Novel inhibitors of chymase

Abstract

The present invention is directed to a compound of formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof, and methods for treating inflammatory and serine protease mediated disorders.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of hydrogen and C 1-4 alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl, and cyclopropyl when n is 0 and one of R 2  or R 3  is phenyl, and benzo fused cycloalkyl, and ring A is optionally substituted with R 2  and R 3 ;
 R 2  is one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, methoxy, C 2-6 alkoxy, C 1-6 alkylthio, —OCF 3 , —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; furthermore, R 2  is optionally oxo when ring A is heteroaryl or benzo fused heterocyclyl; and, wherein any aryl-containing substituent of R 2  is optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6  alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
 and, wherein any of the foregoing C 1-6 alkyl or C 2-6  alkoxy containing substituents of R 2  are optionally substituted with a substituent independently selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens and hydroxy; wherein R 11  and R 12  are independently hydrogen; C 1-6  alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, or —NR 15 R 16 ; or aryl;
 R 15  and R 16  are substituents independently selected from the group consisting of hydrogen, C 1-6  alkyl, and aryl, and said R 15  and R 16  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 
 
 R 3  is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, —OCF 3 , —OCH 2 (C 2-6 )alkenyl, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, —NHC(═O)Cy, —N(C 1-6 alkyl)C(═O)Cy, —(NC(═O)) 2 NH 2 , —C(═O)C 1-4 alkoxy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C 1-6 alkyl)Cy, —C(═O)Cy, —OC(═O)C 1-6 alkyl, —OC(═O)NR 19 R 20 , —C(═O)Oaryl, —C(═O)Oheteroaryl, —CO 2 H, ureido, halogen, hydroxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy, and aryloxy;
 wherein any of the foregoing C 1-6 alkyl or C 1-6  alkoxy containing substituents of R 3  are optionally substituted with one to three substituents independently selected from the group consisting of —NR 21 R 22 , —NH (cycloalkyl), —N(C 1-6 alkyl)(cycloalkyl), —NHCy, —N(C 1-6 alkyl)Cy, aryl, heteroaryl, hydroxy, halogen, —C(═O)NR 23 R 24 , —OC(═O)NR 25 R 26 , —C(═O)C 1-4 alkoxy, and —C(═O)Cy;
 wherein said R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26  are substituents independently selected from the group consisting of hydrogen, C 1-6  alkyl, and aryl, wherein C 1-6  alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and R 17  and R 18 , R 19  and R 20 , R 21  and R 22 , R 23  and R 24  and R 25  and R 26  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 
 
 Cy is a heterocyclyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkylC(═O)C 1-6 alkyl, —C 1-6 alkylC(═O)C 1-6 -alkoxy, C 1-6 alkylC(═O)aryl, —C(═O)(C 1-6 )alkyl, —C(═O)(C 1-6 )alkoxy, —C(═O)aryl, —SO 2 aryl, aryl, heteroaryl, and heterocyclyl; wherein the aryl portion of any aryl-containing substituent of Cy is optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen, hydroxy, NH 2 , NH(C 1-6 alkyl), and —N(C 1-6 )dialkyl; and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents; and heterocyclyl is optionally spiro-fused to said Cy;
 and wherein the C 1-6 alkenyl and C 1-6 alkynyl substituents of R 3  are optionally substituted with aryl or —C(═O)NR 27 R 28 ; wherein said R 27  and R 28  are independently hydrogen; C 1-6 -alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; or aryl; and R 27  and R 28  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 wherein the aryl, heteroaryl, and cycloalkyl substituents of R 3  are optionally substituted with one to three substituents independently selected from R 14 ;
 wherein R 14  is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; 
 
 
 and any one of the foregoing C 1-6 alkyl- or C 1-6 alkoxy-containing substituents of R 14  is optionally substituted on a terminal carbon atom with a substituent selected from —NR 29 R 30 , aryl, heteroaryl, one to three halogen atoms, or hydroxy; wherein R 29  and R 30  are independently hydrogen; C 1-6  alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; or aryl; and R 29  and R 30  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 n is 0 or 1; 
 W is O or S; 
 X is hydrogen or C 1-3 alkyl; 
 Y is independently selected from the group consisting of C 1-6 alkyl substituted with —OSO 2 NH 2  or hydroxy; SO 3 H, CO 2 H, heteroaryl, —OC(═O)NH 2 , and P(═O)OR 5 R 6  provided that when Y is CO 2 H, A and Z must both be bicyclic ring systems; 
 R 5  is selected from the group consisting of hydrogen; C 1-6 alkyl optionally substituted with NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, 1,3-dioxolan-2-yl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6  alkenyl, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R 6  is C 1-6 alkoxy, R 5  and R 6  are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
 provided that R 5  is other than C 1-6 alkyl substituted with di(C 1-6 )alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is OH, and Z-R 4  is 5-chloro-PRD benzothiophen-3-yl; and provided that R 5  is other than C 1-6 alkyl substituted with C 1-6 alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is CH 3 , and Z-R 4  is 5-chloro-benzothiophen-3-yl; 
 
 R 6  is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, heteroaryl, aryl, and hydroxy; wherein C 1-8 alkyl, C 1-8 alkoxy, and C 2-8 alkenyl are optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, aryl, heterocyclyl, heteroaryl, NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, C 1-6 alkyl-carbonyloxy, C 1-6 alkylcarbonylthio, C 1-6 alkoxycarbonyloxy, (C 1-6 )alkylamino-carbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogen atoms, and hydroxy; and when R 6  is C 1-8 alkyl, said C 1-8 alkyl is optionally substituted with one to four additional halogen atoms such that one to three halogen atoms are optionally chlorine and one to seven of the halogen atoms are optionally fluorine;
 wherein the heteroaryl and aryl substituents of R 6  are optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6  alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; 
 
 Z is a bicyclic aryl or bicyclic heteroaryl; provided that when Y is CO 2 H, A and Z must both be a bicycle;
 R 4  is one to three substituents selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylthio, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, halogen, —C(═O)Cy, —C(═O)NR 31 R 32 , aryl, —CO 2 H, oxo, and cyano; wherein C 1-6 alkyl, C 1-6 alkenyl and C 1-6 alkoxy are optionally substituted with —NR 33 R 34 , aryl, heteroaryl, cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and heteroaryl are each optionally substituted with a substituent independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6  alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, one to three halogen atoms, hydroxy, and nitro; 
 wherein said R 31 , R 32 , R 33 , and R 34  are substituents independently selected from the group consisting of hydrogen, C 1-6 -alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and R 31  with R 32  and R 33  with R 34  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 
 
       and pharmaceutically acceptable salts thereof. 
     
     
         2 . The compound of  claim 1  wherein R 1  is hydrogen. 
     
     
         3 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is independently selected from the group consisting of aryl, heteroaryl, and benzo fused heterocyclyl, optionally substituted with R 2  and R 3 . 
     
     
         4 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is a bicyclic ring system of the formula: 
       
         
           
           
               
               
           
         
       
       wherein the a 1  portion of said a 1 a 2  is optionally substituted with R 2 ; and a 2  portion is optionally substituted with R 3 . 
     
     
         5 . The compound of  claim 4  wherein a is aromatic. 
     
     
         6 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is selected from group consisting of naphthyl, benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl, tetralinyl, and benzodioxolyl when n is equal to zero; and A is selected from phenyl, pyridin-2-yl, and pyridin-3-yl when n is equal to one. 
     
     
         7 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is selected from naphthyl and benzothiazolyl when n is equal to zero; and A is selected from phenyl, pyridin-2-yl, and pyridin-3-yl when n is equal to one. 
     
     
         8 . The compound of  claim 1  wherein R 2  is one to three substituents independently selected from the group consisting of C 1-6 alkyl, methoxy, C 2-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 )dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro; wherein C 1-6 alkyl and C 2-6 alkoxy are optionally substituted with a substituent selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens, and hydroxy. 
     
     
         9 . The compound of  claim 1  wherein R 2  is a substituent independently selected from the group consisting of C 1-4 alkyl, methoxy, C 2-4 alkoxy, hydroxy, halogen, and —NH 2 . 
     
     
         10 . The compound of  claim 1  wherein R 2  is C 1-4 alkyl, halogen, or —NH 2 . 
     
     
         11 . The compound of  claim 1  wherein R 3  is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —OCH 2 (C 2-6 )alkenyl, NH 2 , —NH(C 1-6 -alkyl), —N(C 1-6 )dialkyl, —NHC(═O)Cy, —N(C 1-6 alkyl)C(═O)Cy, —C(═O)C 1-4 alkoxy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C 1-6 -alkyl)Cy, —C(═O)Cy, —OC(═O)NR 19 R 20 , halogen, hydroxy, nitro, cyano, aryl, and aryloxy; wherein alkyl and alkoxy are optionally substituted with one to three substituents independently selected from the group consisting of —NR 21 R 22 , —NHcycloalkyl, —N(C 1-6 alkyl)cycloalkyl, —NHCy, —N(C 1-6 alkyl)Cy, aryl, heteroaryl, halogen, —C(═O)NR 23 R 24 , —OC(═O)NR 25 R 26 , —C(═O)(C 1-4 )alkoxy, and —C(═O)Cy; wherein alkenyl is optionally substituted on a terminal carbon with aryl and —C(═O)NR 27 R 28 ; and, wherein aryl and cycloalkyl are optionally substituted with one to three substituents independently selected from R 14 . 
     
     
         12 . The compound of  claim 1  wherein R 3  is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, —NR 19 R 20 , —NHC(═O)Cy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cycloalkyl, halogen, and aryl; wherein alkyl and alkoxy are optionally substituted on a terminal carbon atom, with one to three fluorine atoms, —NH 2 , —NHCy, or —N(C 1-4 alkyl)Cy; and wherein aryl and cycloalkyl are optionally substituted with a group independently selected from R 14 . 
     
     
         13 . The compound of  claim 1  wherein R 3  is one to two substituents independently selected from trifluoromethyl; C 1-4 alkoxy optionally substituted with one to three fluorine atoms; —NH 2 ; —NHC(═O)Cy; or halogen. 
     
     
         14 . The compound of  claim 1  wherein R 3  is NHC(═O)Cy, and Cy is piperadinyl; wherein said piperadinyl is substituted with a substituent selected from the group consisting of C 1-4  alkyl, C 1-4 alkylC(═O)C 1-4 alkyl, —C 1-4 alkylC(═O)C 1-4 alkoxy, C 1-4 alkylC(═O)aryl, —C(═O)(C 1-4 )alkyl, —C(═O)(C 1-4 )alkoxy, —C(═O)aryl, —SO 2 aryl, aryl, heteroaryl, and heterocyclyl; wherein aryl and the aryl portion of the C 1-4 alkylC(═O)aryl, —C(═O)aryl and —SO 2 aryl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxy, NH 2 , NH(C 1-6 -alkyl), or —N(C 1-4 )dialkyl; and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one oxo substituents. 
     
     
         15 . The compound of  claim 1  wherein R 3  is trifluoromethyl, one to two fluorine atoms, chloro, methoxy, trifluoromethoxy, or NH 2 ; furthermore, when A is naphthyl and n is equal to zero, R 3  is (4-{[1-(naphthalen-2-yl-carbonyl)-piperadin-4-yl-carbonyl]-amino}naphthalen-2-yl. 
     
     
         16 . The compound of  claim 1  wherein X is C 1-3 alkyl. 
     
     
         17 . The compound of  claim 1  wherein X is hydrogen. 
     
     
         18 . The compound of  claim 1  wherein Y is independently selected from the group consisting of C 1-3 alkyl substituted with —OSO 2 NH 2  or hydroxy; SO 3 H, CO 2 H, heteroaryl, —OC(═O)NH 2 , and P(═O)OR 5 . 
     
     
         19 . The compound of  claim 1  wherein R 5  is selected from the group consisting of hydrogen; C 1-3 alkyl optionally substituted with NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6  alkenyl, NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R 6  is C 1-8 alkoxy, R 5  and R 6  are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
 and provided that R 5  is other than C 1-3 alkyl substituted with di(C 1-6 )alkylaminocarbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is OH, and Z-R 4  is 5-chloro-benzothiophen-3-yl; and provided that R 5  is other than C 1-3 alkyl substituted with C 1-6 alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is CH 3 , and Z-R 4  is 5-chloro-benzothiophen-3-yl.   
     
     
         20 . The compound of  claim 1  wherein R 5  is selected from the group consisting of hydrogen, C 1-3 alkyl optionally substituted with C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, one to three halogens, or hydroxyl; and aryl; alternatively, when R 6  is C 1-8 alkoxy, R 5  and R 6  are taken together with the atoms to which they are attached to form a 6-7 membered monocyclic ring;
 and provided that when R 5  is C 1-3 alkyl substituted with either di(C 1-6 )alkylaminocarbonyl or C 1-6 alkylcarbonylthio, ring system A is other than 3,4-difluoro-phenyl when n is 1 and Z-R 4  5-chloro-benzothiophen-3-yl.   
     
     
         21 . The compound of  claim 1  wherein R 5  is hydrogen or C 1-3 alkyl optionally substituted with C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6 alkylcarbonylthio, (C 1-6 )alkylaminocarbonyl, or di(C 1-6 )alkylaminocarbonyl; and alternatively, when R 6  is C 1-8 alkoxy, R 5  and R 6  are taken together with the atoms to which they are attached to form a 6-membered monocyclic ring;
 and provided that R 5  is other than C 1-3 alkyl substituted with di(C 1-6 )alkylaminocarbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is OH, and Z-R 4  is 5-chloro-benzothiophen-3-yl; and provided that R 5  is other than C 1-3 alkyl substituted with C 1-6 alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is CH 3 , and Z-R 4  is 5-chloro-benzothiophen-3-yl.   
     
     
         22 . The compound of  claim 1  wherein R 6  is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, heteroaryl, aryl, and hydroxy; wherein alkyl, alkoxy, and alkenyl are optionally substituted on a terminal carbon atom with a substituent independently selected from the group consisting of C 1-4 alkoxy, aryl, heteroaryl, heterocyclyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylthio, C, alkoxycarbonyloxy, (C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, and hydroxy; and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C 1-6 alkoxy, and halogen. 
     
     
         23 . The compound of  claim 1  wherein R 6  is selected from the group consisting of C 1-6 alkyl, C 1-8 alkoxy, heteroaryl, aryl, and hydroxy; wherein alkyl and is optionally substituted on a terminal carbon atom with a substituent selected from C 1-3 alkoxy, aryl, or hydroxy; and alkoxy is optionally substituted on a terminal carbon with a substituent independently selected from the group consisting of C 1-6 alkylcarbonyloxy, and di(C 1-6 )alkylaminocarbonyl; and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C 1-6 alkoxy, and halogen. 
     
     
         24 . The compound of  claim 1  wherein R 6  is selected from the group consisting of methyl, ethyl, methoxypropyl, phenethyl, benzo[1,3]dioxol-5-yl-propyl, hydroxy, and C 1-3 alkoxy optionally substituted with C 1-6 alkylcarbonyloxy, and di(C 1-6 )alkylaminocarbonyl. 
     
     
         25 . The compound of  claim 1  wherein Z is a bicyclic aryl or bicyclic heteroaryl; wherein aryl and heteroaryl are optionally substituted with the group R 4 ; provided that when Y is CO 2 H, A and Z must both be a bicycle. 
     
     
         26 . The compound of  claim 1  wherein Z is independently selected from the group consisting of indolyl, benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl and benzothiazolone. 
     
     
         27 . The compound of  claim 1  wherein Z is indolyl, benzothiophenyl, or naphthalenyl. 
     
     
         28 . The compound of  claim 1  wherein R 4  is one to three substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, aryl(C 2-6 )alkenyl, halogen, —C(═O)Cy, —C(═O)NR 31 R 32 , aryl, —CO 2 H, oxo, and cyano; wherein the alkyl and alkoxy are optionally substituted with a substituent independently selected from the group consisting of —NR 33 R 34 , aryl, one to three halogen atoms, and hydroxy; wherein the aryl is optionally substituted with a substituent independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, aryl, halogen, hydroxy, and nitro. 
     
     
         29 . The compound of  claim 1  wherein R 4  is one to two substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, phenyl(C 2-6 )alkenyl, and —C(═O)(2-(4-phenyl-piperidin-1-carbonyl)). 
     
     
         30 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         31 . A composition made by mixing the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         32 . The method of  claim 1  wherein the disorder is selected from the group consisting of allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia, myocardial infarction, heart failure damage associated with myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid arthritis, bullous pemphigiod and atherosclerosis. 
     
     
         33 . The method of  claim 32  wherein said acute lung injury is adult (acute) respiratory distress syndrome. 
     
     
         34 . The method of  claim 32  wherein said vascular stenosis or restenosis is associated with vascular injury, angioplasty, vascular stents or vascular grafts. 
     
     
         35 . The method of  claim 32  wherein said kidney fibrosis is associated with glomerulonephritis. 
     
     
         36 . The method of  claim 32  wherein the chymase mediated disorder is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, and acute lung injury. 
     
     
         37 . The method of  claim 36  wherein the chymase mediated disorder is asthma. 
     
     
         38 . The method of  claim 36  wherein the chymase mediated disorder is allergic rhinitis. 
     
     
         39 . The method of  claim 36  wherein the chymase mediated disorder is pulmonary fibrosis. 
     
     
         40 . The method of  claim 1  wherein the therapeutically effective amount of the compound of  claim 1  is from about 0.001 mg/kg/day to about 1000 mg/kg/day.