Pyrazolyl-pyrimidine derivatives as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9284298-B2
Application number	US-201214110596-A
Country	US
Kind code	B2
Filing date	Apr 3, 2012
Priority date	Apr 11, 2011
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The present invention relates to pyrazolyl-pyrimidine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity. 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
R1 is hydrogen, halogen or an optionally substituted group selected from amino, straight or branched (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl;
R2 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, (C 3 -C 7 ) cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl;
R3 is a group selected from CN, —CONR″R′″, —CON(OR′″)R″ and COOR″, wherein R″ and R′″ are, each independently, hydrogen or an optionally substituted group selected from straight or branched (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl or, together with the nitrogen atom to which they are bound, R″ and R′″ may form a 5-to 7-membered heteroaryl or heterocyclyl group, optionally containing one additional heteroatom selected from N, O and S;
X is a single bond or a divalent radical selected from —NR′—, —O—, —S—, —SO—, —SO 2 — and —OSO 2 —, wherein R′ is hydrogen or an optionally substituted straight or branched (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl or, together with the nitrogen atom to which they are bound, R′ and R1 may form a 5- to 7-membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R4 is a group selected from hydrogen, halogen and cyano;
or a pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded:
N-tert-butyl-1-(6-methoxypyridin-3-yl)-5-(pyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
methyl 1-(6-methoxypyridin-3-yl)-5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxylate,
methyl 1-(6-methoxypyridin-3-yl)-5-(pyrimidin-4-yl)-1H-pyrazole-3-carboxylate,
1-(6-methoxypyridin-3-yl)-5-(pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid and
[1(6-methoxypyridin-3-yl)-5-(pyrimidin-4-yl)-IH-pyrazol-3-yl](4-methylpiperazin-1-yl)methanone and with the proviso that when R3 is —CONR″R′″, neither R″ nor R′″ are arylalkyl.

2. A compound of formula (I) as defined in claim 1 wherein:
R3 is CN, CONR″R′″ or CON(OR′″)R″, wherein R″ and R′″ are as defined in claim 1 .

3. A compound of formula (I) as defined in claim 1 wherein:
X is a single bond or a divalent radical selected from —NR′, —O—and —S—, wherein R′ is as defined in claim 1 .

4. A compound of formula (I) as defined in claim 1 wherein:
R1 is hydrogen or an optionally substituted group selected from straight or branched (C 1 -C 6 ) alkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl or, together with the nitrogen atom to which they are bound, R′ and R1 may form a 5-to 7-membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S, wherein R′ is as defined in claim 1 .

5. A compound of formula (I) as defined in claim 1 wherein:
R3 is CN, CONR″R′″ or CONHOR′″, wherein R′″ is hydrogen and R″ is as defined in claim 1 .

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which is selected from the group consisting of:
3-{2-[(4-bromo-2-methoxyphenyl)amino]pyrimidin-4-yl}-N-(2,6-diethylphenyl)-1 -methyl-1H-pyrazole-5-carboxamide,
N-(2,6-diethylphenyl)-3-(2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide,
N-(2,6-diethylphenyl)-5-(2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino }pyrimidin-4-yl)-1-methyl-1H-pyrazole-3-carboxamide,
5-{2-[(4-bromo-2-methoxyphenyl)amino]pyrimidin-4-yl}-N-(2,6-diethylphenyl)-1-methyl-1H-pyrazole-3-carboxamide,
3-{2-[(4-bromo-2-methoxyphenyl)amino]pyrimidin-4-yl}-N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxamide,
5-{2-[(4-bromo-2-methoxyphenyl)amino]pyrimidin-4-yl}-N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-5-{2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-5-[2-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyphenyl }amino)pyrimidin-4-yl]-1-methyl-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-5-(2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-5-{2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-5-(2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-3-{2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}-1H -pyrazole-5-carboxamide,
N-(2,6-diethylphenyl)-5-[2-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyphenyl}amino)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
N-(2,6-diethylphenyl)-5-{2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-3-carboxamide,
3-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-ethylphenyl)-1H-pyrazole-5-carboxamide,
5-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-ethylphenyl)-1H-pyrazole-3-carboxamide,
5-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-methylphenyl)-1H-pyrazole-3-carboxamide,
3-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxamide,
5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
5-[2-(methylsulfanyl)pyrimidin-4-yl]-1-(piperidin-4-yl)-1H-pyrazole-3-carboxamide,
3-[2-(methylsulfanyl)pyrimidin-4-yl]-1-(piperidin-4-yl)-1H-pyrazole-5-carboxamide,
3-(2-hydroxypyrimidin-4-yl)-1-(3-methoxybenzyl)-1H-pyrazole-5-carboxamide,
1-(3-methoxybenzyl)-3-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide,
1-tert-butyl-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-{2[4-(piperazin-1-yl)phenoxy]pyrimidin-4-yl}-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-(2-methoxypyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
N-hydroxy-5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
N-benzyl-1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)-N-(propan-2-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)-N-phenyl-1H-pyrazole-3-carboxamide,
1-tert-butyl-N-methyl-5-(2-phenoxypyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-N,N-diethyl-5-(2-phenoxypyrimidin-4-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-N-methyl-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-N-(propan-2-yl-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-N-phenyl-1H-pyrazole-3-carboxamide,
N-benzyl-1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-N-methyl-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-N-(propan-2-yl)-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-N-phenyl-1H-pyrazole-3-carboxamide,
N-benzyl-1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide,
1-tert-butyl-5-[2-(morpholin-4-yl)pyrimidin-4-yl]-N-phenyl-1H-pyrazole-3-carboxamide and
N-benzyl-1-tert-butyl-5-[2-(morpholin-4-yl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide.

7. A process for preparing a compound of formula (I) as defined in claim 1 or the pharmaceutically acceptable salts thereof, characterized in that th

Assignees

• Casuscelli Francesco
• Brasca Maria Gabriella
• Caldarelli Marina
• Cervi Giovanni
• Disingrini Teresa
• Quartieri Francesca
• Nerviano Medical Sciences Srl

Inventors

• Casuscelli Francesco
• Brasca Maria Gabriella
• Caldarelli Marina
• Cervi Giovanni
• Disingrini Teresa
• Quartieri Francesca

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61P31/12

  Antivirals · CPC title