Inhibitors of farnesyl-protein transferase
First Claim
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1. A compound represented by formula I:
- ##STR8## or a pharmaceutically acceptable salt thereof, wherein;
R1a, R1b and R2 are independently selected from the group consisting of;
hydrogen, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R8 O--, R9 S(O)m --, (R8)2 NC(O)--, R8 C(O)NR8 --, CN, NO2, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2, R9 OC(O)NR8 -- and C1 -C6 alkyl, unsubstituted or substituted by 1-3 groups selected from the group consisting of;
halo, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2 and R9 OC(O)NR8 --;
R3 and R4 are independently selected from the group consisting of;
H, F, Cl, Br, --NR82, CF3, NO2, R8 O--, R9 S(O)m --, (R8)2 NC(O)--, R8 C(O)NH--, H2 NC(NH)--, R8 C(O)--, R8 OC(O)--, N3, CN, R9 OC(O)NR8 --, C1 -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
A3 is selected from;
--NR5 S(O)m -- or --S(O)m NR5 --, with m equal to 0, 1 or 2, and R5 selected from the group consisting of;
hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3 -C10 cycloalkyl, and C1 -C6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of;
unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3 -C10 cycloalkyl, --N(R8)2, --CF3, --NO2, (R8)O--, (R9)S(O)m --, (R8)C(O)NH--, H2 NC(NH)--, (R8)C(O)--, (R8)OC(O)--, N3, CN and (R9)OC(O)NR8 --;
R6 and R7 are independently selected from the group consisting of;
hydrogen, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1-6 perfluoroalkyl, F, Cl, Br, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, NO2, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2, R9 OC(O)NR8 -- and C1 -C6 alkyl unsubstituted or substituted by 1-3 groups selected from;
aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2 and R9 OC(O)NR8 --;
each R8 is independently selected from hydrogen, C1 -C6 alkyl, aryl and aralkyl;
each R9 is independently selected from C1 -C6 alkyl and aryl;
A1 and A2 are independently selected from the group consisting of;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR8 --, --NR8 C(O)--, --O--, --N(R8)--, --S(O)2 N(R8)--, --N(R8)S(O)2 --, and S(O)m ;
X represents aryl or heteroaryl;
V is selected from the group consisting of;
hydrogen, heterocyclyl, aryl, C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2 -C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m ;
W represents heterocyclyl;
each n and p independently represents 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen, andt is 1.
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Accused Products
Abstract
The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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Citations
31 Claims
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1. A compound represented by formula I:
- ##STR8## or a pharmaceutically acceptable salt thereof, wherein;
R1a, R1b and R2 are independently selected from the group consisting of;
hydrogen, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R8 O--, R9 S(O)m --, (R8)2 NC(O)--, R8 C(O)NR8 --, CN, NO2, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2, R9 OC(O)NR8 -- and C1 -C6 alkyl, unsubstituted or substituted by 1-3 groups selected from the group consisting of;
halo, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2 and R9 OC(O)NR8 --;R3 and R4 are independently selected from the group consisting of;
H, F, Cl, Br, --NR82, CF3, NO2, R8 O--, R9 S(O)m --, (R8)2 NC(O)--, R8 C(O)NH--, H2 NC(NH)--, R8 C(O)--, R8 OC(O)--, N3, CN, R9 OC(O)NR8 --, C1 -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;A3 is selected from;
--NR5 S(O)m -- or --S(O)m NR5 --, with m equal to 0, 1 or 2, and R5 selected from the group consisting of;
hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3 -C10 cycloalkyl, and C1 -C6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of;
unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3 -C10 cycloalkyl, --N(R8)2, --CF3, --NO2, (R8)O--, (R9)S(O)m --, (R8)C(O)NH--, H2 NC(NH)--, (R8)C(O)--, (R8)OC(O)--, N3, CN and (R9)OC(O)NR8 --;R6 and R7 are independently selected from the group consisting of;
hydrogen, aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1-6 perfluoroalkyl, F, Cl, Br, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, NO2, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2, R9 OC(O)NR8 -- and C1 -C6 alkyl unsubstituted or substituted by 1-3 groups selected from;
aryl, heterocyclyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8 O--, R9 S(O)m --, R8 C(O)NR8 --, CN, (R8)2 NC(NR8)--, R8 C(O)--, R8 OC(O)--, N3, --N(R8)2 and R9 OC(O)NR8 --;each R8 is independently selected from hydrogen, C1 -C6 alkyl, aryl and aralkyl; each R9 is independently selected from C1 -C6 alkyl and aryl; A1 and A2 are independently selected from the group consisting of;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR8 --, --NR8 C(O)--, --O--, --N(R8)--, --S(O)2 N(R8)--, --N(R8)S(O)2 --, and S(O)m ;X represents aryl or heteroaryl; V is selected from the group consisting of;
hydrogen, heterocyclyl, aryl, C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2 -C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m ;W represents heterocyclyl; each n and p independently represents 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 1. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)
- ##STR8## or a pharmaceutically acceptable salt thereof, wherein;
Specification