Compounds and compositions as channel activating protease inhibitors

Abstract

The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase,

1 . A compound of Formula (1): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, wherein 
         wherein -J-(R 10 ) p  together is 
       
       
         
           
           
               
               
           
         
         Z 5 , Z 6  or Z 7  are independently N, O, S, CH, or C when attached to R 10 ; 
         R 1  is —(CR 2 ) 1 —NR 2 , —(CR 2 ) 1 —NRC(═NR)—NR 2 , —(CR 2 ) 1 —C(═NR)—NR 2  or a 5-7 membered nitrogen-containing non-aromatic heterocyclic ring; 
         W—R 2  is a substituent at any position on ring A; 
         W is or —O(CR 2 ) k —, —S(CR 2 ) k —, —S(O)(CR 2 ) k —, —SO 2 (CR 2 ) k — or —OC(O)(CR 2 ) k —; 
         R 2  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, R 6 , —CR 9 ═CR 9 —R 6 , or 
       
       
         
           
           
               
               
           
         
       
       wherein ring E is an optionally substituted 5-7 membered monocyclic or fused carbocyclic or heterocyclic ring; or W—R 2  together form C 1-6  alkyl, a 5-7 membered aryl or —OC(O)NR 7 R 8 ;
 R 3  is NR 7 R 8  or R 6 ; 
 R 4  and R 5  are independently H, C 1-6  alkyl, OH, or C 1-6  alkoxy; 
 R 7  and R 8  are independently H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or —(CR 2 ) 1 —R 6 ; or R 7  and R 8  together with N may form an optionally substituted 5-7 membered monocyclic or fused heterocyclic ring; 
 R 9  is H or C 1-6  alkyl; 
 R 10  is halo, C 1-6  alkyl, C 1-6 alkoxy, OR 11  or —(CR 2 ) 1 —R 11 ; 
 R 6 , R 11  and X are independently an optionally substituted 5-7 membered carbocyclic ring, heterocyclic ring, aryl or heteroaryl; or R 11  is H or C 1-6  alkyl; 
 R is H; 
 i is 0-1; 
 k and l are independently 0-6; 
 m and n are independently 1-6; and 
 p is 0-3. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is —(CH 2 ) 1 —NH 2  or —(CH 2 ) 1 —NHC(═NH)—NH 2 , wherein each 1 is 0-1; or R 1  is piperidinyl. 
     
     
         3 . The compound of  claim 1 , wherein W is —O(CR 2 ) k —, —S(CR 2 ) k —, —S(O)(CR 2 ) k —, —SO 2 (CR 2 ) k — or —OC(O)(CR 2 ) k —; and k is 1. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is an optionally substituted phenyl, C 5-7  cycloalkyl, thienyl, furanyl, piperidinyl, methylenecyclohexyl, 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein R 3  is an optionally substituted phenyl, pyridyl, thiazolyl, piperidinyl, or NR 7 R 8 ; wherein R 7  and R 8  are both H, or R 7  and R 8  together with N form an optionally substituted piperidinyl. 
     
     
         6 . The compound of  claim 1 , wherein R, R 4 , R 5 , R 7  and R 8  are each H. 
     
     
         7 . The compound of  claim 1 , wherein R 6  is an optionally substituted phenyl, C 3-7  cycloalkyl, pyridyl, thiazolyl, piperidinyl, cyclohexanol, imidazolyl, thienyl or furanyl. 
     
     
         8 . The compound of  claim 1 , wherein X is cyclohexyl, phenyl or piperidinyl. 
     
     
         9 . The compound of  claim 1 , wherein J is thiazolyl, or oxadiazolyl. 
     
     
         10 . The compound of  claim 1 , wherein said compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         11 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 10  and a pharmaceutically acceptable excipient. 
     
     
         13 . A method for inhibiting a channel activating protease selected from prostasin and matriptase (MTSP-1), comprising administering to a cell or a tissue, or to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1  or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby inhibiting said channel activating protease. 
     
     
         14 . The method of  claim 13 , wherein said subject is a human or animal. 
     
     
         15 . The method of  claim 13 , wherein said cells are bronchial epithelial cells. 
     
     
         16 . A method for ameliorating a condition mediated by a channel activating protease selected from prostasin and matriptase (MTSP-1), comprising administering to a system or subject in need of such treatment an effective amount of a compound of Formula (1), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, 
       
         
           
           
               
               
           
         
         wherein J is a 5-12 membered monocyclic or fused carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O and/or S; 
         R 1  is —(CR 2 ) 1 —NR 2 , —(CR 2 ) 1 —NRC(═NR)—NR 2 , —(CR 2 ) 1 —C(═NR)—NR 2  or a 5-7 membered nitrogen-containing non-aromatic heterocyclic ring; 
         W—R 2  is a substituent at any position on ring A; 
         W is or —O(CR 2 ) k —, —S(CR 2 ) k —, —S(O)(CR 2 ) k —, —SO 2 (CR 2 ) k — or —OC(O)(CR 2 ) k —; 
         R 2  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, R 6 , —CR 9 ═CR 9 —R 6 , or 
       
       
         
           
           
               
               
           
         
       
       wherein ring E is an optionally substituted 5-7 membered monocyclic or fused carbocyclic or heterocyclic ring; or W—R 2  together form C 1-6  alkyl, a 5-7 membered aryl or —OC(O)NR 7 R 8 ;
 R 3  is NR 7 R 8  or R 6 ; 
 R 4  and R 5  are independently H, C 1-6  alkyl, OH, or C 1-6  alkoxy; 
 R 7  and R 8  are independently H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or —(CR 2 ) 1 —R 6 ; or R 7  and R 8  together with N may form an optionally substituted 5-7 membered monocyclic or fused heterocyclic ring; 
 R 9  is H or C 1-6  alkyl; 
 R 10  is halo, C 1-6  alkyl, C 1-6  alkoxy, OR 11  or —(CR 2 ) 1 —R 11 ; 
 R 6 , R 11  and X are independently an optionally substituted 5-7 membered carbocyclic ring, heterocyclic ring, aryl or heteroaryl; or R 11  is H or C 1-6  alkyl; 
 R is H; 
 is 0-1; 
 k and l are independently 0-6; 
 m and n are independently 1-6; and 
 p is 0-3; 
 and optionally in combination with a second therapeutic agent, thereby treating said condition. 
 
     
     
         17 . The method of  claim 16 , wherein said condition is associated with the movement of fluid across ion transporting epithelia or the accumulation of mucus and sputum in respiratory tissues, or a combination thereof. 
     
     
         18 . The method of  claim 16 , wherein said condition is cystic fibrosis, primary ciliary dyskinesia, lung carcinoma, chronic bronchitis, chronic obstructive pulmonary disease, asthma or a respiratory tract infection. 
     
     
         19 . The method of  claim 16 , wherein said second therapeutic agent is an anti-inflammatory, bronchodilatory, antihistamine, anti-tussive, antibiotic or DNase. 
     
     
         20 . A method for inhibiting a channel activating protease, comprising administering to a cell or a tissue, or to a subject in need thereof, a therapeutically effective amount of the compound of Formula (1) or pharmaceutically acceptable salts or pharmaceutical compositions thereof, 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, wherein 
         J is 
       
       
         
           
           
               
               
           
         
         Z is O or S; 
         R 1  is —(CR 2 ) 1 —NR 2 , —(CR 2 ) 1 —NRC(═NR)—NR 2 , or —(CR 2 ) 1 —C(═NR)—NR 2 ; 
         W—R 2  is a substituent at any position on ring A; 
         W is or —O(CR 2 ) k —, —S(CR 2 ) k —, —S(O)(CR 2 ) k —, —SO 2 (CR 2 ) k — or —OC(O)(CR 2 ) k —; 
         R 2  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, R 6 , —CR 9 ═CR 9 —R 6 , or 
       
       
         
           
           
               
               
           
         
       
       wherein ring E is an optionally substituted 5-7 membered monocyclic or fused carbocyclic or heterocyclic ring; or W—R 2  together form C 1-6  alkyl, a 5-7 membered aryl or —OC(O)NR 7 R 8 ;
 R 3  is NR 7 R 8  or R 6 ; 
 R 4  and R 5  are independently H, C 1-6  alkyl, OH, or C 1-6  alkoxy; 
 R 7  and R 8  are independently H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or —(CR 2 ) 1 —R 6 ; or R 7  and R 8  together with N may form an optionally substituted 5-7 membered monocyclic or fused heterocyclic ring; 
 R 9  is H or C 1-6  alkyl; 
 R 10  is halo, C 1-6  alkyl, C 1-6  alkoxy, OR 11  or —(CR 2 ) 1 —R 11 ; 
 R 6 , R 11  and X are independently an optionally substituted 5-7 membered carbocyclic ring, heterocyclic ring, aryl or heteroaryl; or R 11  is H or C 1-6  alkyl; 
 R is H; 
 i is 0-1; 
 k and l are independently 0-6; 
 m and n are independently 1-6; and 
 p is 0-3; 
 wherein said channel activating protease is matriptase (MTSP-1).