Inhibitors of cathepsin s

Abstract

The present invention provides compounds, compositions and methods for the selective inhibition of cathepsin S. In a preferred aspect, cathepsin S is selectively inhibited in the presence of at least one other cathepsin isozyme. The present invention also provides methods for treating a disease state in a subject by selectively inhibiting cathepsin S.

1 . A method for treating a cathepsin S mediated disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein:  
         Y is  
         
           
             
             
                 
                 
             
           
         
         A is a member selected from the group consisting of —CH 2 —, and —CH 2 CH 2 —;  
         R 5  is independently a member selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkyl substituted C 3 -C 8  cycloalkyl, and benzyl;  
         X is a member selected from the group consisting of —O—CR 1 R 2 —C(═O)-Q, —CR 3 H—O—C(═O)—W, —CH 2 —CHR 3 —C(═O)—W, —CR 3 H—CH 2 —C(═O)—W, —CR 4 H—NH—C(═O)—W, —O—CR 1 R 2 —B—R 6 , —CR 3 H—NH—C(═O)—O-Z, —CHR 4 —NH—C(═O)—R 7 , and —CHR 4 —NH—S(═O) 2 —R 8 ;  
         Q is a heterocycle selected from the group consisting of pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl substituted with 0-2 R Q , wherein Q is connected to —C(═O)— via a ring nitrogen atom;  
         each R Q  is independently a member selected from the group consisting of OH, —S(═O) 2 CH 3 , acetyl, ═O, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3  and NR 10 R 11 ;  
         W is morpholinyl, wherein W is connected to —C(═O)— via the ring nitrogen atom;  
         Z is a heterocycle selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, thiotetrahydropyranyl, thiotetrahydrofuranyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl each substituted with 0-2 R Z , wherein Z is connected to —O—C(═O)— via a ring carbon atom;  
         each R Z  is independently a member selected from the group consisting of OH, —S(═O) 2 CH 3 , acetyl, ═O, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3  and NR 10 R 11 ;  
         B is a member selected from the group consisting of —CH 2 —, —OCH 2 —, —NR 11 CH 2 —, —CH 2 CH 2 — and a bond;  
         each R 1  is independently a member selected from the group consisting of H, a C 1 -C 6  alkyl substituted with 0-2 R 1a , wherein said C 1 -C 6  alkyl is optionally substituted with a heteroatom selected from the group consisting of —O—, —S—, —S(═O)—, and —S(═O) 2 —; a C 2 -C 6  alkenyl, a C 3 -C 6  alkynyl, a C 3 -C 7  cycloalkyl each substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ; phenyl substituted with 0-3 R 1c , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         each R 1a  is independently a member selected from the group consisting of a C 6 -C 10  aryl substituted with 0-3 R 1c , a perfluorophenyl, a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c , a C 3 -C 8  cycloalkyl substituted with 0-2 R 1b , a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b , and a C 1 -C 3  perfluoroalkyl;  
         each R 1b  is independently a member selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;  
         each R 1c  is independently a member selected from the group consisting of a H, OH, F, Cl, Br, CN, NO 2 , COOR 12 , C(═O)NR 12 R 11 , S(═O) 2 NR 12 R 11 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl;  
         each R 2  is independently a member selected from the group consisting of H and C 1 -C 6  alkyl;  
         each R 3  is a C 1 -C 2  alkyl substituted with 1 R 3a ;  
         each R 3a  is independently a member selected from the group consisting of a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 4  is a C 1 -C 2  alkyl substituted with 1 R 4a ;  
         each R 4a  is independently a member selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         R 6  is independently a member selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 1 R 6a  and 0-2 R 1c ; and a 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         each R 6a  is independently a member selected from the group consisting of phenyl substituted with 0-3 R 1c , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         R 7  is a member selected from the group consisting of a 5-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 1 R 6a  and 0-2 R 1c , a phenyl substituted with 0-3 R 1c , OCH 2 Ph, O— tert-Bu, and C 3 -C 6  cycloalkyl;  
         R 8  is a member selected from the group consisting of a phenyl substituted with 0-3 R 1c , and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         each R 10  is independently a member selected from the group consisting of H, C 1 -C 4  alkyl, (C 1 -C 4  alkyl)-C(═O)— and (C 1 -C 4  alkyl)-S(═O) 2 —;  
         each R 11  is independently a member selected from the group consisting of H and C 1 -C 4  alkyl; and  
         each R 12  is independently a member selected from the group consisting of H and C 1 -C 4  alkyl;  
         wherein said cathepsin S mediated disease is chronic pain, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, asthma or rejection of organ transplants or tissue grafts.  
       
     
     
         2 . The method of  claim 1 , wherein said compound has formula Ia:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         R 4  is a C 1 -C 2  alkyl substituted with 1 R 4a ;  
         R 4a  is selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 1b  is independently selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl; and  
         W is morpholinyl, wherein W is connected to —C(═O)— via the ring nitrogen atom.  
       
     
     
         3 . The method of  claim 1 , wherein said compound has formula Ib:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         R 3  is a C 1 -C 2  alkyl substituted with 1 R 3a ;  
         R 3a  is selected from the group consisting of a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 1b  is independently selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl; and  
         W is morpholinyl, wherein W is connected to —C(═O)— via the ring nitrogen atom.  
       
     
     
         4 . The method of  claim 1 , wherein said compound has formula Ic:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         R 3  is a C 1 -C 2  alkyl substituted with 1 R 3a ;  
         R 3a  is selected from the group consisting of a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 1b  is independently selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl; and  
         W is morpholinyl, wherein W is connected to —C(═O)— via the ring nitrogen atom.  
       
     
     
         5 . The method of  claim 1 , wherein said compound has formula Id:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         R 1  is independently a member selected from the group consisting of H, a C 1 -C 6  alkyl substituted with 0-2 R 13 , wherein said C 1 -C 6  alkyl is optionally substituted with a heteroatom selected from the group consisting of —O—, —S—, —S(═O)— and —S(═O) 2 —; a C 2 -C 6  alkenyl, a C 3 -C 6  alkynyl, a C 3 -C 7  cycloalkyl each substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ; phenyl substituted with 0-3 R 1c , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         each R 1a  is independently a member selected from the group consisting of a C 6 -C 10  aryl substituted with 0-3 R 1c , a perfluorophenyl, a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c , a C 3 -C 8  cycloalkyl substituted with 0-2 R 1b , a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b , and a C 1 -C 3  perfluoroalkyl;  
         each R 1b  is independently a member selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;  
         each R 1c  is independently a member selected from the group consisting of a H, OH, F, Cl, Br, CN, NO 2 , COOR 12 , C(═O)NR 12 R 11 , S(═O) 2 NR 12 R 11 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl;  
         each R 2  is independently a member selected from the group consisting of H and C 1 -C 6  alkyl;  
         Q is a heterocycle selected from the group consisting of pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl substituted with 0-2 R Q , wherein Q is connected to —C(═O)— via a ring nitrogen atom; and  
         each R Q  is independently a member selected from the group consisting of OH, —S(═O) 2 CH 3 , acetyl, ═O, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3  and NR 10 R 11 .  
       
     
     
         6 . The method of  claim 5 , wherein: 
 R 1  is a C 1 -C 2  alkyl substituted with 1 R 4a ;    R 4a  is selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;    each R 1b  is independently a member selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;    R 2  is H; and    Q is a member selected from the group consisting of morpholinyl, pyrrolidinyl, piperidyl, and piperazinyl, wherein Q is connected to —C(═O)— via a ring nitrogen.    
     
     
         7 . The method of  claim 1 , wherein said compound has formula Ie:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         R 4  is a C 1 -C 2  alkyl substituted with 1 R 4a ;  
         R 4a  is selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 1b  is independently selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;  
         R 8  is a member selected from the group consisting of a phenyl substituted with 0-3 R 1c , and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ; and  
         each R 1c  is independently a member selected from the group consisting of a H, OH, F, Cl, Br, CN, NO 2 , COOR 12 , C(═O)NR 12 R 11 , S(═O) 2 NR 12 R 11 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl.  
       
     
     
         8 . The method of  claim 1 , wherein said compound has formula If:  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 — 
         R 4  is a C 1 -C 2  alkyl substituted with 1 R 4a ;  
         R 4a  is selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;  
         each R 1b  is independently selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;  
         R 7  is a member selected from the group consisting of a 5-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 1 R 6a  and 0-2 R 1c ; a phenyl substituted with 0-3 R 1c , OCH 2 Ph, O— tert-Bu, and C 3 -C 6  cycloalkyl;  
         each R 1c  is independently a member selected from the group consisting of a H, OH, F, Cl, Br, CN, NO 2 , COOR 12 , C(═O)NR 12 R 11 , S(═O) 2 NR 12 R 11 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl; and  
         each R 6a  is independently a member selected from the group consisting of phenyl substituted with 0-3 R 1c ; a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c .  
       
     
     
         9 . The method of  claim 1 , wherein said compound has formula Ig  
       
         
           
           
               
               
           
         
         wherein:  
         A is —CH 2 —;  
         each R 1  is independently a member selected from the group consisting of H, a C 1 -C 6  alkyl substituted with 0-2 R 1a , wherein said C 1 -C 6  alkyl is optionally substituted with a heteroatom selected from the group consisting of —O—, —S—, —S(═O)— and —S(═O) 2 —; a C 2 -C 6  alkenyl, a C 3 -C 6  alkynyl, a C 3 -C 7  cycloalkyl each substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ; phenyl substituted with 0-3 R 1c , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ;  
         each R 1a  is independently a member selected from the group consisting of a C 6 -C 10  aryl substituted with 0-3 R 1c , a perfluorophenyl, a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c , a C 3 -C 8  cycloalkyl substituted with 0-2 R 1b , a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b , and a C 1 -C 3  perfluoroalkyl;  
         each R 1b  is independently a member selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;  
         each R 1c  is independently a member selected from the group consisting of a H, OH, F, Cl, Br, CN, NO 2 , COOR 12 , C(═O)NR 12 R 11 , S(═O) 2 NR 12 R 11 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl;  
         each R 2  is independently a member selected from the group consisting of H and C 1 -C 6  alkyl;  
         B is a member selected from the group consisting of —CH 2 —, —OCH 2 —, —NR 11 CH 2 —, —CH 2 CH 2 — and a bond;  
         R 6  is independently a member selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 1 R 6a  and 0-2 R 1c ; and a 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ; and  
         each R 6a  is independently a member selected from the group consisting of phenyl substituted with 0-3 R 1c ; a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c .  
       
     
     
         10 . The method of  claim 9 , wherein 
 R 1  is a C 1 -C 2  alkyl substituted with 1 R 4a ;    R 4a  is selected from the group consisting of a tert-butyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R 1b , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R 1b ;    each R 1b  is independently a member selected from the group consisting of a H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3 , —S(═O) 2 CH 3 , and acetyl;    R 2  is H;    R 6  is a 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 1c ; and    B is —CH 2 —.    
     
     
         11 . The method of  claim 1 , wherein said compound has formula Ih:  
       
         
           
           
               
               
           
         
       
       wherein: A is —CH 2 —.  
     
     
         12 . The method of  claim 1 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         (3S)-[3-Cyclopentyl-(2S)-{[5-(3-fluoro-phenyl)-furan-2-carbonyl]-amino}propionylamino]-2-cyclopentoxy-5-oxo-tetrahydrofuran;  
         
           
             
             
                 
                 
             
           
         
       
     
     
         13 . The method of  claim 1 , wherein said cathepsis S mediated disease is chronic neuropathic pain.  
     
     
         14 . The method of  claim 1 , wherein said cathepsin S mediated disease is Alzheimer's disease.  
     
     
         15 . The method of  claim 1 , wherein said cathepsin S mediated disease is multiple sclerosis.  
     
     
         16 . The method of  claim 1 , wherein said cathepsin S mediated disease is rheumatoid arthritis.  
     
     
         17 . The method of  claim 1 , wherein said cathepsin S mediated disease is asthma.  
     
     
         18 . The method of  claim 1 , wherein said cathepsin S mediated disease is rejection of organ transplants or tissue grafts.