Protein kinase conjugates and inhibitors

Patent metadata

Field	Value
Publication number	US-10662195-B2
Application number	US-201615213319-A
Country	US
Kind code	B2
Filing date	Jul 18, 2016
Priority date	Sep 16, 2009
Publication date	May 26, 2020
Grant date	May 26, 2020

Abstract

The invention relates to protein conjugates that contain a protein kinase containing a cysteine residue in the ATP binding site and an inhibitor that is covalently and irreversibly bonded to said cysteine residue, such that the activity of the protein kinase is irreversibly inhibited. The invention also relates to compounds that irreversibly inhibit protein kinases.

First claim

What is claimed is:

1. A compound of formula XIII-b:

or a pharmaceutically acceptable salt thereof, wherein
Ra, Rb, Rc and Rd are independently selected from R, OR, halogen, —CN, C≡C—R, —NRxRy, and C(O)NHRz;
each R, Rx and Ry is independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl;
each Rz is independently hydrogen, aliphatic, or aryl;
R 2 is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl;
X is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—;
Ring A is a 4-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring containing 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 1 is -L-Y;
L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—;
Y is hydrogen, nitrile, C 1-6 aliphatic optionally substituted with one or more OH, NRxRy, oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; and
each R e is independently selected from -Q-Z, OH, oxo, NO 2 , CN, a suitable leaving group, or a C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
Q is a covalent bond or a bivalent C 1-6 saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

Assignees

• Celgene Avilomics Res Inc
• Celgene Car Llc

Inventors

• Singh Juswinder
• Petter Russell Colyn
• Niu Deqiang
• Qiao Lixin
• Kluge Arthur
• Lobb Roy
• Ghosh Shomir
• Zhu Zhendong

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C12N9/1205 Primary

  Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C12N9/96 Primary

  Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates · CPC title