# US 7,608,739 B2 · Mitotic kinesin inhibitors

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- Number: US 7,608,739 B2
- Document ID: US7608739B2
- Status: Granted
- Kind: B2
- Application number: 10/593,504
- Filed: 2005-03-18
- Published: 2008-09-25
- Granted: 2009-10-27
- Earliest claimed: 2004-03-22
- Assignees: Merck & Co., Inc.
- Inventors: Robert M. Garbaccio; Christy M. Olson; Edward S. Tasber; Maricel Torrent
- Web page: https://patentgrep.com/patent/US7608739B2

## CPC

- C07C 215/50: with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 211/53: having the nitrogen atom of at least one of the amino groups further bound to a hydrocarbon radical substituted by amino groups
- C07C 215/16: the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
- C07C 215/20: the carbon skeleton being saturated and containing rings
- C07C 215/24: and acyclic
- C07C 229/18: the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
- C07C 229/30: the carbon skeleton being acyclic and unsaturated
- C07C 237/06: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 237/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 237/12: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups (peptides C07K)
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/04: with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07C 2601/02: with a three-membered ring
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### Claim 1

The compound of the Formula III;
wherein:
R1 is selected from: H, F and OH;
R3 is selected from: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl and (C1-C6)alkyl hydroxyl;
R4 is selected from: H, oxo, OH, halo, CN, NH2, NO2, (C═O)aOb(C1-C10)alkyl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, (C═O)aOb(C3-C6)cycloalkyl, (C═O)aOb(C0-C6)alkylene-aryl, (C═O)aOb(C0-C6)alkylene-heterocyclyl, (C═O)aOb(C0-C6)alkylene-N(Rb)2, C(O)H, (C0-C6)alkylene-CO2H, C(O)N(Rb)2, and S(O)2N(Rb)2; said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and heterocyclyl is optionally substituted with up to three substituents selected from Rb;
R5 is H or CH3;
Ra is selected from: (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl and heterocyclyl; said alkyl, cycloalkyl, aryl and heterocyclyl is optionally substituted with one or more substituents selected from OH,(C1-6)alkyl, (C1-C6)alkoxy, halogen, CO2H, CN, (O)C═O(C1-C6)alkyl, oxo and N(Rc)2;
Rb is independently selected from: H, oxo, OH, halogen, CO2H, CN, (O)C═O(C1-C6)alkyl, N(Rc)2, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)O(C1-C6)alkyl, C═O(C1-C6)alkyl and S(O)2Ra; said alkyl, cycloalkyl, aryl or heterocylyl is optionally substituted with one or more substituents selected from OH, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, CO2H, CN, (O)C═O(C1-C6)alkyl, oxo, N(Rc)2 and optionally substituted heterocyclyl, wherein said heterocyclyl is optionally substituted with (C1-C6)alkyl, oxo or NH2;
Rc is independently selected from: H and (C1-C6)alkyl;
a is 0 or 1;
b is 0 or 1;
p is 1 or 2;
q is 0 or 1;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 of the Formula III;
wherein:
R4 is selected from: H, oxo, OH, halo, CN, NH2, NO2, (C═O)aOb(C1-C10)alkyl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, (C═O)aOb(C3-C6)cycloalkyl, (C═O)aOb(C0-C6)alkylene-aryl, (C═O)aOb(C0-C6)alkylene-heterocyclyl, (C═O)aOb(C0-C6)alkylene-N(Rb)2, C(O)H, (C0-C6)alkylene-CO2H, C(O)N(Rb)2, and S(O)2N(Rb)2; said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and heterocyclyl is optionally substituted with up to three substituents selected from Rb;
and all other substituents and variables are as defined in claim 1;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 3 (depends on 1)

The compound according to claim 1 of the Formula III;
wherein:
R4 is selected from: H, oxo, OH, halo, CN, NH2, NO2, (C═O)aOb(C1-C10)alkyl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, (C═O)aOb(C0-C6)alkylene-N(Rb)2, (C═O)—Rb, C(O)H, (C0-C6)alkylene-CO2H, C(O)N(Rb)2, and S(O)2N(Rb)2; said alkyl, alkenyl, alkynyl, and alkylene is optionally substituted with up to three substituents selected from Rb;
and all other substituents and variables are as defined in claim 1;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 4

A compound which is selected from:
3-[{3-chloro-4-fluorophenyl)(2-hydroxy-1-methylethyl)amino]methyl}phenol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]propan-1-ol;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N-1-[2(dimethylamino)ethyl]alaninamide;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)alaninamide;
methyl N-benzyl-N-(3-chloro-4-fluorophenyl)alanylglycinate;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N-1-(isoxazol-4-ylmethyl)alaninamide;
3-[benzyl(3-chloro-4-fluorophenyl)amino]-2-methylbutan-2-ol;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N-1,N-1-dimethylpropane-1,2-diamine;
N-benzyl-3-chloro-4-fluoro-N-[1-methyl-2-(4-methylpiperazin-1-yl)ethyl]aniline;
2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol;
N-2-(3-chloro-4-fluorophenyl)-N-2-(3-hydroxybenzyl)-N-1-(isoxazol)-4-ylmethyl)alaninamide;
N-2-(3-chloro-4-fluorophenyl)-N-2-(3-hydroxybenzyl)alaninamide;
N-2-(3-chloro-4-fluorophenyl)-N-1-[2-(dimethylamino)ethyl]-N-2-(3-hydroxybenzyl)alaninamide;
Methyl 2-[benzyl(3-chloro-4-fluorophenyl)amino]butanoate;
Methyl 2-[benzyl(3-chloro-4-fluorophenyl)amino]pent-4-enoate;
2-[benzyl(3-chloro-4-fluorophenyl)amino]pent-4-en-1-ol;
N-benzyl-N-(3-chloro-4-fluorophenyl)glycine;
2-[benzyl(3-chloro-4-fluorophenyl)amino]pentan-1-ol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]butan-1-ol;
N-benzyl-3-chloro-N-[1-({3-[(dimethylamino)methyl]piperidin-1-yl}carbonyl)propyl]-4-fluoroaniline;
2-[benzyl(3-chloro-4-fluorophenyl)amino]-N-methyl-N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]butanamide;
2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-methylbutan-1-ol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]pentane-1,5-diol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-cyclopropylpropan-1-ol; and
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N1-[2-dimethylamino)ethyl]-2-methylalaninamide;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 5 (depends on 1)

The TFA salt of a compound according to claim 1 which is
3-[{3-chloro-4-fluorophenyl)(2-hydroxy-1-methylethyl)amino]methyl}phenol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]propan-1-ol;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N-1-[2(dimethylamino)ethyl]alaninamide;
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)alaninamide;
methyl N-benzyl-N-(3-chloro-4-fluorophenyl)alanylglycinate;
3-[benzyl(3-chloro-4-fluorophenyl)amino]-2-methylbutan-2-ol;
2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol;
N-2-(3-chloro-4-fluorophenyl)-N-2-(3-hydroxybenzyl)-N-1-(isoxazol)-4-ylmethyl)alaninamide;
N-2-(3-chloro-4-fluorophenyl)-N-2-(3-hydroxybenzyl)alaninamide;
N-2-(3-chloro-4-fluorophenyl)-N-1-[2-(dimethylamino)ethyl]-N-2-(3-hydroxybenzyl)alaninamide;
N-benzyl-N-(3-chloro-4-fluorophenyl)glycine;
2-[benzyl(3-chloro-4-fluorophenyl)amino]pentan-1-ol;
2-[benzyl(3-chloro-4-fluorophenyl)amino]butan-1-ol;
N-benzyl-3-chloro-N-[1-({3-[(dimethylamino)methyl]piperidin-1-yl}carbonyl)propyl]-4-fluoroaniline;
2-[benzyl(3-chloro-4-fluorophenyl)amino]-N-methyl-N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]butanamide;
2-[benzyl(3-chloro-4-fluorophenyl)amino]pentane-1,5-diol; and
N-2-benzyl-N-2-(3-chloro-4-fluorophenyl)-N1-[2-dimethylamino)ethyl]-2-methylalaninamide;
or stereoisomer thereof.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.