Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-9440969-B2
Application number	US-201414514232-A
Country	US
Kind code	B2
Filing date	Oct 14, 2014
Priority date	Dec 23, 2009
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on each of B-Raf, B-Raf V600E and c-Raf-1 protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including melanoma, glioma, glioblastoma, pilocytic astrocytoma, liver cancer, biliary tract cancer, cholangiocarcinoma, colorectal cancer, lung cancer, bladder cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical cancer, prostate cancer, gastrointestinal stromal tumors, medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia, chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasma cell leukemia, and multiple myeloma.

First claim

What is claimed is:

1. A compound having the chemical structure of Formula I,

or a pharmaceutically acceptable salt or a tautomer or a stereoisomer thereof,
wherein:
R 1 is aryl substituted with one or two trifluoromethyl, trifluoromethoxy, C 1-6 alkyl or halogen;
Ar is selected from the group consisting of:

wherein:
W represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein W is attached at any available position of the 6-membered phenyl ring portion of Ar;
X represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein X is attached at any available position of the 6-membered ring portion of Ar;
Y represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein Y is attached at any available position of the bicyclic ring of Ar;
R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , R 36 , R 70 and R 72 are selected from the group consisting of hydrogen, —C(O)—R 45 , —S(O) 2 —R 46 , and C 1-6 alkyl, wherein C 1-6 alkyl is optionally independently substituted with one or more fluoro, or, when R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , and/or R 36 is C 2-6 alkyl, R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , and R 36 are each optionally independently substituted with one or more C 1-6 alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R 25 , R 27 , R 29 , R 31 , R 33 , R 35 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 71 and R 73 are independently selected from the group consisting of —CN, —C(O)—R 45 , —S(O) 2 —R 46 , —O—R 47 , —N(R 48 )—R 49 , fluoro, chloro, C 1-6 alkyl, and cycloalkylamino, and are attached at any available position of the bicyclic ring of Ar, wherein C 1-6 alkyl is optionally independently substituted with one or more fluoro C 1-6 alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R 45 is independently selected from the group consisting of —O—R 47 , —NH 2 , C 1-6 alkyl, mono-alkylamino, di-alkylamino, and cycloalkylamino;
each R 46 are independently selected from the group consisting of —NH 2 , C 1-6 alkyl, mono-alkylamino, di-alkylamino, and cycloalkylamino;
each R 47 is independently or C 1-6 hydrogen alkyl, wherein C 1-6 alkyl is optionally independently substituted with one or more fluoro, or, when R 47 is C 2-6 alkyl, R 47 is optionally substituted with one or more C 1-6 alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R 48 and R 49 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, or cycloalkyl, wherein C 1-6 alkyl is optionally independently substituted with C 1-6 alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino; and
each p is independently 0, 1, 2 or 3.

2. The compound of claim 1 , wherein Ar is:

3. The compound of claim 2 , wherein p is 0.

4. The compound of claim 2 , wherein R 24 and R 26 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl carbamoyl, C 1-6 alkyl-C(═O)— or C 1-6 alkyl sulfonyl.

5. The compound of claim 2 , wherein R 24 and R 26 are each independently selected from hydrogen, methyl, ethyl, propyl, acetyl, CH 3 NHC(═O)—, methyl sulfonyl or ethyl sulfonyl.

6. The compound of claim 1 , wherein Ar is:

7. The compound of claim 1 , wherein Ar is:

8. The compound of claim 1 , wherein Ar is:

9. The compound of claim 1 , wherein Ar is:

10. The compound of claim 1 , wherein Ar is:

11. The compound of claim 1 , wherein Ar is:

12. The compound of claim 1 , wherein Ar is 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl, 1H-7-indazolyl, 1,3-benzothiazol-4yl, 1,3-benzothiazol-5yl, 1,3-benzothiazol-6yl, 1,3-benzothiazol-7yl, imidazo[1,2-a]pyridine-2-yl, imidazo[1,2-a]pyridine-3-yl, imidazo[1,2-a]pyridine-5-yl, imidazo[1,2-a]pyridine-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridine-8-yl, imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-7-yl, imidazo[1,2-a]pyrimidin-8-yl, 1H-indol-5yl, 1H-indol-2yl, 1H-indol-3yl, 1H-indol-4yl, 1H-indol-6yl, 1H-indol-7yl, 3-methyl-1-H-indol-5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 1-oxo-isoindolin-4-yl, 1-oxo-isoindolin-5-yl, 1-oxo-isoindolin-6-yl, 1-oxo-isoindolin-7-yl, 2-oxo-indolin-4-yl, 2-oxo-indolin-5-yl, 2-oxo-indolin-6-yl or 2-oxo-indolin-7-yl, each of which is optionally substituted with one to two members selected from methyl, amino, CF 3 , CF 3 O, CH 3 O, acetyl, alkoxycarbonyl, t-butoxycarbonyl, dimethylamino, fluoro, chloro or methylaminoethyl.

13. The compound of claim 1 , wherein Ar is 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl, 1H-7-indazolyl, 1-methyl-4-indazolyl, 1-methyl-5-indazolyl, 1-methyl-6-indazolyl, 1-methyl-7-indazolyl, 1-acetyl-4-indazolyl, 1-acetyl-5-indazolyl, 1-acetyl-6-indazolyl, 1-acetyl-7-indazolyl, 1-methylsulfonyl-4-indazolyl, 1-methylsulfonyl-5-indazolyl, 1-methylsulfonyl-6-indazolyl, 1-methylsulfonyl-7-indazolyl, 1-methyl-3-amino-6-indazolyl, 1,3-benzothiazol-4yl, 1,3-benzothiazol-5yl, 1,3-benzothiazol-6yl, 1,3-benzothiazol-7yl, imidazo[1,2-a]pyridine-2-yl, imidazo[1,2-a]pyridine-3-yl, imidazo[1,2-a]pyridine-5-yl, imidazo[1,2-a]pyridine-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridine-8-yl, 7-trifluoromethylimidazo[1,2-a]pyrimidin-2-yl, 7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl, imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-7-yl, imidazo[1,2-a]pyrimidin-8-yl, 1H-indol-5yl, 1H-indol-2yl, 1H-indol-3yl, 1H-indol-4yl, 1H-indol-6yl, 1H-indol-7yl, 3-methyl-1-H-indol-5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, 1-methyl-2-aminobenzimidazol-5-yl, 1-methyl-2-aminobenzimidazol-4-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 1-oxo-isoindolin-4-yl, 1-oxo-isoindolin-5-yl, 1-oxo-isoindolin-6-yl, 1-oxo-isoindolin-7-yl, 2-oxo-indolin-4-yl, 2-oxo-indolin-5-yl, 2-oxo-indolin-6-yl or 2-oxo-indolin-7-yl.

14. The compound of claim 1 , wherein R 1 is 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 3,5-di

Assignees

• Plexxikon Inc

Inventors

• Ibrahim Prabha N
• Wu Guoxian
• Lin Jack
• Spevak Wayne
• Cho Hanna
• Ewing Todd
• Zhang Chao

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D519/00

  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 · CPC title