Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-9682981-B2
Application number	US-201414556709-A
Country	US
Kind code	B2
Filing date	Dec 1, 2014
Priority date	Apr 21, 2010
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described, wherein the compounds have formula Ia:

In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC kinase protein. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC, including rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastoma, neurofibromatosis, osteolytic bone metastases, brain metasteses, gastrointestinal stromal tumors, and giant cell tumors.

First claim

What is claimed is:

1. A compound of Formula Ia,

or a salt thereof,
wherein:
Y 2 is —N═ and R 15 is hydrogen; or Y 2 is —C(H)═ and R 15 is fluoro or chloro;
L 2 is —CH 2 — or —C(O)—;
Cy 2 is cycloalkyl optionally substituted with one or more R 16 ;
R 14 is —N(R 9a )(R 9b );
R 9a is H and R 9b is selected from the group consisting of (i) H, lower alkyl, lower alkyl substituted with one or more fluoro, lower alkyl substituted with lower alkoxy or lower alkyl substituted with hydroxyl and (ii) cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with one to three members selected from lower alkyl, haloalkyl, lower alkoxy or fluoro; or
R 9a and R 9b together with the nitrogen to which they are attached form a 5- or 6-membered ring having from 0 to 1 additional heteroatom selected from O, N or S, each of which is optionally substituted with one to three members selected from lower alkyl, haloalkyl, lower alkoxy or fluoro; and
each R 16 is independently selected from the group consisting of fluoro, —OH, lower alkyl optionally substituted with one or more fluoro, and lower alkoxy optionally substituted with one or more fluoro.

2. A compound selected from the group consisting of:

3. A compound having the formula:

or a salt thereof.

4. A compound having the formula:

or a salt thereof.

5. A compound having the formula:

or a salt thereof.

6. A compound having the formula:

or a salt thereof.

7. A compound having the formula:

or a salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

Assignees

• Plexxikon Inc

Inventors

• Zhang Jiazhong
• Ibrahim Prabha N
• Spevak Wayne
• Tsai Jianming
• Ewing Todd
• Zhang Ying
• Zhang Chao

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

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