Azaindazole compounds as inhibitors of T790M containing EGFR mutants

Patent metadata

Field	Value
Publication number	US-9951064-B2
Application number	US-201615152947-A
Country	US
Kind code	B2
Filing date	May 12, 2016
Priority date	Jun 28, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

This invention relates to novel compounds which are inhibitors of T790M containing EGFR mutants, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the prevention or treatment of cancer.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein,
R1 is C 3 -C 7 heterocycloalkyl, heteroaryl, —O(C 1 -C 6 alkyl), or —NR a R b , wherein said C 3 -C 7 heterocycloalkyl and heteroaryl may be further substituted with one to five R f groups;
R2 is hydrogen, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl or unsubstituted C 1 -C 6 alkyl;
R3 is C 1 -C 6 alkyl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 cycloalkyl, —O(C 1 -C 6 alkyl), CN, —NR a R b , —NHC(O)(C 1 -C 3 alkyl), —C(O)NR a R b , or heteroaryl;
wherein each R f is independently selected from the group consisting of C 1 -C 3 alkyl, alkoxy, amino, hydroxy, alkylamino, amide, urea, oxo, halo, pyrazolyl, imidazolyl, triazolyl, CN, —NHC(O)(C 1 -C 3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamide, sulfoximinyl, —(CH 2 ) m C 3 -C 7 heterocycloalkyl, —O(C 1 -C 6 alkyl), —C(O)OR a ;
wherein each R a is independently H or C 1 -C 6 alkyl, each R b is independently H, C 1 -C 6 alkyl, alkoxy, amino, —(CH 2 ) m C(O)NH 2 , —(CH 2 ) m C 3 -C 7 cycloalkyl, —(CH 2 ) m C 3 -C 7 heterocycloalkyl or —(CH 2 ) m heteroaryl, or R a and R b together may form a C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl or heteroaryl ring, wherein said C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl and heteroaryl may each be further substituted with one to three groups selected from the group consisting of halo, hydroxy, C 1 -C 3 alkyl, amino, oxo, amide, sulfonyl, sulfoxide, sulfoximinyl, sulfonamide, alkoxy, CN and acyl; each m is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R1 is C 3 -C 7 heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein R1 is heteroaryl; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 , wherein R1 is —NR a R b ; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 , wherein R1 is heteroaryl or C 3 -C 7 heterocycloalkyl, R f is sulfonyl or alkoxy, R3 is —NR a R b or heteroaryl, R2 is C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5 , wherein R1 is piperdinyl or pyrazolyl, or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein R f is —SO 2 (cyclopropyl), halo, hydroxy, C 1 -C 6 alkyl or methoxy, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 , wherein R2 is unsubstituted C 1 -C 6 alkyl.

9. A compound according to claim 8 , wherein R3 is C 1 -C 3 alkyl, C 3 -C 7 heterocycloalkyl, heteroaryl, —NR a R b or —C(O)NR a R b ; or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 , wherein R1 is a C 3 -C 7 heterocycloalkyl or heteroaryl selected from the group consisting of piperidinyl and pyrazolyl, wherein said C 3 -C 7 heterocycloalkyl or heteroaryl may be further substituted with one to three R f groups selected from C 1 -C 6 alkyl, alkoxy, hydroxyl, halo, sulfonyl, and sulfonamide; or a pharmaceutically acceptable salt thereof.

11. A compound according claim 1 , wherein R2 is isopropyl or sec-butyl; or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

13. A method of treating cancer comprising administering to a human in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

14. A method of claim 13 , wherein said cancer is non-small cell lunch cancer.

15. A compound, selected from the group consisting of:
4-(6-((2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)thiomorpholine 1,1-dioxide;
1-Isopropyl-N-(2-(4-methoxypiperdin-1-yl)pyrimidin-4-yl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrazolo[4,3-c]pyridine-6-amine;
1-(4-((1-Isopropyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-2-yl)-3,3-dimethylpiperidin-4-ol;
N-(2-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine
N-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine;
2-((6-((2-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)ethanol;
N-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-fluoro-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine;
1-(4-((1-Isopropyl-3-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino) pyrimidin-2-yl)-3,3-dimethylpiperidin-4-ol;
N-(2-(1-((Cyclopropylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-amine;
1-(4-((1-Isopropyl-3-(4-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-2-yl)-3,3-dimethylpiperidin-4-ol;
1-Isopropyl-6-((2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;
1-(4-((1-(sec-Butyl)-3-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-2-yl)-3,3-dimethylpiperidin-4-ol;
2-(1-(1-(sec-Butyl)-6-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)azetidin-3-yl)propan-2-ol;
1-Isopropyl-N-(2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine;
N 6 -(2-(1-(Ethylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-N 3 -(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine-3,6-diamine;
1-(6-(2-(1-(Ethylsulfonyl)-1H-pyrazol-4-yl) pyrimidin-4-ylamino)-1-isopropyl-1H-pyrazolo[4,3-c] pyridin-3-yl)-N,N-dimethylazetidine-3-carboxamide;
1-(6-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl) pyrimidin-4-ylamino)-1-isopropyl-1H-pyrazolo[4,3-c] pyridin-3-yl) pyrrolidin-3-ol;
N-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl) pyrimidin-4-yl)-1-isopropyl-3-(tetrahydrofuran-3-yl)-1H-pyrazolo [4,3-c] pyridin-6-amine;
(±)-cis-3-Fluoro-1-[4-(1-isopropyl-3-morpholin-4-yl-1H-pyrazolo[4,3-c]pyridin-6-ylamino)pyrimidin-2-yl]piperidin-4-ol;
(±)-cis-3-Fluoro-1-{4-[1-isopropyl-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-ylamino]-pyrimidin-2-yl}piperidin-4-ol;
(±)-1-(6-((2-(cis-3-Fluoro-4-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)imidazolidin-2-one;
(±)-2-(cis-3-Fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl]-[1-isopropyl-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amine;
1-(4-(Aminocyclohexyl)methyl)-N 6 -[2-(4-methoxypiperidin-1-yl)-pyrimidin-4-yl]-1H-pyrazolo[4,3-c]pyridine-3,6-diamine;
1-(1-(sec-Butyl)-6-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)imidazolidin-2-one;
(±)-1-(1-(sec-Butyl)-6-((2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)imidazolidin-2-on;
1-(sec-Butyl)-N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-amine;
(R)-1-(6-((2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-3-carbonitrile;
N-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-(tetrahydrofuran-3-yloxy)-1H-pyrazolo[4,3-c]pyridin-6-amine;
1-(6-(2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-

Assignees

• Genentech Inc

Inventors

• Bryan Marian C
• Chan Bryan
• Diederich Francois
• Dotson Jennafer
• Hanan Emily
• Heffron Timothy
• Lainchbury Michael
• Heald Robert
• Seward Eileen M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title