Claims
- 1. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, whereinone of a, b, c and d represents N or N+O−, and the remaining a, b, c and d groups represent CR1 or CR2; each R1 and each R2 is independently selected from H, halo, —CF3, —OR10, —COR10, —SR10, —S(O)tR11 (wherein t is 0, 1 or 2), —N(R10)2, —OC(O)R10, —CO2R10, —OCO2R11, —CN, —NR10COOR11, —SR11C(C(O)OR11, —SR11N(R75)2 (provided that R11 in —SR11N(R75)2 is not —CH2—) wherein each R75 is independently selected from H, —C(O)OR11, benzotriazol-1-yloxy, tetrazol-5-ylthio, 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 and each independently represents 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 the benzene ring (Ring III); R5, R6, and R7 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 R5 is combined with R6 to represent ═O or ═S; provided that for the groups —OR10, —SR10, and —N(R10)2R10 is not H; R10 represents H, alkyl, aryl, or aralkyl; R11 represents alkyl or aryl; X represents N and the optional bond (represented by the dotted line) to carbon atom 11 is absent; the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent —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, ═O, aryl and H, ═NOR10 or —O—(CH2)p—O— wherein p is 2, 3 or 4; R8 represents a heterocyclic ring selected from: said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from: (a) alkyl, (b) substituted alkyl wherein said substituents are selected from: halo, aryl, —OR15, —N(R15)2, heteroaryl, heterocycloalkyl, or cycloalkyl, wherein each R15 group is the same or different, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R15 is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; (c) hydroxyl, with the proviso that carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl; (d) alkyloxy; or (e) arylalkyloxy; Y represents CH2, NR16, O, S, SO, or SO2 wherein R16 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido or arylalkylsulfonamido; n is 0 to 6; Q represents O or N, provided that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1; R12 is selected from: wherein R17 is selected from: (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl wherein the substituents are selected from halo or CN, (6) —C(aryl)3, (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl; R12A is selected from rings 8.0 or 9.1, defined above; said imidazolyl ring 8.0 optionally being substituted with one or two substituents, said imidazole ring 9.0 optionally being substituted with 1-3 substituents, and said pyridyl ring 9.1 optionally being substituted with 1-4 substituents, wherein said optional substituents for rings 8.0, 9.0 and 9.1 are bound to the carbon atoms of said rings and are independently selected from: —NHC(O)R15, —C(R16)2OR19, —OR15, —SR15, F, Cl, Br, alkyl, substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl, or —N(R15)2; R15 is as defined above; each R18 is independently selected from H or alkyl; R19 is selected from H or —C(O)NHR20, and R20 is as defined below; R13 and R14 for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or —CON(R15)2 (wherein R15 is as defined above), —OR15 or —N(R15)2 provided that the —OR15 and —N(R15)2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom, and provided that there can be only one —OH group on each carbon; and the substitutable R13 and R14 groups are optionally substituted with one or more substituents selected from: F, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R13 and R14, for each n, together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring; R9 is selected from: R20 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocyloalkylalkyl, provided that R20 is not H when R9 is group 12.0 or 16.0; when R20 is other than H, then said R20 group is optionally substituted with one or more substituents selected from, halo, alkyl, aryl, —OC(O)R15, —OR15 or —N(R15)2, wherein each R15 group is the same or different, and wherein R15 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R21 is other than H, then said R21 group is optionally substituted with one or more substituents selected from: alkyl, or aryl; and R22 is selected from cycloalkyl, heterocycloalkyl, aryl, substituted aryl, alkyl, substituted alkyl or substituted cycloalkyl.
- 2. The compound of claim 1 having the structure
- 3. The compound of claim 1 having the structure:
- 4. The compound of claim 1 wherein R1 to R4 is independently selected from H, Br, F or Cl; R5 to R7 is H; a is N and the remaining b, c and d substituents are carbon; A and B are H2; and n is 1 to 3.
- 5. The compound of claim 1 wherein R8 is ring 2.0 and the —(CR13R14)n—R12 substituent is in the 2- or 3-position.
- 6. The compound of claim 1 wherein R8 is ring 2.0 and the —(CR13R14)n—R12 substituent is in the 2- or 3-position, and Y is CH2.
- 7. The compound of claim 1 wherein R13 and R14 are H.
- 8. The compound of claim 1 wherein Y is selected from S, SO, or SO2.
- 9. The compound of claim 1 wherein Y is O.
- 10. The compound of claim 1 wherein Y is NR16.
- 11. The compound of claim 1 wherein R9 is group 12.0.
- 12. The compound of claim 1 wherein R9 is group 13.0.
- 13. The compound of claim 1 wherein R9 is group 15.0.
- 14. The compound of claim 1 wherein R1 to R4 is independently selected from H, Br, F or Cl; R5 to R7 is H, a is N and the remaining b, c and d substituents are carbon; A and B are H2; and n is 1 to 3; R8 is ring 2.0 and the —(CR13R14)n—R12 substituent is in the 2- or 3-position, and Y is CH2.
- 15. The compound of claim 2 wherein R1 to R4 is independently selected from H, Br, F or Cl; R5 to R7 is H, a is N and the remaining b, c and d substituents are carbon; A and B are H2; and n is 1 to 3; r5 is ring 2.0 and the —(CR13R14)n—R12 substituent is in the 2- or 3-position, and Y is CH2.
- 16. The compound of claim 15 wherein R13 and R14 are H.
- 17. The compound of claim 16 wherein R12 is 9.0.
- 18. The compound of claim 16 wherein R9 is 12.0.
- 19. The compound of claim 16 wherein R9 is 13.0.
- 20. The compound of claim 16 wherein R9 is 15.0.
- 21. The compound of claim 16 wherein R20 is selected from t-butyl, i-propyl, neopentyl, cyclohexyl, cyclopropylmethyl,
- 22. The compound of claim 15 wherein R9 is selected from 12.0 or 13.0, and wherein R21 for 13.0 is H.
- 23. A method of inhibiting the abnormal growth of cells selected from: pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells or prostate tumor cells in a patient in need thereof by the inhibition of farnesyl protein transferase comprising administering to the patient an effective amount of a compound of claim 1.
- 24. A method of inhibiting farnesyl protein transferase in a patient in need thereof comprising administering to the patient an effective amount of the compound of claim 1.
- 25. A pharmaceutical composition comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.
- 26. A compound selected from:(1) A compound selected from: (2) a compound of the formula: wherein R8 is selected from: (3) a compound of the formula: (4) a compound of the formula: (5) a compound of the formula: (6) a compound of the formula: (7) a compound of the formula: (8) a compound of the formula: (9) a compound of the formula: (10) a compound of the formula: (11) a compound of the formula: (12) a compound of the formula: (13) a compound of the formula: (14) a compound of the formula: wherein R8 is selected from: (15) a compound of the formula: wherein R8 is selected from: (16) a compound of the formula: (17) a compound of the formula: wherein R8 is selected from: (18) a compound of the formula: (19) a compound of the formula: (20) a compound of the formula: (21) a compound of the formula: (22) a compound of the formula: (23) a compound of the formula: (24) a compound of the formula: (25) a compound of the formula: wherein R8 is selected from: (26) a compound of the formula: wherein R9 is selected from: (27) a compound of the formula: wherein R9 is selected from: (28) a compound of the formula: (29) a compound of the formula: wherein R8 is (30) a compound of the formula: wherein R8 is selected from: (31) a compound of the formula: (32) a compound of the formula: (33) a compound of the formula: wherein R8 is selected from: (34) a compound of the formula: wherein R9 is selected from: (35) a compound of the formula: wherein R9 is: (36) a compound of the formula: wherein R8 is selected from: (37) a compound of the formula: wherein R8 is selected from: (38) a compound selected from: wherein R8 is selected from: (39) a compound selected from: wherein R8 is selected from: (40) a compound of the formula: wherein R9 is selected from: (41) a compound selected from: wherein R9 is selected from: (42) a compound of the formula: wherein R8 is selected from: (43) a compound of the formula: wherein R8 is selected from: (44) a compound of the formula: wherein R8 is selected from: (45) a compound of the formula; wherein R8 is selected from: (46) a compound of the formula: (47) a compound of the formula: (48) a compound of the formula: wherein R9 is selected from: (49) a compound of the formula: wherein R9 is selected from: (50) a compound of the formula: wherein R8 is selected from: (51) a compound of the formula: wherein R8 is selected from: (52) a compound of the formula: (53) a compound of the formula: wherein R9 is (54) a compound of the formula: (55) a compound of the formula: (56) a compound of the formula: (57) a compound of the formula: (58) a compound of the formula: (59) a compound of the formula: (60) a compound of the formula: (61) a compound of the formula: (62) a compound of the formula: (63) a compound of the formula: (64) a compound of the formula:
- 27. A compound selected from:(1) a compound of the formula: wherein R8 is (2) a compound of the formula: wherein R8 is (3) a compound of the formula: wherein R8 is selected from: (4) a compound of the formula: (5) a compound of the formula: (6) a compound of the formula: wherein R8 is selected from: (7) a compound of the formula: wherein R9 is selected from: (8) a compound of the formula: (9) a compound of the formula: wherein R9 is (10) a compound of the formula: wherein R8 is (11) a compound of the formula: wherein R8 is (12) a compound selected from: wherein R8 is (13) a compound selected from: wherein R8 is (14) a compound of the formula: wherein R9 is selected from: (15) a compound of the formula: wherein R8 is (16) a compound of the formula: wherein R8 is selected from: (17) a compound of the formula: (18) a compound of the formula:
- 28. A compound selected from:(1) a compound of the formula: wherein R8 is selected from: (2) a compound of the formula: (3) a compound of the formula: (4) a compound of the formula: (5) a compound of the formula: (6) a compound of the formula: wherein R8 is selected from: (7) a compound of the formula: wherein R8 is selected from: (8) a compound of the formula: wherein R8 is selected from: (9) a compound of the formula: (10) a compound of the formula: (11) a compound of the formula: (12) a compound of the formula: wherein R8 is selected from: (13) a compound of the formula: (14) a compound of the formula: wherein R9 is selected from: (15) a compound of the formula: wherein R8 and R9 are selected from: ExampleR9R87511(R), 2(R)2(R/S);7611(S), 2(R)2(R/S);7711(R), 2(R)2(R/S);7811(S), 2(R)2(R/S);7911(R), 2(R)2(R/S);8011(S), 2(R)2(R/S);8111(R), 2(R)4(R/S);8211(S), 2(R)4(R/S);8311(R), 2(R)4(R/S);8411(S), 2(R)4(R/S);8511(R), 2(R)4(R/S); or8611(S), 2(R)4(R/S);(16) a compound of the formula: wherein R8 and R9 are selected from: ExampleR9R88711(R), 2(R)3(R/S);8811(S), 2(R)3(R/S):8911(R), 2(R)3(R/S);9011(S), 2(R)3(R/S);9111(R), 2(R)3(R);9211(S), 2(R)3(R);9311(R), 2(R)3(R);9411(S), 2(R)3(R);9511(R), 2(R)3(S);9611(S), 2(R)3(S);9711(S), 2(R)3(S);9811(S), 2(R)3(S);9911(R), 2(R)3(R/S);10011(S), 2(R)3(R/S);10111(R), 2(R)3(R/S);10211(S), 2(R)3(R/S);10311(R), 2(R)10411(S), 2(R)10511(R), 2(R)10611(S), 2(R)10711(R), 2(R)4(R/S);10811(S), 2(R)4(R/S);10911(R), 2(R)4(R/S); or11011(S), 2(R)4(R/S);(17) a compound of the formula: (18) a compound of the formula: (19) a compound of the formula: (20) a compound of the formula: (21) a compound of the formula: (22) a compound of the formula: (23) a compound of the formula: (24) a compound of the formula: (25) a compound of the formula: (26) a compound of the formula: (27) a compound of the formula: wherein R8 is selected from: (28) a compound of the formula: wherein R9 is selected from: (29) a compound of the formula: wherein R9 is selected from: (30) a compound of the formula: wherein R8 is selected from: (31) a compound of the formula: wherein R8 is: (32) a compound of the formula: wherein R8 is selected from: (33) a compound of the formula: wherein R9 is selected from: (34) a compound of the formula: wherein R9 is selected from: (35) a compound of the formula: wherein R9 is selected from: (36) a compound of the formula: wherein R9 is selected from: (37) a compound of the formula: (38) a compound of the formula: wherein R9 is selected from: (39) a compound of the formula: wherein R9 is selected from: (40) a compound of the formula: wherein R9 is selected from; (41) a compound of the formula: wherein R9 is selected from: (42) a compound of the formula: wherein R8 is selected from: (43) a compound selected from: wherein R9 is selected from: (44) a compound of the formula: wherein R9 is selected from; (45) a compound of the formula: wherein R8 is selected from: (46) a compound of the formula: wherein R9 is selected from: (47) a compound of the formula: wherein R9 is selected from: (48) a compound of the formula: wherein R8 is selected from: (49) a compound of the formula: wherein R9 is selected from; (50) a compound of the formula: (51) a compound of the formula: wherein R9 is selected from; (52) a compound of the formula: wherein R9 is selected from: (53) a compound of the formula: wherein R9 is: (54) a compound of the formula: (55) a compound of the formula: (56) a compound of the formula: (57) a compound of the formula: (58) a compound of the formula: (59) a compound of the formula: (60) a compound of the formula: (61) a compound of the formula: (62) a compound of the formula: (63) a compound of the formula: (64) a compound of the formula: (65) a compound of the formula: (66) a compound of the formula: (67) a compound of the formula: (68) a compound of the formula: (69) a compound of the formula: (70) a compound of the formula: (71) a compound of the formula: (72) a compound of the formula: (73) a compound of the formula: (74) a compound of the formula: (75) a compound of the formula: (76) a compound of the formula: (77) a compound of the formula: (78) a compound of the formula: (79) a compound of the formula: (80) a compound of the formula: (81) a compound of the formula: (82) a compound of the formula: (83) a compound of the formula: (84) a compound of the formula: (85) a compound of the formula: (86) a compound of the formula: (87) a compound of the formula: (88) a compound of the formula: (89) a compound of the formula: (90) a compound of the formula: (91) a compound of the formula: (92) a compound of the formula: (93) a compound of the formula: (94) a compound of the formula: (95) a compound of the formula: (96) a compound of the formula: (97) a compound of the formula: (98) a compound of the formula: (99) a compound of the formula: (100) a compound of the formula: (101) a compound of the formula: (102) a compound of the formula: (103) a compound of the formula: (104) a compound of the formula: (105) a compound of the formula:
- 29. The compound of claim 26 selected from a compound of Examples 47(A) or 140A.
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 60/112,943 filed Dec. 18, 1998.
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Provisional Applications (1)
|
Number |
Date |
Country |
|
60/112943 |
Dec 1998 |
US |