US 9,283,224 B2Granted

Substituted pyrimidinyl-pyrroles active as kinase inhibitors

AssigneeNerviano Medical Sciences S.R.L.

InventorsMaria Gabriella Brasca, Tiziano Bandiera, Jay Aaron Bertrand, Paola Gnocchi, Danilo Mirizzi, Marcella Nesi, Achille Panzeri

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Abstract

The present invention relates to substituted pyrimidinyl-pyrrole compounds of formula (I) which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Janus 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.

Claims14

Dependent claims

A compound of formula (I):

wherein:
R1 is selected from the group consisting of a halogen and a straight or branched C1-C6 alkyl and
R2 is selected from the group consisting of a halogen and a substituted C1-C6 alkyl;
R3 is NR8R9 wherein:
R8 and R9 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R4 is hydrogen, an optionally substituted straight or branched C1-C6 alkyl or NR10R11, wherein:
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, 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 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is hydrogen or an optionally substituted straight or branched C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded:
5-(2-amino-pyrimidin-4-yl)-2-(5-fluoro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2,5-difluoro-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-fluoro-phenyl)-1H-pyrrole-3-carboxamide and
5-(2-amino-pyrimidin-4-yl)-2-(2-chloro-5-fluoro-phenyl)-1H-pyrrole-3-carboxamide.

11 more elements

A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:

5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2,5-dichlorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-cyanophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-fluorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(hydroxymethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(propan-2-yl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2,5-bis(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-cyano-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(piperidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-phenyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(furan-2-ylmethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methoxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-fluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
N-(2-Aminoethyl)-5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(methylamino)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-benzyl-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2,2-dimethylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-hydroxyphenyl)-1H-pyrrole-3-carboxamide,
2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide,
5-(Pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
2-(5-Chloro-2-methylphenyl)-5-(2-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide and
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide.

47 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/112,559Filed 5 Apr 2012
Published: US 2014/0155421 A15 Jun 2014
Granted: 15 Mar 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond

Family

US 2014/0155421 A1Pre-grant publication · published 5 Jun 2014
US 9,283,224 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

wherein:
R1 is selected from the group consisting of a halogen and a straight or branched C1-C6 alkyl and
R2 is selected from the group consisting of a halogen and a substituted C1-C6 alkyl;
R3 is NR8R9 wherein:
R8 and R9 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R4 is hydrogen, an optionally substituted straight or branched C1-C6 alkyl or NR10R11, wherein:
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, 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 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is hydrogen or an optionally substituted straight or branched C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded:
5-(2-amino-pyrimidin-4-yl)-2-(5-fluoro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2,5-difluoro-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-fluoro-phenyl)-1H-pyrrole-3-carboxamide and
5-(2-amino-pyrimidin-4-yl)-2-(2-chloro-5-fluoro-phenyl)-1H-pyrrole-3-carboxamide.

11 more elements

Facts

Application

14/112,559Filed 5 Apr 2012

Published

US 2014/0155421 A15 Jun 2014

Granted

15 Mar 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond