Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase

摘要

A compound of formula V ** Formula ** in which R is selected from the group consisting of H, C1 to C5 alkyl, C1 to C3 alkoxy, and hydroxy; wherein R1, R2, R3, R4, are independently selected from the group consisting of hydrogen, and C1 to C5 alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, arylalkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxyalkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylarylcarbonyl, aryl , haloalkylcarbonyl, and cyanoalkylcarbonyl; wherein A and B are each independently selected from the group consisting of hydrogen, C1 to C5 alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl, carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, lower alkylsulfinyl, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, and aryloxyalkoxy, in which the substituents phenyl, phenoxy, arylalkoxy may optionally be substituted thereto halogen, lower haloalkyl, lower alkyl, lower alkoxy, or lower alkylsulfonyl, wherein "lower" used in conjunction with any of the above groups means C1 to C6 alkyl; wherein one of V and W is a methoxy group and the other is selected from the group consisting of hydrogen, C1 to C5 alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl, carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, lower alkylsulfinyl, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, and aryloxyalkoxy, in which the phenyloxy, aryloxy and aryloxy substituents they themselves are independently optionally substituted one or more times with halogen, lower haloalkyl, lower alkyl, lower alkoxy, or lower alkylsulfonyl, in which "lower" used in conjunction with any of the above groups means C1 to C6, in which two from J, L and M, are selected from the group consisting of hydrogen, C1 to C5 alkyl, halogen, hydroxy, haloal lower chyl, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl, carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, lower alkylsulfinyl, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonylo, phenyloxyloxy, aryloxyloxy, phenyloxy, , and aryloxyalkoxy, in which the phenyl, phenoxy, arylalkoxy and aryloxyalkoxy substituents may themselves be independently optionally substituted one or more times with halogen, lower haloalkyl, lower alkyl, lower alkoxy, or lower alkylsulfonyl, in which "lower" used jointly with any of the above groups means C1 to C6, and in which (a) the other of J, L and M is a substituent selected from the group consisting of piperidine, perhydropyrimidine, morpholine, pyridine, pyrimidine, indole, isoindole , quinoline, isoquinoline, oxazole, thiazole, and imidazole, in which piperidine itself, perhydrop Irimidine, morpholine, pyridine, pyrimidine, indole, isoindole, quinoline, isoquinoline, oxazole, thiazole, or imidazole may be optionally substituted one or more times with C1 to C5 alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, alkoxyalkyl lower, carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, lower alkylsulfinyl, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, or aryloxy-substituted phenyloxy , phenoxy, arylalkoxy or aryloxyalkoxy can themselves be independently optionally substituted one or more times with halogen, lower haloalkyl, lower alkyl, lower alkoxy or lower alkylsulfonyl, wherein "lower" used in conjunction with any of the above groups means C1 to C6, or (b) the other of J, L, and M is selected from the group q which consists of the VIA formula and VIB formula ** Formula ** in which at least one of R32, R33, R34, R35 and R36 is N and any of R32, R33, R34, R35 and R36 other than N is CRx, wherein for each of R32, R33, R34, R35 and R36 other than N, Rx is independently selected from hydrogen, C1 to C5 alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl, carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, lower alkylsulfinyl, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, and aryloxyalkoxy phenyloxy , arylalkoxy and aryloxyalkoxy can themselves be independently optionally substituted one or more times with halogen, lower haloalkyl, lower alkyl, lower alkoxy or lower alkylsulfonyl, in which "lower" used co together with any of the above groups means C1 to C6; wherein R37 is O, NH or NCH3; wherein R38 is N or CH, and when R38 is CH, R37 is NH or NCH3; and wherein R39 and R40 independently are hydrogen or CH3 and pharmaceutically acceptable salts thereof.