Bruton's tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10358446-B2
Application number	US-201615763095-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Oct 14, 2015
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

Bruton's tyrosine kinase (Btk) inhibitors have the following Formula (I):

First claim

What is claimed is:

1. A compound of Formula (I) having the following structure:

wherein:
A is CR 1 ;
B is N;
C and D are CR 1 ;
R 1 is hydrogen, OH, CN, NHOH or CONH 2 ;
R 2 is

—X-E is one of the followings:
(1) X is O, OCR a R b , S(O), S(O) 2 , CR a R b , NR c (C═O), C═ONR c or a bond; and E is a hydrogen, an aryl or a heteroaryl substituted with one to three R 5 substituents; or a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
(2) —X-E is hydrogen, halogen, —OR a , —O(CH 2 ) 1-4 R a , —CN, or —NO 2 ;

R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, OCF 3 , OCF 2 H, C 1-6 alkyl, optionally substituted with one to five fluorines, C 3-6 cycloalkyl, optionally substituted with one to five fluorines, C 1-4 alkoxy, optionally substituted with one to five fluorines, C 1-4 alkylthio, optionally substituted with one to five fluorines, C 1-4 alkylsulfonyl, optionally substituted with one to five fluorines, carboxy, C 1-4 alkyloxycarbonyl, and C 1-4 alkylcarbonyl;
R a and R b are each independently hydrogen, fluorine, or C 1-3 alkyl, optionally substituted with one to five fluorines;

R c is hydrogen or C 1-3 alkyl, optionally substituted with one to five fluorines;
R 3 is a group having a double bond,
a tautomer thereof, or a pharmaceutical acceptable solvate thereof.

2. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

Y is C(═O); OC(═O), NHC(═O), S═O, S(═O) 2 , or NHS(═O) 2 ;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, C 1-6 alkoxyalkyl, C 1-8 alkylaminoalkyl, and C 1-4 alkylphenyl;
or R 7 and R 8 taken together form a bond.

3. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

Y is C(═O); OC(═O), NHC(═O), S═O, S(═O) 2 , or NHS(═O) 2 ;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, C 1-6 alkoxyalkyl, C 1-8 alkylaminoalkyl, and C 1-4 alkylphenyl.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable excipient.

5. A compound selected from the group consisting of

Assignees

• Zibo Biopolar Changsheng Pharmaceutical Co Ltd
• Shanghai Inst Materia Medica Cas

Inventors

• Liao Xibin
• Li Jia
• Lu Zhijian
• Zhou Yubo
• Gao Anhui

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title