Mitotic kinesin inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9499503-B2
Application number	US-201514679866-A
Country	US
Kind code	B2
Filing date	Apr 6, 2015
Priority date	Oct 19, 2004
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders.

First claim

What is claimed is:

1. A compound of the Formula:

and solvates, resolved enantiomers, diastereomers, racemic mixtures and pharmaceutically acceptable salts thereof, wherein:
X is S,
R is Z—NR 2 R 3 ;
R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, —OR 3 , —NR 4 OR 5 , CR b (═NOR c ), C(═O)R a , or —NR 4 R 5 , wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy azido, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —OCH 2 C(═O)OR a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —NR c C(NCN)NR a R b , —OR a ,—OP(═O)(OR a ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
Ar l is phenyl and Ar 2 is pyridyl, wherein said pyridinyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heteorcycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluorornethoxy, OR a , —O(C═O)OR d , —OP(═O)(OR a )(OR a ), NR a R b , —NR b SO 2 R d , —SO 2 NR a R b , SR 6 , SOR 6 , SO 2 R 6 , —C(═O)R a , —C(═O)OR a , —/oC(═O)R a , —OCH 2 C(═O)OR a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b and —NR c C(═O)NR a R b ;
R 2 is hydrogen, —C(═O)R 4 , —SO 2 R 6 , alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, a natural or unnatural amino acid, or a polypeptide of two or more amino acids independently selected from natural and unnatural amino acids, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —OR a ,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;
R 3 is hydrogen, —C(═O)R 4 , alkyl, alkenyl, alkynyl, or saturated or partially unsaturated cycloalkyl, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR d , —OP(═O)(OR a ) 2 , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —OR a , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl,
or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the nitrogen atom to which said R 2 and R 3 are attached, selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —OR a , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;
R 4 and R 5 are independently H trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —NR b C(═O)R d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —NR c C(NCN)NR a R b , —OR a , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl,
or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring which may include 1 to 3 additional heteroatoms, in addition to the heteroatoms to which said R 4 and R 5 are attached, selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═)OR a , —OC(═O)R a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —NR c C(NCN)NR a R b , —OR a , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclyialkyl;
R 6 is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR d , —NR b SO 2 R d , —SO 2 NR a R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —NR b C(═O)OR d , —NR b C(═O)R a , —C(═O)NR a R b , —NR a R b , —NR c C(═O)NR a R b , —NR c C(NCN)NR a R b , —OR a , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;
R a is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or saturated or partially unsaturated heterocyclylakl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on said aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR h , —NR f SO 2 R h , —SO 2 NR e R f , —C(═O)R e , —C(═O)OR e , —OC(═O)R e , —NR f C(═O)OR h , —NR f C(═O)R e , —C(═O)NR e R f , —NR e R f , —NR g C(═O)NR e R f , —NR c C(NCN)NR e R f , —OR

Assignees

• Array Biopharma Inc

Inventors

• Hans Jeremy
• Wallace Eli M
• Zhao Qian
• Lyssikatos Joseph P
• Aicher Thomas D
• Laird Ellen R
• Robinson John
• Allen Shelley

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P31/10

  Antimycotics · CPC title