Substituted amino triazoles useful as acidic mammalian chitinase inhibitors

Abstract

Disclosed are amino triazole compounds substituted by a carboxylate functional group or an bioisosteric polar functional group. Compounds having the carboxylate moiety or carboxylate bioisostere inhibit acidic mammalian chitinase. Also provided are methods of using the compounds to treat asthma reactions caused by allergens.

What is claimed is: 
     
         1 . A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is N, and Z is CR 10 ; or X is CR 11 , and Z is N; 
 R 1  is selected from the group consisting of Y, aryl substituted by Y, and alkyl substituted by Y; 
 Y is —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) z , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), —P(O)(OH) 2 , 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are each independently H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or aryl; or R 2 , taken together with R 6  or R 7 , forms a 5- or 6-membered ring; 
         R 8  is selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl and (C 3 -C 6 )cycloalkyl; 
         R 9  is selected from the group consisting of OH, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, heteroaryl, and heteroaryl(C 1 -C 6 )alkyl; 
         R 10  and R 11  are each independently selected from H and (C 1 -C 6 )alkyl; 
         m is an integer from 0-5; 
         n is an integer from 0-2; 
         further wherein any occurrence of (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —OH, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkoxyl, —SH, —S((C 1 -C 6 )alkyl), (C 1 -C 6 )hydroxyalkyl, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CN, —CF 3 , —C(O)NH 2 , —C(O)NH(R 12 ), —C(O)N(R 12 ) 2 , —N(H)C(O)(R 12 ), —N(R 12 )C(O)(R 12 ), —S(O) 2 NH 2 , —S(O) 2 NH(R 12 ), —S(O) 2 N(R 12 ) 2 , —N(H)S(O) 2 (R 12 ), —N(R 12 )S(O) 2 (R 12 ), —NHC(O)NH 2 , —NHC(O)NH(R 12 ), and —NHC(O)N(R 12 ) 2 ; and 
         each occurrence of R 12  is independently selected from the group consisting of (C 1 -C 6 )alkyl), aryl, and aryl(C 1 -C 6 )alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is Y. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is aryl substituted by Y. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is (C 1 -C 6 )alkyl substituted by Y. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein Y is —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), C(O)N(aryl)((C 1 -C 6 )alkyl), C(O)N(aryl) 2 , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), or 1H-tetrazolyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of:
 CO 2 H;   C(O)NH 2 ;   C(O)NH((C 1 -C 6 )alkyl);   C(O)NH(aryl);   1H-tetrazolyl;   aryl substituted by —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, or 1H-tetrazolyl; and   (C 1 -C 6 )alkyl substituted by CO 2 H, —NHC(O)(C 1 -C 6 )alkyl, —NHC(O)(C 1 -C 6 )haloalkyl, —NHC(O)aryl, —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 )alkyl, —S(O) 2 NH(C 1 -C 6 )haloalkyl, —S(O) 2 NHaryl, —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, or —S(O) 2 NHC(O)aryl.   
     
     
         7 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of:
 1H-tetrazolyl;   aryl substituted by —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, or 1H-tetrazolyl; and   (C 1 -C 6 )alkyl substituted by CO 2 H, —NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —S(O) 2 NH(C 1 -C 6 )alkyl, or —S(O) 2 NHC(O)(C 1 -C 6 )alkyl.   
     
     
         8 . The compound of any one of  claims 1 - 7 , wherein R 2  and R 3  are each independently selected from the group consisting of H and aryl. 
     
     
         9 . The compound of  claim 8 , wherein R 2  and R 3  are both H. 
     
     
         10 . The compound of any one of  claims 1 - 9 , wherein X is N; and Z is CH. 
     
     
         11 . The compound of any one of  claims 1 - 9 , wherein X is CH; and Z is N. 
     
     
         12 . The compound of any one of  claims 1 - 11 , wherein R 8  is selected from the group consisting of halo, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl. 
     
     
         13 . The compound of  claim 12 , wherein R 8  is halo. 
     
     
         14 . The compound of any one of  claims 1 - 13 , wherein m is 1. 
     
     
         15 . The compound of any one of  claims 1 - 14 , wherein R 4 , R 5 , R 6 , and R 7  are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl. 
     
     
         16 . The compound of  claim 15 , wherein R 4 , R 5 , R 6 , and R 7  are each H. 
     
     
         17 . The compound of any one of  claims 1 - 16 , wherein R 9  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and aryl(C 1 -C 6 )alkyl. 
     
     
         18 . The compound of any one of  claims 1 - 17 , wherein n is 0. 
     
     
         19 . The compound of  claim 1 , represented by any one of the following structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . A compound represented by formula (II) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is NH or N(C(R 1 )(R 2 )(R 3 )), and Z is CR 10 ; or X is CHR 11  or C(R 11 )(C(R 1 )(R 2 )(R 3 )), and Z is N; 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are each independently H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or aryl; or R 2 , taken together with R 6  or R 7 , forms a 5- or 6-membered ring; 
 R 8  is selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 3 -C 6 )cycloalkyl; 
 R 9  is selected from the group consisting of Y, aryl substituted by Y, and (C 1 -C 6 )alkyl substituted by Y; 
 Y is —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), —P(O)(OH) 2 , 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 10  and R 11  are each independently selected from H and (C 1 -C 6 )alkyl; 
         m is an integer from 0-5; 
         n is 1 or 2; 
         further wherein any occurrence of (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —OH, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkoxyl, —SH, —S((C 1 -C 6 )alkyl), (C 1 -C 6 )hydroxyalkyl, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CN, —CF 3 , —C(O)NH 2 , —C(O)NH(R 12 ), —C(O)N(R 12 ) 2 , —N(H)C(O)(R 12 ), —N(R 12 )C(O)(R 12 ), —S(O) 2 NH 2 , —S(O) 2 NH(R 1 ), —S(O) 2 N(R 12 ) 2 , —N(H)S(O) 2 (R 12 ), —N(R 12 )S(O) 2 (R 12 ), —NHC(O)NH 2 , —NHC(O)NH(R 12 ), and —NHC(O)N(R 12 ) 2 ; and 
         each occurrence of R 12  is independently selected from the group consisting of (C 1 -C 6 )alkyl), aryl, and aryl(C 1 -C 6 )alkyl. 
       
     
     
         21 . The compound of  claim 20 , wherein R 9  is Y. 
     
     
         22 . The compound of  claim 20 , wherein R 9  is aryl substituted by Y. 
     
     
         23 . The compound of  claim 20 , wherein R 9  is (C 1 -C 6 )alkyl substituted by Y. 
     
     
         24 . The compound of any one of  claims 20 - 23 , wherein Y is —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), C(O)N(aryl)((C 1 -C 6 )alkyl), C(O)N(aryl) 2 , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), or 1H-tetrazolyl. 
     
     
         25 . The compound of  claim 20 , wherein R 9  is selected from the group consisting of:
 CO 2 H;   C(O)NH 2 ;   C(O)NH((C 1 -C 6 )alkyl);   C(O)NH(aryl);   1H-tetrazolyl;   aryl substituted by —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, or 1H-tetrazolyl; and   (C 1 -C 6 )alkyl substituted by CO 2 H, —NHC(O)(C 1 -C 6 )alkyl, —NHC(O)(C 1 -C 6 )haloalkyl, —NHC(O)aryl, —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 )alkyl, —S(O) 2 NH(C 1 -C 6 )haloalkyl, —S(O) 2 NHaryl, —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, or —S(O) 2 NHC(O)aryl.   
     
     
         26 . The compound of any one of  claims 20 - 25 , wherein n is 1. 
     
     
         27 . The compound of any one of  claims 20 - 26 , X is NH; and Z is CH. 
     
     
         28 . The compound of any one of  claims 20 - 26 , wherein X is N(C(R 1 )(R 2 )(R 3 )); and Z is CH. 
     
     
         29 . The compound of  claim 28 , wherein R 2  and R 3  are both H. 
     
     
         30 . The compound of  claim 29 , wherein R 1  is H or (C 1 -C 6 )alkyl. 
     
     
         31 . The compound of any one of  claims 20 - 26 , wherein X is CH 2 ; and Z is N. 
     
     
         32 . The compound of any one of  claims 20 - 31 , wherein R 8  is selected from the group consisting of halo, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl. 
     
     
         33 . The compound of  claim 32 , wherein R 8  is halo. 
     
     
         34 . The compound of any one of  claims 20 - 33 , wherein m is 1. 
     
     
         35 . The compound of any one of  claims 20 - 34 , wherein R 4 , R 5 , R 6 , and R 7  are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl. 
     
     
         36 . The compound of  claim 35 , wherein R 4 , R 5 , R 6 , and R 7  are each H. 
     
     
         37 . A compound represented by formula (III) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is NH or N(C(R 1 )(R 2 )(R 3 )), and Z is CR 10 ; or X is CHR 11  or C(R 11 )(C(R 1 )(R 2 )(R 3 )), and Z is N; 
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 7  are each independently H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or aryl; or R 1  or R 2 , taken together with or R 7 , forms a 5- or 6-membered ring; 
 R 6  is selected from the group consisting of Y, aryl substituted by Y, and (C 1 -C 6 )alkyl substituted by Y; 
 Y is —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), —P(O)(OH) 2 , 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 3 -C 6 )cycloalkyl; 
         R 9  is selected from the group consisting of OH, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, heteroaryl, and heteroaryl(C 1 -C 6 )alkyl; 
         R 10  and R 11  are each independently selected from H and (C 1 -C 6 )alkyl; 
         m is an integer from 0-5; 
         n is an integer from 0-2; 
         further wherein any occurrence of (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —OH, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkoxyl, —SH, —S((C 1 -C 6 )alkyl), (C 1 -C 6 )hydroxyalkyl, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CN, —CF 3 , —C(O)NH 2 , —C(O)NH(R 12 ), —C(O)N(R 12 ) 2 , —N(H)C(O)(R 12 ), —N(R 12 )C(O)(R 12 ), —S(O) 2 NH 2 , —S(O) 2 NH(R 12 ), —S(O) 2 N(R 12 ) 2 , —N(H)S(O) 2 (R 12 ), —N(R 12 )S(O) 2 (R 12 ), —NHC(O)NH 2 , —NHC(O)NH(R 12 ), and —NHC(O)N(R 12 ) 2 ; and 
         each occurrence of R 12  is independently selected from the group consisting of (C 1 -C 6 )alkyl), aryl, and aryl(C 1 -C 6 )alkyl. 
       
     
     
         38 . The compound of  claim 37 , wherein R 6  is Y. 
     
     
         39 . The compound of  claim 37 , wherein R 6  is aryl substituted by Y. 
     
     
         40 . The compound of  claim 37 , wherein R 6  is (C 1 -C 6 )alkyl substituted by Y. 
     
     
         41 . The compound of any one of  claims 37 - 40 , wherein Y is —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), C(O)N(aryl)((C 1 -C 6 )alkyl), C(O)N(aryl) 2 , —C(O)NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —N(H)S(O) 2 (C 1 -C 6 )haloalkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, C(O)N(H)S(O) 2 ((C 1 -C 6 )haloalkyl), or 1H-tetrazolyl. 
     
     
         42 . The compound of  claim 37 , wherein R 6  is selected from the group consisting of:
 CO 2 H;   C(O)NH 2 ;   C(O)NH((C 1 -C 6 )alkyl);   C(O)NH(aryl);   1H-tetrazolyl;   aryl substituted by —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)(SO 2 )aryl, —C(O)N(H)S(O) 2 (C 1 -C 6 )alkyl, —C(O)N(H)S(O) 2 aryl, or 1H-tetrazolyl; and   (C 1 -C 6 )alkyl substituted by CO 2 H, —NHC(O)(C 1 -C 6 )alkyl, —NHC(O)(C 1 -C 6 )haloalkyl, —NHC(O)aryl, —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —N(H)S(O) 2 (C 1 -C 6 )alkyl, —N(H)S(O) 2 aryl, —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 )alkyl, —S(O) 2 NH(C 1 -C 6 )haloalkyl, —S(O) 2 NHaryl, —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, or —S(O) 2 NHC(O)aryl.   
     
     
         43 . The compound of any one of  claims 37 - 42 , wherein n is 1. 
     
     
         44 . The compound of any one of  claims 37 - 43 , X is NH; and Z is CH. 
     
     
         45 . The compound of any one of  claims 37 - 43 , wherein X is N(C(R 1 )(R 2 )(R 3 )); and Z is CH. 
     
     
         46 . The compound of  claim 45 , wherein R 2  and R 3  are both H. 
     
     
         47 . The compound of  claim 46 , wherein R 1  is H or (C 1 -C 6 )alkyl. 
     
     
         48 . The compound of any one of  claims 37 - 43 , wherein X is CH 2 ; and Z is N. 
     
     
         49 . The compound of any one of  claims 37 - 48 , wherein R 8  is selected from the group consisting of halo, (C 1 -C 6 )haloalkyl and (C 1 -C 6 )alkyl. 
     
     
         50 . The compound of  claim 49 , wherein R 8  is halo. 
     
     
         51 . The compound of any one of  claims 37 - 50 , wherein m is 1. 
     
     
         52 . The compound of any one of  claims 37 - 51 , wherein R 4 , R 5 , and R 7  are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl. 
     
     
         53 . The compound of  claim 52 , wherein R 4 , R 5 , and R 7  are each H. 
     
     
         54 . The compound of any one of  claims 37 - 53 , wherein R 9  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and aryl(C 1 -C 6 )alkyl. 
     
     
         55 . The compound of any one of  claims 37 - 54 , wherein n is 0. 
     
     
         56 . A pharmaceutical composition, comprising a compound of any one of  claims 1 - 55 ; and a pharmaceutically acceptable carrier. 
     
     
         57 . A method for treating asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 55 . 
     
     
         58 . A method for treating a reaction caused by an allergen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 55 . 
     
     
         59 . The method of  claim 58 , wherein the reaction caused by an allergen is allergic rhinitis or atopic dermatitis. 
     
     
         60 . The method of  claim 58  or  59 , wherein the allergen is mold, mammal dander, pollen, spores, fungus, dust mites, insects, or a chemical. 
     
     
         61 . A method for treating a fungal or parasitic infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 55 . 
     
     
         62 . A method for assessing the efficacy of an agent for treating asthma in a subject, comprising:
 a) detecting in a subject sample collected at a first point in time, the expression level of acidic mammalian chitinase protein;   b) repeating step a) at one or more subsequent points in time after administration of the agent; and   c) comparing expression level of acidic mammalian chitinase protein detected in step a) with the expression level(s) detected in step b),   wherein a higher expression level of acidic mammalian chitinase protein at the first point in time relative to at least one subsequent point in time indicates that the agent is efficacious in treating asthma.   
     
     
         63 . A method of identifying an agent for treating asthma, comprising:
 a) contacting a sample comprising acidic mammalian chitinase protein with the agent; and   b) determining the ability of the agent to inhibit activity of acidic mammalian chitinase protein, wherein decreased activity of acidic mammalian chitinase protein identifies an agent for treating asthma.   
     
     
         64 . The method of  claim 63 , wherein the activity of acidic mammalian chitinase protein is assessed by fluorescence assay using a reagent that is hydrolyzed by acidic mammalian chitinase protein. 
     
     
         65 . The method of  claim 64 , wherein the reagent is 4-methylumbelliferyl B-D-N,N′-diacetylchitobioside hydrate.