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate stereoisomer thereof, wherein R 3 is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one, two, or three independently selected R 20b substituents.

14. The compound of claim 13 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one R 20b substituent.

15. The compound of claim 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 20b is halogen or CN.

16. The compound of claim 13 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is 1-cyanocyclopropyl or 1-(difluoromethyl)cyclopropyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is C 2-9 heterocycloalkyl, wherein the C 2-9 heterocycloalkyl is optionally substituted with one, two, or three independently selected R 20b substituents.

18. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is H.

19. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is C 1-6 alkyl.

20. The compound of claim 19 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is CH 3 .

21. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is H, halogen, or C 1-6 alkyl.

22. The compound of claim 21 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is H.

23. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

24. A method for inhibiting growth of a cell expressing Son of Sevenless homologue 1, wherein the method comprises contacting the cell expressing Son of Sevenless homologue 1 with a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

25. The method of claim 24 , wherein the cell expressing Son of Sevenless homologue 1 is a cancer cell expressing Son of Sevenless homologue 1.

26. The method of claim 24 , wherein the method further comprises contacting the cell expressing Son of Sevenless homologue 1 with an additional active agent.

27. A method for inhibiting growth of a cell expressing Son of Sevenless homologue 1 in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

28. The method of claim 27 , wherein the subject has cancer.

29. The method of claim 27 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent.

30. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or stereoisomer thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 5, 2022
From: WU, BAOGEN; WANG, XIANGZHU; LI, XIAOMING; CHEN, ZHIYONG; REN, PINGDA; LIU, YI
To: KUMQUAT BIOSCIENCES INC.
Reel/Frame 059834/0161 →
Continuity (4)
Provisional Application 63200353 · Mar 2, 2021
Provisional Application 63249548 · Sep 28, 2021
Provisional Application 63249549 · Sep 28, 2021
Related Publication 20230064360A1 · Mar 2, 2023
Cited By (1)
US 12,195,465