Serine/threonine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9708290-B2
Application number	US-201614993985-A
Country	US
Kind code	B2
Filing date	Jan 12, 2016
Priority date	Mar 1, 2012
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof are provided, which are useful for the treatment of hyperproliferative, pain and inflammatory diseases. Methods of using compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

First claim

What is claimed is:

1. A process for preparing a compound of Formula 10.1, comprising:
(a) coupling a compound having the structure:

with a compound having the structure:

to prepare a compound having the structure:

and
(b) hydrolyzing the compound having the structure:

to prepare a compound of Formula 10.1:

wherein:
X 1 is selected from CH and N;
X 2 is selected from CR 5 and N;
Y 1 is selected from CR 6 and N;
Y 2 is selected from CR 7 and N;
each R 4 , R 5 , R 6 and R 7 is independently selected from hydrogen, halogen and C 1 -C 3 alkyl; and
R 11 is selected from Cl, Br and I.

2. The process of claim 1 wherein a compound of Formula 1.4 is prepared, comprising:
(a) coupling a compound of Formula 1.1:

with a compound of Formula 1.2:

to prepare a compound of Formula 1.3:

and
(b) hydrolyzing the compound of Formula 1.3 to prepare a compound of Formula 1.4:

3. A process for preparing a compound of Formula 10.2, comprising:
reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein:
X 1 is selected from CH and N;
X 2 is selected from CR 5 and N;
Y 1 is selected from CR 6 and N;
Y 2 is selected from CR 7 and N;
R 2 is selected from (a) hydrogen, (b) C 1 -C 6 alkyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (c) C 1 -C 6 alkenyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (d) C 1 -C 6 alkynyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (e) C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from OR f and R g , (f) phenyl optionally substituted with one or more groups selected from OR f and R g , (g) a 3 to 7 membered heterocycle optionally substituted with one or more groups selected from OR f and R g , and (h) a 5 to 6 membered heteroaryl optionally substituted with one or more groups selected from OR f and R g ;
R 3 is selected from (a) (CR h R i ) x -phenyl, wherein the phenyl may be optionally substituted with one or more R j groups, (b) (CR h R i ) x -(5 to 6 membered heteroaryl), wherein the heteroaryl may be optionally substituted with one or more R j groups, (c) (CR h R i ) x -(9 to 10 membered bicyclic heterocycle), wherein the heterocycle may be optionally substituted with one or more R j groups, and (d) (CR h R i ) x -(9 to 10 membered bicyclic heteroaryl), wherein the heteroaryl may be optionally substituted with one or more R j groups;
each R 4 , R 5 , R 6 and R 7 is independently selected from hydrogen, halogen and C 1 -C 3 alkyl;
each R f is independently selected from hydrogen and C 1 -C 6 alkyl optionally substituted with one or more groups selected from oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 ;
each R g is C 1 -C 6 alkyl;
R h and R i are independently selected from hydrogen, OR k and C 1 -C 6 alkyl optionally substituted with OR m ;
each R j is independently selected from halogen, CN, cyclopropyl, C 1 -C 6 alkyl optionally substituted with halogen, and C 1 -C 6 alkoxy optionally substituted with halogen;
R k and R m are independently hydrogen or C 1 -C 3 alkyl;
x is 0 or 1; and
X is Cl, Br, I, OMs or OTf.

4. The process of claim 3 , wherein a compound of Formula 3.2 is prepared, comprising:
reacting a compound of Formula 1.4:

with a compound of Formula 3.1:

to prepare a compound of Formula 3.2:

5. A process for preparing a compound of Formula 10.2, comprising:
reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein:
X 1 is selected from CH and N;
X 2 is selected from CR 5 and N;
Y 1 is selected from CR 6 and N;
Y 2 is selected from CR 7 and N;
R 2 is selected from (a) hydrogen, (b) C 1 -C 6 alkyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (c) C 1 -C 6 alkenyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (d) C 1 -C 6 alkynyl optionally substituted with one or more groups selected from OR f , oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 , (e) C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from OR f and R g , (f) phenyl optionally substituted with one or more groups selected from OR f and R g , (g) a 3 to 7 membered heterocycle optionally substituted with one or more groups selected from OR f and R g , and (h) a 5 to 6 membered heteroaryl optionally substituted with one or more groups selected from OR f and R g ;
R 3 is selected from (a) (CR h R i ) x -phenyl, wherein the phenyl may be optionally substituted with one or more R j groups, (b) (CR h R i ) x -(5 to 6 membered heteroaryl), wherein the heteroaryl may be optionally substituted with one or more R j groups, (c) (CR h R i ) x -(9 to 10 membered bicyclic heterocycle), wherein the heterocycle may be optionally substituted with one or more R j groups, and (d) (CR h R i ) x -(9 to 10 membered bicyclic heteroaryl), wherein the heteroaryl may be optionally substituted with one or more R j groups;
each R 4 , R 5 , R 6 and R 7 is independently selected from hydrogen, halogen and C 1 -C 3 alkyl;
each R f is independently selected from hydrogen and C 1 -C 6 alkyl optionally substituted with one or more groups selected from oxo, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 ;
each R g is

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Blake James F
• Chicarelli Mark Joseph
• Garrey Rustam Ferdinand
• Gaudino John
• Grina Jonas
• Moreno David A
• Mohr Peter J
• Ren Li
• Schwarz Jacob
• Chen Huifen
• Robarge Kirk
• Zhou Aihe

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title