Novel B1 bradykinin receptor antagonists

Abstract

The invention encompasses novel compounds and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for treatment of diseases mediated by B1 bradykinin receptor.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a group of formula (a) or (b): 
 
       
         
           
           
               
               
           
         
         where:
 R 4  is selected from H, C 1-3 alkyl, C 1-4 haloalkyl, F, Cl, Br or I; and 
 R 5  is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15-membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R 6 , R 7  or R 8  independently selected from basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from R 6 , R 7  and R 8  which are selected from R g , C 1-8 alkyl, C 1-4 haloalkyl, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from R 6 , R 7 , R 8 , R 9  and R 10  which are independently selected from Br, Cl, F or I; 
 
         X is —NR 3 — or C(R 3a )(R 3b )— where:
 R 3  is H, phenyl, benzyl or C 1-6 alkyl, the phenyl, benzyl and C 1-6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from R e , R g , C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F and I; 
 
         R 3a  is H, R 8 , halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a , —NR a C 2-6 alkylOR a , benzyl or C 1-6 alkyl, with the benzyl and C 1-6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from R e , R g , C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F or I; and 
         R 3b  is H, F, Cl, OCH 3 , C 1-2 alkyl or CF 3 ; or R 3a  and R 3b  together are C 2-6 alkylenyl to form a spiroalkyl that is substituted by 0, 1, 2 or 3 substituents independently selected from R e , R g , C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)O R b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a ) (═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F and I; 
         R 1  is selected from H, R g , cyano, nitro, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR a , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a , —NR a C 2-6 alkylOR a , benzyl or C 1-6 alkyl, with the benzyl and C 1-6 alkyl being substituted by 0, 1, 2, or 3 groups independently selected from R g , cyano, oxo, nitro, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR a , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F or I; 
         R 1a  is selected from H, F, Cl, (C 1 -C 3 )haloalkyl, or (C 1 -C 3 )alkyl; 
         R 1b  and R 1c  are independently in each instance selected from H, C 1-3 alkyl, C 1-4 haloalkyl, F, Cl, Br or I; 
         R 2  is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R e , R g , C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F or I; 
         R a  is independently, at each instance, H or R b ; 
         R b  is independently, at each instance, phenyl, benzyl or C 1-6 alkyl, the phenyl, benzyl and C 1-6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-3 haloalkyl, —OC 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, or —N(C 1-4 alkyl)C 1-4 alkyl; 
         R d  is independently, at each instance, C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a ; 
         R e  is independently, at each instance, C 1-6 alkyl substituted by 0, 1, 2 or 3 substituents independently selected from R d  and additionally substituted by 0 or 1 substituents selected from R g ; and 
         R g  is independently at each instance a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  or —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F or I; or 
         a pharmaceutically-acceptable salt or hydrate thereof. 
       
     
     
         2 . The compound of  claim 1  wherein the basic moieties are independently selected from amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 alkylaminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
     
     
         3 . The compound of  claim 1  wherein A is a group of formula (a). 
     
     
         4 . The compound of  claim 1  wherein A is a group of formula (b). 
     
     
         5 . The compound of  claim 2  wherein A is a group of formula (a). 
     
     
         6 . The compound of  claim 2  wherein A is a group of formula (b). 
     
     
         7 . The compound of  claim 2  wherein R 1a , R 1b , R 1c  are hydrogen and X is —NH— 
     
     
         8 . The compound of  claim 5  wherein R 1a , R 1b , R 1c  are hydrogen and X is —NH—. 
     
     
         9 . The compound of  claim 6  wherein R 1a , R 1b , R 1c  are hydrogen and X is —NH—. 
     
     
         10 . The compound of  claim 2  wherein R 1a , R 1b , R 1c  are hydrogen and X is —C(R 3a )(R 3b )—. 
     
     
         11 . The compound of  claim 5  wherein R 1a , R 1b , R 1c  are hydrogen and X is —C(R 3a )(R 3b )—. 
     
     
         12 . The compound of  claim 6  wherein R 1a , R 1b , R 1c  are hydrogen and X is —C(R 3a )(R 3b )—. 
     
     
         13 . The compound of  claim 2  wherein R 1  is hydrogen, alkyl, —COOR a , —C(═O)NR a R a  where R a  is H, or phenyl substituted with 0, 1, 2 or 3 substituents independently selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, or nitro and R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is Nor CR 6 ; 
 X 2  is N or CR 7 ; 
 X 3  is N or CR 8 ; 
 X 4  is N or CH; wherein no more than two of X 1 , X 2 , X 3  and X 4  is N; and 
 
       the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1 substituents selected from R g , C 1-8 alkyl, C 1-4 haloalkyl, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  and —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I provided that at least one of R 6 , R 7  and R 8  is a basic moiety. 
     
     
         14 . The compound of  claim 7  wherein R 1  is hydrogen, alkyl, —COOR a , —C(═O)NR a R a  where R a  is H, or phenyl substituted with 0, 1, 2 or 3 substituents independently selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, or nitro and R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is N or CR 6 ; 
 X 2  is N or CR 7 ; 
 X 3  is N or CR 8 ; 
 X 4  is N or CH; wherein no more than two of X 1 , X 2 , X 3  and X 4  is N; and 
 
       the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1 substituents selected from R g , C 1-8 alkyl, C 1-4 haloalkyl, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  and —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I provided that at least one of R 6 , R 7  and R 8  is a basic moiety. 
     
     
         15 . The compound of  claim 8  wherein R 1  is hydrogen, alkyl, —COOR a , —C(═O)NR a R a  where R a  is H, or phenyl substituted with 0, 1, 2 or 3 substituents independently selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, or nitro and R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is Nor CR 6 ; 
 X is N or CR 7 ; 
 X 3  is N or CR 8 ; 
 X 4  is N or CH; wherein no more than two of X 1 , X 2 , X 3  and X 4  is N; and 
 
       the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1 substituents selected from R g , C 1-8 alkyl, C 1-4 haloalkyl, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  and —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I provided that at least one of R 6 , R 7  and R 8  is a basic moiety. 
     
     
         16 . The compound of  claim 10  wherein R 1  is hydrogen, alkyl, —COOR a , —C(═O)NR a R a  where R a  is H, or phenyl substituted with 0, 1, 2 or 3 substituents independently selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, or nitro and R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is Nor CR 6 ; 
 X is N or CR 7 ; 
 X 3  is N or CR 8 ; 
 X 4  is N or CH; wherein no more than two of X 1 , X 2 , X 3  and X 4  is N; and 
 
       the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1 substituents selected from R 1 , C 1-8 alkyl, C 1-4 haloalkyl, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —C(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a  and —NR a C 2-6 alkylOR a , and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I provided that at least one of R 6 , R 7  and R 8  is a basic moiety. 
     
     
         17 . The compound of  claim 2  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         18 . The compound of  claim 2  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         19 . The compound of  claim 7  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         20 . The compound of  claim 7  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         21 . The compound of  claim 8  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         22 . The compound of  claim 8  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         23 . The compound of  claim 9  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         24 . The compound of  claim 9  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         25 . The compound of  claim 10  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         26 . The compound of  claim 10  wherein R 5  is a ring of formula: 
       
         
           
           
               
               
           
         
         where R 7  is amino, cycloalkylaminoC 1-6 alkyl, cycloalkylC 1-6 alkylaminoC 1-6 alkyl, heterocyclylaminoC 1-6 alkyl, heterocyclylC 1-6 alkyl-aminoC 1-6 alkyl, arylaminoC 1-6 alkyl, arylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkoxy, C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkoxy, aminoC 1-6 alkoxy, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-4 alkylamino-C 2-6 alkenyl, 4-8-membered nitrogen-containing heterocyclylC 2-6 alkenyl, heterocyclylC 1-6 aminoC 2-6 alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of the basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, diC 1-6 alkylamino, ═NCN; and C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , C 1-6 alkylamino, haloalkyl, oxo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or diC 1-6 alkylamino. 
       
     
     
         27 . The compound of  claim 17  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         28 . The compound of  claim 18  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         29 . The compound of  claim 19  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         30 . The compound of  claim 20  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         31 . The compound of  claim 21  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         32 . The compound of  claim 22  wherein R 1  is hydrogen, methyl, carboxy, —CONH 2 , phenyl or 4-fluorophenyl; R 2  is phenyl substituted with 0, 1, 2, or 3 substituents independently selected from halo, alkoxy, alkyl, or haloalkyl, R 4  is hydrogen and R 7  is isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)-piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl. 
     
     
         33 . A compound selected from the group consisting of: 
       (R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid; 
       (R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide; 
       (R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic acid; 
       (R)-2-(4-methylbenzenesulfonamido)-3-(1-((r)-7-((pyridin-2-ylmethylamino)methyl)-3,4-dihydro-2h-chromen-4-yl)-1h-1,2,3-triazol-4-yl)propanoic acid, tfa salt; 
       (2R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((neopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic acid; 
       (R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanoic acid tfa salt; 
       (R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-7-((piperidin-1-ylmethyl)chroman-4-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide; 
       (R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (2R)-3-(1-(6-((tert-butylamino)methyl)-1,2,3,4-tertahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide; 
       (R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((4-methylpiperazin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (2R)-2-(4-methylphenylsulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (2R)-3-(1-(6-((tert-butyl-amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide; 
       (2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((4-methylpiperazin-1-yl)methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide; 
       (2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic acid; 
       (2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic acid; 
       N-((S)-1-(1-(6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-4-methylbenzenesulfonamide; 
       4-methyl-N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-chroman-4-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide; 
       4-methyl-N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-hydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)-benzenesulfonamide; 
       N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-7-((tert-butylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamide; 
       N-((R)-2-(1-((R)-7-((tert-butylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-1-(4-fluorophenyl)ethyl)-3-(trifluoromethyl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2h-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-propan-2-yl)-3-(trifluoro-methyl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoro-methyl)benzenesulfonamide; 
       N-((S)-1-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamide; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         35 . A method of treating a disease mediated by Bradykinin 1 in a patient which method comprises treating the patient with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         36 . The method of  claim 35  wherein the disease is inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema. 
     
     
         37 . The method of  claim 35  wherein the disease is pain.