Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-10227357-B2
Application number	US-201314019442-A
Country	US
Kind code	B2
Filing date	Sep 5, 2013
Priority date	Sep 6, 2012
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

Compounds active on c-kit protein kinases or mutant c-kit protein kinases having any mutations are described, as well as methods of making and using such compounds to treat diseases and conditions associated with aberrant activity of the c-kit protein kinases and mutant c-kit protein kinases.

First claim

What is claimed is:

1. A compound of formula:

or a pharmaceutically acceptable salt, a solvate, a tautomer or a deuterated analog thereof, wherein:
R 17 and R 18 are each independently C 1-4 alkyl;
L is a bond, NHSO 2 —, —SO 2 NH—, —NHC(O)—, —C(O)NH—, —SO 2 —, —C(O)O—, —NHC(O)NH— or —C(═NH)NH—;
Z is aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl, C 3-6 cycloalkyl, cycloalkyl-C 1-4 alkyl, or heterocyclyl-C 1-4 alkyl, wherein the aliphatic or aromatic portion of Z is each independently optionally substituted with from 1-3 R d groups, wherein each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heteroaryl, halogen, —CN, —NH 2 , —NO 2 , —N(H)C 1-6 alkyl or —N(C 1-6 alkyl) 2 ,
wherein each R d group is optionally further substituted with C 1-6 alkyl;
R 1 is C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, —C(O)—R g , —C(O)NHR g , wherein R 1 is optionally substituted with from 1-4 R 3 members, wherein
each R 3 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C 1-4 alkyl, —NHR i , NR i R i , —NHC(O)R i , —C(O)NH 2 , —C(O)NHR i , —C(O)NR i R i- , —NHS(O) 2 R i , p-CH 3 C 6 H 4 SO 2 NH—, NH 2 SO 2 —, —SO 2 NHR i , —S(O) 2 NR i R i , —C(O)R i , or —C(O)OR i- ;
each R g is independently aryl, aryl-C 1-2 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 alkyl; and
each R i is independently C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 alkyl.

2. The compound of claim 1 , wherein Z is C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl, or heterocyclyl-C 1-4 alkyl, wherein the aliphatic or aromatic portion of Z is optionally substituted with from 1-3 R d substituents,
wherein each R d is independently selected from —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 haloalkoxy, —NH 2 or —N(C 1-6 alkyl) 2 .

3. The compound of claim 2 , wherein Z is phenyl, benzyl, 1-methylbenzyl, 1-ethylbenzyl, benzylmethyl, 1-naphthalenyl, 2-naphthalenyl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, indanyl, 1,2-benzoxazolyl, 1,3-benzoxazolyl, thiophenyl, thiozolyl, benzothiophenyl, pyrazolyl, pyrrolidinyl, pyridyl, cyclopropyl, pyridylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxazolyl, 2-oxo-pyrrolidinyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,5-oxadiazolyl or isoxazolyl, each of which is optionally substituted with from 1-3 members independently selected from —CH 3 , ethyl, propyl, butyl, isopropyl, —CN, —NO 2 , —NH 2 , —N(CH 3 ) 2 , halogen, —OCH 3 , —OCH(CH 3 ) 2 , -OCD 3 , —CF 3 , —CHF 2 , —OCF 3 , or —OCHF 2 .

4. The compound of claim 1 , wherein R 1 is pyridyl, phenyl, benzyl, pyrazolyl, oxazolyl, thiozolyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclopropylmethyl, cyclopropylcarbonyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, benzoyl, phenylcarbamoyl, piperidinyl, piperazinyl, morpholinyl, cyclopentenyl, cyclohexenyl, 1,2,3,6-tetrahydropyridin-4-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, indanyl, 1,2-benzoxazolyl, or 1,3-benzoxazolyl, each of which is optionally substituted with from 1-4 R 3 members independently selected from halogen, —CH 3 , -CD 3 , —OCH 3 , —CN, —CF 3 , CF 3 O—, —CF 2 H, CHF 2 O—, —N(CH 3 ) 2 , —NHCH 3 , CH 3 CONH—, NH 2 C(O)—, CH 3 NHC(O)—, (CH 3 ) 2 NC(O)—, cyclopropyl, CH 3 SO 2 NH—, cyclopropyl-SO 2 NH—, butyl-SO 2 NH—, p-CH 3 C 6 H 4 SO 2 NH—, NH 2 SO 2 —, CH 3 NHSO 2 —, (CH 3 ) 2 NSO 2 —, morpholinyl, piperidinyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-morpholinylcarbonyl, piperdinylcarbonyl, piperazinylcarbonyl, t-butoxycarbonyl or 2-(4-morpholinyl)-ethyl.

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

6. A pharmaceutical composition comprising a compound of claim 1 and another therapeutic agent.

7. A compound of formula:

Assignees

• Plexxikon Inc

Inventors

• Lin Jack
• Buell John
• Chan Katrina
• Ewing Todd
• Ibrahim Prabha
• Nespi Marika
• Pham Phuongly
• Shi Songyuan
• Spevak Wayne
• Wu Guoxian
• Zhang Jiazhong
• Zhang Ying

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title