2-acylaminothiazoles for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2016257658-A1
Application number	US-201414902319-A
Country	US
Kind code	A1
Filing date	Jul 3, 2014
Priority date	Jul 4, 2013
Publication date	Sep 8, 2016
Grant date	—

Abstract

The present invention relates to inhibitors of the oncogenic protein kinase ALK of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) are useful in the preparation of a medicament, in particular for the treatment of cancer.

First claim

1 . The compounds of formula (I)

wherein:
—R 1 is

i equals zero, 1 or 2
Rx and Rx′ can be the same or different and are a C 1 -C 3 linear or branched alkyl;
X is either oxygen or NRy;
Ry is a C 1 -C 3 linear or branched alkyl or propargyl;
Rz is either hydrogen or C 1 -C 3 linear or branched alkyl;
—R 2 and —R 3 can be the same or different and are hydrogen, linear or branched C 1 -C 3 alkyl or —C≡C—R 4 , provided that at least one of —R 2 and —R 3 is —C≡C—R 4 ;
—R 4 is hydrogen, —CH 2 —O—CPh 3 , cyclohexenyl, C 1 -C 4 alkyl,

Rt and Rt′ can be the same or different and are C 1 -C 3 alkyl optionally substituted with one or more fluorine atoms, C 1 -C 3 alkoxy optionally substituted with one or more fluorine atoms or F;
Ra, Rb and Rc can be the same or different and can be phenyl or C 1 -C 4 linear or branched alkyl;
and pharmaceutically acceptable salts thereof.

2 . The compounds of claim 1 wherein
R 2 is hydrogen or linear or branched C 1 -C 3 alkyl; and
R 3 is —C≡C—R 4 .

3 . The compounds of claim 1 wherein
—R 2 is —C≡C—R 4 ; and
R 3 is hydrogen or linear or branched C 1 -C 3 alkyl.

4 . The compounds of claim 2 , wherein —R 4 is selected from the list of

5 . The compounds of claim 2 , wherein —R 4 is selected from the list of

6 . The compounds of claim 4 wherein —R 1 is

7 . The compounds of claim 4 wherein —R 1 is

8 . The compounds of claim 4 wherein —R 1 is selected from the list of

9 . The compounds of claim 1 selected from the list of
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-(phenylethynyl)phenyl)thiazol-2-yl)benzamide;
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-(p-tolylethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-((4-methoxyphenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(4-methyl-3-(phenylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide
N-(4-(4-methyl-3-(p-tolylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((4-methoxyphenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(4-methyl-3-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide:
N-(4-(3-((2-methoxyphenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3((4-fluorophenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-(4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-methyl-4-(p-tolylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-methyl-4-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3,4-bis((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(4-methyl-3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-methyl-4-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3,4-bis((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
4((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((triethylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
4((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((trimethylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-(cyclohex-1-en-1-ylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-(hex-1-yn-1-yl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-(3-((tert-butyldiphenylsilyl)oxy)prop-1-yn-1-yl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-(3-((triisopropylsilyl)oxy)prop-1-yn-1-yl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((tert-butyldimethylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((tert-butyldiphenylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
5-(4-(4-methylpiperazine-1-carbonyl)phenyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)furan-2-carboxamide;
N-(4-(3-((tert-butyldimethylsilyl)ethynyl)phenyl)thiazol-2-yl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)furan-2-carboxamide;
5-(4-(4-methylpiperazine-1-carbonyl)phenyl)-N-(4-(3-(3-((triisopropylsilyl)oxy)prop-1-yn-1-yl)phenyl)thiazol-2-yl)furan-2-carboxamide;
5-(4-(4-methylpiperazine-1-carbonyl)phenyl)-N-(4-(3-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)furan-2-carboxamide;
4-(4-methylpiperazin-1-yl)methyl)-N-(4-(3-(3-(trityloxy)prop-1-yn-1-yl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-((2-fluorophenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((4-fluorophenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((3,5-bis(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(3-((3,5-bis(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)furan-2-carboxamide;
4-(4-methylpiperazin-1-yl)methyl)-N-(4-(4-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(4-((3,5-bis(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
N-(4-(4-((tert-butyldimethylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;
4-(morpholinomethyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-((3,5-bis(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-(morpholinomethyl)benzamide;
N-(4-(3-((tert-butyldimethylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-(morpholinomethyl)benzamide;
N-(4-(3-((tert-butyldiphenylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-(morpholinomethyl)benzamide;
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((2-(trifluoromethoxy)phenyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
5-(4-(4-methylpiperazine-1-carbonyl)phenyl)-N-(4-(3-((2-(trifluoromethoxy)phenyl)ethynyl)phenyl)thiazol-2-yl)furan-2-carboxamide;
4-(((2-(dimethylamino)ethyl)amino)methyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
4-((1H-tetrazol-1-yl)methyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
4-((1H-imidazol-1-yl)methyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
isopropyl 2-((4-((4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)carbamoyl)benzyl)amino)acetate;
4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)benzamide;
N-(4-(3-ethynylphenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide and
4-((4-(prop-2-yn-

Assignees

• Universita' Degli Studi Di Milano - Bicocca
• Univ Geneve
• Univ Claude Bernard Lyon

Inventors

• Gambacorti-Passerini Carlo
• Mologni Luca
• Scapozza Leonardo
• Bisson William
• Goekjian Peter
• D'ATTOMA Joseph

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D277/46 Primary

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title