Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof

• US 10,646,488 B2
• Filed: 07/13/2017
• Issued: 05/12/2020
• Est. Priority Date: 07/13/2016
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Liu, Yi, Li, Liansheng, Ren, Pingda
• Primary Examiner(s): Havlin, Robert H
• Application Number:
  US15/649,568
• Publication Number:
  US 20180015087A1
• Time in Patent Office: 1,034 Days
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence

Abstract

Conjugates of a cereblon-binding compound and compounds having modulatory activity against G12C mutant KRAS, HRAS or NRAS G12C proteins are provided. Methods associated with preparation and use of such conjugates, pharmaceutical compositions comprising such conjugates and methods to modulate the activity of G12C mutant KRAS, HRAS or NRAS G12C proteins for treatment of disorders, such as cancer, are also provided.

Claims

1. A conjugate having the formula (I):

2. The conjugate of claim 1,

wherein J is oxo.

3. The conjugate of claim 1, wherein Y has one of the following structures:

4. The conjugate of claim 1, wherein R¹ is phenyl or naphthyl.

5. The conjugate of claim 4, wherein R¹ is substituted with halo or hydroxyl or both.

6. The conjugate of claim 1, wherein R¹ has one of the following structures:

7. The conjugate of claim 1, wherein R¹ is indazolyl, indolyl, benzoimidazolyl, benzotriazolyl or quinolinyl.

8. The conjugate of claim 1, wherein R¹ has one of the following structures:

9. The conjugate of claim 1, wherein R^3a and R^4a are each H.

10. The conjugate of claim 1, wherein one or both of R^3a and R^4a and are C₁-C₆ alkyl.

11. The conjugate of claim 10, wherein C₁-C₆ alkyl is methyl.

12. The conjugate of claim 1, wherein B⁴ is N or C—

CN.

13. The conjugate of claim 1, wherein R¹ has one of the following structures:

14. A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable carrier.

15. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 14 to a subject in need thereof.

16. The conjugate of claim 1, having one of the following structures: