Aminopyrimidine compounds as inhibitors of T790M containing EGFR mutants

Patent metadata

Field	Value
Publication number	US-9890152-B2
Application number	US-201514745159-A
Country	US
Kind code	B2
Filing date	Jun 19, 2015
Priority date	Nov 20, 2012
Publication date	Feb 13, 2018
Grant date	Feb 13, 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,
X is CR 3 or N;
R 1 is C 3 -C 7 heterocycloalkyl, heteroaryl, aryl, —O(C 1 -C 6 alkyl), —O(C 3 -C 7 cycloalkyl) 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;
R 2 is hydrogen, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, —(CH 2 ) m C 4 -C 7 heterocycloalkyl, C 1 -C 6 alkyl, alkylamino, alkoxy or —CH 2 O(C 1 -C 3 alkyl);
R 3 is hydrogen, C 1 -C 3 alkyl, CN, COOH, C 3 -C 7 cycloalkyl, heterocycloalkyl, —NHC(O)C 1 -C 6 alkyl, (CH 2 ) m C(O)NR a R b or heteroaryl;
R 4 is hydrogen, C 3 -C 7 heterocycloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, —(CH 2 ) m phenyl or —(CH 2 ) m heteroaryl;
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 3 -C 7 cycloalkyl, —(CH 2 ) m C 3 -C 7 heteocycloalkyl or —(CH 2 ) m heteroaryl, wherein said C 3 -C 7 heterocyloalkyl and heteroaryl may 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, alkoxy, CN and acyl; R a and R b together may form a C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, or heteroaryl ring;
wherein each R f is independently selected from the group consisting of C 1 -C 3 alkyl, alkoxy, amino, hydroxyl, alkylamino, amide, urea, oxo, halo, pyrazolyl, imidazolyl, triazolyl, CN, NHC(O)(C 1 -C 3 alkyl), acyl, sulfonyl, sulfoxide, sulfoximinyl, sulfonamide, amide, —(CH 2 ) m C 3 -C 7 heterocycloalkyl, —O(C 1 -C 6 alkyl), —C(O)OR a ;
each m is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is N; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein X is CR 3 ; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein R 1 is C 3 -C 7 heterocycloalkyl; on a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein R 1 is heteroaryl; or a pharmaceutically acceptable salt thereof.

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

7. The compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein R 2 is hydrogen, —(CH 2 ) m aryl, heteroaryl, C 4 -C 7 hcterocycloalkyl, alkylamino, alkoxy or —(CH 2 ) m O(C 1 -C 3 alkyl); or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein R 4 is hydrogen or C 1 -C 6 alkyl.

10. The compound according to claim 1 , wherein R 3 is hydrogen, C 1 -C 3 alkyl, heteroaryl or —(CH 2 ) m C(O)NR a R b ; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein R 1 is a C 3 -C 7 heterocycloalkyl selected from the group consisting of piperidinyl, piperizinyl, pyrazolyl and pyrrolidinyl, wherein said C 3 -C 7 heterocycloalkyl may be further substituted with one to five R f groups selected from C 1 -C 6 alkyl, alkoxy, halo, hydroxy, sulfonyl, and sulfonamide; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 2 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 10 , wherein R 3 is hydrogen, C 1 -C 3 alkyl or —C(O)NH 2 ; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein R 4 is hydrogen or isopropyl; R f is F, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. The compound according to claim 1 , wherein said compound is:
N-(2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine;
1-Isopropyl-N-(2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine formate salt;
(2-Ethyl-1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
(1-Isopropyl-2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
1-Isopopyl-N 6 -[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-N 2 -methyl-1H-imidazo[4,5-c]pyridine-2,6-diamine;
[2-(2-Ethoxyethoxymethyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl]-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
[2-(2-Dimethylaminoethoxymethyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl]-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
(2-Dimethylaminomethyl-1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine formate salt;
(1-Isopropyl-6-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-ylamino]-1H-imidazo[4,5-c]pyridin-2-yl)methanol;
(1-Isopropyl-2-methoxy-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)pyrimidin-4-yl]amine;
1-[4-(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrimidin-2-yl]piperidin-4-ol;
8-[4-(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrimidin-2-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
[2-(5,6-Dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)pyrimidin-4-yl]-(1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methanesulfonylpiperazin-1-yl)pyrimidin-4-yl]-amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amine;
[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl]-[1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl]amine;
[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl]-[1-(tetrahydropyran-4-yl)-1H-imidazo[4,5-c]pyridin-6-yl]amine;
(1-Ethyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl]-[1-methyl-2-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]pyridin-6-yl]amine;
[2-(2-Fluorobenzyl)-3-methyl-3H-imidazo[4,5-c]pyridin-6-yl]-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl]-[2-(1H-pyrazol-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]amine;
(1-Cyclopentyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-yl]-[3-methyl-2-(l H-pyrazol-4-yl)-3H-imidazo[4,5-c]pyridin-6-yl]amine dihydrochloride;
(1-Cyclopentyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxy-piperidin-1-yl)-pyrimidin-4-yl]amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(1-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]amine;
(1-Isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-(2-morpholin-4-ylpyrimidin-4-yl)amine;
4-(4-((1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)pyrimidin-2-yl)thiomorpholine 1-oxide;
4-(4-((1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)pyrimidin-2-yl)thiomorpholine 1,1-dioxide;
3-{6-[2-(4-Methoxypiperidin-1-yl)pyrimidin-4-ylamino]pyrrolo[3,2-c]pyridin-1-yl}-2,2-dimethylpropionamide;
((R) or (S) 1-sec-Butyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine;
1-[4-(1-Isopropyl-2-methyl-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrimidin-2-yl]piperidine-3,4-diol;
N-(2-(8-Oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-1-isopropyl-l H imidazo[4,5-c]pyridin-6-amine;
(R or S)—N-(2-2-oxa-7-az

Assignees

• Genentech Inc

Inventors

• Bryan Marian C
• Chan Bryan
• Hanan Emily
• Heffron Timothy
• Purkey Hans
• Elliott Richard Leonard
• Heald Robert
• Knight Jamie
• Lainchbury Michael
• Seward Eileen M

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title