Heterocyclic Compounds and Methods For Their Use

Abstract

The present invention relates to heterocyclic compounds useful for antagonizing angiotensin II Type 2 (AT 2 ) receptor. More particularly the invention relates to piperazine and diazepine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT 2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X is —CHR 4 —, —CH 2 CHR 4 — or —C(═O)—; 
         R 1  is —C(═O)CHR 5 R 6 , —C(═O)NR 5 R 6 , —C(═O)CH 2 CHR 5 R 6 , —C(═O)CH═CR 5 R 6 , —C(═S)CHR 5 R 6 , —C(═S)NR 5 R 6 , —C(═S)CH 2 CHR 5 R 6 , —C(═S)CH═CR 5 R 6 , —C(═NR 7 )CHR 5 R 6 , —C(═NR 7 )NR 5 R 6 , —C(═NR 7 )CH 2 CHR 5 R 6  or —C(═NR 7 )CH═CR 5 R 6 ; 
         R 2  is —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C(═O)R 8 , —C(═O)NHR 7 , —SO 2 N(R 7 ) 2 , —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl, —W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl, —W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl; 
         R 3  is a carboxylic acid, —CH 2 CO 2 H, —C(═O)C(═O)OH, —C(═O)NH 2 , —CH 2 C(═O)NH 2 , —CN, —CH 2 CN, a carboxylic acid bioisostere or a —CH 2 -carboxylic acid bioisotere; 
         R 4  is hydrogen or together with R 2  forms a fused cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionally substituted with one or two substituents selected from —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —C 1-6 alkyleneR 9 , —C 2-6 alkenyleneR 9 , —C 2-6 alkynyleneR 9 , —OC 0-6 alkyleneR 9 , —OC 2-6 alkenyleneR 9 , —OC 2-6 alkynyleneR 9 , —C(═O)C 0-6 alkyleneR 9 , —C(═O)C 2-6 alkenyleneR 9 , —C(═O)C 2-6 alkynyleneR 9 , —C(═O)OC 0-6 alkyleneR 9 , —C(═O)OC 2-6 alkenyleneR 9 , —C(═O)OC 2-6 alkynyleneR 9 , —SO 2 NHC 0-6 alkyleneR 9 , —SO 2 NHC 2-6 alkenyleneR 9 , —SO 2 NHC 2-6 alkynyleneR 9 , —NHSO 2 C 0-6 alkyleneR 9 , —NHSO 2 C 2-6 alkenyleneR 9 , —NHSO 2 C 2-6 alkynyleneR 9 , —NH(═O)NHR 10 , —NHC(═O)OR 10  or —CH(OH)CH(OH)R 10 ; 
         R 5  and R 6  are independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —CH 2 cycloalkyl, —CH 2 cycloalkenyl, —CH 2 aryl, —CH 2 heterocyclyl and —CH 2 heteroaryl; provided that both R 5  and R 6  are not hydrogen; 
         R 7  is hydrogen, —C 1-6 alkyl, aryl or —C 1-6 alkylenearyl; 
         R 8  is —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl or —C 2-6 alkylenearyl; 
         R 9  is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl; 
         R 10  is —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl; 
         W is a covalent bond, —SO—, —SO 2 — —C(═O)—, —C(═O)N(H)—, —C 1-4 alkylene-, —C 2-4 alkenylene-, —C 2-4 alkynylene-, —C 1-3 alkyleneQC 1-3 alkylene-, —C 1-4 alkyleneQ-, —C 2-4 alkenyleneQ- or —C 2-4 alkynyleneQ-; 
         Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or -heteroaryl-; 
         Y is a covalent bond, —O—, —S—, —SO—, —SO 2 — —N(R 7 )—, —C(═O)—, —N(R 7 )C(═O)—, —C(═O)N(R 7 )—, —C 1-3 alkylene-, —C 2-3 alkenylene-, —C 2-3 alkynylene-, —C 1-3 alkyleneQC 1-3 alkylene-, -QC 1-4 alkylene-, -QC 2-4 alkenylene-, -QC 2-4 alkynylene-, —C 1-4 alkyleneQ-, —C 2-4 alkenyleneQ-, —C 2-4 alkynyleneQ- -QC 1-4 alkyleneQ-, -QC 2-4 alkenyleneQ- or -QC 2-4 alkynyleneQ-; and Q is —O—, —S—, —SO—, —SO 2 — —N(R 7 )—, —C(═O)—, —N(R 7 )C(═O)— or —C(═O)N(R 7 )—; 
         wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein X is —CH 2 — or —CH 2 CH 2 —. 
     
     
         3 . A compound according to  claim 2  wherein X is —CH 2 —. 
     
     
         4 . A compound according to  claim 1  wherein
 R 1  is —C(═O)CH(aryl)(aryl), —C(═O)CH(aryl)(cycloalkyl), —C(═O)CH(cycloalkyl)(cycloalkyl), —C(═O)N(aryl)(aryl), —C(═O)N(aryl)(cycloalkyl) or —C(═O)N(cycloalkyl)(cycloalkyl) wherein each aryl or cycloalkyl is optionally substituted with one or more substituents selected from —C 1-3 alkyl, —OC 1-3 alkyl and halo. 
 
     
     
         5 . A compound according to  claim 4  wherein R 1  is —C(═O)CH(phenyl)(phenyl), —C(═O)CH (phenyl)(cyclohexyl), —C(═O)CH(cyclohexyl)(cyclohexyl), —C(═O)N (phenyl)(phenyl), —C(═O)N(phenyl)(cyclohexyl) or —C(═O)N(cyclohexyl)(cyclohexyl) wherein each phenyl or cyclohexyl is optionally substituted with one or more substituents selected from —C 1-3 alkyl, —OC 1-3 alkyl and halo. 
     
     
         6 . A compound according to  claim 1  wherein R 2  is —C 1-6 alkyl, —C 2-6 alkenyl cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, heterocyclylaryl, —C 1-4 alkylenecycloalkyl, —C 1-4  alkylenecycloalkenyl, —C 1-4 alkylenearyl, —C 1-4 alkyleneheterocyclyl, —C 1-4 alkylenehetero aryl, —C 2-4 alkenylenecycloalkyl, —C 2-4 alkenylenecycloalkenyl, —C 2-4 alkenylenearyl, —C 2-4 alkenyleneheterocyclyl, —C 2-4 alkenyleneheteroaryl, —C 2-4 alkynylenecycloalkyl, —C 2-4 alkynylenecycloalkenyl, —C 2-4 alkynylenearyl, —C 2-4 alkynyleneheterocyclyl, —C 2-4 alkynyleneheteroaryl heterocyclylaryl, heteroarylaryl heterocyclylC 1-3 alkylenearyl, —C 1-3 alkyleneheterocyclylaryl, —C 1-3 alkyleneheteroarylaryl, —CH 2 C(═O)NHCH 2 cycloalkyl, —CH 2 C(═O)NHCH 2 cycloalkenyl, —CH 2 C(═O)NHCH 2 aryl, —CH 2 C(═O)NHCH 2 heterocyclyl, —CH 2 C(═O)NHCH 2 hetero aryl, —C(═O)NHC 1-3 alkylenecycloalkyl, —C(═O)NHC 1-3 alkylenecycloalkenyl, —C(═O)NHC 1-3 alkylenearyl, —C(═O)NHC 1-3 alkyleneheterocyclyl, —C(═O)NHC 1-3 alkyleneheteroaryl, —CH 2 SO 2 C 1-3 alkylenecycloalkyl, —CH 2 SO 2 C 1-3 alkylenecycloalkenyl, —CH 2 SO 2 C 1-3 alkylenearyl, —CH 2 SO 2 C 1-3 alkyleneheterocyclyl, —CH 2 SO 2 C 1-3 alkyleneheteroaryl, —CH 2 OC 1-3 alkylenecycloalkyl, —CH 2 OC 1-3 alkylenecycloalkenyl, —CH 2 OC 1-3 alkylenearyl, —CH 2 OC 1-3 alkyleneheterocyclyl or —CH 2 OC 1-3 alkyleneheteroaryl;
 wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one or two substituents. 
 
     
     
         7 . A compound according to  claim 6  wherein R 2  is phenyl, benzyl, —CH 2 CH 2 phenyl, —CH 2 CH═CH-phenyl, —CH 2 C≡C-phenyl, —CH 2 C≡C-4-fluorophenyl, —CH 2 CH 2 C≡C-phenyl, —CH 2 CH 2 C≡C-4-fluorophenyl, —CH 2 CH 2 CH 2 phenyl 2-methylbutyl 5-(3-methyl-1-phenylpyrazole) 3-(1,5-diphenylpyrazole) 3-(5-phenylpyrazole) 3-(5-methyl-1-phenylpyrazole), 3-(5-(1-methylethyl)-1-phenylpyrazole 2-(5-phenyloxazole) 5-(5-benzyloxazole) 5-(1-benzyl-3-methylpyrazole) 3-(1-benzyl-5-methylpyrazole, —CH 2 -4-(2-phenyloxazole) 5-(1-benzyl)-3-trifluoromethylpyrazole and -5-(1-benzyl-3-methylpyrazole, wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted. 
     
     
         8 . A compound according to  claim 1  wherein R 3  is —CO 2 H, —CH 2 CO 2 H, —C(═O)NH 2 , —CN, —C(═O)C(═O)OH, —C(═O)NHSO 2 C 1-6 alkyl, —C(═O)NHSO 2 phenyl, —C(O)NHSO 2 N(CH 3 ) 2 , —C(═O)NHSO 2 CF 3 —SO 3 H or —PO 3 H 2 . 
     
     
         9 . A compound according to  claim 8  wherein R 3  is —CO 2 H. 
     
     
         10 . A compound according to  claim 1  wherein R 4  is H. 
     
     
         11 . A compound according to  claim 1  wherein R 2  and R 4  together form a fused aryl, heterocyclyl or heteroaryl ring optionally substituted with one or two substituents selected from -aryl, —C 1-3 alkylenearyl Oaryl, —OC 1-3 alkylenearyl and —C(═O)OC 1-3 alkylenearyl. 
     
     
         12 . A compound according to  claim 11  wherein R 2  and R 4  together form a fused heterocyclyl or heteroaryl ring optionally substituted with phenyl, benzyl Obenzyl, or —CO 2 benzyl. 
     
     
         13 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of treating or preventing neuropathic pain or inflammatory pain in a subject comprising administering a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method of treating or preventing a condition characterized by neuronal hypersensitivity, impaired nerve conduction velocity, a cell proliferative disorder, a disorder associated with an imbalance between bone resorption and bone formation or a disorder associated with aberrant nerve regeneration in a subject comprising administering a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method of producing analgesia in a subject comprising administering a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled)