Substituted 2-amino-fused heterocyclic compounds

Abstract

The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 , R 2 , Z 1 , t, and ring A are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of JNK, such as diabetes, the method comprising administering to a mammal an effective amount of a compound of formula (I).

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is CH or N: 
 Ring A is a 5- or 6-membered ring which may optionally contain at least one heteroatom; 
 R 1  is hydroxy, (C 1 -C 6 )alkoxy, —(C═O)—R 3 , —(C═O)—CR 3 R 4 ) q —O—(CR 3 R 4 ) p —R 3 , —(C═O)—(CR 3 R 4 ) q —O—(CR 3 R 4 ) p —(C═O)—R 3 , —(C═O)—NR 3 R 4 , —(CR 3 R 4 ) q —NR 3 —(C═O)—R 4 , —(C═O)—(CR 3 R 4 ) q —NR 3 —(C═O)—R 4 , —(C═O)—(CR 3 R 4 ) q —(C═O)—NR 3 R 4 , —S(O) k NR 3 R 4 , —S(O) j R 3 , —(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) v (C 6 -C 10 aryl), —(CR 2 R 4 ) v (4-10)-membered heterocyclyl, —(CR 3 R 4 ) q (C═O)(C 1 -C 6 )alkyl, —(CR 3 R 4 ) q (C═O)(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) q (C═O)(CR 3 R 4 ) v (C 6 -C 10 )aryl, —(CR 3 R 4 ) q (C═O)(CR 3 R 4 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 3 R 4 ) q S(O) j (CR 3 R 4 ) v (C 6 -C 10 )aryl, or —(CR 3 R 4 ) q S(O) j (CR 3 R 4 ) v (4-10)-membered heterocyclyl; 
 R 2  is H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 5 , —(C═O)—O—R 5 , —O—(C═O)—R 5 , —NR 5 (C═O)—R 7 , —(C═O)—NR 5 R 6 , —NR 5 R 6 , —NR 5 OR 6 , —S(O) k NR 5 R 6 , —S(O) j (C 1 -C 6 )alkyl, —O—SO 2 —R 5 , —NR 5 —S(O) k —R 6 , —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (C 6 -C 10 )aryl, or —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (4-10)-membered heterocyclyl; 
 each of R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl; 
 any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are optionally substituted with 1 to 3 R 11  substituents each independently selected from oxo, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —O—(C═O)—R 8 , —NR 8 (C═O)—R 10 , —NR 8 (C═O)—O—R 10 , —(C═O)—NR 8 R 9 , —(C═O)—NR 8 R 9a , —NR 8 R 9 , —NR 8 OR 9 , —S(O) k NR 8 R 9 , —S(O) j R 8 , —O—SO 2 —R 8 , —NR 8 —S(O) k —R 9 , —NR 8 —S(O) k —R 9a , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (C 6 -C 10 )aryl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (4-10)-membered heterocyclyl, —(CR 8 R 9 ) v O(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) v O(CR 8 R 9 ) p (C 6 -C 10 )aryl, —(CR 8 R 9 ) v O(CR 8 R 9 ) p (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q S(O) j (CR 8 R 9 ) p (C 6 -C 10 )aryl, or —(CR 8 R 9 ) q S(O) j (CR 8 R 9 ) p (4-10)-membered heterocyclyl; 
 wherein any carbon atoms of each of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 11  are optionally substituted with 1 to 3 R 12  substituents each independently selected from halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —O—(C═O)—R 8 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —NR 8 R 9 , —NR 8 OR 9 , —S(O) k NR 8 R 9 , —S(O) j (C 1 -C 6 )alkyl, —O—SO 2 —R 8 , and —NR 8 —S(O) k —R 9 ; 
 any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , and R 12  are optionally substituted with 1 to 3 R 13  substituents each independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—R 9a , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) p —NR 8 R 9 , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membered heterocyclyl, —(CR 8 R 9 ) p (C═O)(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (C 6 -C 10 )aryl, or —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (4-10)-membered heterocyclyl; 
 each R 8 , R 9 ; and R 10  are independently H or (C 1 -C 6 )alkyl; 
 each R 9a  is independently —(CR 8 R 9 ) o (3-10)-membered cycloalkyl, (CR 8 R 9 ) p (C 6 -C 10 aryl), or —(CR 8 R 9 ) p (4-10)-membered heterocyclyl; 
 p, q, and v are each independently 0, 1, 2, 3, 4, or 5; 
 n and j are each independently 0, 1, or 2; 
 t is 1, 2, 3, or 4; 
 w is 1, 2, or 3, and 
 k is 1 or 2. 
 
     
     
         2 . The compound according to  claim 1 , wherein said compound of formula (I) is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein in each of said compounds (Ia) and (Ib): 
         the dotted lined are optional double bonds; 
         Z 1  is CH or N; 
         Z 2 , Z 3 , Z 4  and Z 5  are each independently C or N; 
         Z 6 , Z 7 , and Z 8  are each independently C, S, O, or N; 
         Wherein R 2  attached to any of Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8  is independently selected from the group consisting of H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 14 , —(C═O)—O—R 14 , —O—(C═O)—R 14 , —NR 14 (C═O)—R 15 , —(C═O)—NR 14 R 15 , —NR 14 R 15 , —NR 14 OR 15 , —S(O) k NR 14 R 15 , —S(O) j R 14 , —O—SO 2 —R 14 , —NR 14 —S(O) k —R 15 , —(CR 14 R 15 ) p (3-10)-membered cycloalkyl, —(CR 14 R 15 ) p (C 6 -C 10 aryl), —(CR 14 R 15 ) p (4-10)-membered heterocyclyl, —(CR 14 R 15 ) q (C═O)(CR 14 R 15 ) p (C 6 -C 10 )aryl, —(CR 14 R 15 ) q (C═O)(CR 14 R 15 ) p (4-10)-membered heterocyclyl, —(CR 14 R 15 ) v O(CR 14 R 15 ) p (C 6 -C 10 )aryl, —(CR 14 R 15 ) v O(CR 14 R 15 ) p (4-10)-membered heterocyclyl, —(CR 14 R 15 ) q S(O) j (CR 14 R 15 ) p (C 6 -C 10 )aryl, and —(CR 14 R 15 ) q S(O) j (CR 14 R 15 ) p (4-10)-membered heterocyclyl; and 
         each of R 14  and R 15  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl. 
       
     
     
         3 . The compound according to  claim 2 , wherein said compound of formula (Ia) is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 2 , wherein said compound of formula (Ib) is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . (canceled) 
     
     
         6 . The compound according to  claim 1 , wherein R 2  is H, halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —(C═O)—R 5 , —(C═O)—NR 6 R 6 , —(CR 6 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q (CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 6 R 6 ) q O(CR 5 R 6 ) v (C 6 -C 10 )aryl, or —(CR 5 R 6 ) q O(CR 5 R 6 ) v (4-10)-membered heterocyclyl. 
     
     
         7 . The compound according to  claim 1 , wherein R 1  is (C 1 -C 6 )alkyl, —(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) v (C 6 -C 10 aryl), or —(CR 3 R 4 ) v (4-10)-membered heterocyclyl. 
     
     
         8 . The compound according to  claim 1 , wherein any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 6  and R 7  are optionally substituted with 1 to 3 R 11  substituents each independently selected from halo, cyano, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —(C═O)—R 8 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —(C═O)—NR 8 R 9a , —NR 8 R 9 , —S(O) j R 8 , —NR 8 —S(O) k —R 9 , —NR 8 —S(O) k —R 9a , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) v (4-1 membered heterocyclyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) p (4-10)-membered heterocyclyl. 
     
     
         9 . The compound according to  claim 1 , wherein any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 11  are optionally substituted with 1 to 3 R 32  substituents each independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, and —NR 8 R 9 . 
     
     
         10 . The compound according to  claim 1 , wherein any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , and R 11  are optionally substituted with 1 to 3 R 13  substituents each independently selected from (C 1 -C 6 )alkyl, —(C═O)—R 8 , —(C═O)—R 9a , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) q —NR 8 R 9 , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, and —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membered heterocyclyl. 
     
     
         11 . The compound according to  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         14 . A method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         15 . A method of treating chronic or acute cardiac failure, cardiac hypertrophy, dilated, hypertrophic or restrictive cardiomyopathy, acute myocardial infarction, post-myocardial infarction, acute or chronic myocarditis, diastolic dysfunction of the left ventricle, systolic dysfunction of the left ventricle, hypertension and nephropathy and nephritis as complications thereof, endothelial dysfunction, arteriosclerosis or post angioplasty restenosis, which comprises administering an effective amount of a compound of  claim 1  to a mammal in need thereof.