NEW INHIBITORS OF THE FARNESIL PROTEINA TRANSFERASA AS ANTITUMOR AGENTS.

摘要

A compound of formula ** see formula ** and its pharmaceutically acceptable salts or solvates, where: R 1 is selected from the group consisting of: ** see formula ** n is 1 to 6; X is selected from the group consisting of O, S, and N; R 2, R 3, R 4, and R 5 are independently selected from the group consisting of: H, Br, Cl, and F; R 5A is selected from the group consisting of a H, a C1 to C6 alkyl group, and a C3 to C6 cycloalkyl group; R 6 and R 7, for each n, are independently selected from the group consisting of: (1) H, (2) C 1 to C 4 alkyl, and (3) a C 3 to C 7 cycloalkyl ring formed by taking R 6 and R 7 together with the carbon atom to which they are attached; R 8 is selected from the group consisting of: R 9 is selected from the group consisting of: a C 1 to C 6 alkyl group, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, and heteroalkyl; or R 9 is selected from the group consisting of: a C1 to C6 alkyl group, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, and heteroalkyl; wherein (1) said cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyl, and heteroalkyl R 9 groups are substituted with 1 to 3 substituents independently selected from the group consisting of: -OH, halo, alkyl, cycloalkyl, -NH 2, -NH (C 1 to C 6 alkyl), -N (C1 to C6 alkyl) 2 where each alkyl group is independently selected, alkoxy, and -CO2R 14 where R 14 is selected from the group consisting of: H and alkyl, provided that the carbon atom, by means of which said group R 9 is attached is attached to the substituent X, is not substituted with a group -OH, -NH2, -NH (C1 to C6 alkyl) or -N (C1 to C6 alkyl ) 2 group; and (2) said C 1 to C 6 alkyl group R 9 is substituted with 1 to 3 substituents independently selected from the group consisting of: -OH, halo, cycloalkyl, -NH 2, -NH (C 1 to C 6 alkyl) , -N (C 1 to C6 alkyl) 2 where each alkyl group is independently selected, alkoxy, and -CO2R 14 where R 14 is selected from the group consisting of: H and alkyl; provided that the carbon atom, by means of which said group R 9 is attached to the substituent X, is not substituted with a group -OH, -NH2, -NH (C1 to C6 alkyl) or -N (C1 to C6 alkyl) 2; R 10 is selected from the group consisting of: cycloalkyl, heterocycloalkyl, cycloalkyl-alkyl, heterocycloalkylalkyl, and heteroalkyl; or R 10 is selected from the group consisting of: cycloalkyl, heterocycloalkyl, cycloalkyl-alkyl, heterocycloalkylalkyl, and heteroalkyl; wherein said R 10 groups are substituted with 1 to 3 substituents independently selected from the group consisting of: -OH, halo, alkyl, cycloalkyl, -NH2, -NH (C1 to C6 alkyl), -N (C1 to C6 alkyl ) 2 where each alkyl group is independently selected, alkoxy, and -CO 2R 14 where R 14 is selected from the group consisting of: H and alkyl; R 11 is selected from the group consisting of: (1) alkyl (2) substituted alkyl, (3) unsubstituted cycloalkyl, (4) substituted cycloalkyl, (5) heterocycloalkyl, and (6) substituted heterocycloalkyl; wherein said substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl groups R 11 are substituted with one or more substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one group -OH each group -OH is attached to a different carbon atom, (2) fluorine, and (3) alkyl; R 11a is selected from the group consisting of: (1) alkyl, (1) substituted alkyl, (3) aryl, and (4) substituted aryl; wherein said R 11a substituted alkyl groups are substituted with one or more substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one -OH group each -OH group is attached to a different carbon atom , (2) -CN, (3) -CF 3, (4) fluorine, (5) alkyl, (6) cycloalkyl, (7) heterocycloalkyl, (8) arylalkyl, (9) heteroarylalkyl, (10) alkenyl and ( 11) heteroalkenyl; and wherein said R 11a substituted aryl groups have one or more substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one -OH group each -OH group is attached to a different carbon atom, (2) -CN, (3) -CF3, (4) halogen, (5) alkyl, (6) cycloalkyl, (7) heterocycloalkyl, (8) arylalkyl, (9) heteroarylalkyl, (10) alkenyl, and (11 ) heteroalkenyl; R 12 is selected from the group consisting of: H and alkyl; R 21, R 22 and R 46 are independently selected from the group consisting of: (1) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl), and (2) -OH provided that only one group of R 21, R 22, and R 48 is -OH, or R 21 and R 22 taken together with the carbon to which they are attached form a cyclic ring selected from the group consisting of: (1) non-substituted aryl, (2 ) aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, -CN, -CF3, OH and alkoxy, and (3) heteroaryl selected from the group consisting of: ** see formula **