Patent ID: 6107329
Filing Date: 2000-08-22
Classification: C07D

Abstract:
A compound of Formula I ##STR4## and the pharmaceutically acceptable salts and prodrugs thereof wherein the dotted line (---) is an optional bond;A is --C(H).dbd., --C((C.sub.1 -C.sub.4)alkyl).dbd., --C(halo).dbd.or --N.dbd., when the dotted line (---) is a bond, or A is methylene or --CH((C.sub.1 -C.sub.4)alkyl)-, when the dotted line (---) is not a bond;R.sub.1, R.sub.10 or R.sub.11 are each independently H, halo, cyano, 4-, 6-, or 7-nitro, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl;R.sub.2 is H;R.sub.3 is H or (C.sub.1 -C.sub.5) alkyl;R.sub.4 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.4) alkyl, phenylhydroxy(C.sub.1 -C.sub.4) alkyl, (phenyl) ((C.sub.1 -C.sub.4)-alkoxy) (C.sub.1 -C.sub.4)alkyl, thien-2- or -3-yl(C.sub.1 -C.sub.4)alkyl or fur-2- or -3-yl(C.sub.1 -C.sub.4)alkyl wherein said R.sub.4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; orR.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1 -C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1 -C.sub.4)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1 -C.sub.4)alkyl, pyridazin-3- or -4-yl(C.sub.1 -C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl (C.sub.1 -C.sub.4)alkyl, pyrazin-2- or -3-yl (C.sub.1 -C.sub.4)alkyl, 1,3,5-triazin-2-yl(C.sub.1 -C.sub.4)alkyl or indol-2-(C.sub.1 -C.sub.4)alkyl, wherein said preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, amino, hydroxy or cyano and said substituents are bonded to carbon; orR.sub.4 is R.sub.15 -carbonyloxymethyl, wherein said R.sub.15 is phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein said preceding R.sub.15 rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or trifluoromethyl and said mono- or di-substituents are bonded to carbon;R.sub.5 is H;R.sub.6 is carboxy, (C.sub.1 -C.sub.8)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR.sub.8 R.sub.9 or C(O)R.sub.12whereinR.sub.8 is H, (C.sub.1 -C.sub.6)alkyl, cyclo (C.sub.3 -C.sub.6) alkyl, cyclo (C.sub.3 -C.sub.6)alkyl (C.sub.1 -C.sub.5)alkyl, hydroxy or (C.sub.1 -C.sub.8)alkoxy; andR.sub.9 is H, cyclo (C.sub.3 -C.sub.8)alkyl, cyclo (C.sub.3 -C.sub.8)alkyl (C.sub.1 -C.sub.5)alkyl, cyclo (C.sub.4 -C.sub.7)alkenyl, cyclo (C.sub.3 -C.sub.7)alkyl(C.sub.1 -Cs)alkoxy, cyclo (C.sub.3 -C.sub.7)alkyloxy, hydroxy, methylene-perfluorinated(C.sub.1 -C.sub.8)alkyl, phenyl, or a heterocycle wherein said heterocycle is pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein said heterocycle rings are carbon-nitrogen linked; orR.sub.9 is (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.8)alkoxy wherein said (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.8)alkoxy is optionally monosubstituted with cyclo (C.sub.4 -C.sub.7)alken-1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl or indolyl and wherein said (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.8)alkoxy are optionally additionally independently mono- or di-substituted with halo, hydroxy, (C.sub.1 -C.sub.5)alkoxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, cyano, carboxy, or (C.sub.1 -C.sub.4)alkoxycarbonyl; andwherein the R.sub.9 rings are optionally mono- or di-substituted independently on carbon with halo, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, hydroxy, hydroxy(C.sub.1 -C.sub.4)alkyl, amino(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino, cyano, carboxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and said R.sub.9 rings may optionally be additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl or halo;with the proviso that no quaternized nitrogen on any R.sub.9 heterocycle is included;R.sub.12 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro- benzo[c][1,2]oxazin-1-yl, 1,4-dihydro-benzo[d][1,2]oxazin-3-yl, 3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl, 3H-benzo[c]isoxazol-1-yl or azepan-1-yl,wherein said R.sub.12 rings are optionally mono-, di- or tri-substituted independently with halo, (C.sub.1 -C.sub.5)alkyl, (C.sub.1 -C.sub.5)alkoxy, hydroxy, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5)alkylcarbamoyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.3)alkoxy, (C.sub.1 -C.sub.5)alkoxycarbonyl, benzyloxycarbonyl, (C.sub.1 -C.sub.5) alkoxycarbonyl (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.4) alkoxycarbonylamino, carboxy(C.sub.1 -C.sub.5)alkyl, carbamoyl(C.sub.1 -C.sub.5)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.5) alkylcarbamoyl(C.sub.1 -C.sub.5) alkyl, hydroxy(C.sub.3 -C.sub.5)alkyl, (C.sub.1 -C.sub.4) alkoxy(C.sub.1 -C.sub.4)alkyl, amino(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and wherein no more than two substituents are selected from oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino and oxo, hydroxyimino or (C.sub.1 -C.sub.6)alkoxyimino are on nonaromatic carbon; andwherein said R.sub.12 rings are optionally additionally mono- or di-substituted independently with (C.sub.1 -C.sub.5)alkyl or halo;with the proviso that when R.sub.6 is (C.sub.1 -C.sub.5)alkoxycarbonyl or benzyloxycarbonyl then R.sub.1 is 5-halo, 5-(C.sub.1 -C.sub.4)alkyl or 5-cyano and R.sub.4 is (phenyl) (hydroxy) (C.sub.1 -C.sub.4)alkyl, (phenyl)((C.sub.1 -C.sub.4)alkoxy) (C.sub.1 -C.sub.4)alkyl, hydroxymethyl or Ar(C.sub.1 -C.sub.2)alkyl, wherein Ar is thien-2- or -3-yl, fur-2- or -3-yl or phenyl wherein said Ar is optionally mono- or di-substituted independently with halo;with the proviso that when R.sub.1 and R.sub.10 and R.sub.11 are H, R.sub.4 is not imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl;with the proviso that when both R.sub.8 and R.sub.9 are n-pentyl, R.sub.1 is 5-chloro, 5-bromo, 5-cyano, 5(C.sub.1 -C.sub.5)alkyl, 5(C.sub.1 -C.sub.5)alkoxy or trifluoromethyl;with the proviso that when R.sub.12 is 3,4-dihydroisoquinol-2-yl, said 3,4-dihydroisoquinol-2-yl is not substituted with carboxy((C.sub.1 -C.sub.4)alkyl;with the proviso that when R.sub.8 is H and R.sub.9 is (C.sub.1 -C.sub.6) alkyl, R.sub.9 is not substituted with carboxy or (C.sub.1 -C.sub.4)alkoxycarbonyl on the carbon which is attached to the nitrogen atom N of NHR.sub.9 ; andwith the proviso that when R.sub.6 is carboxy and R.sub.1, R.sub.10, R.sub.11, and R.sub.5 are all H, then R.sub.4 is not benzyl, H, (phenyl) (hydroxy)methyl, methyl, ethyl or n-propyl.