Serine/threonine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016304519-A1
Application number	US-201615197445-A
Country	US
Kind code	A1
Filing date	Jun 29, 2016
Priority date	Dec 30, 2013
Publication date	Oct 20, 2016
Grant date	—

Abstract

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

First claim

What is claimed is:

1 . A compound of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from CH and N;
X 2 is selected from CH and N;
R 1 is selected from (a) C 1 -C 6 alkyl optionally substituted with one or more groups independently selected from halogen, OR a , NR b R c , oxo, CN, C 3 -C 6 cycloalkyl and a 3 to 7 membered heterocycle; (b) C 3 -C 7 cycloalkyl optionally substituted with one or more groups independently selected from halogen, OR a , CN and C 1 -C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (c) phenyl optionally substituted with one or more groups independently selected from halogen, OR a , CN, C 3 -C 6 cycloalkyl and C 1 -C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (d) a 3 to 7 membered saturated or partially unsaturated heterocyclyl optionally substituted with one or more groups independently selected from halogen, OR a , oxo, CN, C 3 -C 6 cycloalkyl and C 1 -C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (e) a 5 to 6 membered heteroaryl optionally substituted with one or more groups independently selected from halogen, OR e , oxide, CN, C 3 -C 6 cycloalkyl and C r C 3 alkyl optionally substituted with one or more groups independently selected from halogen, oxo and OR d ; and (f) a 7 to 10 membered bicyclic heterocycle optionally substituted with one or more groups independently selected from halogen, OR a , oxo, CN, C 3 -C 6 cycloalkyl and C 1 -C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ;
R 2 is selected from (a) hydrogen; (b) C 1 -C 12 alkyl optionally substituted by one to eight R f groups; (c) C 2 -C 12 alkenyl optionally substituted by one to eight R f groups; (d) OR g ; (e) C 3 -C 7 cycloalkyl optionally substituted with one to six groups selected from halogen; OH; C 1 -C 3 alkyl optionally substituted with halogen, OH or phenyl optionally substituted with halogen; C(═O)O(C 1 -C 3 alkyl), wherein the alkyl may be optionally substituted with halogen or OH; and phenyl optionally substituted with halogen; (f) phenyl optionally substituted with one to four groups selected from halogen, C 1 -C 3 alkyl optionally substituted with halogen, OH or methoxy, and phenoxy optionally substituted with halogen, OH or methoxy; (g) 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to four R h groups; (h) a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one to four R i groups; and (i) a 9 to 10 membered bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to four R h groups;
R 3 is selected from hydrogen and halogen;
R 4 is selected from hydrogen and halogen;
each R a , R b , R c , R d and R e are independently selected from hydrogen and C 1 -C 6 alkyl;
each R f is independently selected from (a) halogen; (b) CN; (c) oxo; (d) OR j ; (e) SR k ; (f) S(O)R k ; (g) S(O) 2 R k ; (h) NR m R n ; (i) C 3 -C 6 cycloalkyl optionally substituted with one to three RP groups; (j) phenyl optionally substituted by one to four R q groups; (k) a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to three groups selected from halogen, oxo and C 1 -C 3 alkyl optionally substituted with halogen; (l) a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to three R s groups; (m) C 7 -C 10 bicyclic cycloalkyl optionally substituted with one to three groups selected from halogen and C 1 -C 3 alkyl optionally substituted with halogen; (n) a 9 to 10 membered bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the bicyclic heterocyclyl may be optionally substituted with one to three groups selected from halogen and C 1 -C 3 alkyl optionally substituted with halogen; (o) a 9 to 10 membered bicyclic heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the bicyclic heteroaryl is substituted with one to three groups selected from halogen, CN and C 1 -C 3 alkyl optionally substituted with halogen; and (p) adamantanyl;
R g is independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and phenyl, wherein the alkyl, cycloalkyl and phenyl may be optionally substituted with halogen;
each R h is selected from halogen; OH; C 1 -C 3 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; C 1 -C 3 alkoxy optionally substituted by halogen or OH; oxo; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; phenoxy wherein the phenoxy optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to four groups selected from halogen, OH, CN, methyl and methoxy;
each R i is selected from halogen; OH; C 1 -C 4 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; C 1 -C 3 alkoxy optionally substituted by halogen or OH; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; benzyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to four groups selected from halogen, OH, CN, methyl and methoxy;
each R j is independently selected from hydrogen, C 1 -C 4 alkyl, cyclopropyl and phenyl, wherein the alkyl and phenyl may be optionally substituted with halogen;
each R k is independently selected from C 1 -C 4 alkyl, C 5 cycloalkyl, phenyl and benzyl, wherein the phenyl may be optionally substituted with halogen;
each R m and R n are independently selected from hydrogen, C 1 -C 2 alkyl and phenyl, wherein the alkyl may be substituted with oxo or phenyl substituted with halogen, and wherein the phenyl may be substituted with halogen;
each R p is independently selected from halogen, OR t , cyclopropyl and C 1 -C 3 alkyl optionally substituted with halogen;
each R q is independently selected from halogen, CN, OR u , SR u , C 3 -C 6 cycloalkyl optionally substituted with halogen, and C 1 -C 3 alkyl optionally substituted with halogen;
each R s is independently selected from halogen, CN, OR w , C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl and benzyl, wherein the alkyl, cycloalkyl, phenyl and benzyl may be optionally substituted with one to three groups selected from halogen and methyl;
each R t is independently selected from hydrogen and C 1 -C 4 alkyl optionally substituted with halogen;
each R u is independently selected from hydrogen and C 1 -C 4 alkyl optionally substituted with halogen; and
each R w is independently selected from hydrogen

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Blake James F
• Cook Adam
• Gaudino John
• Gunawardana Indrani W
• Hicken Erik James
• Hunt Kevin W
• Lyon Michael
• Metcalf Andrew T
• Mohr Peter J
• Moreno David A
• Newhouse Brad
• Ren Li
• Schwarz Jacob
• Chen Huifen
• Gazzard Lewis
• Schmidt Jane
• Do Steve

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title