Chemical compounds, compositions and methods for kinase modulation

Patent metadata

Field	Value
Publication number	US-9738644-B2
Application number	US-201514869637-A
Country	US
Kind code	B2
Filing date	Sep 29, 2015
Priority date	May 21, 2010
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Substituted isoquinolinone compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

First claim

What is claimed is:

1. A method for inhibiting a phosphoinositide 3-kinase (PI3K) in a subject suffering from a disorder selected from a cancer, an inflammatory disease, and an auto-immune disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein
B is hydrogen or a moiety of Formula II:

wherein W c is 6-membered aryl, or cycloalkyl;
q is an integer of 0, 1, 2, 3, or 4;
X is absent or —(CH(R 9 )) z —;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —C(═O)(CHR 9 ) z —, —N(R 9 )—, —N(R 9 )—C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —;
z is an integer of 1, 2, 3, or 4;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
each R 2 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is a 5-membered heteroaryl or a 6-membered heteroaryl, each of which comprises at least one ring nitrogen, and each of which is substituted with 0, 1, 2, or 3 R 13 ;
R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, cyano, alkyl, or amino;
each R 9 is independently hydrogen, alkyl, or heterocycloalkyl;
w d is

R 11 is hydrogen, alkyl, halo, amino, amido, hydroxy, alkoxy, phosphate, urea, or carbonate;
R 12 is hydrogen, alkyl, haloalkyl, alkynyl, alkenyl, halo, —C(O)NH 2 , NH 2 , cyano, aryl, heteroaryl, nonaromatic heterocyclyl, or cycloalkyl;
R a is methyl;
R a′ is hydrogen, alkyl, —NH 2 , cyano, or halogen; and
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen.

2. The method of claim 1 , wherein R 3 is

3. The method of claim 1 , wherein B is:

4. The method of claim 3 , wherein q is 0 or 1.

5. The method of claim 4 , wherein R 1 is hydrogen, alkyl, alkoxy, amido, halo, cyano, or nitro.

6. The method of claim 4 , wherein q is 1 and R 2 is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy, or nitro.

7. The method of claim 1 , wherein Y is —N(R 9 )—.

8. The method of claim 1 , wherein X is —(CH(R 9 )) z —.

9. The method of claim 8 , wherein z is 1.

10. The method of claim 8 , wherein R 9 is hydrogen or alkyl.

11. The method of claim 1 , wherein W d is

12. The method of claim 1 , wherein R 6 , R 7 , and R 8 are independently hydrogen, halo, cyano, or alkyl.

13. The method of claim 2 , wherein B is:

14. The method of claim 13 , wherein q is 0 or 1.

15. The method of claim 14 , wherein R 1 is hydrogen, alkyl, alkoxy, amido, halo, cyano, or nitro.

16. The method of claim 14 , wherein q is 1 and R 2 is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro.

17. The method of claim 2 , wherein Y is —N(R 9 )—.

18. The method of claim 2 , wherein X is —(CH(R 9 )) z —.

19. The method of claim 18 , wherein z is 1.

20. The method of claim 18 , wherein R 9 is hydrogen or alkyl.

21. The method of claim 2 , wherein W d is

22. The method of claim 2 , wherein wherein R 6 , R 7 , and R 8 are independently hydrogen, halo, cyano, or alkyl.

23. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

24. The method of claim 1 , wherein the disorder is an inflammatory disease or an auto-immune disease.

25. The method of claim 24 , wherein the inflammatory disease or auto-immune disease is acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, asthma, emphysema, allergy, dermatitis, or graft versus host disease.

26. The method of claim 25 , wherein the inflammatory disease or auto-immune disease is rheumatoid arthritis.

27. The method of claim 25 , wherein the inflammatory disease or auto-immune disease is asthma.

28. The method of claim 1 , wherein the disorder is a cancer.

29. The method of claim 28 , wherein the cancer is breast cancer, ductal carcinoma, colloid carcinomas, tubular carcinomas, inflammatory breast cancer, ovarian cancer, epithelial ovarian tumors, adenocarcinoma, uterine cancer, cervical cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, epitheliod carcinoma, bladder cancer, transitional cell carcinoma, urothelial carcinomas, small cell cancers, acute lymphocytic leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL),

Assignees

• Infinity Pharmaceuticals Inc

Inventors

• Ren Pingda
• Liu Yi
• Li Liansheng
• Chan Katrina
• Castro Alfredo C
• Evans Catherine A

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title