Substituted quinazolines as serine/threonine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9187462-B2
Application number	US-201214237143-A
Country	US
Kind code	B2
Filing date	Aug 3, 2012
Priority date	Aug 4, 2011
Publication date	Nov 17, 2015
Grant date	Nov 17, 2015

Abstract

Compounds having the formula (I) wherein R 1 , R 2 , R 3 and Ar as defined herein are inhibitors of ERK kinase. Also disclosed are compositions and methods for treating hyperproliferative disorders.

First claim

We claim:

1. A compound according to formula I

wherein:
R 1 is heterocyclyl or heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 hydroxyalkyl, halogen, hydroxy and oxo;
Ar is phenyl or pyridinyl optionally substituted by 1 to 5 groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogen, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 acylamino, cyano and nitro;
R 2 is selected from the group consisting of (a) C 1-10 alkyl, (b) C 1-6 haloalkyl, (c) heterocyclyl or heterocyclyl-C 1-6 alkyl wherein said heterocyclyl or heterocyclyl-C 1-6 alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, 2-oxabicyclo[2.2.1]heptan-5-yl, oxetanyl, piperidinyl, N—C 1-6 alkyl-piperidinyl, 1,1-dioxothietan-3-yl, thietan-3-yl, and N—C 1-6 alkyl-2-oxo-pyrrolidinyl and wherein said heterocyclyl or heterocyclyl-C 1-6 alkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 acyloxy-C 1-2 alkyl, halogen, hydroxy, phenyl, C 1-3 hydroxyalkyl and oxo, (d) C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-6 alkyl wherein said cycloalkyl or C 3-7 cycloalkyl-C 1-6 alkyl are optionally substituted by one to three hydroxy, C 1-3 alkoxy or halo groups, (e) C 1-6 heteroalkyl wherein the heteroalkyl moiety at least includes C 1-6 hydroxyalkyl or C 1-3 alkoxy-C 1-6 alkoxy, (f) heteroaryl wherein said heteroaryl is selected from the group consisting of pyrazolyl and pyridinyl wherein said heteroaryl is optionally independently substituted with one to three groups selected from the group consisting of C 1-6 alkyl groups, C 1-6 haloalkyl and halogen, and (g) C 1-3 cyanoalkyl;
R 3 is hydrogen or halogen; or,

a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is an optionally substituted heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxadiazolyl, oxazolyl, imidazolyl and isoxazolyl.

3. The compound of claim 2 wherein R 1 is optionally substituted 1H-pyrazol-3-yl or 1H-pyrazol-4-yl.

4. The compound of claim 3 wherein R 1 is 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-3-yl or 1-(2-hydroxyethyl)-1H-pyrazol-4-yl.

5. The compound of claim 1 wherein R 1 is an optionally substituted pyrrolidinyl, piperidinyl or morpholinyl.

6. The compound of claim 1 wherein R 1 is pyrrolidin-2-yl or pyrrolidin-3-yl.

7. The compound of claim 1 wherein R 1 is 1-methyl-pyrrolidin-2-yl, 1-methyl-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, 4-fluoro-pyrrolidin-2-yl or 5-methyl-pyrrolidin-2-yl.

8. The compound of claim 1 wherein R 2 is selected from (a) tetrahydropyranyl, (b) tetrahydrofuranyl, (c) oxetanyl, wherein said tetrahydropyranyl, tetrahydrofuranyl and oxetanyl are optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 hydroxyalkyl, C 1-4 acyloxy-C 1-2 alkyl, and halogen, (d) 2-hydroxy-1-methyl-ethan-1-yl, (e) 2,2,2-trifluoro-1-methyl-ethan-1-yl, (f) 1-cyclopropyl-ethan-1-yl, (g) 2-methoxyethyl, (h) 3-fluoropropyl, (i) cyclopropylmethyl, (j) oxetanylmethyl, (k) 4-hydroxycyclohexyl and (l) pyrazolyl wherein said pyrazolyl moiety is optionally substituted with one to three groups independently selected from C 1-6 alkyl, C 1-6 haloalkyl and halogen.

9. The compound of claim 8 wherein R 2 is tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl or 2-hydroxymethyl-tetrahydropyran-4-yl.

10. The compound of claim 8 wherein R 2 is 2-methylpyrazol-3-yl, 2,5-dimethylpyrazol-3-yl or 1,3-dimethylpyrazol-4-yl.

11. The compound of claim 1 wherein R 1 is selected from the group consisting of 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, 1-methyl-pyrrolidin-2-yl, 4-fluoro-pyrrolidin-2-yl and 5-methyl-pyrrolidin-2-yl.

12. The compound of claim 1 wherein R 2 is selected from the group consisting of 1-hydroxypropan-2-yl, isopropyl, 1-cyclopropylethyl, cyclopropylmethyl, 4-hydroxycyclohexyl, 1,1,1-trifluoropropan-2-yl, 3-fluoropropyl, tetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl, (4-tetrahydro-2H-pyran-2-yl)methyl acetate, tetrahydrofuran-3-yl, 3-methyloxetan-3-yl, oxetan-3-ylmethyl, 2-methoxyethyl, 2-methylpyrazol-3-yl, 2,5-dimethylpyrazol-3-yl and 1,3-dimethylpyrazol-4-yl.

13. The compound of claim 1 wherein Ar is selected from the group consisting of 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-methoxyphenyl, 4-difluoromethoxyphenyl, 3-chloro-4-methoxyphenyl, 4-cyano-3-fluorophenyl, 3-chloro-4-cyanophenyl, 3-cyano-4-methoxyphenyl and 3-fluorophenyl.

14. The compound of claim 1 wherein R 3 is hydrogen or fluoro.

15. The compound of claim 1 selected from the group consisting of:
N-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((S)-1-hydroxypropan-2-ylamino)quinazoline-7-carboxamide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-trifluoromethyl-phenyl)-(S)-pyrrolidin-2-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-3-yl)-methyl]-amide;
2-isopropylamino-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-trifluoromethyl-phenyl)-(R)-pyrrolidin-2-yl-methyl]-amide;
N-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-3-yl)methyl)-2-((S)-1-hydroxypropan-2-ylamino)quinazoline-7-carboxamide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-trifluoromethyl-phenyl)-(R)-pyrrolidin-2-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(R)-(3-chloro-4-fluoro-phenyl)-(R)-pyrrolidin-3-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(R)-(3-chloro-4-fluoro-phenyl)-(S)-pyrrolidin-3-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(3-chloro-4-fluoro-phenyl)-(S)-pyrrolidin-3-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(3-chloro-4-fluoro-phenyl)-(R)-pyrrolidin-3-yl-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(R)-(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide;
2-((S)-2-hydroxy-1-methyl-ethylamino)-quinazoline-7-carboxylic acid [(R)-(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide;
2-((S)-2-hydroxy-1-methyl-ethylamino)-quinazoline-7-carboxylic acid [(S)-(4-chloro-3-fluoro-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(3-chloro-4-fluoro-phenyl)-(3-fluoro-pyrrolidin-3-yl)-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-trifluoromethyl-phenyl)-((R)-1-methyl-pyrrolidin-2-yl)-methyl]-amide;
2-(tetrahydropyran-4-ylamino)-quinazoline-7-carboxylic acid [(R)-(4-chloro-3-fluoro-phenyl)-(1-ethyl-1H-pyrazol-3-yl)-methyl]-ami

Assignees

• Blake James F
• Chen Huifen
• Chicarelli Mark Joseph
• Demeese Jason
• Garrey Rustam Ferdinand
• Gaudino John
• Gazzard Lewis
• Kaus Robert J
• Kintz Samuel
• Mohr Peter J
• Moreno David A
• Schwarz Jacob
• Siedem Christopher S
• Wallace Eli M
• Array Biopharma Inc
• Genentech Inc

Inventors

• Blake James F
• Chen Huifen
• Chicarelli Mark Joseph
• Demeese Jason
• Garrey Rustam Ferdinand
• Gaudino John
• Gazzard Lewis
• Kaus Robert J
• Kintz Samuel
• Mohr Peter J
• Moreno David A
• Schwarz Jacob
• Siedem Christopher S
• Wallace Eli M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D493/08

  Bridged systems · CPC title

• A61P35/02

  specific for leukemia · CPC title