Aminopyrimidine derivatives for use as modulators of kinase activity

Patent metadata

Field	Value
Publication number	US-9321760-B2
Application number	US-201214236405-A
Country	US
Kind code	B2
Filing date	Sep 12, 2012
Priority date	Sep 12, 2011
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

Abstract

The invention provides novel heterocyclic amine compounds according to Formula (I) and their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

First claim

The invention claimed is:

1. A compound of Formula (I)

and pharmaceutically acceptable salts, solvates, or solvates of salts thereof, wherein:
X is N or CH;
Y is N or CR 2 ;
E is an unbranched or branched alkyl linker having 1, 2, 3, 4, 5, 6 or 7 C atoms, which may be unsubstituted or mono- or disubstituted with Hal, OH, CN or NH 2 , in which one CH 3 group may be replaced by Cyc 1 , Cyc 2 , CONH 2 , CF 3 , and in which one, two or three CH 2 groups may be replaced by —NH—, or —CO—, and in which one CH group may be replaced by —N—;
R 1 is CN, CONH 2 , Hal, LA, O(LA), Ar, or Cyc 2 ;
R 2 is H, NH 2 , Hal or CN;
Hal is F, Cl, Br or I;
each LA is independently an unbranched or branched, linear saturated or partially unsaturated hydrocarbon chain having 1, 2, 3 4, 5 or 6 C atoms, wherein 1, 2 or 3H atoms may be replaced by Hal or OH;
each Ar is independently a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or, independently of one another, mono- or disubstituted by Hal, LA, OH, SH, O(LA), NH 2 , NH(LA), N(LA) 2 , NO 2 , CN, OCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , CHO and CO(LA), and/or monosubstituted by Cyc 2 or O-Cyc 2 ;
each Cyc 1 is independently a 3, 4, 5 or 6 membered monocyclic aliphatic homo- or heterocycle having 0-2 heteroatoms, selected from O, S and N, which may be mono- or disubstituted by Hal, LA, NH 2 , NH(LA), N(LA) 2 , HO(LA)-;
each Cyc 2 is independently a 5 or 6 membered monocyclic aromatic homo- or heterocycle having 0-3 heteroatoms, selected from O, S and N, which may be mono- or di-substituted by Hal or LA; and
n is 1 or 2.

2. The compound according to claim 1 wherein X is N, and pharmaceutically acceptable salts, solvates, or solvates of salts thereof.

3. Compounds according to claim 1 , selected from:
6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
6-{4-[2-Amino-1-(4-chloro-3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
6-(4-(2-amino-1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine;
2-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide;
6-{4-[(R)-2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile;
6-{4-[3-Azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
(S)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine;
6-{4-[2-Amino-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
6-(4-(2-(azetidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine;
6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine;
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine;
N-{3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide;
6-{4-[2-Amino-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine;
6-{4-[(S)-2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine;
6-(4-(2-amino-1-(4-(trifluoromethyl)-phenyl)ethyl)piperazin-1-yl)-5-vinylpyrimidin-4-amine;
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-ethoxypyrimidin-4-amine;
4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid [(S)-1-(4-chloro-phenyl)-propyl]-amide; and
6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-chloro-pyrimidin-4-ylamine;

and, pharmaceutically acceptable salts, or solvates thereof.

4. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, as active ingredient, together with a pharmaceutically acceptable carrier.

5. A kit consisting of separate packs of
a) an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, and
b) an effective amount of a further medicament active ingredient.

6. The compound according to claim 1 , wherein Y is N or CH, and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

7. The compound according to claim 1 , wherein R 1 is Hal, LA, O(LA), or Cyc 2 , and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

8. The compound according to claim 1 , wherein Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA), and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

9. The compound according to claim 1 , wherein E is a methyl linker which is substituted by aminomethyl, wherein the amino group of the aminomethyl is unsubstituted, or mono- or disubstituted by LA, or E is a methyl linker which is substituted by (azetidin-1-yl)methyl, and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

10. The compound according to claim 1 , wherein
Y is CNH 2 ,
E is —CH(R 3 )—NH—CO— or —CO—NH—CH(R 3 )—,
R 3 is H or LA,
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

11. The compound according to claim 1 , wherein
X is N,
Y is N or CH,
R 1 is Hal, LA, O(LA), or Cyc 2 ,
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

12. The compound according to claim 1 , wherein
X is N,
Y is N or CH,
Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA),
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

13. The compound according to claim 1 , wherein
X is N,
Y is N or CH,
E is a methyl linker which is substituted by aminomethyl, wherein the amino group of the aminomethyl is unsubstituted, or mono- or disubstituted by LA, or E is a methyl linker which is substituted by (azetidin-1-yl)methyl,
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

14. The compound according to claim 1 , wherein
X is N,
Y is CNH 2 ,
E is —CH(R 3 )—NH—CO— or —CO—NH—CH(R 3 )—,
R 1 is Hal, LA, O(LA), Cyc 1 or Cyc 2 ,
R 3 is H or LA,
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

15. The compound according to claim 1 , wherein
X is N,
Y is CNH 2 ,
E is —CH(R 3 )—NH—CO— or —CO—NH—CH(R 3 )—,
R 1 is Hal, LA, O(LA), Cyc 1 or Cyc 2 ,
R 3 is H or LA,
Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA),
and pharmaceutically acceptable salts, solvates, or solvates of salts, thereof.

16. The compound according to claim 1 , wherein
X is N,
Y is CNH 2 ,
E is —CH(R 3 )—NH—CO— or —CO—NH—CH(R 3 )—,
R 3 is H or LA,
Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA),
and pharmaceutically acceptable salts, solvates, or solvates of s

Assignees

• Lan Ruoxi
• Huck Bayard R
• Chen Xiaoling
• Deselm Lizbeth Celeste
• Qiu Hui
• Xiao Yufang
• Neagu Constantin
• Mochalkin Igor
• Johnson Theresa L
• Merck Patent Gmbh

Inventors

• Lan Ruoxi
• Huck Bayard R
• Chen Xiaoling
• Deselm Lizbeth Celeste
• Qiu Hui
• Xiao Yufang
• Neagu Constantin
• Mochalkin Igor
• Johnson Theresa L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title