Cycloalkyl ketoamides derivatives useful as cathepsin k inhibitors

Abstract

Cycloalkyl ketoamide derivatives, which are useful as cathepsin K inhibitors are described herein. The described invention also includes methods of making such cycloalkyl ketoamide derivatives as well as methods of using the same in the treatment of disorders, including osteoporosis, associated with enhanced bone turnover which can ultimately lead to fracture.

1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
         or a salt or solvate thereof:  
         wherein  
         A is the group defined by (Q 3 )-(Q 2 ) n -(Q 1 )-(Q) m -, wherein 
 Q is CH 2  and m is 0, 1, or 2  
 Q 1  is C 3 -C 7  cycloalkylene;  
 Q 2  is C 1 -C 3  alkylene and n is 0 or 1, or  
 Q 2  is OR, where R is C 1 -C 3  alkylene and n is 1,  
 Q 2  is SR, where R is C 1 -C 3  alkylene and n is 1; or  
 Q 2  is N(R′)R, where R′ is hydrogen or C 1 -C 6  alkyl, R is C 1 -C 3  alkylene and n is 1; and  
 Q 3  is aryl, heteroaryl, or aryl or heteroaryl substituted with at least one independently selected R 1  group, wherein said heteroaryl is selected from the group consisting of  
                     
 
         D is C 1 -C 6  alkyl or C 1 -C 6  alkyl substituted with —NR 2 R 3 ;  
         Z is the group defined by —(X) p —(X 1 ) q —(X 2 ), wherein 
 X is C(R′)(R″), wherein R′ is hydrogen or C 1 -C 6  alkyl, R″ is hydrogen and C 1 -C 6  alkyl, and p is 0, 1, or 2,  
 X 1  is C(O)OCH 2 , wherein q is 0 or 1, and  
 X 2  is aryl or heteroaryl wherein said heteroaryl is selected from:  
                     
 
         R 1  is halo, C 1 -C 6  alkyl, aryl, or C 1 -C 6  haloalkyl;  
         R 2  is hydrogen or C 1 -C 6  alkyl;  
         R 3  is hydrogen, C 1 -C 6  alkyl, —C(O)R 4 , or —S(O) 2 NR 5 R 6 ;  
         R 4  is heterocyclyl,  
         R 5  and R 6  are independently selected from hydrogen or C 1 -C 6  alkyl.  
       
     
     
         2 . A compound as claimed in  claim 1 , wherein Q is CH 2  and m is 0 or 1.  
     
     
         3 . A compound as claimed in  claim 1 , wherein Q is CH 2  and m is 1.  
     
     
         4 . A compound as claimed in  claim 1 , wherein Q 1  is selected from the group cyclobutylene, cyclopentylene or cyclohexylene,  
     
     
         5 . A compound as claimed in  claim 1 , wherein Q 1  is cyclobutylene.  
     
     
         6 . A compound as claimed in  claim 1 , wherein Q 2  is C 1 -C 3  alkylene and n is 1.  
     
     
         7 . A compound as claimed in  claim 1 , wherein Q 2  is OR, wherein R is C 1 -C 3  alkylene and n is 1.  
     
     
         8 . A compound as claimed in  claim 1 , wherein Q 2  is SR, wherein R is C 1 -C 3  alkylene and n is 1.  
     
     
         9 . A compound as claimed in  claim 1 , wherein Q 3  is phenyl or phenyl substituted with at least one independently selected R 1  group wherein R 1  is halo or C 1 -C 6  alkyl.  
     
     
         10 . A compound as claimed in  claim 9 , wherein R 1  is halo.  
     
     
         11 . A compound as claimed in  claim 10 , wherein R 1  is fluoro or chloro.  
     
     
         12 . A compound as claimed in  claim 9  wherein, R 1  is methyl.  
     
     
         13 . A compound as claimed in  claim 1 , wherein Q 3  is heteroaryl or heteroaryl substituted with at least one independently selected R 1 , wherein said heteroaryl is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound as claimed in  claim 1 , wherein D is C 1 -C 6 alkyl.  
     
     
         15 . A compound as claimed in  claim 1 , wherein D is n-butyl.  
     
     
         16 . A compound as claimed in  claim 1 , wherein X is C(H)(R″) where R″ is hydrogen and p is 0, 1, or 2.  
     
     
         17 . A compound as claimed in  claim 1 , wherein X is C(R′)(R″) where R″ is hydrogen and p is 0, 1, or 2.  
     
     
         18 . A compound as claimed in  claim 1 , wherein X is C(H)(R″) where R″ is hydrogen and p is 0 or 1.  
     
     
         19 . A compound as claimed in  claim 1 , wherein X is C(H)(R″) where R″ is —CH 3  and p is 1.  
     
     
         20 . A compound as claimed in  claim 1 , wherein X 1  is C(O)OCH 2 , wherein q is 1.  
     
     
         21 . A compound as claimed in  claim 1 , wherein X 1  is C(O)OCH 2 , wherein q is 0.  
     
     
         22 . A compound as claimed in  claim 1 , wherein X 2  is  
       
         
           
           
               
               
           
         
       
     
     
         23 . A compound selected from the group consisting of: 
 (1-benzylcyclohexyl)methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    [1-(4-Fluorobenzyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo {[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    [1-(4-Pyridinylmethyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    [1-(3-pyridinylmethyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    {1-[(2-pyrimidinylsulfanyl)methyl]cyclobutyl}methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    {1-[(2-pyrimidinyloxy)methyl]cyclobutyl}methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    [1-(hydroxymethyl)cyclobutyl]methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    [1-({[4-(4-chlorophenyl)-2-pyrimidinyl]sulfanyl}methyl)cyclobutyl]methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    (1-{3-[(2-chloro-4-pyrimidinyl)oxy]propyl}cyclobutyl)methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    or a salt or solvate thereof.    
     
     
         24 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in  claim 1  or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.  
     
     
         25 . A method of treating osteoporosis in a mammal comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in  claim 1  or a salt or solvate thereof.