Azaindazole compounds as inhibitors of t790m containing egfr mutants

Patent metadata

Field	Value
Publication number	US-2016257682-A1
Application number	US-201615152947-A
Country	US
Kind code	A1
Filing date	May 12, 2016
Priority date	Jun 28, 2013
Publication date	Sep 8, 2016
Grant date	—

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

1 . A compound of Formula (I)

wherein,
R 1 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;
R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl;
R 3 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 R 1 is C 3 -C 7 heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

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

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

5 . A compound of claim 1 , wherein R 1 is heteroaryl or C 3 -C 7 heterocycloalkyl, R f is sulfonyl or alkoxy, R 3 is —NR a R b or heteroaryl, R 2 is C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.

6 . A compound of claim 5 , wherein R 1 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 R 2 is C 1 -C 6 alkyl;

9 . A compound according to claim 8 , wherein R 3 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 R 1 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 R 2 is isopropyl, sec-butyl or 1,1,1-trifluoropropan-2-yl; 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 use of a compound according to claim 1 in the preparation of a medicament for the treatment of cancer.

15 . A method of claim 13 , wherein said cancer is non-small cell lung cancer.

16 . A use of claim 14 , wherein said cancer is non-small cell lung cancer.

17 . The compound of claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

18 . A method of treating cancer comprising co-administering to a human in need thereof a combination of an effective amount of an anti-neoplastic agent in a pharmaceutical composition and a compound according to claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

19 . A method of claim 18 , wherein said cancer is non-small cell lung cancer.

20 . A method of claim 19 , wherein said anti-neoplastic agent is erlotinib or gefitinib.

21 . A use of a combination of an anti-neoplastic agent and a compound according to claim 1 or a pharmaceutically acceptable salt thereof in preparation of a medicament for the treatment of cancer.

22 . A use of claim 21 , wherein said cancer is non-small cell lung cancer.

23 . A use of claim 21 , wherein said anti-neoplastic agent is erlotinib or gefitinib.

Assignees

• Genentech Inc

Inventors

• Bryan Marian C
• Chan Bryan
• Diederich Francois
• Dotson Jennafer
• Hanan Emily
• Heffron Timothy
• Lainchbury Michael

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/5386

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377

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