Aminopyrimidine compounds as inhibitors of t790m containing egfr mutants

Patent metadata

Field	Value
Publication number	US-2016016948-A1
Application number	US-201514745159-A
Country	US
Kind code	A1
Filing date	Jun 19, 2015
Priority date	Nov 20, 2012
Publication date	Jan 21, 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,
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 heterocycloalkyl or —(CH 2 ) m heteroaryl, wherein said C 3 -C 7 heterocycloalkyl 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 -C7cycloalkyl, 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 . A compound of claim 1 , wherein X is N; or a pharmaceutically acceptable salt thereof.

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

4 . A compound according to any one of claims 1 - 3 , wherein R 1 is C 3 -C 7 heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

5 . A compound according to any one of claims 1 - 3 , wherein R 1 is heteroaryl; or a pharmaceutically acceptable salt thereof.

6 . A compound according to any one of claims 1 - 3 , wherein R 1 is —NR a R b ; or a pharmaceutically acceptable salt thereof.

7 . A compound according to any one of claims 1 - 6 , wherein R 2 is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.

8 . A compound according to any one of claims 1 - 6 , wherein R 2 is hydrogen, —(CH 2 ) m aryl, heteroaryl, C 4 -C 7 heterocycloalkyl, alkylamino, alkoxy or —(CH 2 ) m O(C 1 -C 3 alkyl); or a pharmaceutically acceptable salt thereof.

9 . A compound according to any one of the above claims, wherein R 4 is hydrogen or C 1 -C 6 alkyl;

10 . A compound according to any one of claims 1 , 3 - 9 , 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 . A compound according to any one of claims 1 - 4 , 7 - 10 , 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 . A compound according to claim any one of claims 1 - 6 , 9 - 10 , wherein R 2 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof.

13 . A 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 . A compound according to any one of the above claims, wherein R 4 is hydrogen or isopropyl; R f is F, or a pharmaceutically acceptable salt thereof.

15 . A compound of which is any one of Example 1-250, or a pharmaceutically acceptable salt thereof.

16 . A pharmaceutical composition comprising a compound according to any one of the above claims and a pharmaceutically acceptable carrier.

17 . A method of treating cancer comprising administering to a human in need thereof an effective amount of a compound according to any one of claims 1 - 15 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

18 . A use of a compound according to any one of claims 1 - 15 in the preparation of a medicament for the treatment of cancer.

19 . A method of claim 16 , wherein said cancer is non-small cell lung cancer.

20 . A use of claim 17 , wherein said cancer is non-small cell lung cancer.

21 . The compound of claims 1 - 15 or a pharmaceutically acceptable salt thereof for use in therapy.

22 . 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 any one of claims 1 - 15 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

23 . A use of a combination of an anti-neoplastic agent and a compound according to any one of claims 1 - 15 or a pharmaceutically acceptable salt thereof in preparation of a medicament for the treatment of cancer.

24 . A method of claim 22 , wherein said cancer is non-small cell lung cancer.

25 . A use of claim 23 , wherein said cancer is non-small cell lung cancer.

Assignees

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title