Protease inhibitors

Abstract

A compound of formula (I) wherein R 1 to R 15 , P 1 , P 2 , A, B and Q are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as matriptase inhibitors and are useful in the treatment of matriptase dependent conditions, particularly cancer.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         P 1  is a bond, and P 2  is —CH 2 ; 
         A is CH; 
         B is CH or N; 
         R 1  is —NH—SO 2 — ZR 9 R 13 , —NR 4 —CO—ZR 9 R 13 , —CO—NR 7 R 8 , —CO—O—ZR 9 R 13 , —CO—NR 4 —R X —ZR 9 R 13 , or a group of formula (II) 
       
       
         
           
           
               
               
           
         
         wherein the ring portion in formula (II) is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; 
         R 3  is —C(NR 17 )NH 2  or amino C 1-7  alkyl; 
         R 10 , R 14 , and R 15  are independently hydrogen, halogen, hydroxy, C 1-7  alkyl, halogen C 1-7  alkyl, or —C(NR 17 )NH 2 ; 
         Q is hydrogen or halogen; 
         R 4  is hydrogen or C 1-7  alkyl; 
         Z is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; 
         R 9  and R 13  are independently hydrogen, halogen, hydroxy, carboxy, C 1-7  alkyl, carboxy C 1-7  alkyl, hydroxy C 1-7  alkyl, C 1-7  alkoxycarbonyl, R A NH 2 , or —COR B NH 2 ; 
         R A , R B , and R X  are independently a bond or C 1-7  alkyl; 
         R 7  and R 8  are independently hydrogen, amino C 1-7  alkyl, carboxy C 1-7  alkyl, or C 1-7  alkyl, 
         with a proviso that R 7  and R 8  are not simultaneously hydrogen; 
         R 2  is C 1-7  alkyl, amino C 1-7  alkyl, carboxy C 1-7  alkyl, C 1-7  alkoxycarbonyl C 1-7  alkyl, C 1-7  alkylamino, carboxy C 1-7  alkylamino, R D C(NR 17 )NH 2 , or a group of formula (III) 
       
       
         
           
           
               
               
           
         
         y=0-2; R D  is a bond or C 1-7  alkyl; G is CH or N; 
         R 11  is hydrogen, halogen, amino, carboxy, amino C 1-7  alkyl, C 1-7  alkoxycarbonyl, halogen C 1-7  alkoxy, —C(NR 17 )NH 2 , —NHCOR G NH 2 , R J HCOOR U , or —CONR 19 R 20 , 
         R G  is C 1-7  alkyl; R J  is a bond or C 1-7  alkyl; R U  is hydrogen or C 1-7  alkyl; R 12  and R 16  are independently hydrogen, halogen or C 1-7  alkyl; 
         or R 12  and R 16  form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated, or aromatic ring, which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof, wherein said ring is substituted or unsubstituted; 
         R 17  is hydrogen, —OH, C 1-7  alkoxy, —O(CO)OR 18 , or —(CO)OR 18 ; 
         R 18  is C 1-7  alkyl; 
         R 19  and R 20  are independently hydrogen, C 1-7  alkyl, or C 1-7  alkoxy; 
         or a pharmaceutically acceptable salt or ester thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein B is CH. 
     
     
         3 . The compound according to  claim 1 , wherein R 3  is —C(NR 17 )NH 2  and R 10 , R 14 , and R 15  are hydrogen. 
     
     
         4 . The compound according to  claim 1 , wherein R 2  is a group of formula (III), wherein G is CH, y is 0-1, R 11  is —C(NR 17 )NH 2  or amino C 1-7  alkyl, and R 12  and R 16  are hydrogen. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The compound according to  claim 1 , wherein R 1  is a group of formula (II). 
     
     
         8 . The compound according to  claim 7 , wherein the ring portion of formula (II) is a 6 or 10 membered saturated, partially saturated, or aromatic ring. 
     
     
         9 . The compound according to  claim 8 , wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro-quinolinyl, or 3,4-dihydro-1H-quinolinyl. 
     
     
         10 . The compound according to  claim 1 , wherein R 1  is —NR 4 —CO—ZR 9 R 13 , —CO—O—ZR 9 R 13 , or —CO—NR 4 —R X —ZR 9 R 13 . 
     
     
         11 . The compound according to  claim 10 , wherein Z is a 6 or 10 membered saturated, partially saturated, or aromatic ring. 
     
     
         12 . The compound according to  claim 11 , wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl, or quinolinyl. 
     
     
         13 . The compound according to  claim 12 , wherein Z is cyclohexyl or piperidinyl, R 4  is hydrogen, R X  is a bond, R 9  is R A NH 2 , and R 13  is hydrogen. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         15 . A method for the treatment of a matriptase dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         16 . A method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .