SHP2 PHOSPHATASE INHIBITORS AND METHODS OF USE THEREOF

• US 20190307745A1
• Filed: 09/22/2017
• Published: 10/10/2019
• Est. Priority Date: 09/22/2016
• Status: Active Grant

• Current Assignee: D.E. Shaw Research, LLC (D E SHAW & Company LP), Relay Therapeutics, Inc.
• Original Assignee: D.E. Shaw Research, LLC (D E SHAW & Company LP), Relay Therapeutics, Inc.
• Inventors: Albrecht, Brian K., Giordanetto, Fabrizio, Greisman, Jack Benjamin, Maragakis, Paul, Taylor, Alexander M., Walters, Patrick W.
• Granted Patent: US 11,529,347 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/10 Spiro-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the invention. The present invention further relates to, but is not limited to, methods for suppressing tumor cell growth, ameliorating the pathogenesis of systemic lupus erythematosus, and the treatment of various other disorders, including Noonan syndrome, diabetes, neutropenia, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, and other cancers associated with SHP2 deregulation with the compounds and compositions of the invention, alone or in combination with other treatments. Other cancers associated with SHP2 deregulation include HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer, esophageal cancer, gastric cancer, squamous-cell carcinoma of the head and neck (SCCHN), and colon cancer.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

2. The compound of claim 1, wherein R¹ is phenyl, pyridyl, or indolyl, wherein said phenyl, pyridyl, or indolyl is optionally substituted with —

R¹⁰, —

OR¹⁰, —

SR¹⁰, —

N(R¹⁰)₂, —

OSO₂R¹⁰, —

SO₂R¹⁰, —

C(O)N(R¹⁰)₂, halogen, or nitrile.

3. The compound of claim 1, wherein R¹ is phenyl, pyridyl, or indolyl, wherein said phenyl, pyridyl, or indolyl is optionally substituted with —

OR¹⁰, halogen, or nitrile.

4. The compound of claim 1, wherein R¹ is pyridyl, wherein said pyridyl is optionally substituted with —

OR¹⁰, halogen, or nitrile.

5. The compound of claim 1, wherein R¹ is indolyl, wherein said indolyl is optionally substituted with —

OR¹⁰, halogen, or nitrile.

6. The compound of any of claims 1-5, wherein m is an integer selected from 1 or 2;

and n is 1.

7. The compound of any of claims 1-6, wherein R⁴ and R⁵ are independently H, —

OH, —

(C₁-C₃)alkyl, —

O(C₁-C₃)alkyl, —

(C₁-C₃)alkyl-O—

R⁶, —

C(O)NH₂, —

N(R⁶)₂, halogen, —

(C₁-C₃)alkyl-N(R⁶)₂, or nitrile,

wherein said —

(C₁-C₃)alkyl, —

O(C₁-C₃)alkyl, —

(C₁-C₃)alkyl-O—

R⁶, or —

(C₁-C₃)alkyl-N(R⁶)₂, is optionally substituted with one or more substituents selected from the group consisting of —

OH, —

N(R⁶)₂, and halogen;

or R⁴ and R⁵, taken together with the atoms to which they are attached, form a 3-7 membered carbocyclic or heterocyclic ring;

or R⁴ and R⁸, taken together with the atoms to which they are attached, form a 4-7 membered carbocyclic or heterocyclic ring;

or R⁴ is a bond, and R⁴ and R⁸, taken together with the atoms to which they are attached, form a 3-membered carbocyclic or heterocyclic ring; and

each R⁶ is independently H, —

(C₁-C₃)alkyl.

8. The compound of any of claim 1, wherein the compound is selected from:

9. The compound of claim 1, wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound of any of claims 1-9 and a pharmaceutically acceptable carrier.

11. A method of inhibiting SHP2 phosphatase activity in a subject comprising administration of a therapeutically effective amount of the compound of any of claims 1-9, or the composition of claim 10, to a subject in need thereof.

12. The method of claim 11, further comprising administration of a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.

13. The method of claims 11 or 12, wherein the subject is a human.

14. A method of treating a disorder in a subject comprising administration of a therapeutically effective amount of the compound of any of claims 1-9, or the composition of claim 10, to a subject in need thereof.

15. The method of claim 14, further comprising administration of a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.

16. The method of claims 14 or 15, wherein the disorder is Noonan syndrome.

17. The method of claims 14 or 15, wherein the disorder is neutropenia.

18. The method of claims 14 or 15, wherein the disorder is diabetes.

19. The method of claims 14 or 15, wherein the disorder is neuroblastoma.

20. The method of claims 14 or 15, wherein the disorder is melanoma.

21. The method of claims 14 or 15, wherein the disorder is acute myeloid leukemia.

22. The method of claims 14 or 15, wherein the disorder is juvenile leukemia.

23. The method of claims 14 or 15, wherein the disorder is juvenile myelomonocytic leukemia.

24. The method of claims 14 or 15, wherein the disorder is breast cancer.

25. The method of claims 14 or 15, wherein the disorder is lung cancer.

26. The method of claims 14 or 15, wherein the disorder is colorectal cancer.