Substituted benzocycloheptapyridine useful as inhibitors of farnesyl-protein transferase

摘要

The compounds of formula (1.0) are inhibitors of the enzyme, farnesyl protein transferase, and may be used to inhibit the abnormal growth of cells in humans. In formula (1.0): one of a, b, c and d represents N or NR9, wherein R9 is O, CH3 or (CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or each of a, b, c and d are independently selected from CR1 or CR2; R1 and R2 are independently selected from H, halo, CF3, OR10, COR10, SR10, S(O)tR11 (wherein t is 0, 1 or 2), SCN, N(R10)2, NR10R11, NO2, OC(O)R10, CO2R10, OCO2R11, CN, NHC(O)R10, NHSO2R10, CONHR10, CONHCH2CH2OH, NR10COOR11, SR11C(O)OR11, SR11N(R75)2; wherein each R75 is independently selected from H and C(O)OR11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, OR10 or CO2R10; R3 and R4 are the same or different selected from H, any of the substituents of R1 and R2; or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring, to ring III; R5 and R6 (y=0) or R5, R6 and R7 (y=1) each independently represents H, CF3, COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with OR10, SR10, S(O)tR11, NR10COOR11, N(R10)2, NO2, COR10, OCOR10, OCO2R11, CO2R10, OPO3R10; or one of R5, R6 and R7 can be taken in combination with R40 as defined below to represent (CH2)r wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, CF3 or aryl; or R5 is combined with R6 or R7 to represent =0 or =S; R10 independently represents H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl or NR40R42 wherein R40 and R42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; R11 represents alkyl or aryl; the dotted line represents an optional double bond, such that when a double bond is present, A and B independently represent NO2, R10, halo, OR11, OCO2R11 or OC(O)R10; and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, (OR11)2, H and halo, dihalo, alkyl and H, (alkyl)2, H and OC(O)R10, H and OR10, oxy, aryl and H, =NOR10 or O-(CH2)p-O wherein p is 2, 3 or 4; y is 0 or 1; n is 0 to 6; T is CO; SO; SO2; or CR30R31 wherein R30 and R31 independently represent H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; and Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, OR40, SR40, CR40R42, NR40R42, or other group depicted above.