SUBSTITUTED TRICYCLIC COMPOUNDS

摘要

1. A compound of the formula (I) wherein; Z is cyclohexenyl, or phenyl, R<20> is benzyl, optionally substituted with one or two substituents selected from the group: halogen, lower alkyl, phenoxy, benzyl, -OCF3, or pyridylmethyl, cyclohexylmethyl, cyclopentylmethyl, naphthylmethyl; R<21> is CF3 phenyl; R<1> is -NHNH2, -NH2, or -CONH2; R<2>' is selected from the group consisting of -OH, and -O(CH2)tR<5>' where R<5>' is H, -CN, -NH2, -CONH2, -CONR<9>R<10> -NHSO2R<15>; -CONHSO2R<15>, where R<15> is -(C1-C6)alkyl or -CF3; phenyl or phenyl substituted with -CO2H or -CO2(C1-C4)alkyl; and -(La)-(acidic group), wherein -(La)- is an acid linker having an acid linker length of 1 to 7 and t is 1-5; R<3>' is selected from above-mentioned non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof. 2. A compound of the formula (II) wherein; Z is cyclohexenyl, or phenyl; R<21> is CF3 phenyl; R<1> is -NHNH2 or -NH2; R<2> is selected from the group consisting of -OH and -O(CH2)m R<5> where R<5> is H, -CO2H, -CONH2, -CO2(C1-C4 alkyl); -P(O)(R<6>R<7>), where R<6> and R<7> are each independently -OH or -O(C1-C4)alkyl; -SO3H, -SO3(C1-C4 alkyl), tetrazolyl, -CN, -NH2, -NHSO2R<15>; -CONHSO2R<15>, where R<15> is -(C1-C6)alkyl or -CF3, phenyl or phenyl substituted with -CO2H or -CO2(C1-C4)alkyl wherein m is 1-3; R<3> is H, -O(C1-C4)alkyl, halo, -(C1-C6)alkyl, phenyl, -(C1-C4)alkylphenyl; phenyl substituted with -(C1-C6)alkyl, halo, or -CF3; -CH2OSi(C1-C6)alkyl, furyl, thiophenyl, (C1-C6)hydroxyalkyl; or -(CH2)nR<8> where R<8> is H, -CONH2, -NR<9>R<10>, -CN or phenyl where R<9> and R<10> are independently -(C1-C4)alkyl or -phenyl(C1-C4)alkyl and n is 1 to 8; R<4> is H, -(C5-C14)alkyl, -(C3-C14)cycloalkyl, pyridyl, phenyl or phenyl substituted with -(C1-C6)alkyl, halo, -CF3, -OCF3, -(C1-C4)alkoxy, -CN, -(C1-C4)alkylthio, -phenyl(C1-C4)alkyl, -(C1-C4)alkylphenyl, phenyl, phenoxy or naphthyl; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof. 3. A compound of formula (II) as claimed in Claim 2 wherein R<1> is-NH2; and Z is phenyl. 4. A compound as claimed in any one of Claims 2 or 3, wherein R<5> is H, NH2, -CONH2, -SO3H, -SO3(C1-C4 alkyl), tetrazolyl, -CN, -NH2, -NHSO2R<15>; -CONHSO2R<15>, where R<15> is -(C1-C6)alkyl or -CF3, phenyl or phenyl substituted with -CO2H or -CO2(C1-C4)alkyl. 5. A compound of formula (II) as claimed in any one of Claims 2-4 wherein R<3> is halo, -(C1-C6) alkyl, phenyl, -(C1-C4)alkylphenyl; phenyl substituted with -(C1-C4)alkyl, halo, or -CF3; -CH2OSi(C1-C6)alkyl, furyl, thiophenyl or (C1-C6)hydroxy alkyl. 6. A compound of formula (II) as claimed in any one of Claims 2-5 wherein R<4> is pyridyl, phenyl substituted with (C5-C6) alkyl, -CF3, -OCF3, -CN, -(C1-C4)alkylphenyl, phenoxy or naphthyl. 7. A compound of formula (II) as claimed in any one of Claims 2-6 wherein R<4> is hydrogen. 8. A compound of formula (II) as claimed in any one of Claims 2-7 wherein R<1> is -NH2 and R<2> is -O(CH2)mR<5> where R<5> is -H, -CO2H or, -P(O)(R<6>R<7>), where R<6> and R<7> are -OH. 9. A compound of formula (II) as claimed in any one of Claims 2-7 where R<2> is -O(CH2)mR<5> where R<5> is -H, -CO2(C1-C4 alkyl), phenyl or phenyl substituted with -CO2H or -CO2(C1-C4 alkyl). 10. A compound of formula (II) as claimed in any one of Claims 2-7 wherein R<2> is -O(CH2)m R<5> where R<5> is -P(O)(R<6>R<7>), and R<6> and R<7> are -O(C1-C4 alkyl), or when one of R<6> and R<7> is -O(C1-C4 alkyl), the other is -OH. 11. A compound of formula (II) as claimed in any one of Claims 2-10 where R<3> is -H, -O(C1-C4 alkyl) or -(CH2)nR<8> where n = 2 and R<8> is H or phenyl. 12. A compound of formula (II) as claimed in any one of Claims 2-10 where R<3> is H, or -O(C1-C4 alkyl). 13. A compound of formula (II) as claimed in any one of Claims 2-10 where R<3> is -(CH2)n R<8> where R<8> is -NR<9>R<10>, -C(O)NH2 or -CN where R<9> and R<10> are -(C1-C4)alkyl. 14. A compound of formula (II) as claimed in any one of Claims 2-13 where R<4> is phenyl. 15. A compound of formula (II) as claimed in any one of Claims 2-13 where R<4> is phenyl substituted at the 2- and 6- position of the phenyl ring with -(C1-C4)alkyl, -(C1-C4)alkoxy, halo or phenyl. 16. A compound of formula (II) as claimed in any one of Claims 2-13 where R<4> is phenyl substituted at the 3- or 5-position of the phenyl ring with -(C1-C4)alkyl, -(C1-C4)alkoxy, halo or phenyl. 17. A compound of formula (II) as claimed in any one of Claims 2-13 where R<4> is -(C6-C14)alkyl or -(C6-C14)cycloalkyl. 18. A compound of formula (II) as claimed in any one of Claims 2-17 where R<5> is H, -CO2H, -CO2(C1-C4 alkyl), -P(O)(R<6>R<7>), -NHSO2(C1-C6)alkyl, -CONHSO2(C1-C6)alkyl, tetrazolyl, phenyl, or phenyl substituted with -CO2H or -CO2(C1-C4 alkyl) where R<6> and R<7> are each independently -OH or -O(C1-C4 alkyl) and m is 1-3; 19. A compound of formula (II) as claimed in any one of Claims 2-18 where R<5> is H, -CO2H, -CO2(C1-C4 alkyl), -P(O)(R<6>R<7>), phenyl, or phenyl substituted with -CO2H or -CO2(C1-C4 alkyl) where R<6> and R<7> are each independently -OH or -O(C1-C4 alkyl) and m is 1-3. 20. A compound of formula (II) as claimed in any one of Claims 2-17 where R<5> is H, -CO2H, -CO2(C1-C4 alkyl); -P(O)(R<6>R<7>), where R<6> and R<7> are each independently -OH or -O(C1-C4)alkyl; -SO3H, -SO3(C1-C4 alkyl), tetrazolyl, -CN, -NH2, -NHSO2R<15>; -CONHSO2R<15>, where R<15> is -(C1-C6)alkyl or -CF3, phenyl or phenyl substituted with -CO2H or -CO2(C1-C9)alkyl where m is 1-3. 21. A compound of formula (II) as claimed in any one of Claims 2-20 where Z is cyclohexenyl. 22. A compound of formula (II) as claimed in any one of Claims 2-20 where Z is phenyl. 23. A compound as claimed in any one of Claims 2-22 which is selected from the group consisting of; 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid sodium salt; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; methyl ether [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-(1H-tetrazol-5-yl-methyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide; {9-benzyl-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid; {9-(3-fluorobenzyl)-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid; {9-(3-methylbenzyl)-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid; {9-benzyl-5-carbamoyl-2-(4-trifluoromethylphenyl)-carbazol-4-yl}oxyacetic acid; 9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide; 9-benzyl-4-(2-trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide; 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide; [5-carbamoyl-2-pentyl-9-benzylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(1-methylethyl)-9-benzylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-benzyl-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-phenyl-9-benzylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(4-chlorophenyl)-9-benzylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(2-furyl)-9-benzylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-benzyl-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid lithium salt; {9-[(2-fluorophenyl-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid; {9-[(2-pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-chloro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [5-carbamoyl-9-(benzyl)-2-[[(propen-3-yl)oxy]methyl]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(benzyl)-2-[(propyloxy)methyl]carbazol-4-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxycarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl)oxy)carbazole-4-carboxamide; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)carbazole-4-carboxamide; and [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or