Novel compounds and compositions as cathepsin inhibitors

Abstract

The present invention relates to novel cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

1 . A compound or a related chemical entity of the compound, having a backbone structure of a formula selected from the group consisting of Formulae I and II:  
     
       
         
         
             
             
         
       
     
     wherein X 2 , X 3 , X 4 , X 5  and X 7  are general substituents.  
   
   
       2 . A compound of  claim 1  or a related chemical entity of a compound of  claim 1 , having a backbone structure of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein X 2 , X 3 , X 4 , X 5  and X 7  are general substituents.  
   
   
       3 . A compound of  claim 1  or a related chemical entity of a compound of  claim 1 , having a backbone structure of Formula II:  
     
       
         
         
             
             
         
       
     
     wherein X 2  and X 5  are general substituents.  
   
   
       4 . A compound or a related chemical entity of the compound, having a backbone structure of Formula III:  
     
       
         
         
             
             
         
       
     
     wherein A 1  is —O—, —N(R)— or —SO 2 —; 
 A 2  is —H, —F, —OH, or —O—R;  
 A 3  is cyano or —C(O)—X 3 ; and  
 X 2 , X 3 , X 4 , X 7 and R are general substituents.  
 
   
   
       5 . A compound of  claim 1  or a related chemical entity of a compound of  claim 1 , wherein X 2 , X 3 , X 4 , X 5  and X 7  are popular substituents.  
   
   
       6 . A compound of  claim 2  or a related chemical entity of a compound of  claim 2 , wherein X 2 , X 3 , X 4 , X 7  and R are popular substituents.  
   
   
       7 . A compound of  claim 1 , wherein: 
 X 2  is a substituted alkyl motif or a sulfonyl alkyl motif;    X 3  is a heterocyclic motif or an amide motif;    X 4  and X 7  are independently —H, —R or                          or X 4  and X 7  taken together with the carbon atom to which both X 4  and X 7  are attached form a 3-6 membered cycloalkyl group;    X 5  is —H, —F, —OH or —O—R; and    R is an alkyl group with straight or branched-chain containing 1-6 carbon atoms.    
   
   
       8 . A compound of  claim 4 , wherein: 
 X 2  is a substituted alkyl motif or a sulfonyl alkyl motif;    X 3  is a heterocyclic motif or an amide motif;    X 4  and X 7  are independently —H, —R or                          X 4  and X 7  taken together with the carbon atom to which both X 4  and X 7  are attached form a 3-6 membered cycloalkyl group; and    R is an alkyl group with straight or branched-chain containing 1-6 carbon atoms.    
   
   
       9 . A compound of  claim 7 , wherein X 3  is a heterocyclic motif  
   
   
       10 . A compound of  claim 8 , wherein A 3  is —C(O)—X 3  and X 3  is a heterocyclic motif.  
   
   
       11 . A compound of  claim 7 , wherein X 3  is an amide motif.  
   
   
       12 . A compound of  claim 8 , wherein A 3  is —C(O)—X 3  and X 3  is an amide motif.  
   
   
       13 . A compound of  claim 7 , wherein X 7  is —H, X 4  is an alkyl group with straight or branched-chain containing 1-4 carbon atoms or  
     
       
         
         
             
             
         
       
     
     and X 5  is —H or —F.  
   
   
       14 . A cmpound of  claim 13 , wherein X 5  is —H.  
   
   
       15 . A compound of  claim 14 , wherein X 4  is —CH 2 CH 3 , —CH 2 CH 2 CH 3 —(CH 3 ) 3  or  
     
       
         
         
             
             
         
       
     
   
   
       16 . A compound of  claim 1 , having a backbone structure of Formula I, wherein X 2  is a substituted alkyl motif or a sulfonyl alkyl motif, X 3  is a heterocyclic motif or an amide motif, X 4  is —CH 2 CH 3 , —CH 2 CH 2 CH 3 —C(CH 3 ) 3  or  
     
       
         
         
             
             
         
       
     
     X 5  and X 7  are —H.  
   
   
       17 . A related chemical entity of a compound of  claim 16 .  
   
   
       18 . A compound of  claim 1  selected from the group consisting of: 
 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,    (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,    (R)-2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,    N-[(S)-1-(5-Ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyramide,    (R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,    (R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,    4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    (R)-2-Cyclohexylmethyl-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyramide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    (R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    (S)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(5-methyl-thiophen-2-ylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    (R)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    (R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of diastereoisomers),    4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl)-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers),    (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl-amide,    3-Phenylmethanesulfonyl-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide,    (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,    (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid [(S)-1-(oxazole-2-carbonyl)-propyl]-amide,    (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,    (S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    (R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    (R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid [(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    (R)-5-Cyclopropyl-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    (R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(1-isobutyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    R)-2-(1-Cyclopropylmethyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (R)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    (R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (S)-2-(2-Benzenesulfonyl-ethyl)-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,    (S)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-[2-(propane-2-sulfonyl)-ethyl]-butyramide,    2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide,    (S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-2-oxo-pentanoic acid (pyridin-4-ylmethyl)-amide,    (S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-2-oxo-pentanoic acid diethylamide,    N-((S)-1-Ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl)-4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyramide,    (S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-2-oxo-pentanoic acid phenethyl-amide, and    (S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-2-oxo-pentanoic acid (2-pyridin-2-yl-ethyl)-amide.    
   
   
       19 . A compound of  claim 1  selected from the group consisting of: 
 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,    (R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,    N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,    N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyramide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,    4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of diastereoisomers),    4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers),    (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide,    (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,    (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,    (S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide, and    (R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide.    
   
   
       20 . A related chemical entity of a compound of  claim 18 .  
   
   
       21 . A related chemical entity of a compound of  claim 19 .  
   
   
       22 . A method of synthesizing a compound of formula Y:  
     
       
         
         
             
             
         
       
     
     where Ry is benzyl, iso-butyl or cyclopropylmethyl, comprising the steps of (a) reacting  
     
       
         
         
             
             
         
       
     
     with  
     
       
         
         
             
             
         
       
     
     to afford  
     
       
         
         
             
             
         
       
     
     and then (b) reacting the  
     
       
         
         
             
             
         
       
     
     with  
     
       
         
         
             
             
         
       
     
     to afford a compound of formula Y.  
   
   
       23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or a related chemcial entity of a compound of  claim 1 , in combination with a pharmaceutically acceptable excipient.  
   
   
       24 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 4  or a related chemcial entity of a compound of  claim 4 , in combination with a pharmaceutically acceptable excipient.  
   
   
       25 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 16  in combination with a pharmaceutically acceptable excipient.  
   
   
       26 . A method for treating a disease in an animal in which inhibition of Cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of  claim 1  or a related chemical entity of a compound of  claim 1 .  
   
   
       27 . A method for treating a disease in an animal in which inhibition of Cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of  claim 4  or a related chemical entity of a compound of  claim 4.