US 7,745,639 B2Granted

Mitotic kinesin inhibitors

AssigneesMerck & Co., Inc., Merck Sharp & Dohme Corp.

InventorsMichael J. Breslin, Paul J. Coleman, Christopher D. Cox, J. Christopher Culberson, George D. Hartman, Brenda J. Mariano, Maricel Torrent

Life of this patent

Estimating the term…

Abstract

The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Claims4

Dependent claims

A compound selected from:

3-[1-acetyl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[3-(2-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-acetyl-3-(2-chlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-acetyl-3-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(3-bromophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2,5-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Propionyl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Isobutyryl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
1-Acetyl-3-(2-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
1-Acetyl-3-(3-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-(3-hydroxyphenyl)-N,N-dimethyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N,N-diethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
1-acetyl-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazole
3-(2,5-difluorophenyl)-N,5-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N,N,5-trimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-ethyl-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-(hydroxymethyl)-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
ethyl [3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]acetate
ethyl [3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]acetate
ethyl 2-[3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]propanoate
3-(2,5-difluorophenyl)-5-[3-(dimethylamino)propyl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N-ethyl-5-{3-[(1H-imidazol-2-ylcarbonyl)amino]propyl}-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(2-aminoethyl)-3-(2,5-difluorophenyl)-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(3-aminopropyl)-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(3-aminobutyl)-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-[3-(benzoylamino)propyl]-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-[4-(dimethylamino)butyl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-[4-(dimethylnitroryl)but-1-yl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-[4-(benzylamino)butyl]-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-5-{4-[(pyridin-4-ylmethyl)amino]butyl}-4,5-dihydro-1H-pyrazole-1-carboxamide
and
5-(3-amino-3-phenylpropyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
or a pharmaceutically acceptable salt or stereoisomer thereof.

35 more elements

A compound selected from:

and
R2
R5
R6
R1′
2,5-dichlorophenyl
H
Ph
NMe2
2-fluoro-5-cyanophenyl
H
Ph
NMe2
2-fluoro-5-bromophenyl
H
Ph
NMe2
2-fluoro-5-chlorophenyl
H
Ph
NMe2
2-fluoro-5-nitrophenyl
H
Ph
NMe2
R2
R5
R6
R1′
2,5-difluorophenyl
H
3-hydroxyphenyl
NMe2
2,5-difluorophenyl
H
4-hydroxyphenyl
NMe2
2,5-difluorophenyl
H
3-aminophenyl
NMe2
2,5-difluorophenyl
H
3-(acetylamino)phenyl
NMe2
2,5-difluorophenyl
H
3-carboxyphenyl
NMe2
R2
R5
R6
R1′
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
R2
R5
R6
R1′
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
R2
R5
R6
R1′
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
2,5-difluorophenyl
H
Ph
R2
Rsub
R6
R1′
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
R2
Rsub
R6
R1′
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
R2
Rsub
R6
R1′
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
2,5-difluorophenyl
NH2
Ph
R2
Rsub
R6
R1′
2,5-difluorophenyl
NH2
3-hydroxyphenyl
NMe2
2,5-difluorophenyl
NH2
4-hydroxyphenyl
NMe2
2,5-difluorophenyl
NH2
3-aminophenyl
NMe2
2,5-difluorophenyl
NH2
3-(acetylamino)phenyl
NMe2
2,5-difluorophenyl
NH2
3-carboxyphenyl
NMe2
2,5-difluorophenyl
NH2
3-tetrazolylphenyl
NMe2
R2
Rsub
R6
R1′
2,5-dichlorophenyl
NH2
Ph
NMe2
2-fluoro-5-cyanophenyl
NH2
Ph
NMe2
2-fluoro-5-bromophenyl
NH2
Ph
NMe2
2-fluoro-5-chlorophenyl
NH2
Ph
NMe2
2-fluoro-5-nitrophenyl
NH2
Ph
NMe2
R2
Rsub′
R6
R1′
2,5-difluorophenyl
phenyl
Ph
NMe2
2,5-difluorophenyl
4-trifluoromethylphenyl
Ph
NMe2
2,5-difluorophenyl
4-chlorophenyl
Ph
NMe2
2,5-difluorophenyl
CO2Me
Ph
NMe2
2,5-difluorophenyl
CONH2
Ph
NMe2
R2
Rsub″
R6
R1′
2,5-difluorophenyl
phenyl
Ph
NMe2
2,5-difluorophenyl
4-trifluoromethylphenyl
Ph
NMe2
2,5-difluorophenyl
4-chlorophenyl
Ph
NMe2
2,5-difluorophenyl
CO2Me
Ph
NMe2
2,5-difluorophenyl
4-cyanophenyl
Ph
NMe2
R2
W—R5
R6
R1′
2,5-difluorophenyl
—CH2CF2CH2NH2
Ph
NMe2
2,5-difluorophenyl
—CH2OCH2CH2NH2
Ph
NMe2
2,5-difluorophenyl
—CH2CH2CH(CHF2)NH2
Ph
NMe2
2,5-difluorophenyl
—CH2OCF2CH2NH2
Ph
NMe2
2,5-difluorophenyl
—CH2CH2CF2CH2NH2
Ph
NMe2
2,5-difluorophenyl
—CH2CH2CH2CH(CHF2)NH2
Ph
NMe2
2,5-difluorophenyl
—CH2CH(OH)CH2CH2NH2
Ph
NMe2
2,5-difluorophenyl
—CH2CH(OH)CH2NH2
Ph
NMe2
and
2,5-difluorophenyl
—CH2C(O)CH2CH2NH2
Ph
NMe2
or a pharmaceutically acceptable salt or stereoisomer thereof.

272 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/506,702Filed 4 Mar 2003 · us provisional application
Priority: 8 Mar 2002
Published: US 2005/0119484 A12 Jun 2005
Granted: 29 Jun 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 35/00
Antineoplastic agents
C04B 35/632
Using additives specially adapted for forming the products , e.g.. binder binders: organic additives
C07D 231/06
Not condensed with other rings: having one double bond between ring members or between a ring member and a non-ring member

Family

Application60/362,922Us provisional application · filed 8 Mar 2002
US 2005/0119484 A1Pre-grant publication · published 2 Jun 2005
US 7,745,639 B2This patent

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

Timeline

Citations

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Abstract

A compound selected from:

3-[1-acetyl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[3-(2-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-acetyl-3-(2-chlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-acetyl-3-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(3-bromophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Acetyl-3-(2,5-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Propionyl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
3-[1-Isobutyryl-3-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol
1-Acetyl-3-(2-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
1-Acetyl-3-(3-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole
3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-(3-hydroxyphenyl)-N,N-dimethyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N,N-diethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
1-acetyl-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazole
3-(2,5-difluorophenyl)-N,5-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N,N,5-trimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-ethyl-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-(hydroxymethyl)-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
ethyl [3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]acetate
ethyl [3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]acetate
ethyl 2-[3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]propanoate
3-(2,5-difluorophenyl)-5-[3-(dimethylamino)propyl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N-ethyl-5-{3-[(1H-imidazol-2-ylcarbonyl)amino]propyl}-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(2-aminoethyl)-3-(2,5-difluorophenyl)-N-methyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(3-aminopropyl)-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-(3-aminobutyl)-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-[3-(benzoylamino)propyl]-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-[4-(dimethylamino)butyl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-5-[4-(dimethylnitroryl)but-1-yl]-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
5-[4-(benzylamino)butyl]-3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
3-(2,5-difluorophenyl)-N-ethyl-5-phenyl-5-{4-[(pyridin-4-ylmethyl)amino]butyl}-4,5-dihydro-1H-pyrazole-1-carboxamide
and
5-(3-amino-3-phenylpropyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
or a pharmaceutically acceptable salt or stereoisomer thereof.

35 more elements

Facts

Application

10/506,702Filed 4 Mar 2003 · us provisional application

Priority

8 Mar 2002

Published

US 2005/0119484 A12 Jun 2005

Granted

29 Jun 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 35/00
Antineoplastic agents
C04B 35/632
Using additives specially adapted for forming the products , e.g.. binder binders: organic additives
C07D 231/06
Not condensed with other rings: having one double bond between ring members or between a ring member and a non-ring member