Substituted pyrroles active as kinases inhibitors

Patent metadata

Field	Value
Publication number	US-9688661-B2
Application number	US-201314418555-A
Country	US
Kind code	B2
Filing date	Jul 24, 2013
Priority date	Aug 2, 2012
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The present invention relates to substituted pyrrole compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Jak family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
Ring W is a pyrrole;
R1 is a substituted aryl;
R2 is CONR6R7 wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R6 and R7, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R3 is hydrogen, halo or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R4 is an optionally substituted group

wherein:
R8 is hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, COR9, CONR10R11 and SO 2 R12,
wherein:
R9 is a group optionally substituted selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R10 and R11, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is a group optionally substituted selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;

R5 is hydrogen, halo or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
or a pharmaceutically acceptable salt thereof.

2. A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
5-(6-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide (compd 189);
2-(5-Chloro-2-methylphenyl)-5-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 190);
5-(6-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxamide (compd 197);
2-(5-Chloro-2-ethylphenyl)-5-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 198);
5-(6-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (compd 204);
2-[2-Chloro-5-(trifluoromethyl)phenyl]-5-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 205);
5-(6-Aminopyrimidin-4-yl)-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (compd 211);
5-[6-(Methylamino)pyrimidin-4-yl]-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (compd 212);
5-(6-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (compd 218);
2-[2-Ethyl-5-(trifluoromethyl)phenyl]-5-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 219);
4-(6-Aminopyrimidin-4-yl)-1-(5-chloro-2-ethylphenyl)-1H-pyrrole-2-carboxamide (compd 235);
1-(5-Chloro-2-ethylphenyl)-4-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (compd 236);
4-(6-Aminopyrimidin-4-yl)-1-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxamide (compd 256);
5-(6-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-methyl-1H-pyrrole-3-carboxamide (compd 301);
2-(5-Chloro-2-ethylphenyl)-N-methyl-5-6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 302);
5-(6-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide (compd 321);
2-[2-Ethyl-5-(trifluoromethyl)phenyl]-N-methyl-5-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (compd 322);
5-(6-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide (compd 331) and
5-(6-Aminopyrimidin-4-yl)-3-(5-chloro-2-methylphenyl)-1-(2-hydroxyethyl)-1H-pyrrole-2-carboxamide (compd 335).

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

4. A pharmaceutical composition, according to claim 3 , further comprising one or more chemotherapeutic agents.

5. A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Brasca Maria Gabriella
• Bindi Simona
• Caldarelli Marina
• Nesi Marcella
• Orrenius Sten Christian
• Panzeri Achille

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title