Serine/threonine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9763942-B2
Application number	US-201615197479-A
Country	US
Kind code	B2
Filing date	Jun 29, 2016
Priority date	Dec 30, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Compounds of Formula I or a stereoisomer, tautomer 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 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 compound of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
X 1 is 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 1 -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) C 1 -C 10 alkyl optionally substituted with one to four R f groups; (b) C 3 -C 6 cycloalkyl optionally substituted with halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; (c) a 4 to 6 membered heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to four R g groups; (d) phenyl optionally substituted with one to four groups selected from halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; (e) 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 groups selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; (f) C 8 -C 10 bicyclic cycloalkyl optionally substituted with halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; and (g) 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 halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
R 3 is selected from hydrogen and halogen;
R 4 is selected from hydrogen and halogen;
each R a , R b , R d and R e are independently selected from hydrogen and C 1 -C 6 alkyl;
each R f is selected from (a) halogen; (b) hydroxy; (c) C 1 -C 3 alkoxy; (d) NR k R m ; (e) C 3 -C 6 cycloalkyl optionally substituted with one or more R h groups; (f) a 4 to 6 membered heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one or more groups selected from halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl optionally substituted with halogen, —C(═O)O(C 1 -C 6 alkyl) and phenyl; (g) phenyl optionally substituted with one or more R j groups; and (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 or more R j groups;
each R g is selected from (a) halogen; (b) C 1 -C 3 alkyl optionally substituted with halogen, C 1 -C 3 alkoxy, or phenyl optionally substituted with two groups selected from halogen and C 1 -C 3 alkoxy; (c) C 1 -C 3 alkoxy optionally substituted with halogen; (d) phenyl optionally substituted with halogen or C 1 -C 3 alkoxy; and (e) 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 or two groups selected from halogen and C 1 -C 3 alkoxy;
each R h is selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and phenyl optionally substituted with C 1 -C 3 alkoxy, wherein the alkyl, alkoxys and phenyl may be optionally substituted with halogen;
each R j is selected from halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy, wherein the alkyl and alkoxy may be optionally substituted with halogen; and
each R k and R m are independently selected from hydrogen and C 1 -C 3 alkyl.

2. The compound of claim 1 , wherein the compound has the structure of Formula VIII:

3. The compound of claim 1 , wherein the compound has the structure of Formula IX:

4. The compound of claim 1 , wherein R 3 and R 4 are hydrogen.

5. The compound of claim 1 , wherein R 1 is selected from methyl, ethyl, isopropyl, tert-butyl, isobutyl, 2-hydroxyethyl, 1-hydroxymethylpropyl, 1-hydroxypropan-2-yl, 2-methoxy-1-methyl-ethyl, 2-hydroxypropyl, 2-hydroxy-1-hydroxymethyl-ethyl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1,2-dihydroxypropan-3-yl, acetyl, 2,2,2-trifluoro-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxymethyl-ethyl, 2-fluoro-1-methyl-ethyl, 2-fluoro-1-fluoromethyl-ethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, 2-morpholin-4-yl-ethyl, 2,2-difluoro-1-methyl-ethyl, oxetan-3-ylmethyl, 2-methyl-1-morpholinopropan-2-yl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 2-o-tolyl, 4-fluoro-2-methylphenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 4-fluoro-2-trifluoromethylphenyl, 4-cyano-2-fluorophenyl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, 3,5-dimethylisoxazol-4-yl, 2-methylpyridin-4-yl, 4-chloropyridin-2-yl, 2-methylpyridin-3-yl, 2-methylpyridin-4-yl, 2-ethoxypyridin-4-yl, 2-cyclopropylpyridin-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 2-ethyl-2H-pyrazol-3-yl, 1-benzyl-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 2-isopropyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-methylthiazol-2-yl, 1-methyl-1H-[1,2,4]triazol-3-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 5-chloropyrazin-2-yl, 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, oxetan-3-yl, 3-methyloxyetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyran-3-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran-4-yl, 2-hydroxymethyltetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl, 1-methylpiperidin-4-yl, 1-methyl-5-oxo-pyrrolidin-3-yl, tetrahydrofuran-3-yl, cyclopropyl, cyclopentyl, cyclobutyl, 3-hydroxycyclopentyl, 3,3-difluorocyclopentyl, 4-hydroxycyclohexyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl and 4,4-difluorocyclohexyl.

6. The compound of claim 1 , wherein R 1 is selected from (S)-2-hydroxy-1-methyl-ethyl, (S)-1-hydroxymethyl-propyl, (1S,3S)-3-hydroxycyclopentyl, tetrahydropyran-4-yl, isopropyl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl and 1-methyl-1H-1,2,4-triazol-5-yl.

7. The compound of

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Blake James F
• Cook Adam
• Gunawardana Indrani W
• Hunt Kevin W
• Lyon Michael
• Metcalf Andrew T
• Mohr Peter J
• Moreno David A
• Newhouse Brad
• Ren Li
• Tang Tony P
• Thomas Allen A
• Schwarz Jacob
• Schmidt Jane
• Gazzard Lewis
• Chen Huifen

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P29/00

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