IP Library › Granted Patent US 7,745,639
Granted Patent B2
US 7,745,639 · App. 10/506,702 · Granted Jun 29, 2010

Mitotic kinesin inhibitors

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Quick Facts
Patent No.
US 7,745,639
App. No.
10/506,702
Granted
Jun 29, 2010
Kind
B2
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.

Claims (321)

1. 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.

2. The compound which is selected from:

3-[1-acetyl-3-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol

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.

3. A compound selected from:

and

R 2

R 5

R 6

R 1′

2,5-dichlorophenyl

H

Ph

NMe 2

2-fluoro-5-cyanophenyl

H

Ph

NMe 2

2-fluoro-5-bromophenyl

H

Ph

NMe 2

2-fluoro-5-chlorophenyl

H

Ph

NMe 2

2-fluoro-5-nitrophenyl

H

Ph

NMe 2

R 2

R 5

R 6

R 1′

2,5-difluorophenyl

H

3-hydroxyphenyl

NMe 2

2,5-difluorophenyl

H

4-hydroxyphenyl

NMe 2

2,5-difluorophenyl

H

3-aminophenyl

NMe 2

2,5-difluorophenyl

H

3-(acetylamino)phenyl

NMe 2

2,5-difluorophenyl

H

3-carboxyphenyl

NMe 2

R 2

R 5

R 6

R 1′

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

R 2

R 5

R 6

R 1′

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

R 2

R 5

R 6

R 1′

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

2,5-difluorophenyl

H

Ph

R 2

R sub

R 6

R 1′

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

R 2

R sub

R 6

R 1′

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

R 2

R sub

R 6

R 1′

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

2,5-difluorophenyl

NH 2

Ph

R 2

R sub

R 6

R 1′

2,5-difluorophenyl

NH 2

3-hydroxyphenyl

NMe 2

2,5-difluorophenyl

NH 2

4-hydroxyphenyl

NMe 2

2,5-difluorophenyl

NH 2

3-aminophenyl

NMe 2

2,5-difluorophenyl

NH 2

3-(acetylamino)phenyl

NMe 2

2,5-difluorophenyl

NH 2

3-carboxyphenyl

NMe 2

2,5-difluorophenyl

NH 2

3-tetrazolylphenyl

NMe 2

R 2

R sub

R 6

R 1′

2,5-dichlorophenyl

NH 2

Ph

NMe 2

2-fluoro-5-cyanophenyl

NH 2

Ph

NMe 2

2-fluoro-5-bromophenyl

NH 2

Ph

NMe 2

2-fluoro-5-chlorophenyl

NH 2

Ph

NMe 2

2-fluoro-5-nitrophenyl

NH 2

Ph

NMe 2

R 2

R sub′

R 6

R 1′

2,5-difluorophenyl

phenyl

Ph

NMe 2

2,5-difluorophenyl

4-trifluoromethylphenyl

Ph

NMe 2

2,5-difluorophenyl

4-chlorophenyl

Ph

NMe 2

2,5-difluorophenyl

CO 2 Me

Ph

NMe 2

2,5-difluorophenyl

CONH 2

Ph

NMe 2

R 2

R sub″

R 6

R 1′

2,5-difluorophenyl

phenyl

Ph

NMe 2

2,5-difluorophenyl

4-trifluoromethylphenyl

Ph

NMe 2

2,5-difluorophenyl

4-chlorophenyl

Ph

NMe 2

2,5-difluorophenyl

CO 2 Me

Ph

NMe 2

2,5-difluorophenyl

4-cyanophenyl

Ph

NMe 2

R 2

W—R 5

R 6

R 1′

2,5-difluorophenyl

—CH 2 CF 2 CH 2 NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 OCH 2 CH 2 NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 CH 2 CH(CHF 2 )NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 OCF2CH 2 NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 CH 2 CF 2 CH 2 NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 CH 2 CH 2 CH(CHF 2) NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 CH(OH)CH 2 CH 2 NH 2

Ph

NMe 2

2,5-difluorophenyl

—CH 2 CH(OH)CH 2 NH 2

Ph

NMe 2

and

2,5-difluorophenyl

—CH 2 C(O)CH 2 CH 2 NH2

Ph

NMe 2

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

Assignments (4)
CHANGE OF NAME Recorded Aug 29, 2012
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 028866/0511 →
MERGER Recorded Aug 27, 2012
From: MERCK SHARP & DOHME CORP.
To: SCHERING CORPORATION
Reel/Frame 028850/0515 →
CHANGE OF NAME Recorded Jan 27, 2010
From: MERCK & CO., INC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 023852/0595 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2009
From: BRESLIN, MICHAEL J.; COLEMAN, PAUL J.; COX, CHRISTOPHER D.; CULBERSON, J. CHRISTOPHER; HARTMAN, GEORGE D.; MARIANO, BRENDA J.; TORRENT, MARICEL
To: MERCK & CO., INC.
Reel/Frame 023453/0320 →