Substituted ethynyl heterobicyclic compounds as tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10144737-B2
Application number	US-201415309396-A
Country	US
Kind code	B2
Filing date	Oct 20, 2014
Priority date	May 19, 2014
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The present disclosure provides a compound of formula (I) and the use thereof for the therapeutic treatment of human cancers including B-cell lymphoma and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

First claim

What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein Z is selected from the group consisting of —(CH 2 ) m —, —O(CH 2 ) m —, and —(CH2) m O(CH 2 ) m —; and where m is an integer from 1-3;
W is CH or N;
R is a cyclic group selected from the group consisting of phenyl, naphthalenyl, benzodioxolyl, benzofuranyl, benzothiophenyl, thiophenyl, quinolinyl, cyclohexyl, furanyl, pyrazolyl, tetrahydropyranyl, and indazolyl, wherein R is either unsubstituted or substituted with one or more of R 3 , R 4 and R 5 ;
R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloheteroalkyl, aryl, and heteroaryl; or R 1 and R 2 may combine with an atom or atoms to which they are attached to form 3- to 12-membered heterocyclic, C 6-12 aryl, or 5- to 12-membered heteroaryl, wherein R 1 and R 2 are independently either unsubstituted or substituted with a substituent selected from the group consisting of —C(O)CH═CH 2 , —C(O)CH═CHCH 2 N(CH 3 ) 2 , —C(O)CH═CHCH 2 NH(CH 3 ), —C(O)CH═CHCH 3 ,

provided that at least one of R 1 and R 2 is not hydrogen; and
R 3 , R 4 and R 5 are each independently selected from the group consisting of H, halogen, —CN, —CF 3 , —OCF 3 , —OR 9 , alkyl;
wherein R 9 is alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —OCH 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, —OCH 3 , —OCF 3 , —CH 3 , —CF 3 , and —CN.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 combine the nitrogen to which they are attached to form an unsubstituted or substituted piperazinyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the piperazinyl is substituted with a substituent selected from the group consisting of —C(O)CH═CH 2 , —C(O)CH═CHCH 2 N(CH 3 ) 2 , and

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is an unsubstituted or substituted pyrrolidinyl, an unsubstituted or substituted piperidinyl, or an unsubstituted or substituted phenyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrrolidinyl substituted with a substituent selected from the group consisting of —C(O)CH═CH 2 , —C(O)CH═CHCH 2 N(CH 3 ) 2 , —C(O)CH═CHCH 2 NH(CH 3 ), —C(O)CH═CHCH 3

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting:

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

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting:

11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting:

12. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, having a formula

Assignees

• Eternity Bioscience Inc
• Jiangsu Hengrui Medicine Co

Inventors

• Zhang Minsheng
• Yan Yinfa

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

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title