BACKGROUND WO 95/10516, published April 20, 1995 and WO 97/23478, published July 3, 1997 disclose tricyclic compounds useful for inhibiting farnesyl protein transferase.

WO 98/54966 published December 10,1998 discloses methods of treating cancer by administering at least two therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is an inhibitor of prenyl-protein transferase (e. g. , a farnesyl protein transferase inhibitor).

Farnesyl Protein Transferase (FPT) Inhibitors are known in the art, see for example U. S. 5,874, 442 issued February 23, 1999. Methods of treating proliferative diseases (e. g. , cancers) by administering an FPT inhibitor in conjunction with an antineoplastic agent and/or radiation therapy are also known, see for example U. S.

6, 096, 757 issued August 1, 2000.

Shih et al.,"The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo", Cancer Chemother Pharmacol (2000) 46: 387-393 discloses a study of the combination of SCH 66336 with paclitaxel, and SCH 66336 with docetaxel on certain cancer cell lines.

WO 01/45740 published June 28,2001 discloses a method of treating cancer (breast cancer) comprising administering a selective estrogen receptor modulator (SERM) and at least one farnesyl transferase inhibitor (FTI). FTI-277 is the exemplified FTI.

The WEB site http : l/www. osip. com/press/Dr/07-25-01 discloses a press release of OSI Pharmaceuticals. The press release announces the initiation of a Phase III clinical trial evaluating the use of the epidermal growth factor inhibitor Tarceva (TM) (OSI-774) in combination with Carboplatin (ParaplatinO) and Paclitaxel (Taxol@) for the treatment of Non Small Cell Lung Cancer.

The WEB site http : l/cancertrials. nci. nih. qov/types/lung/iressa12100. html in a disclosure posted 12/14/00 discloses the following list of open clinical trials for

advanced (stage IIIB and IV) non-small cell lung cancer, from NCI's clinical trials database: (1) phase))) Randomized Study of ZD 1839 (IRESSA, an epidermal growth factor inhibitor) combined with gemcitabine and cisplatin in chemotherapy- naive patients with Stage IIIB or IV non-small cell lung cancer; and (2) phase III Randomized Study of ZD 1839 (IRESSA, an epidermal growth factor inhibitor) combined with paclitaxel and carboplatin in chemotherapy- naive patients with Stage IIIB or IV non-small cell lung cancer.

WO 01/56552 published August 9,2001 discloses the use of an FPT inhibitor for the preparation of a pharmaceutical composition for treating advanced breast cancer. The FPT inhibitor may be used in combination with one or more other treatments for advanced breast cancer especially endocrine therapy such as an antiestrogen agent such as an estrogen receptor antagonist (e. g. , tamoxifen) or a selective estrogen receptor modulator or an aromatase inhibitor. Other anti-cancer agents which may be employed include, amongst others, platinum coordination compounds (such as cisplatin or carboplatin), taxanes (such as paclitaxel or docetaxel), anti-tumor nucleoside derivatives (such as gemcitabine), and HER2 antibodies (such as trastzumab).

WO 01/62234 published August 30, 2001 discloses a method of treatment and dosing regimen for treating mammalian tumors by the discontinuous administration of a famesyl transferase inhibitor over an abbreviated one to five day dosing schedule.

Disclosed is a regimen wherein the farnesyl protein transferase inhibitor is administered over a one to five day period followed by at least two weeks without treatment. It is disclosed that in previous studies farnesyl protein transferase inhibitors have been shown to inhibit the growth of mammalian tumors when administered as a twice daily dosing schedule. It is further disclosed that the administration of a famesyl protein transferase inhibitor in a single dose daily for one to five days produced a marked suppression of tumor growth lasting one to at least 21 days. It is also disclosed that the FTI may be used in combination with one or more other anti-cancer agents such as, platinum coordination compounds (e. g., cisplatin or carboplatin), taxane compounds (e. g., paclitaxel or docetaxel), anti-tumor nucleoside derivatives (e. g. , gemcitabine), HER2 antibodies (e. g., trastzumab), and estrogen receptor antagonists or selective estrogen receptor modulators (e. g. , tamoxifen).

WO 01/64199 published September 7,2001 discloses a combination of particular FPT inhibitors with taxane compounds (e. g., paclitaxel or docetaxel) useful in the treatment of cancer.

In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The FPT inhibitor compounds of this invention are represented by the formula : or a pharmaceutical acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or N+O-, and the remaining a, b, c, and d groups represent carbon, wherein each carbon has an R1 or R2 group bound to said carbon; or each of a, b, c, and d is carbon, wherein each carbon has an R'or R2 group bound to said carbon; the dotted line (---) represents optional bonds; X represents N or CH when the optional bond (to C11) is absent, and represents C when the optional bond (to C11) is present; when the optional bond is present between carbon atom 5 (i. e. , C-5) and carbon atom 6 (i. e. , C-6) (i. e. , there is a double bond between C-5 and C-6) then there

is only one A substituent bound to C-5 and there is only one B substituent bound to C-6, and A or B is other than H; when the optional bond is not present between carbon atom 5 and carbon atom 6 (i. e. , there is a single bond between C-5 and C-6) then there are two A substituents bound to C-5, wherein each A substituent is independently selected, and two B substituents bound to C-6, wherein each B substituent is independently selected, and wherein at least one of the two A substituents or one of the two B substituents is H, and wherein at least one of the two A substituents or one of the two B substituents is other than H, (i. e. , when there is a single bond between C-5 and C-6 one of the four substituents (A, A, B, and B) is H and one is other than H); A and B are independently selected from the group consisting of : (1)-H ; (2)-R9 ; (3) -R9-C (O)-R9 ; (4)-R9-C02-R9a ; - pR ; (6)-C (O) N (R9) 2, wherein each R9 is the same or different; (7) -C (O) NHR9 ; (8) -C (O) NH-CH2-C (O)-NH2 ; (9) -C (O) NHR26 ; (10)- (CH2) pC (R9)-O-Ra ; (11)- (CH2), 11CH (Rg) 2, provided that p is not 0, and wherein each R9 is the same or different; (12) -(CH2)pC(O)R9; (13)- (CH2) pC (O) Razz (14)- (CH2) pC (O) N (R9)2, wherein each R9 is the same or different; (15) -(CH2) pC (O) NH (R9) ; (16)- (CH2) pC (O) N (R26) 2, wherein each R26 is the same or different ; (17)- (CH2) pN (R9)-R9a, (e. g.-CH2-N (CH2-pyridine)-CH2-imidazole) ; (18)- (CH2) pN (R26) 2, wherein R26 is the same or different (e. g., - (CH2) p-NH-CH2-CH3); (19)- (CH2) pNHC (O) Rio ; (20)- (CH2) pNHC (O) 2R5° ;

(21)- (CH2) pN (C (O) R27a) 2 wherein each R27a is the same or different; (22) -(CH2)pNR51C(O)R27 ; (23) -(CH2)pNR51C(O)R27 wherein R51 is not H, and R51 and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring consisting ; (24) -(CH2)pNR51C(O)NR27 ; (25) -(CH2)pNR51C(O)NR27 wherein R5'is not H, and R5'and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring ; (26)- (CH2) pNR5'C (O) N (R27a)2, wherein each R27a is the same or different; (27) -(CH2)pNHSO2N(R51)2, wherein each R5'is the same or different; (28) -(CH2)pNHCO2R50 ; (29)- (CH2) pNC (O) NHR61 ; (30) -(CH2)pCO2R51; (31)-NHR9 ; (32)

wherein R30 and R31 are the same or different, and each p is independently selected; provided that for each

group when one of R30 or R31 is selected from the group consisting of :-OH, =0, -OR9a, -NH2, -NHR9a, -N(R9a)2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining R30 or R31 is selected from the group consisting of : H, alkyl, aryl (e. g. , phenyl), and arylalkyl (e. g., benzyl) ; (33)

wherein R30, R3', R32 and R33 are the same or different; provided that when one of R30 or R31 is selected from the group consisting of : -OH, =O, -OR9a, -NH2, -NHR9a, -N(R9a)2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining R3° or R31 is selected from the group consisting of: H, alkyl, aryl (e. g., phenyl), and arylalkyl (e. g. , benzyl) ; and provided that when one of R32 or R33 is selected from the group consisting of :-OH, =O, -OR9a, -NH2, -NHR9a, -N (R) 2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining R32 or R33 is selected from the group consisting of: H, alkyl, aryl (e. g., phenyl), and arylalkyl (e. g., benzyl) ; (34) -alkenyl-CO2R9a ; (35) -alkenyl-C(O)R9a ; (36) -alkenyl-CO2R51 ; (37)- alkenyl-C(O)-R27a; (38) (CH2) p-alkenyl-CO2-R51 ; (37) -(CH2)pC=NOR51 ; and (39)- (CH2) p-phthalimid ; p is 0, 1,2, 3 or 4 ; each R1 and R2 is independently selected from the group consisting of: (1) H; (2) Halo ; (3)-CF3, (4)-OR ; (5) -COR10, (6) -SR10; (7) -S (O)tR15 wherein t is 0,1 or 2; (8)-N -N(R10)2; (9)-NO2 ; (10) -OC (O) Rio ; (11)-CO2R (12) -OCO2R15; (13) -CN; (14) -NR10COOR15;

(15) -SR15C(O)OR15 ; (16) -SR15N(R13)2 provided that R15 in -SR15N(R13)2 is not-CH2 and wherein each R is independently selected from the group consisting of: H and -C (O) OR ; (17) benzotriazol-1-yloxy ; (18) tetrazol-5-ylthio ; (19) substituted tetrazol-5-ylthio ; (20) alkynyl ; (21) alkenyl ; and (22) alkyl, said alkyl or alkenyl group optionally being substituted with halogen, -OR10 or -CO2R10; R and R are the same or different and each independently represent H, and any of the substituents of R1 and R2 ; R5, R6, R7 and R7a each independently represent: H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with-S (O)tR15, -NR10COOR15, -C(O)R10, or-CO2R, or R5 is combined with R6 to represent =O or =S; R8 is selected from the group consisting of: (2.0) (3.0) (4.0) (5.0) R9 is selected from the group consisting of: (1) unsubstituted heteroaryl ; (2) substituted heteroaryl ; (3) arylalkoxy ; (4) substituted arylalkoxy ; (5) heterocycloalkyl ; (6) substituted heterocycloalkyl ; (7) heterocycloalkylalkyl ; (8) substituted heterocycloalkylalkyl ;

(9) unsubstituted heteroarylalkyl ; (10) substituted heteroarylalkyl ; (11) unsubstituted heteroarylalkenyl ; (12) substituted heteroarylalkenyl ; (13) unsubstituted heteroarylalkynyl ; and (14) substituted heteroarylalkynyl ; wherein said substituted R9 groups are substituted with one or more (e. g. , 1,2 or 3) substituents selected from the group consisting of : (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); <BR> <BR> <BR> (2)-Co2R14 ;<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (3)-CH2OR14, (4) halogen (e. g. , Br, Cl or F), (5) alkyl (e. g. methyl, ethyl, propyl, butyl or t-butyl) ; (6) amino; (7) trityl ; (8) heterocycloalkyl ; (9) cycloalkyl, (e. g., cyclopropyl or cyclohexyl) ; (10) arylalkyl ; (11) heteroaryl ; (12) heteroarylalkyl and wherein R14 is independently selected from : H ; alkyl ; aryl, arylalkyl, heteroaryl and heteroarylalkyl ; R9a is selected from the group consisting of: alky and arylalkyl ; R9b is selected from the group consisting of : (1) -C (O) R9a ; (2)-SO2R9a ; (3) -C (O) NHR9a ; (4) -C (O) OR9a ; and (5) -C (O) N (R9c) 2;

Each R is independently selected from the group consisting of: H, alkyl and arylalkyl ; R10 is selected from the group consisting of: H ; alkyl ; aryl and arylalkyl ; R"is selected from the group consisting of: (1) alkyl ; (2) substituted alkyl ; (3) unsubstituted aryl ; (4) substituted aryl ; (5) unsubstituted cycloalkyl ; (6) substituted cycloalkyl ; (7) unsubstituted heteroaryl ; (8) substituted heteroaryl ; (9) heterocycloalkyl ; (10) substituted heterocycloalkyl ; (11) unsubstituted alkenyl (e. g.,-CH2CH=CH2) ; (12) -N (alkyl) 2 wherein each alkyl is independently selected (e. g., -N (CH3) 2) : (13) unsubstituted arylalkyl ; and (14) substituted arylalkyl ; wherein said substituted alkyl R"groups are substituted with one or more (e. g. 1,2 or 3) substituents selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g., Br, Cl or F); and (3) -CN ; and wherein said substituted cycloalkyl, and substituted heterocycloalkyl Rr1 groups are substituted with one or more (e. g. 1,2 or 3) substituents selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g. , Br, Cl or F); and

(3) alkyl ; and wherein said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyl R11 groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g,. Br, Cl or F); (3) alkyl ; (4) -CF3 ; (5) -CN; and (6) alkoxy (e. g.,-OCH3) ; Ra is selected from the group consisting of: (1) H; (2) OH; (3) alkyl ; (4) substituted alkyl ; (5) aryl ; (6) substituted aryl ; (7) unsubstituted cycloalkyl ; (8) substituted cycloalkyl ; (9) unsubstituted heteroaryl ; (10) substituted heteroaryl ; (11) heterocycloalkyl ; (12) substituted heterocycloalkyl ; (13) ; (14) unsubstituted arylalkyl ; (15) substituted arylalkyl ; (16) unsubstituted alkenyl ; (17) unsubstituted arylacyl (e. g.,-C (O) phenyl) ; and (18) unsubstituted heteroarylalkyl (e. g.,-CH2-pyridyl) ; wherein said substituted alkyl R"a groups are substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of:

(1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2)-CN ; (3)-CF3 ; (4) halogen (e. g,. Br, Cl or F); (5) cycloalkyl ; (6) heterocycloalkyl ; (7) arylalkyl ; (8) heteroarylalkyl ; and (9) heteroalkenyl ; and wherein said substituted cycloalkyl, and substituted heterocycloalkyl R11a groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) -CN; (3)-CF3 ; (4) halogen (e. g,. Br, Cl or F); (5) alkyl ; (6) cycloalkyl ; (7) heterocycloalkyl ; (8) arylalkyl ; (9) heteroarylalkyl ; (10) alkenyl ; and (11) heteroalkenyl ; and wherein said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyl Regroups have one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of : (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom);

(2) -CN; (3) -CF3 ; (4) halogen (e. g. , Br, Cl or F); (5) alkyl ; (6) cycloalkyl ; (7) heterocycloalkyl ; (8) arylalkyl ; (9) heteroarylalkyl ; (10) alkenyl ; (11) heteroalkenyl ; (12) aryloxy (e. g.,-O-phenyl) ; and (13) alkoxy (e. g. ,-OCH3) ; R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and-alkyl-(piperidine Ring V) (wherein said piperidine Ring V is as described below, see, for example, paragraph (8) in the definition of R21, Ra and and ; R'5 is selected from the group consisting of: alkyl and aryl ; R2', R22 and R46 are independently selected from the group consisting of: (1) -H; (2) alkyl (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) unsubstituted aryl, (e. g. phenyl) ; (4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen,-CF3 and OH; (5) unsubstituted cycloalkyl, (e. g. cyclohexyl) ; (6) substituted cycloalkyl substituted with one or more substituents independently selected from the group consisting of : alkyl, halogen,-CF3 and OH ; (7) heteroaryl of the formula, (8) heterocycloalkyl of the formula :

(i. e. , piperidine Ring V) wherein R44 is selected from the group consisting of: (a)-H, (b) alkyl, (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (c) alkylcarbonyl (e. g. , CH3C (O)-) ; (d) alkyloxy carbonyl (e. g.,-C (O O-t-C4H9,-C (O) OC2H5, and -C (O) OCH3); (e) haloalkyl (e. g., trifluoromethyl) ; and (f)-C (O) NH (R51) ; (9)-NH2 provided that only one of R2', R, and R46 group can be -NH2, and provided that when one of R21, R22, and R46 is-NH2 then the remaining groups are not-OH; (10) -OH provided that only one of R21, R22, and R46 group can be - OH, and provided that when one of R21, R22, and R46 is-OH then the remaining groups are not-NH2 ; and (11) alkyl substituted with one or more substituents (e. g. , 1-3, or 1-2, and preferably 1) selected from the group consisting of:-OH and -NH2, provided that there is only one-OH or one-NH2 group on a substituted carbon; (12) alkoxy (e. g.,-OCH3) ; or (13) R21 and R22 taken together with the carbon to which they are bound form a cyclic ring selected from the group consisting of: (a) unsubstituted cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl) ; (b) cycloalkyl substituted with one or more substituents independently selected from the group consisting of : alkyl, halogen,-CF3 and OH ; (c) unsubstituted cycloalkenyl

(d) cycloalkenyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen,-CF3 and OH; (e) heterocycloalkyl, e. g. , a piperidyl ring of the formula :

wherein R is selected from the group consisting of: (1)-H, (2) alkyl, (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) alkylcarbonyl (e. g., CH3C (O)-) ; (4) alkyloxy carbonyl (e. g.,-C (O) 0-t-C4H9, -C(O) OC2H5, and-C (O) OCH3) ; (5) haloalkyl (e. g., trifluoromethyl) ; and (6)-C (o) NH (R51) ; (f) unsubstituted aryl (e. g., phenyl) ; (g) aryl substituted with one or more substituents independently selected from the group consisting of: alkyl (e. g., methyl), halogen (e. g., Cl, Br and F),-CN,-CF3, OH and alkoxy (e. g. , methoxy); and (i) heteroaryl selected from the group consisting of:

R26 is selected from the group consisting of: (1) -H; (2) alkyl (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) alkoxy (e. g., methoxy, ethoxy, or propoxy); (4) -CH2-CN;

(5) R9 ; (6) -CH2CO2H ; (7) -C (O) alkyl ; and (8) CH2CO2alkyl ; R27 is selected from the group consisting of: (1)-H ; (2) -OH; (3) alkyl (e. g., methyl, ethyl, propyl, or butyl) ; and (4) alkoxy ; R27a is selected from the group consisting of: (1) alkyl (e. g. methyl, ethyl, propyl, or butyl) ; and (2) alkoxy ; R30, R31, R32 and R33 are independently selected from the group consisting of: (1) -H; (2) -OH; (3) =O ; (4) alkyl ; (5) aryl (e. g., phenyl) ; (6) arylalkyl (e. g., benzyl) ; (7) -OR9a ; (8) -NH2; (9) -NHR9a ; (10) -N (R9a) 2 wherein each R9a is independently selected ; - ; (12)-NHR9b ; and (13) -N (R9a) R9b ; R50 is selected from the group consisting of: (1) alkyl ; (2) unsubstituted heteroaryl ; (3) substituted heteroary; and (4) amino;

wherein said substituents on said substituted Regroups are independently selected from the group consisting of: alkyl (e. g., methyl, ethyl, propyl, and butyl) ; halogen (e. g., Br, Cl, and F); and-OH ; R51 is selected from the group consisting of: H, and alkyl (e. g., methyl, ethyl, propyl, butyl and t-butyl) ; and provided that: (1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom; and (2) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with more than one heteroatom; and (3) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with a heteroatom and a halo atom; and (4) a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and (5) a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and (6) the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms; and (7) when A and B are independently selected from the group consisting of substituents (1) to (31) and (34) to (39), then R8 is not H; and (8) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (2.0), then R"is selected from the group consisting of substituents (11) to (14) ; and (9) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (3.0), then R"is selected from the group consisting of substituents (11) to (14); and (10) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (4. 0), then: (a) Rta is selected from the group consisting of substituents (13) to (18), and R12 is as defined above, or (b) R"a is selected from the group consisting of substituents (1) to (12), and R'2 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or

(c) Rla is selected from the group consisting of substitutents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V) ; and (11) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (5.0), then at least one of R21, R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13); and (12) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and R30 to R33 are selected from the group consisting of substituents (1) to (6), then R8 is selected from the group consisting of: (a) (2.0) wherein R"is selected from substituents (11) to (14), (b) (3.0) wherein R11 is selected from substituents (11) to (14), (c) (4.0) wherein (i) R11a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1.0, or (ii) R''a is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (iii) R11a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl-(piperidine Ring V), and (d) (5. 0) wherein at least one of R2', R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13); and (13) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-NH2 (i. e., substituent (8)), and R8 is (2.0), then R8 is not (14) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is -N3 (i. e., substituent (11) ), and R8 is (2.0), then R8 is not

This invention also provides pharmaceutical compositions comprising an effective amount of a compound of this invention (e. g. , a compound of formula 1.0) and a pharmaceutically acceptable carrier.

This invention also provides a method of inhibiting famesyl protein transferase in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e. g., a compound of formula 1.0).

This invention also provides methods of treating (or inhibiting) tumors (i. e., cancers) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e. g. , a compound of formula 1.0).

This invention also provides methods of treating (or inhibiting) tumors (i. e., cancers) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e. g. , a compound of formula 1.0) in combination with at least one chemotherapeutic agent (also know in the art as antineoplastic agent or anticancer agent).

This invention also provides methods of treating (or inhibiting) tumors (i. e., cancers) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e. g. , a compound of formula 1. 0) in combination with at least one chemotherapeutic agent (also know in the art as antineoplastic agent or anticancer agent) and/or radiation.

This invention also provides methods of treating (or inhibiting) tumors (i. e., cancers) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e. g. , a compound of formula 1.0) in combination with at least one signal transduction inhibitor.

In the methods of this invention the compounds of this invention (e. g. , a compound of formula 1.0) can be administered concurrently or sequentially (i. e., consecutively) with the chemotherapeutic agents or the signal transduction inhibitor.

DETAILED DESCRIPTION OF THE INVENTION As described herein, unless otherwise indicated, the use of a drug or compound in a specified period (e. g. , once a week, or once every three weeks, etc.,) is per treatment cycle.

As used herein, the following terms have the following meanings unless otherwise described : AD HPLC is a HPLC column from Chiral Technologies ; AUC-represents"Area Under the Curve" ; BOC-represents tert-butyloxycarbonyl ; CBZ-represents-C (O) OCH2C6H5 (i. e., benzyloxycarbonyl) ; CH2CI2-represents dichloromethane ; CIMS-represents chemical ionization mass spectrum; Cmpd-represents Compound; DBU-represents 1, 8-Diazabicyclo [5.4. 0] undec-7-ene ; DEAD-represents diethylazodicarboxylate ; DEC-represents EDCI which represents 1- (3-dimethyl-aminopropyl)-3- ethylcarbodiimide hydrochloride ; DMF-represents N, N-dimethylformamide ; DPPA-represents diphenylphosphoryl azide Et-represents ethyl ; Et3N-represents TEA which represents triethylamine ; EtOAc-represents ethyl acetate; EtOH-represents ethanol ; FAB-represents FABMS which represents fast atom bombardment mass spectroscopy; HOBT-represents 1-hydroxybenzotriazole hydrate; HRMS-represents high resolution mass spectroscopy; IPA-represents isopropanol ; i-PrOH-represents isopropanol ; Me-represents methyl ; MeOH-represents methanol ;

MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum ; MS-represents mass spectroscopy; NMM-represents N-methylmorpholine ; OD HPLC is a HPLC column from Chiral Technologies; PPh3-represents triphenyl phosphine; Ph-represents phenyl ; Pr-represents propyl ; SEM-represents 2, 2- (Trimethylsilyl) ethoxymethyl ; TBDMS-represents tert-butyldimethylsilyl ; t-BUTYL-represents-C- (CH3) 3; TFA-represents trifluoroacetic acid; THF-represents tetrahydrofuran; Tr-represents trityl ; Tf-represents S02CF3 ; at least one-represents one or more- (e. g. 1-6), more preferrably 1-4 with 1,2 or 3 being most preferred; alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2-12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms; alkoxy-represents an alkyl moiety, alkyl as defined below, covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy and the like ; alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, more preferably one to four carbon atoms ; even more preferably one to two carbon atoms; alkylcarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (-CO-), for example,-COCH3 ; alkyloxycarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (-CO-) through an oxygen atom, for example, - (O)-OC2H5 ;

alkynyl-represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2-12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 2 to 4 carbon atoms ; amino-represents an-NH2 moiety ; antineoplastic agent-represents a chemotherapeutic agent effective against cancer; aryl-represents a carbocyclic group containing from 6 to 15 carbon atoms in the unsubstituted carbocyclic group and having at least one aromatic ring (e. g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment of said aryl group, said aryl group being unsubstituted or substituted, said substituted aryl group having one or more (e. g., 1 to 3) substituents independently selected from the group consisting of: halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, -C(O)N(R18)2, -SO2R18, -SO2N(R18)2, amino, alkylamino, dialkylamino, -COOR23 and -NO2 (preferably said substitutents are independently selected from the group consisting of: alkyl (e. g., C1-C6 alkyl), halogen (e.g., Cl and Br), -CF3 and -OH), wherein each R18 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl and cycloalkyl, and wherein R23 is selected from the group consisting off alkyl and aryl ; arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined above; arylheteroalkyl-represents a heteroalkyl group, as defined below, substituted with an aryl group, as defined above; aryloxy-represents an aryl moiety, as defined above, covalently bonded to an adjacent structural element through an oxygen atom, for example, 4-phenyl (i. e., phenoxy); compound-with reference to the antineoplastic agents, includes the agents that are antibodies : concurrently-represents (1) simultaneously in time (e. g. , at the same time), or (2) at different times during the course of a common treatment schedule : consecutively-means one following the other; cycloalkenyl-represents unsaturated carbocyclic rings of from 3 to 20 carbon atoms in the unsubstituted ring, preferably 3 to 7 carbon atoms, said cycloalkenyl ring comprising at least one (usually one) double bond, and said cycloalkenyl ring being

unsubstituted or substituted, said substituted cycloalkenyl ring having one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of: alkyl (e. g., methyl and ethyl), halogen,-CF3 and-OH ; cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms in the unsubstituted ring, preferably 3 to 7 carbon atoms, said cycloalkyl ring being unsubstituted or substituted, said substituted cycloalkyl ring having one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of : alkyl (e. g. , methyl and ethyl), halogen,-CF3 and-OH ; for example, 1-substituted cycloalkyl rings, such as, for example,

or or or lk alkyl wherein said alkyl is generally a Ci-Ce alkyl group, usually a Cl-C2 alkyl group, and preferably a methyl group; thus, examples of cycloalkyl rings substituted at the 1- position with methyl include but are not limited to:

cycloalkylalkyl-represents an alkyl group, as defined above, substituted with a cycloalkyl group, as defined above; different-as used in the phrase"different antineoplastic agents"means that the agents are not the same compound or structure; preferably,"different"as used in the phrase"different antineoplastic agents"means not from the same class of antineoplastic agents; for example, one antineoplastic agent is a taxane, and another antineoplastic agent is a platinum coordinator compound; effective amount-represents a therapeutically effective amount; for example, the amount of the compound (or drug), or radiation, that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor; for example, in the treatment of lung cancer (e. g. , non small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain; also, for example, a therapeutically effective amount of the FPT inhibitor is that amount which results in the

reduction of farnesylation ; the reduction in famesylation may be determined by the analysis of pharmacodynamic markers such as Prelamin A and HDJ-2 (DNAJ-2) using techniques well known in the art; halo (or halogen)-represents fluoro, chloro, bromo or iodo; haloalkyl-represents an alkyl group, as defined above, substituted with a halo group; heteroatom-represents a O, N or S atom; heteroalkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from two to twenty carbon atoms, preferably two to six carbon atoms interrupted by 1 to 3 heteroatoms selected from the group consisting of :-O-,-S-and-N-, provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another; heteroalkyl-represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from the group consisting of :-O-,-S-and-N-, provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another ; heteroalkynyl-represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from two to twenty carbon atoms, preferably two to six carbon atoms interrupted by 1 to 3 heteroatoms selected from the group consisiting of :-0-,-S-and-N-provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another; heteroaryl-represents unsubstituted or substituted cyclic groups, having at least one heteroatom selected from the group consisting of: O, S or N (provided that any O and S atoms are not adjacent to one another), said heteroaryl group comprises O and S atoms, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the unsubstituted heteroaryl group preferably containing from 2 to 14 carbon atoms, wherein said substituted heteroaryl group is substitued with one or more (e. g. , 1,2 or 3) of the same or different R3A (as defined for formula 1.1) groups, examples of heteroaryl groups include but are not limited to: e. g. , 2-or 3-fury, 2-or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4-or 5-imidazolyl, 2-, 4-or 5-pyrimidinyl, 2-pyrazinyl, 3-or 4- pyridazinyl, 3-, 5-or 6- [1, 2, 4-triazinyl], 3-or 5- [1, 2, 4-thiadizolyl], 2-, 3-, 4-, 5-, 6-or 7- benzofuranyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, triazolyl, 2-, 3-or 4-pyridyl, or 2-, 3-or 4-pyridyl N-oxide, wherein pyridyl N-oxide can be represented as:

heteroarylalkenyl-represents an alkenyl group, as defined above, substituted with a heteroaryl group, as defined below ; heteroarylalkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined above; heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as defined below ; heterocycloalkyl-represents a saturated carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from the group consisting of:-O-, -S- or - NR24 wherein R24 is selected from the group consisting of: H, alkyl, aryl, and -C (O) N (R'8) Z wherein R18 is as above defined, examples of heterocycloalkyl groups include but are not limited to: 2-or 3-tetrahydrofuranyl, 2-or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2-or 3-pyrrolidinyl, 1-, 2-, 3-, or 4-piperizinyl, 2-or 4-dioxanyl, morpholinyl, and heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as above; "in association with"-means, in reference to the combination therapies of the invention, that the agents or components are adminstered concurrently or sequentially ; patient-represents a mammal, such as a human; sequentially-represents (1) administration of one component of the method ( (a) compound of the invention, or (b) chemotherapeutic agent, signal transduction inhibitor and/or radiation therapy) followed by administration of the other component or

components ; after adminsitration of one component, the next component can be administered substantially immediately after the first component, or the next component can be administered after an effective time period after the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component.

The positions in the tricyclic ring system are:

A"+"or a"-"in Ring II in the compounds below indicates the" (+)-isomer" or "(-)-isomer", respectively.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example :

N HO =/N HO C _N wCH3 I CI / CI represents N N N ce N N °J°t ° SCH3 r"r'cH3 CH3 OH OH/-N 0 NaH N N _NwCHa CI ; N mN N represents N and N N CNg CNg N N O''d O''O CH3 + SCH3 CH3 H3C N N H2N N H2 -2 62 0 (@ represents S ! L t L loSo 13 oW N O O H3C O O

Those skilled in the art will appreciate that the numbers"1"and"2"in a formula, e. g., represent Isomers 1 and 2, respectively. One of the isomers is and one of the isomers is: For example, for the isomers one isomers is

and one isomers is: For the compounds of this invention, Isomer 1 means that the compound is the first isomer to be obtained from the separation column being used to separate the diastereomer mixture (e. g. , the first isomer obtained by HPLC) or is a derivative of that first isomer. Isomer 2 means that the compound is the second isomer to be obtained from the separation column being used to separate the diastereomer mixture (e. g. , the second isomer obtained by HPLC) or is a derivative of that second isomer.

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) (preferably (32) ) or (33), then at least one of R30 to R33 is selected from the group consisting of substituents (7) to (13).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), then at least one of R30 to R33 is selected from the group consisting of substituents (7), (9), (10), (12) and (13).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to

R33 is-NH2, and R8 is (2.0), then R"is selected from the group consisting of substituents (3) to (10).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is -NH2, and R8 is (2. 0), then R"is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-N3, and R8 is (2.0), then R"is selected from the group consisting of substituents (3) to (10).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-N3, and R8 is (2.0), then R"is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-NH2, and R8 is (3.0), then R"is selected from the group consisting of substituents (1) to (14).

In an embodiment of the compounds of formula 10, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-NH2, and R8 is (3.0), then R11 is selected from the group consisting of substituents (3) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R33 is-NH2, and Ra ils (3. 0), then R"is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R33 is-N3, and R8 is (3. 0), then R"is selected from the group consisting of substituents (1) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to

R33 is-N3, and R8 is (3. 0), then R11 is selected from the group consisting of substituents (3) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-N3, and R8 is (3. 0), then R"is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R33 is NH2, and R8 is (4. 0), then: (a) R"a is selected from the group consisting of substituents (1) to (4) and (7) to (12), and R12 is as defined above for formula 1. 0, or (b) R"a is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is NH2, and R8 is (4.0), then: (a) R'la is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1.0, or (b) R"a is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of : cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (c) R"a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R33 is N3, and R8 is (4.0), then : (a) R'la is selected from the group consisting of substituents (1) to (4) and (7) to (12), and R12 is as defined above for formula 1.0, or (b) Rua is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R12 is selected from the group consisting of : cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is N3, and R8 is (4.0), then: (a) R11a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1. 0, or (b) R11a is

selected from the group consisting of substitutents (1) to (12), and R'2 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (c) R11a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-NH2, and R"is (5.0), then at least one of R2', R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32) ), and at least one of R30 to R33 is-N3, and R8 is (5.0), then at least one of R21, R22, and Ras is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13).

In an embodiment of formula 1. 0 : (1) when at least one of A and B (preferably B) is substitutent (32), and R30 and R31 are selected from the group consisting of substituents (1) to (6), then R8 is selected from the group consisting of : (a) (2.0) wherein R11 is selected from substituents (11) to (14), (b) (3.0) wherein R"is selected from substituents (11) to (14), (c) (4.0) wherein (i) R'1a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1.0, or (ii) R11a is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of : cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (iii) R"a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl-(piperidine Ring V), and (d) (5.0) wherein at least one of R2r, R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13); and (2) when at least one of A and B (preferably B) is substituent (32), and at least one of R30 or R31 is-NH2 (e. g., R30 is-NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (2. 0), then R8 is not (3) when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is-N3 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (2.0), then R8 is not In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), then at least one of R30 or R31 is selected from the group consisting of substituents (7), (9), (10), (12) and (13).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (2.0), then R"is selected from the group consisting of substituents (3) to (10).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (2. 0), then R11 is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -N3 (e. g., R30 is wN3 and R31 is H or alkyl (e. g. ,-CH3)), and R8 is (2.0), then R11 is selected from the group consisting of substituents (3) to (10).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R3'is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g. ,-CH3)), and R8 is (2. 0), then R11 is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -NH2 (e. g., R30 is

-NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (3.0), then R"is selected from the group consisting of substituents (1) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (3.0), then R"is selected from the group consisting of substituents (3) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (3. 0), then R is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (3.0), then R"is selected from the group consisting of substituents (1) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (3. 0), then R11 is selected from the group consisting of substituents (3) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g. ,-CH3)), and R8 is (3. 0), then R11 is selected from the group consisting of substituents (11) to (14).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g., -CH3)), and R8 is (4.0), then: (a) R11a is selected from the group consisting of substituents (1) to (4) and (7) to (12), and R'2 is as defined above for formula 1 0, or (b) R11a is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -NH2 (e.g., R30 is -NH2 and R3'is H or alkyl (e. g.,-CH3)), and R8 is (4.0), then: (a) RI"is selected from the group consisting of substituents (13) to (18), and R 2 is as defined above for

formula 1.0, or (b) Rla is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (c) R11a is selected from the group consisting of substituents (13) to (18), and R'2 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (4.0), then: (a) R11a is selected from the group consisting of substituents (1) to (4) and (7) to (12), and R'2 is as defined above for formula 1. 0, or (b) R11a is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R12 is selected from the group consisting of : cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is -N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g., -CH3)), and R8 is (4. 0), then: (a) R11a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1.0, or (b) R11a is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (c) R11a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-NH2 (e. g., R30 is -NH2 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (5. 0), then at least one of R, R and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13).

In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R30 or R31 is-N3 (e. g., R30 is -N3 and R31 is H or alkyl (e. g.,-CH3)), and R8 is (5. 0), then at least one of R, R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13).

Those skilled in the art will appreciate that the compounds of formula 1.0 are also represented by compounds of formula 1.1 :

or a pharmaceutically acceptable salt or solvate thereof, wherein: (A) one of a, b, c and d represents N or N+O-, and the remaining a, b, c, and d groups represent CR' (i. e. , carbon with an R'group) wherein each R'group on each carbon is the same or different; or (B) each a, b, c, and d group represents CR' (i. e. , carbon with an R'group) wherein each R'group on each carbon is the same or different; (C) the dotted lines (---) represent optional bonds; (D) X represents N or CH when the optional bond (to C11) is absent, and represents C when the optional bond (to C11) is present; (E) when the optional bond is present between carbon atom 5 (i. e. , C-5) and carbon atom 6 (i. e. , C-6) (i. e. , there is a double bond between C-5 and C-6) then there is only one A substituent bound to C-5 and there is only one B substituent bound to C-6, and A or B is other than H; (F) when the optional bond is not present between carbon atoms 5 and 6 (i. e. , there is a single bond between C-5 and C-6) then: (1) there are two A substituents bound to C-5 wherein each A substituent is independently selected ; and (2) there are two B substituents bound to C-6 wherein each B substituent is independently selected; and (3) at least one of the two A substituents or one of the two B substituents is H ; and

(4) at least one of the two A substituents or one of the two B substituants is other than H ; (i. e. , when there is a single bond between C-5 and C-6 one of the four substituents (A, A, B, and B) is H and one is other than H); (G) A and B is independently selected from the group consisting of : (1) -H; (2) -R9; - R9-C(O)-R9 ; (4)-Rs-C02-R9a ; (5) -(CH2)pR26 ; (6) -C (O) N (R9) 2, wherein each R9 is the same or different; (7) -C (O) NHR9 ; (8) -C (O) NH-CH2-C (O)-NH2 ; (9) -C (O) NHR26 ; (10)- (CH2) pC (R9)-O-R9a ; (11) -(CH2)p-1CH(R9)2, provided that p is not 0, and wherein each R9 is the same or different; (12)- (CH2) pC (O) R9 ; (13) -(CH2)pC(O)R27a; (14)-(CH2) pC (O) N (R9) 2, wherein each R9 is the same or different; (15) -(CH2) pC (O) NH (R9) ; (16) -(CH2) pC (O) N (R26)2, wherein each R26 is the same or different; (17) -(CH2) pN (R9)-R9a (e. g.-CH2-N (CH2-pyridine)-CH2-imidazole) ; (18)- (CH2) pN (R26)2, wherein each R26 is the same or different (e. g., -(CH2)p-NH-CH2-CH3) ; (19)- (CH2) pNHC (O) R5° ; (20)-(CH2) pNHC (O) 2R5° ; (21)- (CH2) pN (C (O) R27a)2 wherein each R 27a is the same or different; (22) -(CH2)pNR51C(O)R27, (23) -(CH2)pNR51C(O)R27 wherein R5'is not H, and R51 and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring; (24) -(CH2)pNR51C(O)NR27,

(25) -(CH2)pNR51C(O)NR27 wherein R51 is not H, and R51 and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring; (26) -(CH2)pNR51C(O) N (R27a)2, wherein each R27a is the same or different; (27) -(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different ; (28) -(CH2)pNHCO2R50; (29)- (CH2) pNC (O) NHR51; (30) -(CH2)pCO2R51; (31)-NHR9 ; (32) wherein R30 and R31 are the same or different, and each p is independently selected ; provided that for each

group when one of R30 or R31 is selected from the group consisting of:-OH, =O, -OR9a, -NH2, -NHR9a, -N(R9a)2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining R30 or R31 is selected from the group consisting of : H, alkyl, aryl (e. g., phenyl), and arylalkyl (e. g., benzyl) ; (33)

wherein R30, R31, R32 and R33 are the same or different; provided that when one of R30 or R31 is selected from the group consisting of :-OH, =O, -OR9a, -NH2, -NHR9a, - N(R9a)2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining R30 or R31 is selected from the group consisting of: H, alkyl, aryl (e. g., phenyl), and arylalkyl (e. g., benzyl) ; and provided that when one of R32 or R33 is selected from the group consisting of :-OH, =O, -OR9a, -NH2, -NHR9A, -N (R9a) 2, -N3, -NHR9b, and-N (R9a) R9b, then the remaining

R32 or R33 is selected from the group consisting of: H, alkyl, aryl (e. g., phenyl), and arylalkyl (e. g., benzyl) ; (34) -alkenyl-CO2R9a ; (35) -alkenyl-C(O)R9a ; (36) -alkenyl-CO2R51 ; (37) -alkenyl-C(O)-R27a ; (38) (CH2) p-alkenyl-CO2-R51 ; (39) -(CH2)pC=NOR51; and (40)- (CH2) p-Phthalimid ; (H) p is 0, 1, 2, 3 or 4 ; (I) R'is selected from the group consisting of: (1) H; (2) halo ; (3) -CF3 : (4) -OR10 ; (5) COR : (6) -SR10 ; -S(O)tR15; (8)-N -N(R10)2 ; (9) -NO2 ; (10) -OC (O) R (11) CO2R (12) -OCO2R15; (13) -CN; (14) -NR10COOR15; (15) -SR15C(O)OR15; (16) -SR15N(R13)2 wherein each R is independently selected from the group consisting of: H and-C (O) OR, and provided that R15 in-SR N (R) 2 iS not-CH2; (17) benzotriazol-1-yloxy ; (18) tetrazol-5-ylthio ;

(19) substituted tetrazol-5-ylthio ; (20) alkynyl ; (21) alkenyl : (22) alkyl ; (23) alkyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, -OR10 and -CO2R10; (24) alkenyl substituted with one or more (e. g. , 1,2 or 3) substitutents independently selected from the group consisting of: halogen,-OR and -CO2R10; (J) Each R3A is independently selected from the group consisting of: (1) halo ; (2) -CF3; (3)-OR ; (4) COR ; (5) -SR10 ; (6) -S(O)tR15; (7)-N (R) 2 ; (8)-NO2 ; (9) -OC (O) R ; (10) C02R 10 ; (11) -OCO2R15; (12) -CN ; (13) -NR10COOR15; (14) -SR15C(O)OR15; (15) -SR15N(R13)2 wherein each R13 is independently selected from the group consisting of: H and-C (O) OR, and provided that R15 in SR N (R) 2 is not-CH2; (16) benzotriazol-1-yloxy ; (17) tetrazol-5-ylthio ;

(18) substituted tetrazol-5-ylthio ; (19) alkynyl ; (20) alkenyl ; (21) alkyl ; (22) alkyl substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of: halogen, -OR10 and - COUR ; and (23) alkenyl substituted with one or more (e. g. , 1,2 or 3) substitutents independently selected from the group consisting of : halogen,-OR and -CO2R10; (K) m is 0,1 or 2; (L) t is 0, 1 or 2 (M) R5, R6, R7 and R7a are each independently selected from the group consisting of: (1) H; (2) -CF3 ; (3)-COR ; (4) alkyl ; (5) unsubstituted aryl : (6) alkyl substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of: -S(O)tR15, -NR10COOR15, -C(O)R10, and -CO2R10; and (7) aryl substituted with one or more (e. g. , 1,2, or 3) groups selected from the group consisting of:-S (O) tR15, -NR10COOR15, -C(O)R10, and -CO2R10; or (N) R together with R6 represents =0 or =S; (O) R8 is selected from the group consisting of:

(P) R9 is selected from the group consisting of: (1) unsubstituted heteroaryl ; (2) substituted heteroaryl ; (3) unsubstituted arylalkoxy ; (4) substituted arylalkoxy ; (5) heterocycloalkyl ; (6) substituted heterocycloalkyl ; (7) heterocycloalkylalkyl ; (8) substituted heterocycloalkylalkyl ; (9) unsubstituted heteroarylalkyl ; (10) substituted heteroarylalkyl ; (11) unsubstituted heteroarylalkenyl ; (12) substituted heteroarylalkenyl ; (13) unsubstituted heteroarylalkynyl and (14) substituted heteroarylalkynyl ; wherein said substituted R9 groups are substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of: (1)-OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2)-Co2R14 ; (3)-CH20R14, (4) halogen (e. g., Br, Cl or F), (5) alkyl (e. g. methyl, ethyl, propyl, butyl or t-butyl) ; (6) amino; (7) trityl ; (8) heterocycloalkyl ; (9) cycloalkyl, (e. g. cyclopropyl or cyclohexyl) ; (10) arylalkyl ; (11) heteroaryl ; (12) heteroarylalkyl and (13)

wherein R'4 is independently selected from the group consisting of: H; alkyl : aryl, arylalkyl, heteroaryl and heteroarylalkyl ; (Q) R9a is selected from the group consisting of: alky and arylalkyl ; (R) R9b is selected from the group consisting of: (1) -C (O) R9a ; (2)-SO2R9a ; <BR> <BR> <BR> (3)-C (O) NHR9a ;<BR> <BR> <BR> <BR> <BR> <BR> (4) -C (O) OR9a ; and (5) -C (O) N (R9C) 2 ; (S) Each R9c is independently selected from the group consisting of: H, alkyl and arylalkyl ; (T) R'° is selected from the group consisting of: H ; alkyl ; aryl and arylalkyl ; (U) R11 is selected from the group consisting of: (1) alkyl ; (2) substituted alkyl ; (3) unsubstituted aryl ; (4) substituted aryl ; (5) unsubstituted cycloalkyl ; (6) substituted cycloalkyl ; (7) unsubstituted heteroaryl ; (8) substituted heteroaryl ; (9) heterocycloalkyl ; and (10) substituted heterocycloalkyl ; (11) unsubstituted alkenyl (e. g., -CH2CH=CH2) ; (12) -N (alkyl)2 wherein each alkyl is independently selected (e. g., -N (CH3) 2 ; (13) unsubstituted arylalkyl ; and (14) substituted arylalkyl ; wherein said substituted alkyl R11 groups are substituted with one or more (e. g. 1,2 or 3) substituents selected from the group consisting of:

(1)-OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g. , Br, Cl or F); and (3) -CN; and wherein said substituted cycloalkyl, and substituted heterocycloalkyl R11 groups are substituted with one or more (e. g. 1, 2 or 3) substituents selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g., Br, Cl or F) ; and (3) alkyl ; and wherein said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyl R11 groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) halogen (e. g,. Br, Cl or F); (3) alkyl ; (4)-CF3 ; (5) -CN; and (6) alkoxy (e. g.,-OCH3) ; (V) R11a is selected from the group consisting of : (1) H; (2) OH; (3) alkyl ; (4) substituted alkyl : (5) unsubstituted aryl ; (6) substituted aryl ; (7) unsubstituted cycloalkyl ; (8) substituted cycloalkyl ;

(9) unsubstituted heteroaryl ; (10) substituted heteroaryl ; (11) heterocycloalkyl ; (12) substituted heterocycloalkyl ; (13)-OR9a ; (14) unsubstituted arylalkyl ; (15) substituted arylalkyl ; (16) unsubstituted alkenyl ; (17) unsubstituted arylacyl (e. g.,-C (O) phenyl) ; and (18) unsubstituted heteroarylalkyl (e. g.,-CH2-pyridyl) ; and wherein said substituted alkyl Rr1a groups are substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) -CN; (3) -CF3; (4) halogen (e. g,. Br, Cl or F) ; (5) cycloalkyl ; (6) heterocycloalkyl ; (7) arylalkyl ; (8) heteroarylalkyl ; and (9) heteroalkenyl ; and wherein said substituted cycloalkyl, and substituted heterocycloalkyl Rila groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2) -CN; (3)-CF3 : (4) halogen (e. g,. Br, Cl or F); (5) alkyl ;

(6) cycloalkyl ; (7) heterocycloalkyl ; (8) arylalkyl ; (9) heteroarylalkyl ; (10) alkenyl and (11) heteroalkenyl ; and wherein said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyl R'' groups have one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of : (1) -OH, provided that when there is more than one-OH group then each-OH group is bound to a different carbon atom (i. e., only one-OH group can be bound to a carbon atom); (2)-CN ; (3)-CF3 ; (4) halogen (e. g., Br, Cl or F); (5) alkyl ; (6) cycloalkyl ; (7) heterocycloalkyl ; (8) arylalkyl ; (9) heteroarylalkyl ; (10) alkenyl ; (11) heteroalkenyl ; (12) aryloxy (e. g.,-O-phenyl) ; and (13) alkoxy (e. g.,-OCH3) ; (W) R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and-alkyl- (piperidine Ring V) (wherein said piperidine Ring V is as described below, see, for example, paragraph (8) in the definition of R2', RZ and R46) ; (X) R'5 is selected from the group consisting of: alkyl and aryl ; (Y) R21, R22 and R46 are independently selected from the group consisting of: (1) H : (2) alkyl (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) unsubstituted aryl (e. g. phenyl) ;

(4) substituted aryl substituted with one or more substituents independently selected from the group consisting of : alkyl, halogen, CF3 and OH ; (5) unsubstituted cycloalkyl, (e. g. cyclohexyl) ; (6) substituted cycloalkyl substituted with one or more substituents independently selected from: alkyl, halogen, CF3 or OH; (7) heteroaryl of the formula, (8) piperidine Ring V: wherein R44is selected from the group consisting of: (a) H, (b) alkyl, (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (c) alkylcarbonyl (e. g., CH3C (O)-) ; (d) alkyloxy carbonyl (e. g.,-C (O) 0-t-C4H9,-C (O) OC2H5, and - C (O) OCH3); (e) haloalkyl (e. g., trifluoromethyl) ; and (f) -C(O) NH (R51) ; (9) -NH2 provided that only one of R21, R22, and R46 group can be -NH2, and provided that when one of R21, R22, and R46 is-NHz then the remaining groups are not-OH; (10) -OH provided that only one of R21, R22, and R46 group can be -OH, and provided that when one of R2', R22, and R46 is-OH then the remaining groups are not-NH2; and (11) alkyl substituted with one or more substituents (e. g. , 1-3, or 1-2, and preferably 1) selected from the group consisting of :-OH and-NH2, and provided that there is only one-OH or one-NH2 group on a substituted carbon;

(12) alkoxy (e. g.,-OCH3) ; or (13) R21 and R22 taken together with the carbon to which they are bound form a cyclic ring selected from the group consisting of: (a) unsubstituted cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl) ; (b) cycloalkyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH; (c) unsubstituted cycloalkenyl

wherein R44 is selected from the group consisting of: (1)-H, (2) alkyl, (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) alkylcarbonyl (e. g. , CH3C (O)-) ; (4) alkyloxy carbonyl (e. g.,-C (O) O-t-C4H9, -C (O) OC2H5, and-C (O) OCH3); (5) haloalkyl (e. g., trifluoromethyl) ; and (6) -C (O) NH (R5') ; (f) unsubstituted aryl (e. g., phenyl) ; (g) aryl substituted with one or more substituents independently selected from the group consisting of: alkyl (e. g., methyl), halogen (e. g., Cl, Br and F),-CN,-CF3, OH and alkoxy (e. g. , methoxy); and (i) heteroaryl selected from the group consisting of:

(Z) R26 is selected from the group consisting of: (1) H; (2) alkyl (e. g., methyl, ethyl, propyl, butyl or t-butyl) ; (3) alkoxy (e. g., methoxy, ethoxy, propoxy); (4)-CH2-CN ; (5) R9 ; (6) -CH2CO2H ; (7) -C (O) alkyl and (8) CH2CO2alkyl ; (AA) R27 is selected from the group consisting of : (1) H; (2) -OH; (3) alkyl (e. g., methyl, ethyl, propyl, or butyl), and (4) alkoxy ; (AB) R27a is selected from the group consisting of: (1) alkyl (e. g., methyl, ethyl, propyl, or butyl) ; and (2) alkoxy ; (AC) R30, R31, R32 and R33 are independently selected from the group consisting of: (1) -H ; (2) -OH; (3) =O ; (4) alkyl ; (5) aryl (e. g. phenyl) ; (6) arylalkyl (e. g., benzyl) ; (7)-OR9a ; (8) -NH2; (9)-NHR9a ; (10) -N (R9a) 2 wherein each R9a is independently selected ;

(11)-N3 ; <BR> <BR> <BR> (12)-NHR9b ; and<BR> <BR> <BR> <BR> <BR> (13) -N (R9a) R9b ; (AD) R50 is selected from the group consisting of: (1) alkyl ; (2) unsubstituted heteroaryl ; (3) substituted heteroaryl ; and (4) amino ; wherein said substituents on said substituted heteroaryl group are independently selected from one or more (e. g. , 1,2 or 3) substitutents selected from the group consisting of: alkyl (e. g., methyl, ethyl, propyl, or butyl) ; halogen (e. g. , Br, Cl, or F); and-OH; (AE) R5'is selected from the group consisting of : H and alkyl (e. g., methyl, ethyl, propyl, butyl and t-butyl) ; and (AF) provided that (1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom; and (2) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with more than one heteroatom; and (3) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with a heteroatom and a halo atom; and (4) a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and (5) a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and (6) the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms; and (7) when A and B are independently selected from the group consisting of substituents (1) to (31) and (34) to (39), then R8 is not H; and

(8) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (2.0), then R"is selected from the group consisting of substituents (11) to (14); and (9) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (3.0), then R"is selected from the group consisting of substituents (11) to (14); and (10) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (4.0), then: (a) R"a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above, or (b) R11a is selected from the group consisting of substituents (1) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (c) R11a is selected from the group consisting of substitutents (13) to (18), and R'2 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V); and (11) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R8 is (5. 0), then at least one of R2', R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13); and (12) when at least one of A and B (preferably B) is substituted (32) or (33) (preferably (32) ), and R30 to R33 are selected from the group consisting of substituents (1) to (6), then R8 is selected from the group consisting of: (a) (2.0) wherein R11 is selected from substituents (11) to (14), (b) (3.0) wherein R11 is selected from substituents (11) to (14), (c) (4.0) wherein (i) R"a is selected from the group consisting of substituents (13) to (18), and R12 is as defined above for formula 1.0, or (ii) R'la is selected from the group consisting of substitutents (1) to (12), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), or (iii) R"a is selected from the group consisting of substituents (13) to (18), and R12 is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl- (piperidine Ring V), and

(d) (5.0) wherein at least one of R2', R22, and R46 is selected from the group consisting of substituents (8) (g), (8) (h), (9), (10), (11), (12) and (13); and (13) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R33 is-NH2 (i. e., substituent (8) ), and R8 is (2.0), then R8 is not (14) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R30 to R is-N3 (i. e. , substituent (11)), and R8 is (2.0), then R is not When there is a single bond between C-5 and C-6, then there are two A substituents bound to C-5 and there are two B substituents bound to C-6 A IB A A BB i. e., represents 5 6 5 6 and each A and each B are independently selected, and at least one of the two A substituents or one of the two B substituents is H, and at least one of the two A substituents or one of the two B substituants is other than H (i. e. , when there is a single bond between C-5 and C-6 one of the four substituents (A, A, B, and B) is H and one is other than H).

The substituted R9 groups can be substituted on any portion of the group that has substitutable carbon atoms. For example, a group that has a ring moiety (e. g. , a heterocycloalkyl or heteroaryl ring) bound to a hydrocarbon moiety (e. g., alkyl, alkenyl or alkynyl) can be substituted on the ring moiety and/or the hydrocarbon moiety.

Thus, for example, substitued heteroarylalkyl can be substituted on the heteroaryl moiety and/or the alkyl moiety.

Piperidine Ring V includes the rings: Examples of Ring V include, but are not limited to:

One embodiment of this invention is directed to compounds of formula 1.1 wherein the C-5 to C-6 double bond is present, A is H, and B is the group:

wherein p of the- (CH2) p-moiety of said B group is 0, and wherein p of the

moiety of said B group is 1, and all other substitutents are as defined for formula 1.1.

Preferably R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl (e. g. , substituted imidazolyl). Most preferably R9 is a substituted heteroaryl, more preferably substituted imidazolyl, even more preferably an N-alkylimidazolyl, and still more preferably

Preferably R30 is selected from the group consisting of: -OH, -NH2, -OR9a (wherein R9a is C1 to C3 alkyl), N3, and -NHR9b, and R31 is selected from the group consisting of: H and alkyl (e. g., methyl). Most preferably (1) R30 is-OH and R3'is H; (2) R30 is -NH2 and R31 is H; (3) R30 is-OR9a (wherein R9a is C1 to C3 alkyl), and R31 is H or alkyl (e. g., C1-C6, C1-C4, Ci-C2, said alkyl group preferably being methyl), and preferably H ; (4) R30 is N3, and R31 is H or alkyl (e. g., C1-C6, C1-C4, Ci-C2, said alkyl group preferably being methyl), and preferably H; or (5) R30 is -NHR9b (wherein R9b is as defined for formula 1.1), and R31 is H or alkyl (e. g., C1-C6, Ci-C4, C1-C2, said alkyl group preferably being methyl), and preferably H. More preferably R30 is-NH2 or -NHR9b, and R31 is H. Still more preferably R30 is -NH2 and R31 is H. Preferably X is N. Preferably a is N. Preferably b is CR1 wherein R'is H. Preferably c is CR1 wherein R1 is H or halo (e. g., Br or Cl), and most preferably H. Preferably d is is CR1 wherein R'is H. Preferably R5, R6, R7, and R7a are H. Preferably m is 1 and R3A is halo (e. g. , Br or Cl), and most preferably Cl. When m is 1, R3A is preferably at the C-8 position, i. e. , preferably R3A is 8-halo and most preferably 8-Cl. R8 is preferably 2.0, 3.0, 4.0 or 5.0. When R8 is 2.0, R11 is preferably alakyl (e. g., Ci to C4), most preferably t-butyl or isopropyl, and more preferably isopropyl. Preferably R8 is 2.0. Preferably the compounds of this embodiment have the stereochemistry shown in formulas 1.5A, 1. 6A or 1 7A.

One embodiment of this invention is directed to compounds of formula 1.1 having the formula : wherein: (1) a, b, c, d, R3A, R5, R6, R, R, R8 and X are as defined for formula 1.1 ; (2) B is the group:

(3) in said B group: (a) p of the- (CH2) p- moiety is 0; (b) p of the moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety then R30 is selected from the group consisting of:-OH, or-NH2 (preferably-OH), and R3'is alkyl, most preferably Ci-Ce alkyl, more preferably Ci-C4 alkyl, still more preferably Ci-C2 alkyl, and even more preferably methyl ; (d) when p is 2 or 3 for the moiety

then: (1) for one-CR30R31-moiety, R30 is selected from the group consisting of:-OH or-NH2, and R3'is alkyl, most preferably C1- C6 alkyl, more preferably Ci-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl ; and (2) for the remaining -CR30R3'-moieties R30 and R3'are hydrogen; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R31-moiety when R30 is-OH or-NH2.

Another embodiment of this invention is directed to compounds of formula 1. 1 having the formula : wherein: (1) R8 and X are as defined for formula 1.0 ; (2) B is the group :

(3) in said B group : (a) p of the- (CH2) p- moiety is 0; (b) p of the moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety

then R30 is selected from the group consisting of :-OH or-NH2, and R31 is alkyl, most preferably Ci-Ce alkyl, more preferably C,- C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl ; (d) when p is 2 or 3 for the moiety

then : (1) for one -CR30R31- moiety, R30 is selected from the group consisting of :-OH or-NH2, and R31 is alkyl, most preferably C1- C6 alkyl, more preferably Ci-C4 alkyl, still more preferably Ci-C ? alkyl, and even more preferably methyl ; and (2) for the remaining -CR30R31- moieties R30 and R3'are hydrogen; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring

nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CF30R31- moiety when Ris-OHor-NH2 ; (4) a is N; (5) b, c and d are CR1 groups wherein all of said R1 substitutents are H, or one R1 substituent is halo (e. g. , Br, Cl or F) and the remaining two Rr substituents are hydrogen; (6) m is 1, and R3A is halo (e. g. , Br or CI), or m is 2 and each R3A is the same or different halo (e. g. , Br or Cl) ; and (7) R5, R6, Ruz and R a are H.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula :

wherein: (1) R8 is as defined for formula 1.0 ; (2) B is the group:

(3) in said B group: (a) p of the -(CH2)p- moiety is 0; (b) p of the moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety

then R30 is selected from the group consisting of:-OH or-NH2, and R3 is alkyl, most preferably Ci-Ce alkyl, more preferably Ci- C4 alkyl, still more preferably Ci-C2 alkyl, and even more preferably methyl ; (d) when p is 2 or 3 for the moiety then: (1) for one -CR30R31- moiety, R30 is selected from the group consisting of:-OH or-NH2, and R31 is alkyl, most preferably Cl- Ce alkyl, more preferably C1-C4 alkyl, still more preferably C,-C2 alkyl, and even more preferably methyl ; and (2) for the remaining -CR30R31- moieties R30 and R31 are hyårogen ; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent WR30R31-moiety when R30 is -OH or -NH2 ; (4) a is N ;

(5) b, c and d are CR'groups wherein all of said R1 substituents are H, or one R1 substituent is halo (e. g. , Br, Cl or F) and the remaining two R substituents are hydrogen; (6) m is 1, and R3A is halo (e. g., Br or Cl), or m is 2 and each R3A is the same or different halo (e. g. , Br or Cl) ; (7) X is N or CH; and (8) R5, R, R7, and R7a are H.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula : wherein: (1) a, b, c, d, R3A, R5, R6, R, R7a, R8 and X are as defined for formula 1.1 ; (2) B is the group: (3) in said B group: (a) p of the- (CH2) p- moiety is 0; (b) p of the moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety

then (i) R30 is-OH, and R3'is H; or (ii) R30 is-NH2, and R3'is H; or (iii) R30 is selected from the group consisting of : (1)-OR9a wherein R9a is Ci to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e. g., -OR9a is -OCH3 ; (2)-N3 ; 93) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl) ; (d) when p is 2 or 3 for the moiety then: (i) for one -CR30R31- moiety (1) R30 is-OH, and R31 is H; or (2) R30 is-NH2, and R31 is H; or (3) R30 is selected from the group consisting of: (a) -OR9a wherein R9a is Ci to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e. g.,-OR9a is -OCH3 ; (b) -N3;

(c)-NHR9b wherein R9b is as defined for formula 1.1 ; and (d) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g. , C1-C6 alkyl, C1-C2 alkyl, and methyl) ; and (ii) for the remaining UR30R31-moieties R30 and R3' are hydrogen; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R31-moiety when R30 is selected from the group consisting of : -OH, -NH2, -OR9a, -N3, and -NHR9b.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula : wherein : (1) R8 and X are as defined for formula 1.0 ; (2) B is the group:

(3) in said B group: (a) p of the- (CH2) p- moiety is 0; (b) p of the moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety then (i) R30 is-OH, and R31 is H ; or (ii) R30 is-NH2, and R31 is H; or (iii) R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C, to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e. g., -OR9a is-OCH3 ; (2) -N3 ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4)-N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 : and R31 is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl) ; (d) when p is 2 or 3 for the moiety

then: (i) for one -CR30R31- moiety , is-OH, and R31 is H ; or (2) R30 is-NH2, and R31 is H ; or (3) R30 is selected from the group consisting of: (a) -OR9a wherein R9a is C1 to C3 alkyl, preferably C,-C2 alkyl, and more preferably methyl, e. g.,-OR9a is -OCH3; (b) -N3; (c) -NHR9b wherein R9b is as defined for formula 1.1 ; and (d) -N (R9a) R9b wherein Ruz and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C2 alkyl, and methyl) ; and (ii) for the remaining-CR30R3'-moieties R30 and R3 are hydrogen; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R31-moiety when R30 is selected from the group consisting of : -OH, -NH2, -OR9a, -N3, and -NHR9b ;

(4) a is N ; (5) b, c and d are CR'groups wherein all of said R1 substituents are H, or one R1 substituent is halo (e. g., Br, Cl or F) and the remaining two R1 substituents are hydrogen; (6) m is 1, and R3A is halo (e. g. , Br or Cl), or m is 2 and each R3Ais the same or different halo (e. g. , Br or Cl) ; and (7) R5, R6, R, and R7a are H.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula: wherein: (1) R8 is as defined for formula 1.0 ; (2) B is the group: (3) in said B group: (a) p of the -(CH2)p- moiety is 0; (b) p of the moiety is 1 to-3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety

then (i) R30 is-OH, and R31 is H; or (ii) R30 is-NH2, and R31 is H; or (iii) R30 is selected from the group consisting of: (1) -OR9a wherein R9a is Ci to C3 alkyl, preferably Cl-C2 alkyl, and more preferably methyl, e. g., -OR9a is-OCH3 ; ) -N3; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of : H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl) ; (d) when p is 2 or 3 for the moiety then: (i) for one -CR30R31- moiety (1) R30 is-OH, and R3'is H; or (2) R30 is -NH2, and R31 is H; or (3) R30 is selected from the group consisting of: (a) -OR9a wherein R9a is C1 to C3 alkyl, preferably Cl-C2 alkyl, and more preferably methyl, e. g.,-OR9a is -OCH3; (b)-N3 ;

(c)-NHR9b wherein R9b is as defined for formula 1.1 ; and (d) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R3'is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, Cl-C2 alkyl, and methyl) ; and (ii) for the remaining -CR30R31- moieties R30 and R3 are hydrogen; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR30R31- moiety when R30 is selected from the group consisting of :-OH,-NH2,-OR9a, -N3, and -NHR9b ; (4) a is N; (5) b, c and d are CR'groups wherein all of said R'substituents are H, or one R1 substituent is halo (e. g. , Br, Cl or F) and the remaining two R' substituents are hydrogen; (6) m is 1, and R3A is halo (e. g., Br or CI), or m is 2 and each R3A is the same or different halo (e. g. , Br or Cl) ; (7) X is N or CH; and (8) R5, R6, R7, and Ruz are H.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula : wherein: (1) a, b, c, d, R3A, R5, R6, R7, R7a, R8 and X are as defined for formula 1. 1; (2) B is the group :

(3) in said B group: (a) p of the -(CH2)p- moiety is 0; (b) p of the moiety is 1; (c) (i) R30 is-OH, and R is H; or (ii) R30 is-NH2, and R3'is H; or (iii) R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., -OR9a is-OCH3) ; (2) -N3; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and

(4) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of : H and alkyl (e. g., C,-C6 alkyl, Ci-C4 alkyl, C1-C2 alkyl, and methyl) ; and (d) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R31-moiety when R30 is selected from the group consisting of : -OH, -NH2, -OR9a, -N3, and -NHR9b.

Another embodiment of this invention is directed to compounds of formula 1.4E having the formula : wherein: (1) R8 and X are as defined for formula 1.0 ; (2) B is the group: (3) in said B group: (a) p of the- (CH2) p- moiety is 0 ; (b) p of the

moiety is 1; (c) (i) R30 is -OH, and R31 is H; or (ii) R30 is-NH2, and R31 is H; or (iii) R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., - OR9a is-OCH3) ; ( (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -N (R9a) R9b wherein R9a and R9b is as defined for formula 1. 1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl) ; and (e) R9 is unsubstituted heteroaryl (e. g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R3'-moiety when R30 is selected from the group consisting of : -OH, -NH2, -OR9a, -N3, and -NHR9b ; (4) a is N ;

(5) b, c and d are CR1 groups wherein all of said R1 substituents are H, or one R'substituent is halo (e. g., Br, Cl or F) and the remaining two R1 substituents are hydrogen ; (6) m is 1, and R3A is halo (e. g. , Br or Cl), or m is 2 and each R3A is the same or different halo (e. g. , Br or CI) ; and (7) R5, R6, R7, and R'a are H.

Another embodiment of this invention is directed to compounds of formula 1.1 having the formula : wherein : (1) R8 is as defined for formula 1.0 ; (2) B is the group: (3) in said B group: (a) p of the- (CH2) p-moiety is 0; (b) p of the moiety is 1; (c) (i) R30 is -OH, and R3'is H ; or (ii) R30 is-NH2, and R31 is H : or

(iii) R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., -OR9a is -OCH3) ; (2) -N3 ; (3) -NHR9b wherein R9b is as defined for formula 1. 1 ; and (4) -N (R) R9b wherein R9a and R9b is as defined for formula 1.1 ; and R3'is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, Ci-C4 alkyl, Ci-C2 alkyl, and methyl) ; and (e) R9 is unsubstituted heteroaryl (e g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e. g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent-CR30R3'-moiety when R30 is selected from the group consisting of : -OH, -NH2, -OR9a, -N3, and -NHR9b ; (4) a is N ; (5) b, c and d are CR'groups wherein all of said R'substituents are H, or one R'substituent is halo (e. g. , Br, Cl or F) and the remaining two R1 substituents are hydrogen; (6) m is 1, and R3A is halo (e. g. , Br or CI), or m is 2 and each R3A is the same or different halo (e. g. , Br or CI) ; (7) X is N or CH; and (8) R5, R6, R7, and R7a are H.

Another embodiment of this invention is directed to compounds of formulas 1.2, 1. 3, 1. 4, 1. 4A, 1. 4B, 1.4C, 1.4D, 1.4 E, and 1.4F wherein X is CH.

Another embodiment of this invention is directed to compounds of formulas 1.2, 1. 3, 1.4, 1.4A, 1. 4B, 1.4C, 1. 4D, 1.4 E, and 1. 4F wherein X is CH, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formulas 1.2, 1.3, 1. 4, 1.4A, 1. 4B, 1.4C, 1.4D, 1.4 E, and 1.4F wherein X is N.

Another embodiment of this invention is directed to compounds of formulas 1.2, 1. 3, 1.4, 1.4A, 1. 4B, 1.4C, 1.4D, 1.4 E, and 1.4F wherein X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4 wherein p is 1 for the moiety

and R30 is-NH2.

Another embodiment of this invention is directed to a compound of formula 1.4 wherein p is 1 for the moiety R30 is-NH2, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4D wherein p is 1 for the moiety

R30 is-NH2, R31 is-CH3, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1. 4B, or a compound of formula 1.4C wherein R30 is - OH, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1. 4B, or a compound of formula 1.4C wherein R30 is ZH, R31 is H. and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.4B, or a compound of formula 1.4C wherein R30 is WH, R3'is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1. 4B, or a compound of formula 1.4C wherein R30 is -NH2, and R 31 is H.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1. 4B, or a compound of formula 1.4C wherein R30 is -NH2, and R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.4B, or a compound of formula 1.4C wherein R30 is -NH2, and R3'is H, X is N, and the optional bond between C5 and C6 is present (i. e., there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.4B, or a compound of formula 1.4C wherein R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g.,-OR9a is-OCH3) ; (2)-N3 ; (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R3'is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl).

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.4B, or a compound of formula 1.4C wherein R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., -OR9a is-OCH3) ; (2) -N3 : (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and

R31 is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, Cl-C4 alkyl, Ci-C2 alkyl, and methyl), and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1. 4B, or a compound of formula 1.4C wherein R30 is selected from the group consisting of: (1)-OR9a wherein R9a is Ci to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e.g., -OR9a is -CH3); (2) -N3; (3) -NHR9b wherein R9b is as defined for formula 1.1; and (4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is-OH, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1. 4D wherein R30 is -OH, R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is WH, R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is -NH2, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is-NH2, and R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is-NH2, and R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C1 to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g.,-OR9a is-OCH3) ; (2)-N3 ; (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and

(4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and 31 iS selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, C1-C4 alkyl, Ci-C2 alkyl, and methyl).

Another embodiment of this invention is directed to a compound of formula 1. 4D wherein R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C, to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., -OR9a is-OCH3) ; (2) -N3 : (3) -nhr9B wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, Ci-C4 alkyl, Ci-C2 alkyl, and methyl), and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g., -OR9a is -OCH3); - ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, Ci-C4 alkyl, C1-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is-OH, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is-OH, R3'is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is OH, R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1. 4E wherein R30 is-NH2, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1. 4E wherein R30 is -NH2, and R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1. 4E wherein R30 is-NH2, and R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C1 to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g.,-OR9a is-OCH3) ; (2)-N3 ; (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, C1-C4 alkyl, Ci-C2 alkyl, and methyl).

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of: (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g.,-OR9a is-OCH3) ; (2) -N3 ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl), and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of : (1) -OR9a wherein R9a is C1 to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g., -OR9a is-OCH3) ; (2)-Ns ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R3'is selected from the group consisting of: H and alkyl (e. g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is-OH, and R3'is H.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is-OH, R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is-OH, R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R3° is-NH2, and R31 is H.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is-NH2, and R31 is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is -NH2, and R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of: (1)-OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e. g., -OR9a is -OCH3) ; (2)-Ns ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of : H and alkyl (e. g., Ci-Ce alkyl, C1-C4 alkyl, Ci-C2 alkyl, and methyl).

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of: (1) -OR9a wherein R9a is Ci to C3 alkyl, preferably Cl-C2 alkyl, and more preferably methyl (e. g., -OR9a is -OCH3) ; (2)-N3 ; (3) -NHR9b wherein R9b is as defined for formula 1.1 ; and (4) -NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R3'is selected from the group consisting of: H and alkyl (e. g., Ci-Ce alkyl, Ci-C4 alkyl, C1-C2 alkyl, and methyl), and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of:

(1)-OR9a wherein R9a is C, to C3 alkyl, preferably Ci-C2 alkyl, and more preferably methyl (e. g.,-OR9a is-OCH3) ; (2)-N3 : (3)-NHR9b wherein R9b is as defined for formula 1.1 ; and (4)-NR9a R9b wherein R9a and R9b is as defined for formula 1.1 ; and R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C4 alkyl, Ci-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is -OR9a and R31 is H.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is-OR9a, R31 is H, and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-OR9a, R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is-N3 and R31 is H.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is-N3, R31 is H, and X is N.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R is-N3. R is H, X is N, and the optional bond between C5 and C6 is present (i. e., there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1. 4F wherein R30 is -NHR9b and R31 is H.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is -NHR9b, R31 is H, and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-NHR9b, R3'is H, X is N, and the optional bond between C5 and C6 is present (i. e., there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is-NR9aR94 and R3'is H.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is -NR9aR9b, R31 is H, and X is N.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is-NR9aR9b, R31 is H, X is N, and the optional bond between C5 and C6 is present (i. e., there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-OR9a and R3'is alkyl (e. g., methyl).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1. 4E or 1. 4F wherein R30 is-OR9a, R3'is alkyl (e. g., methyl), and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is -OR9a, R31 is alkyl (e. g., methyl), X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-N3 and R3'is alkyl (e. g., methyl).

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-N3, R31 is alkyl (e. g., methyl), and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1. 4E or 1.4F wherein Wo is-N3, R3'is alkyl (e. g., methyl), X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-NHR9b and R31 is alkyl (e. g., methyl).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1. 4E or 1.4F wherein R30 is-NHR9b, R3'is alkyl (e. g., methyl), and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is -NHR9b, R31 is alkyl (e. g., methyl), X is N, and the optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-NR9aR9b and R31 is alkyl (e. g., methyl).

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 isNR9aR9b. R31 is alkyl (e. g., methyl), and X is N.

Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F wherein R30 is-NR9aR9b, R31 is alkyl (e. g., methyl), X is N, and the

optional bond between C5 and C6 is present (i. e. , there is a double bond between C5 and C6).

Another embodiment of this invention is directed to compounds of formulas 1.4D, 1.4E and 1.4F, wherein for the R3° substituent-NHR9b, 9b is preferably -C (O) R9a, and more preferably-C (O) R9a wherein R9a is alkyl.

Another embodiment of this invention is directed to compounds of formulas 1. 4D, 1.4E and 1. 4F, wherein for the R30 substituent -NHR9b, 9b is preferably - C (O) R9a, and more preferably-C (O) R9a wherein R9a is alkyl ; and R31 is H.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R8 is formula 2.0 wherein R11 is as defined for formula 1.0.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R8 is formula 3.0 wherein R11 is as defined for formula 1.0.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1. 4D, 1.4E and 1.4F wherein R8 is 4.0 wherein R11a and R12 are as defined for formula 1.0.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1. 4D, 1.4E and 1.4F wherein R8 is 5.0 wherein R21, R22, and R46 are as defined for formula 1.0.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F, wherein R8 is formula 2.0 wherein R"is alkyl (e. g., isopropyl or t-butyl).

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F, wherein R8 is formula 2.0 wherein R"is alkyl (e. g., isopropyl or t-butyl, and preferably isopropyl), R30 is-NH2 and R31 is H.

Another embodiment of this invention is directed to compounds of formulas 1.4D, 1.4E and 1.4F, wherein for the R30 substituent-NHR9b, 9b is preferably - C (O) R9a, and more preferably-C (O) R9a wherein R9a is alkyl, and R8 is formula 2.0 wherein R11 is alkyl (e. g., isopropyl or t-butyl).

Another embodiment of this invention is directed to compounds of formulas 1. 4D, 1.4E and 1. 4F, wherein for the R30 substituent-NHR9b, 9b is preferably

- C (O) R9a, and more preferably-C (O) R9a wherein R9a is alkyl, and R31 is H, and R8 is formula 2.0 wherein R"is alkyl (e. g., isopropyl or t-butyl).

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein substituent a in Ring I is N, and substituents b, c, and d in Ring I are CR groups, and all of said R1 substituents are H.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein substituent a in Ring I is N, and substituents b, c, and d in Ring I are CR'groups, and said R'substituent at C-3 is halo and said R'substituents at C-2 and C-4 are hydrogen.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1. 4D, 1.4E and 1.4F wherein m is 1 and R3A is halo.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1. 4D, 1.4E and 1.4F wherein m is 1 and R3A is Cl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein m is 1 and R3A is halo at the C-8 position.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein m is 1 and R3A is Cl at the C-8 position.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1. 4D, 1.4E and 1.4F wherein m is 2, and each R3A is the same or different halo, and said halo substitution is at the C-7 and C-8 position or the C-8 and C-10 position.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is unsubstituted heteroaryl or substituted heteroaryl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is substituted heteroaryl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is substituted heteroaryl wherein said heteroaryl is mono substituted.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is unsubstituted imidazolyl or substituted imidazolyl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is substituted imidazolyl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is substituted imidazolyl wherein said imidazolyl is mono substituted and the substituent is alkyl (e. g., C1 to C3 alkyl, or Cl to C2 alkyl), and preferably said substituent is methyl.

Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R9 is.

In another embodiment, R8 is 2.0 in formula 1.2 wherein R"is as defined for formula 1.0.

In another embodiment, R8 is 3. 0 in formula 1.2 wherein R"is as defined for formula 1.0.

In another embodiment, R8 is 4.0 in formula 1.2 wherein R11a and R12 are as defined for formula 1.0.

In another embodiment, R8 is 5.0 in formula 1.2 wherein R, R22, and R46 are as defined for formula 1.0.

In another embodiment, R8 is 2.0 in formula 1.3 wherein R"is as defined for formula 1.0.

In another embodiment, R8 is 3.0 in formula 1.3 wherein R11 is as defined for formula 1.0.

In another embodiment, R8 is 4. 0 in formula 1.3 wherein R a and R12 are as defined for formula 1.0.

In another embodiment, R8 is 5.0 in formula 1 3 wherein R2', R22, and R46 are as defined for formula 1.0.

In another embodiment, R8 is 2.0 in formula 1.4 wherein R"is as defined for formula 1. 0.

In another embodiment, R8 is 3.0 in formula 1.4 wherein R"is as defined for formula 1.0.

In another embodiment, R8 is 4.0 in formula 1.4 wherein R"a and R12 are as defined for formula 1.0.

In another embodiment. R8 is 5.0 in formula 1.4 wherein R21, R22, and R46 are as defined for formula 1.0.

Preferably, in formulas 1.3 and 1.4, all R'substituents are H, or R'at C-3 is halo and R'at C-2 and C-4 is hydrogen, most preferably all R'substituents are hydrogen.

Preferably, in formulas 1.3 and 1.4, when m is 1 then R3A is preferably Cl at the C-8 position.

In formulas 1.3 and 1.4, when m is 2, then the substitution is 7, 8-dihalo, or 8, 10-dihalo.

Preferably, in formulas 1.3 and 1.4, the optional double bond between C5 and C6 is present, i. e., preferably there is a double bond between C5 and C6.

Preferably, in formulas 1.2 and 1.3 X is N.

Preferably, in formula 1.4 X is N.

Another embodiment of this invention is directed to compounds of formula 1.4 having the formula : wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R"is alkyl, more preferably 2.0 wherein R"is t-butyl or isopropyl, and even more preferably 2.0 wherein R"is isopropyl.

Another embodiment of the invention is directed to compounds of formula 1.5 having the formula :

wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R"is alkyl, more preferably 2.0 wherein R"is t-butyl or isopropyl, and even more preferably 2.0 wherein R"is isopropyl.

Thus, one embodiment of the invention is directed to compounds of formula 1.5 having the formula :

wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R"is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2. 0 wherein R11 is isopropyl.

Another embodiment of the invention is directed to compounds of formula 1.5 having the formula :

wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R"is alkyl, more preferably 2.0 wherein RX1 is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl.

In formulas 1. 2, 1.3, 1.4, 1. 5, 1.6, and 1. 7, R9 is preferably : Another embodiment of this invention is directed to compounds of formula 1. 4D, 1.4E or 1.4F having the formula : wherein all substituents are as defined for formulas 1.4D, 1.4E or 1.4F. Compounds of formula 1.5A include compounds wherein R8 is 2. 0, and include compounds wherein R8 is 2.0 wherein R11 is alkyl (e. g., Ci to C4, such as, isopropy or t-butyl).

Preferably R8 is 2.0, R11 is ispropyl, R30 is -NH2, and R31 is H.

Another embodiment of the invention is directed to compounds of formula 1.5A having the formula :

wherein all substituents are as defined for formulas 1. 4D, 1.4E or 1.4F. Compounds of formula 1.5A include compounds wherein R8 is 2.0, and include compounds wherein R8 is 2.0 wherein R11 is alkyl (e. g., Ci to C4, such as, isopropy or t-butyl).

Preferably Ra is 2. 0, R"is isopropyl, R30 is-NH2, and R31 is H.

Thus, one embodiment of the invention is directed to compounds of formula 1.5A having the formula : wherein all substituents are as defined for formulas 1.4D, 1.4E or 1. 4F. Compounds of formula 1. 5A include compounds wherein R8 is 2.0, and include compounds wherein Ra is 2.0 wherein R". is alkyl (e. g., C1 to C4, such as, isopropy or t-butyl).

Preferably R8 is 2.0, R11 is isopropyl, R30 is-NH2, and R31 is H.

Another embodiment of the invention is directed to compounds of formula 1.5A having the formula :

wherein all substituents are as defined for formulas 1.4D, 1.4E or 1.4F. Compounds of formula 1.5A include compounds wherein R8 is 2.0, and include compounds wherein R8 is 2.0 wherein R11 is alkyl (e. g., C, to C4, such as, isopropy or t-butyl).

Preferably R8 is 2.0, R11 is isopropyl, R30 is -NH2, and R31 is H.

In formulas 1.4D, 1.4E, 1. 4F, 1. 5A, 1.6A, and 1. 7A, R9 is preferably: The compounds of formula 1.0 include the R isomer:

wherein : X is N or CH ; a is N or C (N or Cor'in 1. 1A) ; and the optional bond between C-5 and C-6 is present and B is H, or the optional bond between C-5 and C-6 is absent and each B is H.

The compounds of formula 1. 0 also include the S isomer:

wherein : X is N or CH (preferably N); a is N or C (a is N or CR'in 1. 1 B) ; and the optional bond between C-5 and C-6 is present and A is H, or the optional bond between C-5 and C-6 is absent and each A is H (preferably the optional bond between C-5 and C-6 is present).

In one embodiment of the compounds of formula 1.0, R', R2, R3, and R4 are independently selected from the group consisting of : H and halo, more preferably H, Br, F and Cl, and even more preferably H and Cl. Representative compounds of formula 1.0 include dihalo (e. g. , 3, 8-dihalo) and monohalo (e. g., 8-halo) substituted compounds, such as, for example : (a) 3-bromo-8-chloro, (b) 3, 8-dichloro, (c) 3-bromo, (d) 3-chloro, (e) 3-fluor, ( 8-chloro or (g) 8-bromo.

In one embodiment of the compounds of formula 1. 1, each R1 is independently selected from the group consisting of: H and halo, most preferably H, Br, F and Cl, and more preferably H and Cl. Each R3 is independently selected from the group consisting of: H and halo, most preferably H, Br, F and Cl, and more preferably H and Cl. Representative compounds of formula 1.1 include dihalo (e. g., 3, 8-dihalo) and monohalo (e. g., 3-halo or 8-halo) substituted compounds, such as, for example: (a) 3- bromo-8-chloro, (b) 3, 8-dichloro, (c) 3-bromo, (d) 3-chloro, (e) 3-fluor, (f) 8-chloro or (g) 8-bromo.

In one embodiment of the invention, substituent a in compounds of formula 1.0 is preferably C or N, with N being preferred, and substituent a in compounds of formula 1.1 is Cor'or N, with N being preferred.

In one embodiment of the invention, R8 in compounds of formula 1.0 is selected from the group consisting of: In one embodiment of the invention, R8 in compounds of formula 1.0 is 2.0 or 4.0 ; and preferably R8 is 2.0.

In one embodiment of the invention, for compounds of formula 1.0, R"a is selected from the group consisting of : alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, heteroaryl, substituted heteroaryl, unsubstituted cyloalkyl and substituted cycloalkyl, wherein: (1) said substituted aryl and substituted heteroaryl R'groups are substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of : halo (preferably F or CI), cyano,-CF3, and alkyl ;

(2) said substituted cycloalkyl R"a groups are substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of: fluoro, cyano,-CF3, and alkyl ; and (3) said substituted alkyl R11a groups are substituted with one or more (e. g. , 1,2 or 3) substituents selected from the group consisting of: fluoro, cyano and CF3.

In one embodiment of the invention, for compounds of formula 1.0, R11a is selected from the group consisting of : alkyl, unsubstituted aryl, substituted aryl, unsubstituted cyloalkyl, and substituted cycloalkyl, wherein: (1) said substituted aryl is substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of: halo, (preferably F or CI),-CN and CF3 ; and (2) said substituted cycloalkyl is substituted with one or more (e. g. , 1,2 or 3) substituents independently selected from the group consisting of : fluoro, - CN and CF3.

In one embodiment of the invention, for compounds 1.0, R11a is selected from the group consisting of: methyl, t-butyl, phenyl, cyanophenyl, chlorophenyl, fluorophenyl, and cyclohexyl. In another embodiment, R'la is selected from the group consisting of: t-butyl, cyanophenyl, chlorophenyl, fluorophenyl and cyclohexyl. In another embodiment, R1'a is cyanophenyl (e. g., p-cyanophenyl).

In one embodiment of the invention, for compounds of formula 1. 0, R"is selected from the group consisting of alkyl, unsubstituted cycloalkyl, and substituted cycloalkyl, wherein said substituted cycloalkyl group is substituted with 1,2 or 3 substituents independently selected from the group consisting of: fluoro and alkyl (preferably methyl or t-butyl). Examples of R"groups include : methyl, ethyl, propyl, isopropyl, t-butyl, cyclohexyl or substituted cyclohexyl. In one embodiment of the invention, R"is selected from the group consisting of : methyl, isopropyl, t-butyl, cyclohexyl and fluorocyclohexyl (preferably p-fluorocyclohexyl). In one embodiment of the invention, R"is selected from the group consisting of: methyl, isopropyl, t-butyl, and cyclohexyl. In one embodiment of the invention R"is t-butyl or cyclohexyl. In one embodiment of the invention R"is t-butyl for 2.0, and R"is methyl for 3. 0. In one embodiment of this invention R"is isopropyl.

In one embodiment of the invention, for compounds of formula 1. 0, R12 is selected from the group consisting of: H and methyl. In one embodiment of the invention, R12 is H.

In one embodiment of the invention, for compounds of formula 1. 0, R5, R6, R' and R7a are H In one embodiment of the invention, for compounds of formula 1.0, R9 is selected from the group consisting of: (1) unsubstituted heteroaryl ; (2) substituted heteroaryl ; (3) arylalkoxy ; (4) substituted arylalkoxy ; (5) heterocycloalkyl ; (6) substituted heterocycloalkyl ; (7) heterocycloalkylalkyl ; (8) substituted heterocycloalkylalkyl ; (9) heteroarylalkyl ; (10) substituted heteroarylalkyl ; (11) heteroarylalkenyl and (12) substituted heteroarylalkenyl ; wherein said substituted R9 groups are substituted with one or more substituents (e. g., 1,2, or 3) independently selected from the group consisting of: (1) -OH; (2) -CO2R14, wherein R14 is selected from the group consisting of: H and alkyl (e. g., methyl and ethyl), preferably alkyl, most preferably methyl or ethyl ; (3) alkyl substituted with one or more-OH groups (e. g., 1,2, or 3, preferably 1), for example,- (CH2) qOH wherein, q is 1-4, with q = 1 being preferred ; (4) halo (e. g., Br, F, I, or CI) ; (5) alkyl, usually C,-C6 alkyl, preferably C1-C4 alkyl (e. g., methyl, ethyl, propyl, isopropyl, t-butyl or butyl, preferably isopropyl, or t-butyl) ; (6) amino; (7) trityl ;

(8) heterocycloalkyl ; (9) arylalkyl (e. g. benzyl) ; (10) heteroaryl (e. g. pyridyl) and (11) heteroarylalkyl ; In one embodiment of the invention, for the compounds of formula 1.0, R9 is selected from the group consisting of: (1) heterocycloalkyl ; (2) substituted heterocycloalkyl ; (3) heterocycloalkylalkyl ; (4) substituted heterocycloalkylalkyl ; (5) unsubstituted heteroarylalkyl ; (6) substituted heteroarylalkyl ; (7) unsubstituted heteroarylalkenyl and (8) substituted heteroarylalkenyl ; wherein said substituted R9 groups are substituted with one or more substituents (e. g., 1,2, or 3) independently selected from the group consisting of : (1) -OH; (2)-Co2R14 wherein R14 is selected from the group consisting of : H and alkyl (e. g., methyl or ethyl), preferably alkyl, and most preferably methyl and ethyl ; (3) alkyl, substituted with one or more-OH groups (e. g. , 1,2, or 3, preferably 1), for example- (CH2) qOH wherein, q is 1-4, with q = 1 being preferred.

(4) halo (e. g., Br or CI) ; (5) alkyl, usually Ci-Cg alkyl, preferably Ci-C4 alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl) ; (6) amino; (7) trityl ; (8) heterocycloalkyl ; (9) arylalkyl ; (10) heteroaryl and (11) heteroarylalkyl ; In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of :

(1) heterocycloalkyl ; (2) substituted heterocycloalkyl ; (3) heterocycloalkylalkyl ; (4) substituted heterocycloalkylalkyl ; (5) unsubstituted heteroarylalkyl ; (6) substituted heteroarylalkyl ; (7) unsubstituted heteroarylalkenyl and (8) substituted heteroarylalkenyl ; wherein said substituted R9 groups are substituted with one or more substituents (e. g., 1, 2, or 3) independently selected from the group consisting of: (1) halo (e. g., Br, or CI) ; (2) alkyl, Usually Cl-C6 alkyl, preferably Cl-C4 alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl) ; (3) alkyl, substituted with one or more (i. e. 1, 2, or 3, preferably 1) -OH groups, (e. g.- (CH2) qOH wherein q is 1-4, with q=1 being preferred).

(4) amino; (5) trityl ; (6) arylalkyl, and (7) heteroarylalkyl.

In one embodiment of the invention, R9 is selected from the group consisting of: (1) heterocycloalkylalkyl ; (2) substituted heterocycloalkylalkyl ; (3) unsubstituted heteroarylalkyl and (4) substituted heteroarylalkyl ; wherein said substituted R9 groups are substituted with one or more substituents (e. g., 1,2, or 3) independently selected from the group consisting of : (1) halo (e. g., Br, or CI) ; (2) alkyl, usually Cl-C6 alkyl, preferably Cl-C4 alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl and t-butyl, most preferably t-butyl) ; (3) amino ; and

(4) trityl.

In one embodiment of the invention, for formula 1 0, R9 is selected from the group consisting of (1) heterocycloalkylalkyl ; (2) substituted heterocycloalkylalkyl ; (3) unsubstituted heteroarylalkyl and (4) substituted heteroarylalkyl ; wherein said substituted R9 groups are substituted with one or more substituents (e. g., 1,2, or 3) independently selected from the group consisting of: (1) halo (e. g., Br, or CI) ; and (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t- butyl) In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of: (1) piperidinyl ; (2) piperizinyl ; (3)-(CH2) p-piperidinyl ; (4)-(CH2) p-piperizinyl ; (5) -(CH2)p-morpholinyl and (6)-(CH2) p-imidazolyl ; wherein p is 0 to 1, and wherein the ring moiety of each R9 group is optionally substituted with one, two or three substituents independently selected from the group consisting of: (1) halo (e. g., Br, or CI) ; and (2) alkyl, usually Ci-Ce alkyl, preferably C1-C4 alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl).

In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of : (1)-piperizinyl ; (2)-(CH2) p-piperidinyl ; (3)- (CH2) p-imidazolyl ; and (4)- (CH2) p-morpholinyl,

wherein p is 1 to 4, and the ring moiety of each R9 group is optionally substituted with one, two or three substituents independently selected from the group consisting of: methyl, ethyl, and isopropyl.

In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of :-(CH2)-imidazolyl, wherein said imidazolyl ring is optionally substituted with 1,2, or 3 substituants, preferably 1, independently selected from the group consisting of : methyl or ethyl.

In one embodiment of the invention, for formula 1.0, R9 is -(CH2)-(2-methyl)-imidazolyl.

In one embodiment of the invention, for formula 1.0, at least one of R21, R22 and R46 is other than H or alkyl. In one embodiment of the invention, R2'and R22 is H and R46 is other than H or alkyl. In one embodiment of the invention, R21 and R22 is H and R46 is selected from the group consisting of: heteroaryl and heterocycloalkyl.

In one embodiment of the invention, for formula 1.0, said heteroaryl groups for said R21, R22 or R46 are independently selected from the group consisting of : 3-pyridyl, 4-pyridyl, 3-pyridyl-N-Oxide and 4-pyridyl-N-Oxide. In one embodiment of the invention, said heteroaryl groups for said R21, R22 or R46 are independently selected from the group consisting of: 4-pyridyl and 4-pyridyl-N-Oxide. In one embodiment of the invention, said heteroaryl group for said R2', R22 or R46 is 4-pyridyl-N-Oxide.

In one embodiment of the invention, for formula 1. 0, said heterocycloalkyl groups for R21, R22, or R46 are selected from piperidines of Ring V: wherein R44 is -C(O)NHR@@. In one embodiment of the invention, R"is-C (0) NH2. tn one embodiment of the invention, piperidine Ring V is: and in one embodiment of the invention Ring V is:

Thus, in one embodiment of the invention, for formula 1.0, R21, R22 and R46 are independently selected from the group consisting of : (1) H; (2) aryl (most preferably phenyl) ; (3) heteroaryl and (4) heterocycloalkyl (i. e. , Piperidine Ring V) wherein at least one of R, R22, or R46 is other than H, and in one embodiment of the invention R21 and R22 are H and R46 is other than H, and in one embodiment of the invention R2'and R22 are H and R46 is selected from the group consisting of: heteroaryl and heterocycloalkyl, and in one embodiment of the invention R21 and R22 are H and R46 is Piperidine Ring V; wherein the definitions of heteroaryl and Piperidine Ring V are as described above.

In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of: (1) -H; (2) -R9; (4) -R9-CO2-R9a ; (5) -C (O) NHR9 ; (6) -C (O) NH-CH2-C (O)-NH2 ; (7) -C (O) NHR26 ; (8)- (CH2) p (R9) 2 wherein each R9 is the same or different; (10) -(CH2)pC(O)R27a; (11) -(CH2)pC(O)N(R9)2, wherein each R9 is the same or different; (12)- (CH2) pC (O) NH (R9) ; (13)- (CH2) pNHC (O) R5o ;

(14)- (CH2) pNHC (0) 2R50; (15)- (CH2) pN (C (O) R27a) 2 wherein each R27ais the same or different : (16) -(CH2)pNR51C(O)R27 ; (17) -(CH2)pNR51C(O)R27 wherein R51 is not H, and R51 and R27, taken together with the atoms to which they are bound, form a 5 or 6 memebered heterocycloalkyl ring; (18) -(CH2pNR51C(O)NR27 ; (19) -(CH2)pNR51C(O)NR27 wherein R5'is not H, and R5'and R27, taken together with the atoms to which they are bound, form a 5 or 6 membered heterocycloalkyl ring; (20) -(CH2)pNR51C(O) N (R27a) 2, wherein each R27a is the same or different; (21)- (CH2) pNHS02N (R5') 2, wherein each R5'is the same or different; (22) -(CH2)pNHCO2R50 ; (23) -(CH2)pCO2R51; (24)-NHR9 ; (25)

wherein R30 and Rare the same or different and (26)

wherein R30 R31 R32 and R33 are the same or different.

In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of: (1) -H; <BR> <BR> (2) -R9;<BR> (3) -R9-C(O)-R9; (4) -R9-CO2-R9a; (5) -C (O) NHR9 ;

(6) -(CH2)p(R9) 2, wherein each R9 is the same or different; (7)- (CH2) pC (O) R9 ; (8)- (CH2) pC (O) N (R9) 2, wherein each R9 is the same or different; -(CH2)pC(O)NH(R9) ; (10)- (CH2) pNR5'C (O) R27 ; (11) -(CH2)pNR51C(O)R27 wherein R51is not H, and R51 and R27, taken together with the atoms to which they are bound, form a 5 or 6 membered heterocycloalkyl ring ; (12) -(CH2)pNR51C(O)NR27; (13) -(CH2)pNR51C(O)NR27 wherein R51 is not H, and R51 and R27, taken together with the atoms to which they are bound, form a 5 or 6 membered heterocycloalkyl ring ; (14)-NHR9 ; and (15)

wherein R30 and Rare the same or different.

Examples of A and B include but are not limited to :

wherein p is 0,1, 2,3 or 4.

Examples of A and B also include but are not limited to:

Examples of A and B also include but are not limited to :

Thus, examples of B include but are not limited to:

Preferred examples of B include :

More preferred examples of B include : A most preferred example of B is: Examples of R8 groups include, but are not limited to:

Examples of R8 also include, but are not limited to:

Examples of Ra also include, but are not limited to: Examples of R8 also include, but are not limited to:

In one embodiment of the invention, for formula 1. 0, when the optional bond between C-5 and C-6 is present (i. e. , there is a double bond between C-5 and C-6), then one of A or B is H and the other is R9, and R9 is selected from the group consisting of: (1) heteroaryl ;

(2) substituted heteroaryl ; (3) arylalkyl ; (4) substituted arylalkyl ; (5) arylalkoxy ; (6) substituted arylalkoxy ; (7) heterocycloalkyl ; (8) substituted heterocycloalkyl ; (9) heterocycloalkylalkyl ; (10) substituted heterocycloalkylalkyl ; (11) unsubstituted heteroarylalkyl ; (12) substituted heteroarylalkyl ; (13) alkenyl ; (14) substituted alkenyl ; (15) unsubstituted heteroarylalkenyl ; and (16) substituted heteroarylalkenyl, wherein said substituted R9 groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH; (2)-Co2R14 ; (3) -CH2OR14, (4) halo, (5) alkyl (e. g. methyl, ethyl, propyl, butyl or t-butyl) ; (6) amino; (7) trityl ; (8) heterocycloalkyl ; (9) arylalkyl ; (10) heteroaryl and (11) heteroarylalkyl, wherein R'4 is independently selected from the group consisting of: H; and alkyl, preferably methyl and ethyl.

In one embodiment of the invention, for formula 1. 0, when there is a double bond between C-5 and C-6, A is H and B is R9. In one embodiment of the invention,

for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the group consisting of: (1) arylalkyl ; (2) substituted arylalkyl ; (3) arylalkoxy ; (4) substituted arylalkoxy ; (5) heterocycloalkyl ; (6) substituted heterocycloalkyl ; (7) heterocycloalkylalkyl ; (8) substituted heterocycloalkylalkyl ; (9) unsubstituted heteroarylalkyl ; (10) substituted heteroarylalkyl ; (11) alkenyl ; (12) substituted alkenyl ; (13) unsubstituted heteroarylalkenyl ; and (14) substituted heteroarylalkenyl, wherein said substituted R9 groups are substituted with one or more (e. g. 1,2 or 3) substituents independently selected from the group consisting of: (1) -OH; (2) halo, (preferably Br); (3) alkyl (e. g. methyl, ethyl, propyl, butyl, or t-butyl) ; (4) amino; and (5) trityl.

In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the group consisting of: (1) heterocycloalkylalkyl ; (2) substituted heterocycloalkylalkyl ; (3) unsubstituted heteroarylalkyl ; and (4) substituted heteroarylalkyl ; wherein said substituents for said substituted R9 groups are the same or different alkyl groups (e. g., Ci-C4 alkyl).

In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the group consisting of: (1) unsubstituted heteroaryl (C1-C3) alkyl ; and (2) substituted heteroaryl (Ci-C3) alkyl ; wherein the substituents for said substituted R9 group are as defined above.

In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the grooup consisting of: (1) unsubstituted heteroaryl (Ci-C3) alkyl, with unsubstituted heteroaryi-CH2-being preferred; and (2) substituted heteroaryl (Ci-C3) alkyl, with substituted heteroaryl-CH2-being preferred; wherein the substituents for said substituted R9 groups are selected from one or more (e. g. 1, 2 or 3, with one being preferred) of the same or different alkyl groups (e. g., -CH3,-C2H5,-C3H4, with-CH3 being preferred).

In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the group consisting of: (1)-CH2-imidazolyl ; (2) substituted imidazolyl-CH2-; (3)-(CH2) 2-imidazolyl ; (4) substituted imidazolyl- (CH2) 2- ; (5)-(CH2) 3-imidazolyl ; (6) substituted imidazolyl- (CH2) 3- ; (7) -CH2-piperazinyl and (8)-CH2-morpholinyl ; wherein the substituents for said substituted R9 groups are selected from one or more (e. g. 1,2 or 3, with one being preferred) of the same or different alkyl groups (e. g., -CH3,-C2H5,-C3H4, with-CH3 being preferred). Preferably, the substituted imidazolyl groups are selected from the group consisting of: with the substituted imidazolyl :

being most preferred.

In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is substituted imidazolyl-CH2-, with being preferred.

In one embodiment of the invention, for formula 1.0, when B is H and A is R9, and there is a double bond between C-5 and C-6, the R9 groups for A are those described above for B.

In one embodiment of the invention, for formula 1.0, when the optional bond between C-5 and C-6 is not present (i. e, there is a single bond between C-5 and C-6), each A and each B are independently selected and the definitions of A and B are the same as those described above when the optional bond is present, provided that when there is a single bond between C-5 and C-6 then one of the two A substituents or one of the two B substituents is H (i. e. , when there is a single bond between C-5 and C-6 one of the four substituents (A, A, B, and B) has to be H).

In one embodiment of the invention, for compounds of formula 1.0, there is a double bond between C-5 and C-6.

Compounds of formula 1.0, having C-11 R-and S-stereochemistry include :

wherein: X is N or C ; Q is Br or Cl ; and Y is alkyl, arylalkyl, or heteroarylalkyl.

This invention is also directed to compounds selected from the group consisting f

This invention is also directed to compounds selected from the group consisting of:

Representative compounds of formula 1.0 include but are not limited to compounds selected from the group consisting of :

Preferred compounds of the invention are selected from the group consisting of:

Preferred compounds of the invention are also selected from the group consisting of:

More preferred compounds of the invention are selected from the group consisting of:

More preferred compounds of the invention are also selected from the group consisting of : Most preferred compounds of the invention are selected from the group consisting of:

Most preferred compounds of the invention also include :

Compounds of the formula: had an FPT IC50 within the range of <0.5 nM to 7.9 nM, and a Soft Agar IC50 within the range of <0. 5 nM to 18 nM.

Compounds of the formula :

had an FPT IC50 within the range of 0.18 nM to 1.2 nM, and a Soft Agar IC50 within the range of <0.5 nM to 1 nM.

Another embodiment of this invention is directed to compounds selected from the group consisting of: Another embodiment of this invention is directed to compounds selected from the group consisting of :

Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Certain compounds of the invention may exist in different isomeric (e. g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.

Certain tricyclic compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e. g. , acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the

conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceutical acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

The compounds of the invention (e. g. , compounds of formula 1.0) can exist in unsolvated as well as solvate forms, including hydrated forms, e. g. , hemi-hydrate. In general, the solvate forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

The compounds of this invention: (i) potently inhibit famesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a famesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.

The compounds of this invention inhibit famesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e. g. , ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount (e. g. , a therapeutically effective amount) of one or more (e. g. , one) compounds of this invention. The administration of the compounds of this invention to patients, to inhibit famesyl protein transferase, is useful in the treatment of the cancers described below.

This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount (e. g. , a therapeutically effective amount) of one or more (e. g. , one) compounds of this

invention. Abnormal growth of cells refers to cell growth independent of normal regulator mechanisms (e. g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene ; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

This invention also provides a method for inhibiting or treating tumor (i. e., cancer) growth by administering an effective amount (e. g. , a therapeutical effective amount) of one or more (e. g. , one) compounds of this invention to a mammal (e. g. , a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount (e. g. , a therapeutical effective amount) of the above described compounds.

The present invention also provides a method of treating proliferative diseases, especially cancers (i. e, tumors), comprising administering an effective amount (e. g. , a therapeutically effective amount) of one or more (e. g., one) compounds of the invention, described herein, to a mammal (e. g. , a human) in need of such treatment in combination with an effective amount of at least one anti-cancer agent (i. e., a chemotherapeutic agent) and/or radiation.

The present invention also provides a method of treating proliferative diseases, especially cancers (i. e. , tumors), comprising administering an effective amount (e. g. , a therapeutically effective amount) of one or more (e. g. , one) compounds of the invention to a mammal (e. g. , a human) in need of such treatment in combination with an effective amount of at least one signal transduction inhibitor.

Examples of proliferative diseases (tumors, i. e. , cancers) which may be inhibited or treated include, but are not limited to: (A) lung cancer (e. g., lung adenocarcinoma and non small cell lung cancer); (B) pancreatic cancers (e. g. , pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma) ; (C) colon cancers (e. g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma);

(D) myeloid leukemias (for example, acute myelogenous leukemia (AML), CML, and CMML) ; (E) thyroid follicular cancer; (F) myelodysplastic syndrome (MDS); (G) bladder carcinoma; (H) epidermal carcinoma; (I) melanoma ; (J) breast cancer ; (K) prostate cancer; (L) head and neck cancers (e. g. , squamous cell cancer of the head and neck); (M) ovarian cancer ; (N) gliomas ; (O) cancers of mesenchymal origin (e. g. , fibrosarcomas and rhabdomyosarcomas) ; (P) sarcomas; (Q) tetracarcinomas ; (R) nuroblastomas ; (S) kidney carcinomas; (T) hepatomas; (U) non-Hodgkin's lymphom ; (V) multiple myeloma ; and (W) anaplastic thyroid carcinoma.

For example, embodiments of this invention include methods of treating cancer wherein said cancer is selected from the group consisting of: pancreatic cancers, lung cancers, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck cancers, melanomas, breast cancers, prostate cancers, ovarian cancers, bladder cancers, gliomas, epidermal cancers, colon cancers, non-Hodgkin's lymphomas, and multiple myelomas comprising administering to said patient an effective amount of a compound of this invention.

Also for example, embodiments of this invention include methods of treating cancer wherein said cancers are selected from the group consisting of: lung cancer (e. g., non-small cell lung cancer), head and neck cancer (e. g. , squamous cell cancer

of the head and neck), bladder cancer, breast cancer, prostate cancer, and myeloid leukemias (e. g. , CML and AML), non-Hodgkin's lymphom and multiple myeloma.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering a therapeutically effective amount of one or more (e. g. , one) compounds of the invention and therapeutically effective amounts of at least two different antineoplastic agents selected from: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloid, (12) antibodies that are inhibitors of aVp3 integrins, (13) small molecules that are inhibitors of aVß3 integrins, (14) folate antagonists, (15) ribonucleotide reductase inhibitors, (16) anthracyclines, (17) biologics ; (18) thalidomide (or related imid), and (19) Gleevec.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutical effective amounts of one or more (e. g. , one) compounds of the invention and an antineoplastic agent selected from: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are antibodies, and (4) VEGF inhibitors that are small molecules. Radiation therapy can also be used in conjunction with the above combination therapy, i. e. , the above method using a combination of compounds of the invention and antineoplastic agent can also comprise the administration of a therapeutically effect amount of radiation.

This invention also provides a method of treating leukemias (e. g. , acute myeloid leukemia (AML), and chronic myeloid leukemia (CML) ) in a patient in need of such treatment comprising administering therapeutical effective amounts of one or more (e. g., one) compounds of the invention and: (1) Gleevec and interferon to treat CML; (2) Gleevec and pegylated interferon to treat CML; (3) an anti-tumor nucleoside derivative (e. g. , Ara-C) to treat AML; or (4) an anti-tumor nucleoside derivative (e. g., Ara-C) in combination with an anthracycline to treat AML.

This invention also provides a method of treating non-Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutically effective

amounts of one or more (e. g. , one) compounds of the invention and: (1) a biologic (e. g. , Rituxan); (2) a biologic (e. g. , Rituxan) and an anti-tumor nucleoside derivative (e. g., Fludarabine) ; or (3) Genasense (antisense to BCL-2).

This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutical effective amounts of one or more (e. g. , one) compounds of the invention and: (1) a proteosome inhibitor (e. g. , PS-341 from Millenium) ; or (2) Thalidomide (or related imid).

This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1. 0); (b) at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies ; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aVp3 integrins; (13) small molecule inhibitors of aVp3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors; (16) anthracyclines ; (17) biologics ; (18) Thalidomide (or related Imid) ; and

(19) Gleevec.

This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) at least two different antineoplastic agents selected from the group consisting of : (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies ; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aVp3 integrins; or (13) small molecule inhibitors of aVß3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors; (16) anthracyclines ; (17) biologics ; and (18) Thalidomide (or related Imid).

This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ;

(b) at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives ; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aV03 integrins ; or (13) small molecule inhibitors of aVp3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors; (16) anthracyclines ; and (17) biologics.

This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) at least two different antineoplastic agents selected from the group consisting of : (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies ; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ;

(7) estrogen receptor antagonists or selective estrogen receptor modulators; (8) anti-tumor nucleoside derivatives ; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aVß3 integrins; and (13) small molecule inhibitors of aV3 integrins.

This invention also provides a method of treating non small cell lung cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1. 0); (b) at least two different antineoplastic agents selected from the group consisting of : (1) taxanes ; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives ; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aVß3 integrins; and (13) small molecule inhibitors of aV3 integrins.

This invention also provides a method of treating non small cell lung cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of :

(a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) at least two different antineoplastic agents selected from the group consisting of : (1) taxanes; (2) platinum coordinator compounds; (3) anti-tumor nucleoside derivatives; (4) topoisomerase inhibitors; and (5) vinca alkaloid.

This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) carboplatin ; and (c) paclitaxel.

This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g., a compound of formula 1.0) ; (b) cisplatin ; and (c) gemcitabine.

This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) carboplatin ; and (c) gemcitabine.

This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of:

(a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g., a compound of formula 1.0) ; (b) Carboplatin ; and (c) Docetaxel.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g., a compound of formula 1.0) ; (b) an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies; and (4) VEGF kinase inhibitors that are small molecules.

This invention also provides a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) one or more antineoplastic agents selected from the group consisting of: (1) taxanes; and (2) platinum coordinator compounds.

This invention also provides a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1. 0); (b) at least two different antineoplastic agents selected from the group consisting of : (1) taxanes : (2) platinum coordinator compounds; and (3) anti-tumor nucleoside derivatives (e. g., 5-Fluorouracil).

This invention also provides a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Gleevec ; and (c) interferon (e. g., Intron-A).

This invention also provides a method of treating CML in a patient in need of such treatment comprising administering therapeutical effective amounts of : (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Gleevec ; and (c) pegylated interferon (e. g., Peg-lntron, and Pegasys).

This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) an anti-tumor nucleoside derivative (e. g. , Cytarabine (i. e. , Ara- C)).

This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) an anti-tumor nucleoside derivative (e. g. , Cytarabine (i. e. , Ara- C) ); and (c) an anthracycline.

This invention also provides a method of treating non-Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Rituximab (Rituxan).

This invention also provides a method of treating non-Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Rituximab (Rituxan); and (c) an anti-tumor nucleoside derivative (e. g., Fludarabine (i. e. , F-ara- A).

This invention also provides a method of treating non-Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Genasense (antisense to BCL-2).

This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutical effective amounts of : (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) a proteosome inhibitor (e. g. , PS-341 (Millenium)).

This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of this invention (i. e., a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Thalidomide or related imid.

This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of formula 1.0) ; (b) Thalidomide.

This invention is also directed to the methods of treating cancer described herein, particularly those described above, wherein in addition to the administration of the FPT inhibitor and antineoplastic agents radiation therapy is also administered prior to, during, or after the treatment cycle.

It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i. e., the Ras gene itself is not activated by mutation to an oncogenic form--with said inhibition or treatment being accomplished by the administration of an effective amount (e. g. a therapeutically effective amount) of one or more (e. g. , one) compounds of the invention to a mammal (e. g. , a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e. g. , neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

The compounds of the invention useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as Ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer.

Without wishing to be bound by theory, it is believed that these compounds inhibit ras famesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.

The method of treating proliferative diseases (cancers, i. e. , tumors), according to this invention, includes a method for treating (inhibiting) the abnormal growth of cells, including transformed cells, in a, by administering, concurrently or sequentially, an effective amount of a compound of this invention and an effective amount of a chemotherapeutic agent and/or radiation.

In preferred embodiments, the methods of the present invention include methods for treating or inhibiting tumor growth in a patient in need of such treatment by administering, concurrently or sequentially, (1) an effective amount of a compound of this invention and (2) an effective amount of at least one antineoplastic agent, microtubule affecting agent and/or radiation therapy. For example, one embodiment

of these methods is directed to a method of treating cancers selected from the group consisting of: lung cancer, prostate cancer and myeloid leukemias.

The methods of treating proliferative diseases, according to this invention, also include a method for treating (inhibiting) proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i. e. , the ras gene itself is not activated by mutation to an oncogenic form. This method comprises administering, concurrently or sequentially, an effective amount of a compound of this invention and an effective amount of an antineoplastic agent and/or radiation therapy to a patient in need of such treatment.

Examples of such proliferative diseases which may be treated include : the benign proliferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e. g. , neu, src, abl, Ick, lyn, fyn).

For radiation therapy, y-radiation is preferred.

The methods of treating proliferative diseases (cancers, i. e. , tumors), according to this invention, also include a method for treating (inhibiting) the abnormal growth of cells, including transformed cells, in a patient in need of such treatment, by administering, concurrently or sequentially, an effective amount of a compound of this invention and an effective amount of at least one signal transduction inhibitor.

Typical signal transduction inhibitors include but are not limited to: (i) Bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) ; (ii) Epidermal growth factor (EGF) receptor inhibitor such as, for example, Kinase inhibitors (Iressa, OSI-774) and antibodies (Imclone : C225 [Goldstein et al.

(1995), Clin Cancer Res. 1: 1311-1318], and Abgenix: ABX-EGF) and (iii) HER-2/neu receptor inhibitors such as, for example, Herceptin (trastuzumab).

Embodiments of the methods of treatment of this invention are directed to the use of a combination of drugs (compounds) for the treatment of cancer, i. e. , this invention is directed to a combination therapy for the treatment of cancer. Those skilled in the art will appreciate that the drugs are generally administered individually as a pharmaceutical composition. The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention.

The antineoplastic agents are usually administered in the dosage forms that are readily available to the skilled clinician, and are generally administered in their normally prescribed amounts (as for example, the amounts described in the Physician's Desk Reference, 56 Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742 the disclosure of which is incorporated herein by reference thereto), or the amounts described in the manufacture's literature for the use of the agent).

For example, the FPT inhibitor can be administered orally (e. g. , as a capsule), and the antineoplastic agents can be administered intravenously, usually as an IV solution. The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention.

The FPT inhibitor and the antineoplastic agents are administered in therapeutically effective dosages to obtain clinically acceptable results, e. g. , reduction or elimination of symptoms or of the tumor. Thus, the FPT inhibitor and antineoplastic agents can be administered concurrently or consecutively in a treatment protocol.

The administration of the antineoplastic agents can be made according to treatment protocols already known in the art.

The FPT inhibitor and antineoplastic agents are administered in a treatment protocol that usually lasts one to seven weeks, and is repeated typically from 6 to 12 times. Generally the treatment protocol lasts one to four weeks. Treatment protocols of one to three weeks may also be used. A treatment protocol of one to two weeks may also be used. During this treatment protocol or cycle the FPT inhibitor is administered daily while the antineoplastic agents are administered one or more times a week. Generally, the FPT inhibitor can be administered daily (i. e. , once per day), preferably twice per day, and the antineoplastic agent is administered once a week or once every three weeks. For example, the taxanes (e. g., Paclitaxel (e. g., Taxon@) or Docetaxel (e. g., Taxotere@)) can be administered once a week or once every three weeks.

However, those skilled in the art will appreciate that treatment protocols can be varied according to the needs of the patient. Thus, the combination of compounds (drugs) used in the methods of this invention can be administered in variations of the protocols described above. For example, the FPT inhibitor can be administered discontinuously rather than continuously during the treatment cycle. Thus, for

example, during the treatment cycle the FPT inhibitor can be administered daily for a week and then discontinued for a week, with this administration repeating during the treatment cycle. Or the FPT inhibitor can be administered daily for two weeks and discontinued for a week, with this administration repeating during the treatment cycle.

Thus, the FPT inhibitor can be administered daily for one or more weeks during the cycle and discontinued for one or more weeks during the cycle, with this pattern of administration repeating during the treatment cycle. This discontinuous treatment can also be based upon numbers of days rather than a full week. For example, daily dosing for 1 to 6 days, no dosing for 1 to 6 days with this pattern repeating during the treatment protocol. The number of days (or weeks) wherein the FPT inhibitor is not dosed does not have to equal the number of days (or weeks) wherein the FPT inhibitor is dosed. Usually, if a discontinuous dosing protocol is used, the number of days or weeks that the FPT inhibitor is dosed is at least equal or greater than the number of days or weeks that the FPT inhibitor is not dosed.

The antineoplastic agent could be given by bolus or continuous infusion. The antineoplastic agent could be given daily to once every week, or once every two weeks, or once every three weeks, or once every four weeks during the treatment cycle. If administered daily during a treatment cycle, this daily dosing can be discontinuous over the number of weeks of the treatment cycle. For example, dosed for a week (or a number of days), no dosing for a week (or a number of days, with the pattern repeating during the treatment cycle.

The FPT inhibitor can be administered orally, preferably as a solid dosage form, more preferably a capsule, and while the total therapeutical effective daily dose can be administered in one to four, or one to two divided doses per day, generally, the therapeutically effective dose is given once or twice a day, preferably twice a day. The FPT inhibitor can be administered in an amount of about 50 to about 400 mg once per day, and can be administered in an amount of about 50 to about 300 mg once per day. The FPT inhibitor is generally administered in an amount of about 50 to about 350 mg twice a day, usually 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day.

If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician.

Upon completion of the therapy cycles, the patient can be continued on the FPT inhibitor at the same dose that was administered in the treatment protocol, or, if the dose was less than 200mg twice a day, the dose can be raised to 200 mg twice a day.

This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose).

The antineoplastic agents used with the FPT inhibitor are administered in their normally prescribed dosages during the treatment cycle (i. e. , the antineoplastic agents are administered according to the standard of practice for the administration of these drugs). For example : (a) about 30 to about 300 mg/m2 for the taxanes; (b) about 30 to about 100 mg/m2 for Cisplatin ; (c) AUC of about 2 to about 8 for Carboplatin ; (d) about 2 to about 4 mg/m2 for EGF inhibitors that are antibodies ; (e) about 50 to about 500 mg/m2 for EGF inhibitors that are small molecules ; (f) about 1 to about 10 mg/m2 for VEGF kinase inhibitors that are antibodies; (g) about 50 to about 2400 mg/m2 for VEGF inhibitors that are small molecules ; (h) about 1 to about 20 mg for SERMs ; (i) about 500 to about 1250 mg/m2 for the anti-tumor nucleosides 5-Fluorouracil, Gemcitabine and Capecitabine ; (j) for the anti-tumor nucleoside Cytarabine (Ara-C) 100-200mg/m2/day for 7 to 10 days every 3 to 4 weeks, and high doses for refractory leukemia and lymphoma, i. e. , 1 to 3 gm/m2 for one hour every 12 hours for 4-8 doses every 3 to four weeks; (k) for the anti-tumor nucleoside Fludarabine (F-ara-A) 10- 25mg/m2/day every 3 to 4 weeks; (I) for the anti-tumor nucleoside Decitabine 30 to 75 mg/m2 for three days every 6 weeks for a maximum of 8 cycles ; (m) for the anti-tumor nucleoside Chlorodeoxyadenosine (CdA, 2-CdA) 0.05-0. 1 mg/kg/day as continuous infusion for up to 7 days every 3 to 4 weeks; (n) about 1 to about 100 mg/m2 for epothilones ; (o) about 1 to about 350 mg/m2 for topoisomerase inhibitors; (p) about 1 to about 50 mg/m2 for vinca alkaloid ; (q) for the folate antagonist Methotrexate (MTX) 20-60 mg/m2 by oral, IV or IM every 3 to 4 weeks, the intermediate dose regimen is 80-250 mg/m2 IV over 60 minutes every 3 to 4 weeks, and the high dose regimen is 250-1000mg/m2 IV given with leucovorin every 3 to 4 weeks; (r) for the folate antagonist Premetrexed (Alimta) 300-600 mg/m2 (10 minutes IV infusion day 1) every 3 weeks; (s) for the ribonucleotide reductase inhibitor Hydroxyurea (HU) 20-50 mg/kg/day (as needed to bring blood cell counts down); (t) the platinum coordinator compound Oxaliplatin (Eloxatin) 50-100 mg/m2 every 3 to 4 weeks (preferably used for

solid tumors such as non-small cell lung cancer, colorectal cancer and ovarian cancer) ; (u) for the anthracycline daunorubicin 10-50 mg/m2/day IV for 3-5 days every 3 to 4 weeks; (v) for the anthracycline Doxorubicin (Adriamycin) 50-100 mg/m2 IV continuous infusion over 1-4 days every 3 to 4 weeks, or 10-40 mg/m2 IV weekly ; (w) for the anthracycline Idarubicin 10-30 mg/m2 daily for 1-3 days as a slow IV infusion over 10-20 minutes every 3 to 4 weeks; (x) for the biologic interferon (Intron-A, Roferon) 5 to 20 million IU three times per week; (y) for the biologic pegylated interferon (Peg-intron, Pegasys) 3 to 4 micrograms/kg/day chronic sub cutaneous (until relapse or loss of activity); and (z) for the biologic Rituximab (Rituxan) (antibody used for non-Hodgkin's lymphom) 200-400mg/m2 IV weekly over 4-8 weeks for 6 months.

Gleevec can be used orally in an amount of about 200 to about 800 mg/day.

Thalidomide (and related imids) can be used orally in amounts of about 200 to about 800 mg/day, and can be contiuously dosed or used until relapse or toxicity.

See for example Mitsiades et al.,"Apoptotic signaling induced by immunomodulatory thalidomide analoqs in human multiple myeloma cells ; therapeutic implications", Blood, 99 (12): 4525-30, June 15, 2002, the disclosure of which is incorporated herein by reference thereto.

For example, Paclitaxel (e. g., Taxons can be administered once per week in an amount of about 50 to about 100 mg/m2 with about 60 to about 80 mg/m2 being preferred. In another example Paclitaxel (e. g., Taxons can be administered once every three weeks in an amount of about 150 to about 250 mg/m2 with about 175 to about 225 mg/m2 being preferred.

In another example, Docetaxel (e. g., Taxotere@) can be administered once per week in an amount of about 10 to about 45 mg/m2 In another example Docetaxel (e. g., Taxotere@) can be administered once every three weeks in an amount of about 50 to about 100 mg/m2.

In another example Cisplatin can be administered once per week in an amount of about 20 to about 40 mg/m2. In another example Cisplatin can be administered once every three weeks in an amount of about 60 to about 100 mg/m2.

In another example Carboplatin can be administered once per week in an amount to provide an AUC of about 2 to about 3. In another example Carboplatin can

be administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

Thus, in one example (e. g. , treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Paclitaxel (e. g., Taxo) is administered once per week in an amount of about 50 to about 100 mg/m2 with about 60 to about 80 mg/m2 being preferred; and (3) Carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

In another example (e. g. , treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Paclitaxel (e. g., Taxo) is administered once per week in an amount of about 50 to about 100 mg/m2 with about 60 to about 80 mg/m2 being preferred; and (3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

In another example (e. g., treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day ; (2) Docetaxel (e. g., Taxotere@) is administered once per week in an amount of about 10 to about 45 mg/m2 ; and (3) Carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

In another example (e. g. , treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Docetaxel (e. g., Taxotere@) is administered once per week in an amount of about 10 to about 45 mg/m2 ; and

(3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

Thus, in one example (e. g., treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Paclitaxel (e. g., Taxo) is administered once every three weeks in an amount of about 150 to about 250 mg/m2, with about 175 to about 225 mg/m2 being preferred, and with 175 mg/m2 being most preferred; and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8, and preferably 6.

In a preferred example of treating non small cell lung cancer: (1) the FPT inhibitor is administered in an amount of 100 mg administered twice a day; (2) Paclitaxel (e. g., Taxol is administered once every three weeks in an amount of 175 mg/m2 ; and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of 6.

In another example (e. g. , treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Paclitaxel (e. g., Taxo) is administered once every three weeks in an amount of about 150 to about 250 mg/m2, with about 175 to about 225 mg/m2 being preferred; and (3) Cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

In another example (e. g. , treating non small cell lung cancer) : (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Docetaxel (e. g., Taxotere) is administered once every three weeks in an amount of about 50 to about 100 mg/m2 ; and

(3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

In another example (e. g. , treating non small cell lung cancer): (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Docetaxel (e. g., Taxotere) is administered once every three weeks in an amount of about 50 to about 100 mg/m2 ; and (3) Cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

In a preferred example for treating non small cell lung cancer using the FPT inhibitor, Docetaxel and Carboplatin : (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; (2) Docetaxel (e. g., Taxotere) is administered once every three weeks in an amount of about 75 mg/m2 ; and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 6.

In the above examples the Docetaxel (e. g., Taxotere and Cisplatin, the Docetaxel (e. g., Taxotere@) and Carboplatin, the Paclitaxel (e. g., Taxon and Carboplatin, or the Paclitaxel (e. g., Taxo) and Cisplatin are preferably administered on the same day.

In another example (e. g. , CML): (1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day; (2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally ; and (3) interferon (Intron-A) is administered in an amount of about 5 to about 20 million IU three times per week.

In another example (e. g., CML) : (1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day;

(2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally ; and (3) pegylated interferon (Peg-Intron or Pegasys) is administered in an amount of about 3 to about 6 micrograms/kg/day.

In another example (e. g. , non-Hodgkin's lymphom) : (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; and (2) Genasense (antisense to BCL-2) is administered as a continuous IV infusion at a dose of about 2 to about 5 mg/kg/day (e. g. , 3 mg/kg/day) for 5 to 7 days every 3 to 4 weeks.

In another example (e. g., multiple myeloma) : (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; and (2) the proteosome inhibitor (e. g., PS-341-Millenium) is administered in an amount of about 1. 5mg/m2 twice weekly for two consecutive weeks with a one week rest period.

In another example (e. g., multiple myeloma) : (1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; and (2) the Thalidomide (or related imid) is administered orally in an amount of about 200 to about 800 mg/day, with dosing being continuous until relapse or toxicity.

In the above examples the Taxotere and cisplatin, the Taxotere and carboplatin, the Taxol and carboplatin, or the Taxol and cisplatin are preferably administered on the same day.

Antineoplastic agents that can be used in combination with the FPT inhibitor are: (1) taxanes such as paclitaxel (TAXOL) and/or docetaxel (Taxotere@) ; (2) platinum coordinator compounds, such as, for example, carboplatin, cisplatin and oxaliplatin ;

(3) EGF inhibitors that are antibodies, such as: HER2 antibodies (such as, for example trastuzumab (Herceptin@), Genentech, Inc.), Cetuximab (Erbitux, IMC- C225, ImClone Systems), EMD 72000 (Merck KGaA), anti-EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (Center of Molecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibody ICR-62 (ICR, Sutton, England) ; Herzyme (Elan Pharmaceutical Technologies and Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB 569 (Wyeth-Ayerst), GW 572016 (GlaxoSmithKline), Cl 1033 (Pfizer Global Research and Development), trastuzmab- maytansinoid conjugate (Genentech, Inc.), mitumomab (Imclone Systems and Merck KGaA) and Melvax II (Imclone Systems and Merck KgaA); (4) EGF inhibitors that are small molecules, such as, Tarceva (TM) (OSI- 774, OSI Pharmaceuticals, Inc.), and Iressa (ZD 1839, Astra Zeneca) ; (5) VEGF inhibitors that are antibodies such as: bevacizumab (Genentech, Inc.), and IMC-1C11 (ImClone Systems), DC 101 (a KDR VEGF Receptor 2 from ImClone Systems); (6) VEGF kinase inhibitors that are small molecules such as SU 5416 and SU 6688 (both from Sugen, Inc.) ; (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), such as tamoxifen, idoxifene, raloxifene, trans-2, 3-dihydroraloxifene, levormeloxifene, droloxifene, MDL 103,323, and acolbifene (Schering Corp. ); (8) anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine ; (9) epothilones such as BMS-247550 (Bristol-Myers Squibb), and EP0906 (Novartis Pharmaceuticals) ; (10) topoisomerase inhibitors such as topotecan (Glaxo SmithKline), and Camptosar (Pharmacia) ; (11) vinca alkaloid, such as, navelbine (Anvar and Fabre, France), vincristine and vinblastine ; and (12) antibodies that are inhibitors of aVß3 integrins, such as, LM-609 (see, Clinical Cancer Research, Vol. 6, page 3056-3061, August 2000, the disclosure of which is incorporated herein by reference thereto).

Preferred antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin, gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa,

bevacizumab, navelbine, IMC-1C11, SU5416 or SU6688. Most preferred antineoplastic agents are selected from : paclitaxel, docetaxel, carboplatin, cisplatin, navelbine, gemcitabine, or Herceptin.

In general when more than one antineoplastic agent is used in the methods of this invention, the antineoplastic agents are administered on the same day either concurrently or consecutively in their standard dosage form. For example, the antineoplastic agents are usually administered intravenously, preferably by an IV drip using IV solutions well known in the art (e. g. , isotonic saline (0. 9% NaCI) or dextrose solution (e. g., 5% dextrose)).

When two or more antineoplastic agents are used, the antineoplastic agents are generally administered on the same day; however, those skilled in the art will appreciate that the antineoplastic agents can be administered on different days and in different weeks. The skilled clinician can administer the antineoplastic agents according to their recommended dosage schedule from the manufacturer of the agent and can adjust the schedule according to the needs of the patient, e. g. , based on the patient's response to the treatment. For example, when gemcitabine is used in combination with a platinum coordinator compound, such as, for example, cisplatin, to treat lung cancer, both the gemcitabine and the cisplatin are given on the same day on day one of the treatment cycle, and then gemcitabine is given alone on day 8 and given alone again on day 15 Thus, one embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound, wherein said FPT inhibitor is administered every day, said taxane is administered once per week per cycle, and said platinum coordinator compound is administered once per week per cycle. Preferably the treatment is for one to four weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical

effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound, wherein said FPT inhibitor is administered every day, said taxane is administered once every three weeks per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. Preferably the treatment is for one to three weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, paclitaxel, and carboplatin. Preferably, said FPT inhibitor is administered every day, said paclitaxel is administered once per week per cycle, and said carboplatin is administered once per week per cycle. Preferably the treatment is for one to four weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, paclitaxel, and carboplatin. Preferably, said FPT inhibitor is administered every day, said paclitaxel is administered once every three weeks per cycle, and said carboplatin is administered once every three weeks per cycle. Preferably the treatment is for one to three weeks per cycle.

Preferably, non small cell lung cancer is treated in the methods described in the above embodiments.

Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the FPT inhibitor, administering a therapeutically effective amount of carboplatin once a week per cycle, and administering a therapeutical effective amount of paclitaxel once a week per cycle, wherein the treatment is given for one to four weeks per cycle. Preferably said FPT inhibitor is administered twice per day. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the FPT inhibitor, administering a therapeutically effective amount of carboplatin once every three weeks per cycle, and

administering a therapeutically effective amount of paclitaxel once every three weeks per cycle, wherein the treatment is given for one to three weeks. Preferably said FPT inhibitor is administered twice per day. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of the FPT inhibitor twice a day, administering carboplatin once per week per cycle in an amount to provide an AUC of about 2 to about 8 (preferably about 2 to about 3), and administering once per week per cycle about 60 to about 300 mg/m2 (preferably about 50 to 100mg/m2, more preferably about 60 to about 80 mg/m2) of paclitaxel, wherein the treatment is given for one to four weeks per cycle. In a more preferred embodiment said FPT inhibitor is administered in amount of about 75 to about 125 mg twice a day, with about 100 mg twice a day being preferred. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

In a preferred embodiment, this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of the FPT inhibitor twice a day, administering carboplatin once every three weeks per cycle in an amount to provide an AUC of about 2 to about 8 (preferably about 5 to about 8, most preferably 6), and administering once every three weeks per cycle about 150 to about 250 mg/m2 (preferably about 175 to about 225 mg/m2, most preferably 175 mg/m2) of paclitaxel, wherein the treatment is given for one to three weeks. In a more preferred embodiment said FPT inhibitor is administered in an amount of about 75 to about 125 mg twice a day, with about 100 mg twice a day being preferred. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

Other embodiments of this invention are directed to methods of treating cancer as described in the above embodiments except that in place of paclitaxel and carboplatin the taxanes and platinum coordinator compounds used together in the methods are : (1) docetaxel (Taxotere0) and cisplatin ; (2) paclitaxel and cisplatin ; and (3) docetaxel and carboplatin. In the methods of this invention cisplatin is preferably used in amounts of about 30 to about 100 mg/m2. In the methods of this invention docetaxel is preferably used in amounts of about 30 to about 100 mg/m2.

In another embodiment this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, a taxane, and an EGF inhibitor that is an antibody. Preferably the taxane used is paclitaxel, and preferably the EGF inhibitor is a HER2 antibody (more preferably Herceptin) or Cetuximab, and most preferably Herceptin is used. The length of treatment, and the amounts and administration of the FPT inhibitor and the taxane are as described in the embodiments above. The EGF inhibitor that is an antibody is administered once a week per cycle, and is preferably administered on the same day as the taxane, and more preferably is administered consecutively with the taxane. For example, Herceptin is administered in a loading dose of about 3 to about 5 mg/m2 (preferably about 4 mg/m2), and then is administered in a maintenance dose of about 2 mg/m2 once per week per cycle for the remainder of the treatment cycle (usually the cycle is 1 to 4 weeks). Preferably the cancer treated is breast cancer.

In another embodiment this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of: (1) the FPT inhibitor; (2) a taxane; and (3) an antineoplastic agent selected from: (a) an EGF inhibitor that is a small molecule ; (b) a VEGF inhibitor that is an antibody; or (c) a VEGF kinase inhibitor that is a small molecule.

Preferably, the taxane paclitaxel or docetaxel is used. Preferably the antineoplastic agent is selected from: tarceva, Iressa, bevacizumab, SU5416 or SU6688. The length of treatment, and the amounts and administration of the FPT inhibitor and the taxane

are as described in the embodiments above. The VEGF kinase inhibitor that is an antibody is usually given once per week per cycle. The EGF and VEGF inhibitors that are small molecules are usually given daily per cycle. Preferably, the VEGF inhibitor that is an antibody is given on the same day as the taxane, and more preferably is administered concurrently with the taxane. When the EGF inhibitor that is a small molecule or the VEGF inhibitor that is a small molecule is administered on the same day as the taxane, the administration is preferably concurrently with the taxane. The EGF or VEGF kinase inhibitor is generally administered in an amount of about 10 to about 500 mg/m2. Preferably the cancer treated is non small cell lung cancer.

In another embodiment this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, an anti-tumor nucleoside derivative, and a platinum coordination compound.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, an anti-tumor nucleoside derivative, and a platinum coordination compound, wherein said FPT inhibitor is administered every day, said anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum coordinator compound is administered once per week per cycle.

Although the treatment can be for one to four weeks per cycle, the treatment is preferably for one to seven weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, an anti-tumor nucleoside derivative, and a platinum coordination compound, wherein said FPT inhibitor is administered every day, said an anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. Although the treatment can be for one to four weeks per cycle, the treatment is preferably for one to seven weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, gemcitabine, and cisplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per

week per cycle, and said cisplatin is administered once per week per cycle.

Preferably the treatment is for one to seven weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, gemcitabine, and cisplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per week per cycle, and said cisplatin is administered once every three weeks per cycle.

Preferably the treatment is for one to seven weeks.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, gemcitabine, and carboplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per week per cycle, and said carboplatin is administered once per week per cycle.

Preferably the treatment is for one to seven weeks per cycle.

Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of the FPT inhibitor, gemcitabine, and carboplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per week per cycle, and said carboplatin is administered once every three weeks per cycle. Preferably the treatment is for one to seven weeks per cycle.

Preferably, non small cell lung cancer is treated in the methods using gemcitabine in the embodiments described above.

In the above embodiments using gemcitabine, the FPT inhibitor and the platinum coordinator compound are administered as described above for the embodiments using taxanes. Gemcitabine is administered in an amount of about 500 to about 1250 mg/m2. The gemcitabine is preferably administered on the same day as the platinum coordinator compound, and more preferably consecutively with the platinum coordinator compound, and most preferably the gemcitabine is administered after the platinum coordinator compound.

Another embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient the FPT inhibitor and an antineoplastic agent selected from: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are

antibodies, and (4) VEGF kinase inhibitors that are small molecules all as described above. The treatment is for one to seven weeks per cycle, and generally for one to four weeks per cycle. The FPT inhibitor is administered in the same manner as described above for the other embodiments of this invention. The small molecule antineoplastic agents are usually administered daily, and the antibody antineoplastic agents are usually administered once per week per cycle. The antineoplastic agents are preferably selected from: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416 or SU6688. Preferably non small cell lung cancer is treated.

In the embodiments of this invention wherein a platinum coordinator compound is used as well as at least one other antineoplastic agent, and these drugs are administered consecutively, the platinum coordinator compound is generally administered after the other antineoplastic agents have been administered.

Other embodiments of this invention include the administration of a therapeutically effective amount of radiation to the patient in addition to the administration of the FPT inhibitor and antineoplastic agents in the embodiments described above. Radiation is administered according to techniques and protocols well know to those skilled in the art.

Another embodiment of this invention is directed to a pharmaceutical composition comprising at least two different antineoplastic agents and a pharmaceutical acceptable carrier for intravenous administration. Preferably the pharmaceutical acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e. g. , 5% dextrose).

Another embodiment of this invention is directed to a pharmaceutical composition comprising the FPT inhibitor and at least two different antineoplastic agents and a pharmaceutical acceptable carrier for intravenous administration.

Preferably the pharmaceutical acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e. g. , 5% dextrose).

Another embodiment of this invention is directed to a pharmaceutical composition comprising the FPT inhibitor and at least one antineoplastic agent and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e. g. , 5% dextrose).

In the method of treating embodiments, and in the pharmaceutical composition embodiments, the FPT inhibitor is preferably a compound selected from the compounds of formulas 1.4, 1.4D, 1.4E, 1.4F, 1.5, 1. 5A, 1. 6, 1.6A, 1.7, and 1.7A.

Those skilled in the art will appreciate that the compounds (drugs) used in the methods of this invention are available to the skilled clinician in pharmaceutical compositions (dosage forms) from the manufacture and are used in those compositions. So, the recitation of the compound or class of compounds in the above described methods can be replaced with a recitation of a pharmaceutical composition comprising the particular compound or class of compounds. For example, the embodiment directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound, includes within its scope a method of treating cancer comprising administering to a patient in need of such treatment therapeutical effective amounts of a pharmaceutical composition comprising the FPT inhibitor (1.0), a pharmaceutical composition comprising a taxane, and a pharmaceutical composition comprising a platinum coordination compound.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.

The amount and frequency of administration of the FPT inhibitor and the antineoplastic agents will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the cancer being treated.

The antineoplastic agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the antineoplastic agent can be varied depending on the cancer being treated and the known effects of the antineoplastic agent on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e. g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents.

The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

The particular choice of antineoplastic agent will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.

The determination of the order of administration, and the number of repetitions of administration of the antineoplastic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the cancer being treated and the condition of the patient.

Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of an antineoplastic agent according to the individual patient's needs, as the treatment proceeds. All such modifications are within the scope of the present invention.

The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e. g., pain, cough (for lung cancer), and shortness of breath (for lung cancer) ), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e. g. , CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

CHEMOTHERAPEUTIC AGENTS Classes of compounds that can be used as chemotherapeutic agents (antineoplastic agent/microtubule affecting agents) include but are not limited to : alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.

Alkylating agents (including nitrogen mustard, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine,

Cyclophosphamide (Cytoxan@), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) : Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (including vinca alkaloid, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) : Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commercially available as Taxons and is described in more detail below in the subsection entitled"Microtubule Affecting Agents"), paclitaxel derivatives (e. g. taxotere), Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.

Hormones and steroids (including synthetic analogs) : 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl- testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.

Synthetics (including inorganic complexes such as platinum coordination complexes) : Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

Other chemotherapeutics include Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabinbe, Reloxafine, and Droloxafine.

Particularly preferred are the antineoplastic agents selected from Cyclophasphamide, 5-Fluorouracil, Temozolomide, Vincristine, Cisplatin, Carboplatin, and Gemcitabine. Most preferrably, the antineoplastic agent is selected from Gemcitabine, Cisplatin and Carboplatin.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the"Physicians'Desk

Reference" (PDR), e. g. , 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

MICROTUBULE AFFECTING AGENTS As used herein, a microtubule affecting agent (e. g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound) is a compound that interferes with cellular mitosis, i. e. , having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents which disrupt microtubule formation.

Microtubule affecting agents useful in the invention are well known to those of skill in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e. g. , NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol@, NSC 125973), paclitaxel derivatives (e. g. , Taxotere, NSC 608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodermolide (see Service, (1996) Science, 274: 2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e. g., Bulinski (1997) J. Cell Sci. 110 : 3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94: 10560-10564; Muhlradt (1997) Cancer Res. 57: 3344- 3346; Nicolaou (1997) Nature 387: 268-272 ; Vasquez (1997) Mol. Biol. Cell. 8: 973- 985 ; Panda (1996) J. Biol. Chem. 271: 29807-29812.

Particularly preferred agents are compounds with paclitaxel-like activity. These include, but are not limited to paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives (e. g. Taxol and Taxotere) are available commercially. In addition, methods of making paclitaxel and paclitaxel derivatives and analogues are well known to those of skill in the art (see, e. g. , U. S.

Patent Nos: 5, 569,729 ; 5, 565, 478; 5, 530,020 ; 5,527, 924; 5, 508, 447; 5,489, 589; 5,488, 116 ; 5, 484,809 ; 5, 478,854 ; 5, 478, 736; 5, 475,120 ; 5, 468, 769; 5,461, 169; 5, 440, 057; 5, 422, 364; 5,411, 984; 5, 405, 972; and 5, 296, 506).

More specifically, the term"paclitaxel"as used herein refers to the drug commercially available as Taxon (NSC number: 125973). Taxons inhibits eukaryotic

cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc.

Inst. 82: 1247-1259).

Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e. g. , a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41: 37-47).

Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disrupted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated by disruption of the mitotic apparatus, e. g. , disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e. g., microtubule compaction, increased chromosome number, etc.).

Compounds with possible tubulin polymerization activity can be screened in vitro. For example, the compounds are screened against cultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells. Detailed protocols for this screening method are described by Porter (1995) Lab. Anim. Sci., 45 (2): 145-150.

Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U. S.

Patent No. 5,569, 720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.

Methods for the safe and effective administration of the above-mentioned microtubule affecting agents are known to those skilled in the art. In addition, their

administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the"Physicians'Desk Reference" (cited above).

General Preparative Schemes The following processes may be employed to produce compounds of the invention.

Pyridyl Tricvclic Compounds One skilled in the art will appreciate that the compounds of the invention represented by Formula 1, wherein one of a, b, c or d is N or N+-O-can be prepared according to the following schemes: Scheme 1: 0 bu N N t-suc) K N ' - t-BuOK' 3C 0 Ether 3 CHyCl2 » Triflic Acid N Ra Rs Rs 1a 1b la n il " r" O O N ci ci ci ci +. --- N N N N i I Rs ré rus R8 k8 R 8 k8 R R'R' 1f 1e 1d

The synthesis of 5-bromo tricyclic compound 1 b begins with bridgehead olefin 1a (J Med Chem (1998), 41,1561-1567) which is treated with dibromo dimethylhydantoin in triflic acid media. Further treatment of the vinylbromide with potassium t-butoxide in the presence of the appropriate secondary amine gives the 5 and 6-substituted enamine adducts. Y represents-CH2-,-0-or-NH-. When y1 is NH (piperazine case), acylations, sulfonylations and amide formation can be carried out using standard procedures. Treatment of these amine adducts with HO (aq) at the appropriate temperatures results in the formation of the 5 and 6 azaketones, 1f and le respectively.

Scheme 2:

(wherein Rx represents R9) In cases where secondary enamines were required, synthesis from 1f and 1e- azaketones were utilized as outlined in scheme 2. Thus, the appropriate ketone and amine was refluxed in toluene in the presence of p-toluene sulfonic acid in a Dean Stark apparatus.

Scheme 3 :

EtO EtO Br CuC) Br. CuCI) NaBH4 CI Et0 O C MeOH CI OC ; onc NEt3 N Pd (OAc) 2 cat R8 Bu4NBr N N 3b zu 1 b 4h 3 Re LAH HO Mu0 N moo R's N R"N mscl ci , MsCI <t. CI 1 N */ . H N DMF N 8 90°C N8 3R8 Ici I R$ 3c RUS" 3d 3e Chiral separation Seperation (wherein R"represents H or alkyl (e. g., methly and ethyl).

Synthesis of 3-carbon spaced analogs can be prepared as outlined in Scheme 3. Thus, subjecting tricyclic vinyl bromide 1 b to a Heck type reaction using ethyl acrylate and catalyzed by PdO gives the a-P un-saturated ester 3a. Reduction of the conjugated double bond was carried out using copper chloride-sodium borohydride reducing reagent. The ester was further reduced to alcohol using lithium aluminum hydride. Treatment of the alcohol with methanesulfonyl chloride in an appropriate aprotic solvent, followed by displacement with an appropriate sodium salt resulted in the desired imidazole targets. In most cases, separation of isomers were effected at this point. Where the R8 group of 3e was a BOC group, deprotection using HCI-dioxane gave the hydrochloride salts of amines. Using standard chemistry, these amines were converted to ureas, carbamates, sulfonamides and amides.

Those skilled in the art will recognize that when a metal hydride, such as NaH, is used in the conversion of 3d to 3e in Scheme 3, reduction of the C5-C6 double bond can take place. This is exemplified in Preparative Example 59 Step B.

Scheme 4 : PREPARATION OF 6-SUBSTITUTED CARBON ANALOGUES ° TfO OTf 'Na (NI ; 'N +'N N N N N I I I I Nu N N N I R8 R$ R$ R4b if ii 4a separate 4b 1 1i 4a NEt3 O | NEt3 cat Bu4NBr 4h HO OEt cucl CuCI ci NaBH4 1. msci Cl MEOH-ci 2. lmidazole ollc N N I I N N N Rs Ra NJ 4e 4d R 4c M r

Separate (wherein R"represents H or alkyl (e. g., methly and ethyl).

Preparation of 6-substituted 3-carbon spaced imidazole compounds was carried out as outlined in scheme 4. A mixture of ketones If and 1 i were treated with N-phenytrifluoromethane sulfonimide to give a seperable mixture of 5 and 6-tricyclic triflate compounds. The 6-trilate adduct was converted to the desired 3-carbon spaced analogs using similar protocol as described for the 5-bromo tricyclic compounds outlined in scheme 3.

Scheme 5: SYNTHESIS OF 2-CARBON SPACER ANALOGUES R'N N OTf SnBu3 ci HN-// Cl Tri-2-furylPhosphine 1 N NMP NMP Pd2 (dba) 3 Buli (10 % mol) CI LiCI N THF 120C A8 ka Sealed tube R 5a N "5a"N 4b is

5b (wherein R'represents H or alkyl (e. g., methly and ethyl).

Two carbon spaced analogs were prepared as outlined in scheme 5. Thus, triflate 4b was subjected to Stille chemistry, by reacting with tributylvinyl stannate catalyzed by an appropriate Pd° to afford the tricyclic vinyl compound 5b. The 2- carbon spaced compounds were obtained by treating the tricylic compound with the appropriate imidazole that had been previously treated with Buli-THF in a sealed tube and refluxed at 120 °C. Further funtionalization was carried out as previously described. Suberane compounds were prepared in a similar way.

Scheme 6: c Ms0 N H2N 0 0 NNa '- \ CI CI N l O N-Hydrazine I (N' 0 1 N DMF N N 6b R8 R8 1 3d 6a Acylated sulfonylated etc Products

Scheme 6 illustrates a method of making amine 6b through phthalimido displacement of a mesylate followed by hydazine hydrolysis of the phthalimido moiety. Amine 6b can be converted to targets that have acyl, sufonyl, carbamoyl and urea functionalities.

Scheme 7

Lactams 7a can be prepared from amine 6b by reacting with bromo butanoyl acid chloride as outlined in Scheme 7.

Scheme 8: PREPARATION OF CYCLIC UREAS

Cyclic urea can be prepared from the mesylate shown above by treating with the salt of the cyclic urea 8a as outlined in scheme 8.

Scheme 9: PREPARATION OF 5-SUBSTITUTED PROPANOIC ACID DERIVATIVES : EtO>gO R9 HO 0 9 1 R-N 0 DEC-HO8T /or (COCI) 2 Citric Acid N (R9) 2NH ci N N 1 N NJ 3b R8 NJ R N 9a 9b Ru Fui8 Ra R9 DEC-HOBT LiOH _ C or (COCi) 2 CI Citric Acid (R9) 2NH N''N ce N 3a N N ré ru R 8 R8 N 9d R8

Amides from 3-carbon spaced carboxylic acid 9a and 9c can be prepared as outlined in Scheme 9 using either DEC-HOBT mediated protocol or from the appropriate acid chloride.

Scheme 10: i OO (O O Ms0 O 0 N N (N) (N) ci (N) N \ cri N H ci HCI (N) Dioxane ci N I N CN _ BOC C N, N axa con) - v o BOC 10a 10b H O-r ol10 H T H (N) N TMSI N CH3CN ci ci CN' N N ,, N R 18 R R 10d 10c

Preparation of piperazine compounds off the bridgehead starts from mesylate aa which is reacted with CBZ-protected piperazine. The BOC group is then removed and the resulting amine 10c is functionalized appropriately. Removal of CBZ group off the piperazine is effected with TMSI.

Mesylate aa is prepared by first carbonylating compound H from Scheme 14 using Pd°, triphenyl phosphine, carbon monoxide, DBU, in methanol to give the carboethoxy product. The carboethoxy product is then reduced with lithium aluminum hydride to give the resulting alcohol. This alcohol is converted to the mesylate aa using mesyl chloride and triethylamine.

Scheme 11 : C-SUBSTITUTED IMIDAZOLE-3-METHYLENE-PIPERIDINES

Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichloromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl chloride, p-toluenesulfonyl chloride, or thionyl chloride, followed by elimination using an appropriate base such as triethylamine gives 12e. Removal of the trityl group with acid such as trifluoroacetic acid or hydrochloric acid gives the double bond compound 12f which is then hydrogenated using an appropriate catalyst such as

platinum oxide under from 1 to 55 psi of hydrogen in an appropriate solvent such as ethanol gave the desired product 12g.

Alternatively the ester 12a can be saponified with an appropriate base such as lithium hydroxide to obtain the acid 12h. Converting the acid 12h to the"Weinreb amide"followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichloromethane at ambient temperature yields the adduct 12c (shown in Scheme 12 below).

Scheme 12: Scheme 12a : /Tr/Tr /-non HO N Rio 0 NX Rio R'o R R3 periodina R R J R2- _-J 5 H Ra N R5 H Ra T 7 R6 (_ ;-- P. Rua ka N R8 fk8 R R° 12c 12j

Compounds of type 12L were prepared as shown above. Oxidation of the hydroxyl compound 12c can be accomplished with the Dess Martin periodinane to obtain 12j. Reaction with a grignard reagent gave 12k. The trityl group is removed under standard conditions mentioned above to give the desired compound 12L.

Scheme 13: C-Substituted Imidazole Single Methylene Bridgehead Compounds

Single methylene bridgehead C-Imidazole derivatives (13c) were prepared as shown above. Compound 13a was first converted to bromide 13b. Treatment of compound 13b with C-imidazole cuprates (prepared from corresponding iodo imidazole) yielded the adduct 13c.

Scheme 14: Preparation of one-methylene piperazines Ketone A is brominated with brominating reagents such as NBS, with a small amount of an activator such as benzoyl peroxide, in solvents such as dichloromethane at elevated temperature, such as 80-100° C to give dibromo compound B.

A B Dibromo compound B is reacted with a base such as DBU in a solvent such as dichloromethane at temperatures from 0°C to room temperature to give vinylbromides C and D. These vinylbromides are separated by chromatography such as silica gel flash chromatography using solvents mixtures such as ethyl acetate and hexane.

Alternatively, vinylbromides C and D can be separated by crystallization from solvents such as dichloromethane.

C D The ketone groups of separated vinylbromides C and D are reduced to the corresponding alcohols E and F with a reducing agent such as NaBH4 in solvents such as methanol or ethanol at temperatures of 0°C to room temperature.

E F The resulting alcohols functions of E and F are converted to a leaving group, such as a halide, with reagents such as SOCIz in solvents such as dichloromethane containing a base such as 2, 6-lutidine and running the reaction at 0°C to room temperature. The resulting intermediate halides are reacted, without purification, with piperazine or a protected piperazine, such as BOC-piperazine in a solvent such as dichloromethane at room temperature giving intermediates G and H.

The vinylhalide intermediates are carbonylated with CO gas under a pressure of about 100 psi and a temperature of 80°C to 100°C using a palladium catalyst such as PdCts and triphenyl phosphine in toluene and containing DBU and an alcohol such as methanol. If methanol is used, methyl esters I and J are obtained.

The ester functions are of I and J are reduced to hydroxymethyl functions of K and L. This can be done directly by first removing the protecting BOC group with TFA or HCI-dioxane and then reducing with a reducing agent such as DIBAL-H, followed by reintroduction of the BOC group with di-tert-butyl dicarbonate. Alternatively, the ester function is hydrolyzed with LiOH and water followed by neutralization with citric acid. The resulting carboxylic acids are then converted into a function that is easily reduced, such as a mixed anhydride or an acyl imidazole. This is done by reacting the resulting carbocylic acids with a chloroformate to form the mixed anhydride or with carbonydiimidazole to form the acyl imidazole (Synlett. (1995), 839). The resulting activated carboxylic acids are reduced with NaBH4 in solvents such as methanol, ethanol or aqueous THF.

The hydroxy functions of K and L are converted into leaving groups such as a methanesulfonate or an arylsulfonate such as a tosylat, by reacting with the appropriate sulfonyl chloride in dichloromethane containing a base such as triethylamine. The sulfonate leaving groups can be displaced by nucleophiles such amines. The nucloephile (Nuc in structures O and P below) can also be basic heterocycles such as imidazole or a substituted imidazole. In the case of an imidazole, the anion of the imidazole is first formed with NaH in DMF and then reacted with the above sulfonate. Displacement of the sulfonates with a nucleophile gives O and P, which can be converted to the compounds of this invention 1.0, by first removing the BOC protecting group and then forming the desired amide, urea, carbamate or sulfonamide on the resulting amine by methods well known in the art. Nuc Nuc R'R3 RI R3 1 . L7. Ra N RH k7l 7a , a ""-JR7a "T-"'rf7a N R \N/R BOC BOC O P Formula (1. 0) Formula (1. 0) Scheme 15: Preparation of one-methylene piperidenes

The vinylhalide or vinyltriflate intermediates A'and B' (Scheme 10) are carbonylated with CO gas under a pressure of about 100 psi and a temperature of 80°C to 100°C using a palladium catalyst such as PdCI2 and triphenyl phosphine in toluene and containing DBU and an alcohol such as methanol. If methanol is used, methyl esters C'and D1 are obtained. Intermediates Ca and D1 are reacted as are intermediates 11 and Ja (see Scheme 15a below) following essentially the same procedure as in Scheme 14 to yield compounds of Formula 1.0 of this invention.

Scheme 15a:

Alternatively, intermediates A¹ and B¹ can be reacted with tin vinylether E¹, in the presence of PdCl2, as described in Tetrahedron, (1991), 47,1877, to yield vinylethers F1 and G1 (Scheme 15a). Allowing F'and G'to stand until aldehyde is visible by NMR (at least two weeks) and then reacting with Hg (OAc) 2, Kl followed by NaBH4, as described in J. Chem. Soc. , Perkin Trans. , (1984), 1069 and Tet. Lett., (1988), 6331, yields mixtures H', I1 and J1, and Kl. Intermediates H'and J are separated and reacted, as are intermediates K'and L', following essentially the same procedure as in Scheme 14 to yield compounds of Formula 1.0, of this invention.

Those skilled in the art will appreciate that Schemes 11,12, 12a, 13,14, 15 and 15a using reactants having the moieties

(related to formula 1. 0), for example, are also representative of reactants having the moieties:

(related to compounds of formula 1.1).

Scheme 16: Branching on the methylene chain "R R3 31 3 31 N-'/. neat R" ( ; 02Et R Y-, OH C02Et R' 1. Ph3P ;) 2 imidazol X Br t R3 Bu ri r 1 I + R , Bu4NBr N R3 R3t N\ K2CO3 DMF ; 100 INR N, ION R I R TosNHNH 2 DBU toluene reflux R@l R C 1\/N 30 R39 /, I \ CI se R R

(wherein R represents R8, and R"represents R10) In Scheme 16, compounds with substitution along the chain can be synthesized starting with a substituted ethyl acrylate derivative. Addition of imidazole across the olefin followed by reduction gives the terminal alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituted olefin gives the saturated derivative.

Scheme 17: C-linked imidazoles

(wherein R represents R8) In Scheme 17, the synthesis of the C-linked imidazoles proceeds through the Heck reaction of the appropriately substituted vinyl imidazole with the appropriate vinyl bromide. Selective reduction of the resulting di-substituted olefin gives the target compound. A similar procedure can be carried out with differentially N-substituted imidazoles to give N-alkyl imidazole derivatives.

Subervl Compounds One skilled in the art will appreciate that the compounds of the invention represented by Formula 1.0, wherein a, b, c and d are C (or a, b, c, and d are CR'in formula 1.1) can be prepared according to Scheme 18: Scheme 18: Preparation of suberyl analoaues Br B Br B _ Meon 4 0 p oh 4a1 4b1 4c1 Br Br mgcl SOC12 Br N . Etococi t v Me- 2. H+, A ci N N 4f 3. R8 N 4al Me R8 O //-,-OEt Pdo O EtO EtO HO Et \ PzOz \ /.-H 1 / DIBAL-H N 4g N N 4i R CI Et3N mso 1_ N Ms0 u (+)-isomer Im-Na (-isomer 4k 7 4j N 4k N 4j Chiral AD 1 18

Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989,32, 2261-2268). Reduction of ketone to alcohol 4c was carried out with NaBH4. The alcohol was converted to chloride 4d and then treated

with N-methylpiperidine Grignard reagent to give piperidine derivative 4e.

Demethylation was effected with ethyl chloroformate followed by acid hydrolysis and subsequent derivitization (i. e sulfonylation, acylation and carbomylation etc. ).

Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycyclic bridgehead was carried out in a similar way as described in scheme 3.

Scheme 19:

Me cl ci 2) Chiral Chrom. N No N I BOC I : SUL ; HO H z H 0// N' BrMg N '\ CI ' CI i i N N r N + N 2) Chiral Chromatography N N N N I Boc Boc Scheme 20: Br Br CI AD column ---z/ zinc U 50% Cl C BOC I BOC

N N HO HO,, , N N 1 1) Silica Col. CI 2) OD Column N = N N N N N rNA N N I I Boc Boc Scheme 21: Br Br Br ci Chiral HPLC ci-ci gNß rNA N N N N N C + C N N N N N BOC BOC Boc

N N HO HO N _N 1 1 1) Li (Et) 3BH 1 C-- N = N = 2) Chiral Chrom. 0 cl C C I I Boc Boc (isomer 1) (isomer 2) Ratio of (Isomer 1): ( isomer 2) is about 10 : 1 Preparation of substituted 5-acetyl-imidazoles

Scheme 22: Ho HaC N NTr * ci 1. NaH, Mel N 2. 2. TFA ci 3. (Boc) 20, TEA or introduction of R8 4. OD HPLC N N 0 0 oa * Chiral center, formula represents Isomer 1 or Isomer 2 Scheme 23:

N3 NU N3 NU * 1. TFA i 2. Introduction of Rg N 3. AD HPLC 0X0 I * Chiral center, formula represents Isomer 1 or Isomer 2 * Chiral center, formula represents Isomer 1 or Isomer 2, wherein Isomer 1 of the amine is obtained from Isomer 1 of the azide, and Isomer 2 of the amine is obtained from Isomer 2 of the azide Scheme 24: @ CI * * zon CI w/ CI 1 I ci ci N Attachment of R"--,-FA Zon N N O O O O

1020 Rgb NH\N R9b_ NH\N NH N NH N * \ * \1 Attachment of R N N oN N H. TFA 1021 R8

1022 * Chira ! center, formula represents Isomer 1 or Isomer 2, wherein Isomer 1 of 1022 is obtained from Isomer 1 of the starting amine, and Isomer 2 of 1022 is obtained from Isomer 2 of the starting amine Each isomer (Isomer 1 and Isomer 2) of the starting amine was reacted with an acid chloride or anhydride to obtain an amide group, with an isocyanate to obtain a urea, with an chlorocarbonate to obtain a carbamate, with a sulfonylchloride to obtain a sulfonamide in an appropriate solvent such as dichloromethane and an equal equivalent of base such as triethylamine to obtain the desired product compound 1020. Compound 1020 can then be treated with trifluoroacetic acid to obtain compound 1021. Compound 1021 can then be reacted with an acid chloride or anhydride to obtain an amide group, with an isocyanate to obtain a urea, with an chlorocarbonate to obtain a carbamate, with a sulfonylchloride to obtain a sulfonamide in an appropriate solvent such as dichloromethane and an equal equivalent of base such as triethylamine to obtain the desired product compound 1022.

Scheme 25:

N3 N N3 N 11-, 1 1 ' v HCI/dioxane N CH2C2 _ N N I » 040 N3 N_ *3 N cl ce ci ci N Introduction N N N NON H R * Chiral center, formula represents Isomer 1 or Isomer 2 Scheme 26: Bu \ CI Separation i on a Chiracel AD N- column OU N O O

Ho --, I-11 1. NaH, Mel CI \ 2. TFA N N 3. (Boc) 20, TEA or introduction of R 8 ON 4. OD HPLC R8 O O O O * Chiral center, formula represents Isomer 1 or Isomer 2 Scheme 27: HO N N3 N ZON CI w CI ci DPPA, DBU ci N C CH3Ph O O O O N3 N N3 NU N N 1. TFA N 2. Introduction of R8 ; 3. AD HPLC ON ON ils O O N3 N H2N N * * 1 N 1. PPh3 N ci 2. THF/H20 ci or SnC N N ON N) R8 R8 * Chiral center, formula represents Isomer 1 or Isomer 2

Scheme 28:

N3 N N3 N * 1 * 1 - - HCI/dioxane '6""'6 No N I O O N3 N N3 N , + N, =< N * N * N ci Introduction ci of R8 No (N) H R8 * Chiral center, formula represents Isomer 1 or Isomer 2 Scheme 29: H2N N NHR9bNN \ 1 * \ 1 CI 9b I CI Introduction of R 9b '0''0 Boc Boc

NHR9t \N NHR v N * v1 N-N Introduction of R8 w CI ON (N) H I R8 * Chiral center, formula represents Isomer 1 or Isomer 2 In order to obtain a compound with an R9b group, the amine (starting reactant), was reacted with an acid chloride or anhydride to obtain an amide group, with an isocyanate to obtain a urea, with an chloroformate to obtain a carbamate, or with a

sulfonylchloride to obtain a sulfonamide, in an appropriate solvent, such as dichloromethane, and an equal equivalent of a base, such as triethylamine, to obtain a compound with the desired R9b substitutent. The R9b substituted compound can then be treated with trifluoroacetic acid to remove the BOC group to give the piperidine compound with an unsubstituted nitrogen. To introduce the desired R group the piperidine compound with the unsubstituted nitrogen can be reacted with an acid chloride or anhydride to obtain an amide group, with an isocyanate to obtain a urea, with an chloroformate to obtain a carbamate, or with a sulfonylchloride to obtain a sulfonamide, in an appropriate solvent, such as dichloromethane, and an equal equivalent of a base, such as triethylamine, to obtain the compound with the desired Ra substituent.

Scheme 30

NN-N\j-N- N3 N3 2 N3 N3 Separat z : nua (AD HPL ) R7a' J R7a 7a Ré ru I I I N BOC BOC BOC NNÆ NN.--- NH2 NH2 Erz Ph3 R4 N R5. N H R4 7R SnCI2/MeOH N 7 \ R7a'- R7a BOC BOC 1 1 NANo N^N- BOC BOC 1 2 NH2 2 NH2 Rs Rt Rs Ph3' 2 ph3 2 R or R N 7R SnC'2/MeOH N 7R 6 R-1' 6 r\ R N N BOC BOC

wherein "IM" represents imidazolyl in the compound CO(IM)2.

Scheme 31 NI\N- 1 or 2 N3 1 or 2 N3 Ior 2 N3 Ri R3 RI R3 ''ra FRe up R R2XR4 X N R BOC NN N% N- boy N-N-N- 1 or 2 N3 1 or 2 N3 R\. R3 R R3 3 Attachement of Rs .. , N H'7R4 Rs (1 R s r1 1 R XNy R xi R7a N N H R H) g N^N N^N- R 1 Or 2 N3 1 or 2 NH2 R2< \- PPh \V \/ I Or Rz 1 R R3 RI R R H 4SnCI2/MeOH H R7a R7a N N 72 78 R R ka R8 NN- NN 1 or 2 NH2 1 OI'2 NHR9b R R3 Attachement of R9b N \p5 N 5 2 f \N H Ra. IN R N R ! i Rua Ruz R8 R8

wherein the R8 group is attached using the corresponding isocyanate, chloroformate, sulfonyl chloride or acid chloride of the group to be attached, and wherein the R9b group is attached using the corresponding isocyanate, chloroformate, sulfonyl chloride or acid chloride of the group to be attached.

Compounds of this invention are exemplified in the following examples, which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. Compounds of the invention can be made according to the procedures described herein and those described in WO 02/18368 A1 published March 7,2002.

PREPARATIVE EXAMPLE 2 Step A

6 11 Compound 6 from Preparative Example 1, Step D, of WO 02/18368 A1, (10 g, 21.7 mmol) was hydrolyzed in the same manner as described in Preparative Example 1, Step A, of WO 02/18368 A1, to give the title compound (11). MH+ = 389.

Step B

11 12 To the amine product from Preparative Example 2, Step A (20 g, 0.5 mol) and triethylamine (10.4 g, 14.4 mL, 1.02 mol) dissolved in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (8.8 g, 6mL, 0.77 mol). After stirring at room temperature overnight, the solution was diluted with dichloromethane, washed with saturated NaHC03 and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo afforded the crude product that was purified by flash chromatography on a silica gel column, eluting with 1% CH30H (saturated with ammonia)-CH2Cl2 to give the title compound (12). MS (FAB) m/z 469 (MH+).

Step C

13 14 Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manner as described in Preparative Example 1, Step E, of WO 02/18368 A1, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH+).

Step D

15 16 The product from Preparative Example 2, Step C (22.5 g) was dissolved in 150 mL of conc. HCI and stirred for 16 h. The reaction mixture was poured into ice, basified with conc. NH40H and then extracted with CH2CI2 to give a mixture of compounds (15) and (16). MS (FAB) m/z 405 (MH+).

PREPARATIVE EXAMPLE 2A Step A

17 18 Separation of compound of Preparative Example 2 Step B by HPLC using a Chiralpack AD column eluting with 40-50% isopropanol : 60-50% hexane-0.2% diethylamine gave enantiomeric amines (17) and (18).

Compound 17: mp = 118-119; [alD =+ 136. 9° (9.00 mg/2mL, MeOH) ; MS (FAB) m/z 469 (MH+).

Compound 18: mp = 119-120; [a] D22 = -178.2° (9.90 mg/2mL, MeOH) ; MS (FAB) m/z 469 (MH+).

Step B

31 32 Product 17 from Preparative Example 2A, Step A (21.25 g, 45.3 mmol) was treated in the same manner as described in Preparative Example 1, Step E, of WO 02/18368 A1, to give 22.2 g of a mixture of compounds (31) and (32). MS (473) (MH+).

PREPARATIVE EXAMPLE 4 Step A

11 23 To a solution of title compound (11) from Preparative Example 2, Step A (20 g, 51.32 mmole) in CH30H/H20 (400 ml, 50: 1) was added di-tert-butyl dicarbonate (16.8 g, 77.0 mmole). The pH was adjusted to 9 and the mixture was stirred for 4 h. The solvent was removed, then water was added. The mixture was extracted with CH2CI2.

The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness affording the title compound (23). MS 491 (MH+).

Step B Following a similar procedure as in Preparative Example 3, Step A, of WO 02/18368 A1, the title compound (24) was prepared. MS 509 (MH+).

Step C

24 25 To a solution of the title compound from Preparative Example 4, Step B (19.62 g. 38.5 mmole) in ethanol (150 ml) was added platinum (IV) oxide (1.962 g). The reaction stirred over night at room temperature under H2 balloon pressure atmosphere. After monitoring the reaction, an additional 2% (by weight) of platinum (IV) oxide was added and the reaction stirred for 6 more hours, under H2 balloon pressure atmosphere. The mixture was filtered through celite and concentrated to dryness to afford the title compound (25) as a white solid. MS 511 (MH+).

Step D

25 26 Dissolved product from Preparative Example 4, Step C (2. 0 g, 3.9 mmole) in THF (30 ml) and cooled to 0°C in an ice bath. To the reaction was added diisobutylaluminum hydride (7.8 ml, 7.8 mmole). The reaction was allowed to stir and come to room temperature over night. The reaction did not go to completion. The mixture was cooled in an ice bath (0°C) and fresh diisobutylaluminum hydride/toluene (7.8 ml) was added. After the reaction stirred for 4 more hours, it was still not complete. The reaction mixture was cooled to 0°C, and an additional 3.9 ml of diisobutylaluminum hydride as added. The reaction stirred for 3 more hours. The crude reaction mixture was then extracted with ethyl acetate: 10% citric acid, and 1.0 N NaOH. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired title compound (26) MS 471 (MH+).

Step E

26 27 Following a similar procedure described in Preparative Example 3, Step C, of WO 02/18368 A1, the title compound (27) was prepared. MS 549 (MH+).

Step F

27 28 To a solution of the title compound from Preparative Example 4, Step E (1.6 g, 3. 01 mmole) in DMF (50 ml) was added imidazolylsodium (Aldrich) (0.407 g, 4.52

mmole). The reaction mixture was heated to 90°C for 2 h. The reaction was cooled and the DMF was removed. Saturated sodium bicarbonate was added and the mixture was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography eluting with 2% CH30H : saturated with ammonia-CH2CI2, to afford the title compound (28). MS 519 (MH+).

Step G

28 29 Dissolved the product from Preparative Example 4, Step F (0.55 g, 1. 08 mmole) in 4 N dioxane/HCI (20 ml). The reaction mixture was stirred for 3 h at room temperature and then concentrated to dryness to afford the title compound (29) as a light yellow solid. HRMS 419 (MH+).

EXAMPLE 506 Diasteromeric separation of product (795. 1) :

795.1 from Example 489, Step B, of WO 02/18368 A1, was done by PREP HPLC using the Prep Chiralcel OD Column and eluting with 20% IPA/HEXANES+0. 2% DEA (initial mobile phase), then 25% IPA/HEXANES + 0.2% DEA (final mobile phase) to give 795.1 isomer-1 (i. e., 795. 1 a) and 795.1 isomer-2 (i. e. , 795. 1 b).

Isomer-12 - MH+=536. 1 (CDCL3,400 MHz) 8. 437 (d, 1H), 8.22 (d, 1H), 7.54 (s, 1H), 7. 49 (d, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.19 (m, 1H), 7.10 (s, 1H), 6.57 (s, 1 H), 4.57 (s, 1H), 3.86 (s, 3H), 3.21 (br, s, 4H), 2.24 (m, 2H), 1.98 (m, 2H), 1.90 (s, 3H), 1.41 (s, 9H). m. p. 195-197 °C.

Isomer-2-MH+=536. 1 (CDCL3, 400MHz) 8. 47 (d, 1H), 7.64 (d, 1H) 7.64 (d, 1H), 7.54 (s, 1H), 7.5 (s, 1H), 7.35 (d, 1H), 7.23 (m, 1H), 7.21 (m, 1H), 7.22 (m, 1H), 7.14 (s, 1H), 6.8 (d, 1H), 4.59 (s, 1H), 3.76 (s, 3H), 3.23 (br. s. 4H), 2.23 (m, 2H), 1.99 (m, 2H), 1.87 (s, 3H), 1.41 (s, 9H). m. p. 206-208 °C.

Example 507

Compound 795. 1b (isomer 2,0. 093g, 0.173 mmoles) was converted to 795.2b by reacting it with CH2Cl2(5.0ml)/TFA(1. 0 ml) at room temperature under N2.

The same procedure was used to prepare 795.2a (isomer 1) from 795. 1a.

EXAMPLE 508 Br Br Br \ CI, % \ CI 1 i \ ce N AD COLUMN N-N 50% N N N N N N N N BOC BOC BOC

365 365a 365b Separations of enantiomers 365a and 365b is accomplished by chiral HPLC using a Chiralpak AD column and eluting with IPA (20%) hexanes (80%) + 0.2% DEA.

Isomer 365a: retention time = 7.65 min ; MH+= 492.

Isomer 365b: retention time = 12. 16 min ; MH+= 492, m. p. 95-100 °C.

(For compound 365 see WO 02/18368 A1).

PREPARATIVE EXAMPLE 73 Step A 880 881 Dissolve (880) (2eq. 14. 2mmol) in THF (20mut), add 1M LiOH (16ml) and stir at room temperature for 1 hour or until reaction is complete. evaporate to dryness, then evaporate 3x with toluene, to obtain crude (881) as a solid.

Step B

Take crude (881) from Step A, and dissolve in DMF (60ml), and add NH (OMe) Me (3.14g), DEC (6.14g), HOBT (2.16g), NMM (1 1rnl), and stir at room temperature over night. Add 1.0 N HCL until acetic (pH=2), wash with diethyl ether.

Add, while stirring, K2CO3 until basic-pH=8, saturate with NaCI, and extract with (4x). CH2CI2. Dry with MgS04, filter and evaporate to obtain product (882) (3. 23g).

Step C

Took crude (882) (14. 2mmol), and dissolve in THF (100moi). Cool in an iced bath and add MeMgBr (3 Molar in diethyl ether) ; (22. 2mi), dropwise over 10 minutes, under N2. Let warm to 40°C and stir for 4 hours or until reaction is complete. Cool in an iced bath and add saturated NH4Cl. Extract with ethyl acetate and then 3x with CH2CI2. Dry with MgSO4. filter and evaporate. Store under vacuum to obtain crystals- (883) (1. 78g, 74%).

Step D

Dissolve 365 (0.24g, 0. 49mmol) in THF (2. 5ml). Cool under N2 to-78°C, add (1) (BuLi, 2.5M, 0. 2ml) and stir the resulting dark brown solution for 15 minutes.

Dissolved 883 (0.116g) from Step C in 0.5 mL of THF and add to reaction and stir at

- 78°C for 3 hours. Add reaction mixture to brine and extract with ethyl acetate (2x).

Dry with MgS04, filter and evaporate to obtain a yellow solid. Purified crude (0.29g) by Prep Plate Chromatography to afford 0.0. 15g, 42% yield of the desired product (795.1).

EXAMPLE 509 Ho Oh ho 3 H H C \ N H3C N 3 \ N c \"N 3 11 H3 N OD Column N N N N N N 0A0T 0A0t oAOf 795. 1 795. 1 795. 1 Isomer-1 Isome-2 (i. e., 795. 1a) (i. e, 795. 1b)

Compound 795.1 is separated into the two diasteromers (isomer-1 and isomer- 2) by chiral HPLC using a Chiralpak OD column and using IPA (20%) hexanes (80%) + 0.2% DEA as described in EXAMPLE 506.

EXAMPLE 510 Step A

HORN 5-Formyl-l-Methyllmidazole N I ci \ CI 0 N N N n-BuLi/2. 5N in Hexanes N 56% Boc THF 365a-75°C (actone/dry ice) ° °t 884

365a [0. 9g, 1. 83 mmol] was dissolved in dry THF (15mut) and cooled to-75°C (dry ice/acetone bath). (N-BuLi) [ (2. 5N in Hexanes); 0.24g, 1. 5ml, 3. 74mmo1], was added dropwise at -75°C and stirred for-20 minutes. 5-Formyl-1-Methyl Imidazole (0.3g, 2.75 mmol in 2ml THF was added quickly and stirred at-75°C for 3 hours. TLC with (H2O-Ethyl Acetate). Reaction completed. Worked up by adding 10ml. of H20 and extracted with Ethyl Acetate and washed with brine, dried over MgS04, filtered and evaporated to give crude product. Crude was purified by Flash Chromatography (silica gel column) using CH2CI2/5% CH30H (15% NH40H) to give 0. 54g of compound 884,56% yield.

Step B.

885 Starting material 884 (0. 54G) was dissolved in CH2CI2, and Mon02 (5g) was added and stirred at room temperature overnight. TLC in 75% CH2CI2/25% EtoAc/ 5% MeOH (15% NH40H). Filtered off the inorganics and evaporated to dryness to give 0. 49g of 885,90% yield. step C

0. 35g, 1.71 mmol of (CH3) 3 S+ # was dissolved in dry DMSO (5ml) and THF (5ml). Sodium hydride (0.068 g, 1.71 mmol) was added, stirred for 10 minutes. The mixture was cooled to 0°C. Starting material 885 (0. 3g, 0.577 mmol) in (DMSO-THF 1: 1,5 ml) was added and stirred at 0°C for 6 hours and then stored in the refrigerator for 18 hours. Quench with H20. Extracted with Ethyl Acetate and washed with brine, dried over MgS04, filtered and evaporated to give 0. 310g of product, 886.

Step D

Dissolved 886 (0. 28g, 0.48 mmol) in THF (5mi), added Li (Et) 3BH (0. 8ml, 0. 8mmol). After stirring for 1 hour, added to reaction ~ 1 Oml of 1 N HCL and stirred for 5 min. Added saturated sodium bicarbonate slowly until basic, and extracted with Ethyl Acetate (3X). Organic was dried over MgS04, filtered and evaporated to give crude product. Column chromatography on 12g of silica and eluting with 2% to 4% MeOH NH40H/CH2CI2to gave 170 mg, 66% yield of pure product, 887.

Step E

HO HO wI Nl Nl CI / C /\ I C) 0 HO//, Chiral OD Column N'r N N N + N Prep HPLC N 20% tPA/HEX/0. 2% DEA N N N 887 888a 888b 887 was separated by Chiral Prep HPLC using a Chiral Technologies OD column and eluting with 20% Isopropanol/Hexanes/0. 2% DEA to give Compounds; 888a and 888b.

EXAMPLES 511-513 Each isomer, 795.2a and 795.2b from Example 507 was dissolved in CH2CI2, treated with the corresponding isocyanates and stirred at room temperature overnight.

The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel chromatography to afford compounds of the formula : wherein R is defined in Table 55 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 55 Example Isomer 1 Isomer 2 Data Data 511 m. p. 200-202 °C m. p. 197-200 °C 512 H m. p. 185-190 °C m. p. 200-205 OC OZON H 513 , CN m. p. 210-214 °C m. p. 185-190 °C O N H EXAMPLE 536 Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous DMF at room temperature under nitrogen, followed by addition of the corresponding carboxylic acids, and the appropriate reagents : EDC, HOBT, and NMM. Reactions were then stirred at room temperature overnight. Solvents were removed via rotary evaporator yielding an oily residue. Residue was taken up in dichloromethane and washed with 1.0 N NaOH. Dry over Na2SO4, filtered and concentrated. Crudes were purified by Prep TLC using dichloromethane/methanol to give compounds of the formulas :

wherein R is defined in Table 57 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 57 Example R Data Data Isomer 1 Isomer 2 536 m. p. 175-180 °C 015r I

EXAMPLES 566-567 Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous CH2CI2 followed by Et3N. Reactions were then treated with the corresponding sulfonyl chlorides and stirred at room temperature over night. Quench reaction with 1.0 N NaOH and extracted with CH2CI2. Organic layer was dried over MgS04, filtered and concentrated. Purification by column chromatography eluting with methanol-CH2CI2 afforded compounds of the formula :

wherein R is defined in Table 59 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 59 Example R Data Data Isomer 1 Isomer 2 566 1 m. p. 185-188 °C 217. 5 OC zu 567 O_ CI m =182-186°C - *Isomer 1 for Example 567 would b obtained if one were to follow the described

procedure.

EXAMPLES 590-603 Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous methylene chloride at room temperature. The reaction was cooled to 0°C and TEA was added in. The respective chloroformates were then added dropwise, and reactions were stirred at 0°C for until completed. Reactions were basified with 1.0 N NaOH to pH = 8-10 followed by extraction with dichloromethane. Organic layer was combined, dried with MgS04, filtered and concentrated to yield crude products. Purification by Prep TLC using methylene chloride/acetone (95%/5%) afforded the compounds:

wherein R is defined in Table 61 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 61 R Data Data Example _ _ Isomer 1 Isomer 2 590 590 |/ 0WoW 179. 8-182. 4"C 591 oWoA 195-200 °C 193. 5-197. 5 °C 592 00 165. 9-167. 9 OC 0RoX. ou O 163. 8-186. 6"C 594 mp = 173-175°C o 173. 9-176. 2"C 595 T * 0won zozo 0 0 172-174 UC 596 180-182 OC 0--0 165-170 OC 185-188. 5 uC 597 °o 184. 3-186. 6 °C 191. 2-192. 9"C 598 once CCI3 179. 8-182. 5"C 599, N ! Con * _ 175-178 °C 600'\ 600 175-180 OC 0 J"0-4 175-177 °C 173-176 UC 601 O=o oo 602, 177-180 OC O 04 169. 4-173. 2 UC 164. 4-167. 2"C 603 CCF3

*Isomer 1 for these examples would be obtained if one were to follow the described procedure.

PMR data for Example 592, isomer 1, (CD3CI) 8.44 (d, 1 H), 8.23 (d, 1 H), 7. 54 (s, 1 H), 7.48 (d, 1H), 7.37 (d, 1H), 7.32 (dd, 1H), 7.18 (dd, 1H), 7.10 (s, 1H), 6.58 (s, 1H), 4.87 (m, 1 H), 4.58 (s, 1 H), 3.86 (s, 3H), 3.25 (br s, 4H), 2.26 (br s, 2H), 1.99 (m, 2H), 1.90 (s, 3H), 1.21 (d, 6H).

PREPARATIVE EXAMPLE 74

(wherein R is alkyl (e. g., ethyl) or cycloalkyl (e. g., cyclohexyl)) Dissolve Phosgene (3mL, 1.93M in Toluene) in anhydrous ethyl ether and cooled to 0°C. A mixture of cyclohexyl alcohol (200 mg, 2 mmol) and pyridine (0.18 mL, 2.2 mmol) in ethyl ether (4 mL) was added in dropwise. After addition, reaction was allowed to warm to room temperature while stirring overnight. MgSO4 was then added into reaction and the mixture was stirred for 5 min. After filtration, N2 was bubbled into the solution for 30 min. It was then concentrated to 0.5 mL, diluted with CH3Ph (10 mL) and stored as a stock solution at 4°C.

PREPARATIVE EXAMPLE 75 Step A

889 890 15.4 g (115 mmole) of CuCI2 and 17 mL (144 mmol) of t-butyl nitrite was added to 400 mL of dry CH3CN. The reaction mixture was cooled to 0° C and 25 g of ketone

(564)? was added. The reaction was warmed to room temperature and stirred for two days. The mixture was concentrated under vacuum. Then 1 N HO was added to the residue until the pH was neutral, then NH40H was added until the pH was basic. After extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated under vacuum to give compound 890. Altematively, the corresponding alcohol of 889 can be reacted as above followed by oxidation with Mn02 in CH2CI2 to give compound 890.

Step B

Compound 890 from Step A above was reacted in essentially the same manner as in Preparative Example 23, Steps A-D, of WO 02/18368, to get Compounds 891 and 892.

SteP C Br Br Br gr ci ci ci ci 1 AD Column BOC BOC N N Br 891 891 a ci ci I D (N) N C N BOC

891b 891 was separated into the respective enantiomers 891 a and 891 b, using a Chiral AD Prep HPLC Column as described in Example 508.

Step D Br 6r Br Br c AD Column (N) (N) + BOC BOC 892 892a Br ci cri N N t N) BOC 892b

The 6-bromo substituted Compound 892 was separated into the enantiomers 892a and 892b using a Chiral AD Prep HPLC Column as described in Example 507.

PREPARATIVE EXAMPLE 76 Step A 891a 893

Reacted 891a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

Step B "I, N N N4N HO HO ho H3C H3C 1 H3C 2 ci ci ci ci ci ci N V V OD Column Nr Y (N)-N) + tÑ) C) CN C N N N 0A0T 00 OO 893a 893b 893

Chromatograph 893 by chiral HPLC using a Chiralcel OD column and eluting with IPA (20%) and hexanes (80%) with 0.2% DEA to obtain 893a (i. e. , isomer 1), and 893b (i. e., isomer 2).

PREPARATIVE EXAMPLE 77 Step A

891 b 894 Reacted 891 b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

SteoB

\N1N NN H H 1 ci N CN OD COLUMN N N N C) C N N 9 N5N I I N BOC BOC HO 894 894a ci ci N N N N I BOC 894b Chromatograph 894 by chiral HPLC using a Chiralcel OD column and eluting with IPA (20%) and hexanes (80%) with 0.2% DEA to obtain 894a (i. e. , isomer 1), and 894b (i. e. , isomer 2).

PREPARATIVE EXAMPLE 78 Step A ho HO Br 3CX N Cl < Cl Cl < Cl ci-ci ci ci __f C C -- x I 00 0-0 892a 895 a

Reacted 892a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 895.

Step B \ \ H$4) H) H3C N H3C N ci ci ci cl OD Column N N r N oAof okof 895 895a HO Cl > 2 'A" N 2 N N N 895b

Chromatograph Compound 895 by chiral HPLC using a Chiralcel OD column and eluting with IPA (20%) and hexanes (80%) with 0.2% DEA to obtain 895a (i. e., isomer 1), and 895b (i. e. , isomer 2).

PREPARATIVE EXAMPLE 79 Step A

Reacted 892b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 896.

Step B \ \ HO - HO HO N HO N- 1- CI C CI ci ci OD Column ci ci N N Nss N N CON + 896 896a H N Ho Holz H3c N CI \ CI 2 N N N 00 896b

Chromatograph 896 by chiral HPLC using a Chiralcel OD column and eluting with IPA (20%) and hexanes (80%) with 0.2% DEA to obtain 896a (i. e. , isomer 1), and 896b (i. e., isomer 2).

PREPARATIVE EXAMPLE 80

Compound 893a, and 893b, are converted to 897a, and 897b, by reacting them with CH2CI2/TFA at room temperature under N2, for 2 hours. Concentrated under vacuum. Dissolve residue in CH2CI2, and wash with 1.0 NAOH. Dry over MgS04, filter and concentrate to give 897a (i. e., isomer 1) and 897b (i. e. , isomer 2).

PREPARATIVE EXAMPLE 81

Following essentially the same procedure as in Preparative Example 80, Compounds 894a and 894b were individually reacted with TFA/CH2CL2 at room temperature under N2, for 2 hours, to get compounds 898a (i. e. , isomer 1) and 898b (i. e., isomer 2).

PREPARATIVE EXAMPLE 82

Using essentially the same procedure as in Preparative Example 80,895a and 895b were individually reacted with TFA/CH2CL2 at room temperature under N2, for 2 hours, to get compounds: 899a (i. e. , isomer 1) and 899b (i. e. , isomer 899b).

PREPARATIVE EXAMPLE 83

Using essentially the same procedure as in Preparative Example 80,896a and 896b were individually reacted with TFA/CH2CL2 at room temperature under N2, for 2 hours, to get compounds: 900a (i. e. , isomer 1) and 900b (i. e., isomer 2).

PREPARATIVE EXAMPLE 84 COzMe /1 c 9 _ 1) DBU, Ph3 o PdCl2/toluene 901 2) CO, 100 psi 902 MeOH, 80°C

Starting material 901 (25g, 78 mmol) was combined with DBU (15.7 ML, 105. 3mmol, 1.35 eq. ); Ph3P (9.44g 0. 39mmol, 0.5 eq. ); PdCI2 (1. 38g, 7. 8mmol, 0.1 eq. ) ; MeOH (50ML)/Toluene (200ML) in a flask and reacted in a Parr Shaker under CO, 100 psi at 80°C. When completed, the reaction was treated with H2O and extracted with Ethyl Acetate. Dried over MgS04 and evaporated to get a black syrup.

(71g) Column chromatography (silica gel) and eluting with Hexanes, then 20% Ethyl Acetate/Hexanes to 40% E/H to give produce ! 902, (39g).

PREPARATIVE EXAMPLE 85 902 CH2Cl2 903 Dissolve (Bu) 4NNO3 (21.15g) in CH2CI2 (220ML) and cool in an ice bath under N2 and dripped in TFAA (9.8ML) and stir for 15 minutes. The resulting yellow solution is added slowly to a solution of starting material 902, (18.97g) in CH2CI2 (200ML) while cooling in an ice bath (0°C). Stir at 0°C for 15-20 minutes, then allowed to war to room temperature for 3 hours. Reaction was treated with saturated NaHC03 and extracted with CH2CI2. Isolated the organic layer and dried over MgSO4, evaporated to dryness t give product as a syrup. Crude was chromatograph (twice) on Si02 using Hexanes, then eluting with 20% & 40% Ehyl Acetate/Hexanes). 30-40% yield of product 903 (7. 89g).

PREPARATIVE EXAMPLE 86

Ra-Ni ( (50% in H20), 50g), is washed with ETOH (5X, then decanted), the washed with MeOH (3X), then added to starting material 903 (7.89g) in MeOH (80ML), the resulting mixture is stirred under H2 (balloom) overnight. Reaction is monitored by TLC. Added more RaNi (25g, washed 5X with ETOH, then 3X w/ MeOH). When completed reaction is filtered, the insoluble dark solid is washed with CH2CL2/MeOH until the color of the washings became light, combined filtration and evaporated to dryness to get a brown solid 904 (3. 88g of product).

PREPARATIVE EXAMPLE 87

Suspend starting material 904 (0.5g) in CH3CN (20ML), add CuBr (0. 42g) and cool in an ice bath under N2. Add t-BuONO (0. 28g) and allow to stir and warm to room temperature. After 2 hours stir at 75° C, stir-2 hours. After reaction is complete, add reaction to 1 N HCL and stir. Then add Conc. NH40H until blue (basic).

Extract with CH2CI2, isolate the organic layer, dried over MgS04, filter and concentrated to give product 905.

PREPARATIVE EXAMPLE 88

905 906 Starting material 905 (3g, 7. 92mmol) is stirred in MeOH (100ML) at 0°C in an ice/H2O bath, then NaBH4 is added to the cold solution in portions. Stir at 0°C for 1 hour, then at room temperature for 1 hour. Add (20ML) of 1.0 N HCL, stir for 10 minutes, basified with saturated NaHC03, added to brine, extract with Ethyl Acetate, dried over MgS04, filtered and evaporated to dryness to give 3. 6g of compound 906.

PREPARATIVE EXAMPLE 89

SOC12 (2-1 ML) was added to the solution of 906 (3.5g) in CH2CI2 (50ML), stirred at room temperature for 5 hours. Additional (1.0 ML) of SOCI2 was added, stirred for 2 hours, then overnight. Monitored reaction progress by TLC. Reaction mixture was evaporated to dryness and dried under vacuum to give 3.6g of crude product 907.

PREPARATIVE EXAMPLE 90 COzMe C02Me Br U >} _CI Boc-Piperaåne ~ CC N Cri Y TEA 907 CH3CN 80°C N/ 0 I-0+ 908

Boc-Piperazine (2.2g, 2.5 eq. ) was added to a mixture of starting material 907 (1.78g, 4. 68mmol) and TEA (1. 9ML, 3 eq) was stirred in CH3CN (100ML), under N2, heat to 80°C for 5 hours. TLC then stirred at 80°C over the weekend. Reaction is treated with 1. ON HCI and extracted with ethyl acetate, wash with brine followed by 1. ON NaOH, dried over MgS04. Filter and evaporated reaction to dryness to give crude 908 (62% yield).

PREPARATIVE EXAMPLE 91

12ML of a 10% LiOH solution (-4M) was added to a solution of starting material 908 (1.6g) in MEOH (50ML) and reaction was stirred at 60°C. A solid precipitated out. Mixture is stirred overnight. Reaction became a clear-yellow solution. Reaction was treated with 10% K2HP04, and extracted with ethyl acetate, washed with brine, dried over MgS04, and evaporated to dryness to give 1.5g of compound 909.

PREPARATIVE EXAMPLE 92

Combined starting materials 909 (1. 5g,-7. 8mmol) ; NHCH30CH3. HCI ; NMM; HOBT; & DMAP in CH2CI2 (20ML) and stirred for 10 minutes, then EDC (0. 64g, 1.2 eq. ) was added and stirred overnight at room temperature. Reaction was treated with 1 N HCI, extracted with ethyl acetate, washed with brine followed by 1 N NaOH. dried over MgS04, filtered and evaporated the filtrate to dryness to give 1. 45g) crude compound 910.

PREPARATIVE EXAMPLE 93 NH, 0 Br ci Br ci CH3MgBr/THF Quant. N N olOX olOX 910 911

A 3M solution of CH3MgBr/Ether (3.8 ML, 4.5 eq) was added dropwise to a solution of 910 (1.45g, 2.5 mmol) in THF (50ML), a dark brown solution resulted.

Reaction was stirred under N2 at room temperature for 2 hours. Reaction was then treated with a saturated NH4CI solution and extracted with ethyl acetate. Washed with brine and dried over MgS04, filtered and evaporated to dryness to get a yellow solid compound, which after column chromatography gave 1. 33g of compound 911 as a racemic mixture.

PREPARATIVE EXAMPLE 94

Starting material 911 (0.90g) was dissolved in CH2CI2 (35ML) and TFA (35ML) and stirred at room temperature overnight. Washed with 1.0 N NaOH, dried over MgS04, filtered and evaporated to dryness to give compound 912.

PREPARATIVE EXAMPLE 95 o 0 oS B 1/ CI gr 1/ CI AD COLUMN N 1 N N N N H H H H 912 912a +

912 was separated into its enantiomers by Chiral Prep HPLC using a Chiral AD Column and eluting with 10% IPA/90% Hexanes+0. 2% DEA to give compounds 912a and 912b.

PREPARATIVE EXAMPLE 96

Starting material 912a (0.284g 0. 656mmol) was dissolved in CH2CI2 (5ML), TEA (1. 83ML, 2.0 eq. ) and (BOC) 20 (0.215g, 1. 5eq), and stirred at room temperature overnight. Reaction was evaporated and crude was purified by column chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0. 3g of compound 913a.

PREPARATIVE EXAMPLE 97

913b Starting material 9121 b (0.254g 0. 587mmol) was dissolved in CH2CI2 (5ML), TEA (1. 64ML, 2.0 eq. ) and (BOC) 20 (0.192g, 1. 5eq), and stirred at room temperature overnight. Reaction was evaporated and crude was purified by column

chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0. 255g of compound 913b.

PREPARATIVE EXAMPLE 98 Step A

Suspended commercially available (from Acros) 915 (30g, 68.8 mmol) in dry THF (600ml) under dry N2. Stirred at room temperature under N2 until it formed a clear solution. Added CH31 (50ml, 114g, 803. 2mmol) at room temperature, dropwise, under dry N2. Stirred the suspension at room temperature under N2 for 4 days, followed by TLC- (10% MeOH-2M NH3/CH2CI2). Filtered the suspension, washed solid with dry THF. Dried the solid under house Vacuum at 40°C to give 31. 11g of a brown solid, compound 916.

Step B

Suspended 916 (31. 1g, 53.79 mmol) in 200ML of 50% HOAC/H20 and heat under reflux overnight. Follow by TLC. When completed, allowed to cool to room temperature, filtered the resulting suspension. Washed with 50% HOAC/H20.

Evaporated to dryness. Suspended the solid in CH2CI2. Basified to pH 10-11 with 1 N NaOH. Separated CH2CI2 layer and extracted the aqueous phase 3x with CH2CL2 Combined organic layers and washed with Saturated NaCI solution. Dried over MgS04, evaporated to dryness to give 914 (8.68g of an off-white solid).

PREPARATIVE EXAMPLE 99

EtMgBr (3Molar in Et2O) solution (2. 89mmol, 963uL, 5.5eq.) was dripped into a solution of 914 (0.656g, 3. 15mmol, 6eq. ) in CICH2CH2CI (6ML) for 30 minutes. To the white suspended mixture, 913a (0. 280g, 0. 525mmol) was then added and stirred at 60°C for 3 hours. Reaction was treated with saturated NH4CI at 0°C by pouring the reaction into the cold NH4CI. Extracted with Ethyl Acetate, dried over MgS04 and evaporated to dryness. Column Chromatography (SiO2) eluted with 1%, 2% & 3% MEOH/CH2CI2gave 0.054g of compound 917.

Step B N N HO N HO N 1 Br ci Br ei OD Chiral Column = 1 = I 0 0 O 917 N + N HO'y""N HO 04 OloX 2 917 917a N I N C ND N 917b

917 was separated by HPLC using a Chiral OD Column and eluting with 20% IPA/Hexanes to give 917a (isomer 1) and 917b (isomer 2).

PREPARATIVE EXAMPLE 100

EtMgBr (3Molar in Et20) solution (791uL), was dripped into a solution of 914 (0.518g, 3. 15mmol, 6eq. ) in CICH2CH2CI (6ML), for 30 minutes. To the white suspended mixture, 913b (0. 280g, 0. 525mmol) was then added and stirred at 60°C for 3 hours. Reaction was treated with saturated NH4CI at 0°C by pouring the reaction into the cold NH4CI. Extracted with Ethyl Acetate, dried over MgS04 and evaporated to dryness. Column Chromatography (SiO2), eluted with 1 %, 2% & 3% MEOH/ CH2CI2 gave 0. 054g of compound 918.

Step B N N v HO''N HO N 1 Br ci Br ci N OD Chiral Column N .---0. N N O O O O 918 918a N HO N 2 gr N 1 2 fyn N 0 0 + 918b

918 was separated by HPLC using a Chiral OD Column and eluting with 20% IPA/Hexanes to give Isomers 918a'H NMR (400MHz, CDCl3, TMS) 8 1.419 (s, 9H), 1.457 (s, 1H), 1.894 (s, 3H), 2.05-1. 87 (m, 2H), 2.30-2. 15 (m, 2H), 3.214 (broad, 1 H), 3.540 (s, 1 H), 3.738 (s, 1 H), 3.760 (s, 1 H), 3.888 (s, 3H), 4.540 (s, 1H), 6.479 (s, 1H), 7.128 (s, 1H), 7.260 (d, 1H), 7.340 (s, 2H), 7.627 (d, J=2. 4Hz, 1H), 8.221 (s, 1H), 8.486 (d, J=2.8Hz, 1H). (21) Mp = 188-190 °C, and 918b.

PREPARATIVE EXAMPLE 101

Compound 917a was converted to 919a by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2CI2, and washed with 1.0 NaOH. Isolated organics are dried over MgSO4, filtered and concentrated to give compound 919a.

PREPARATIVE EXAMPLE 102

Compound Carmen 917b was converted to 919b by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2Cl2, and washed with 1.0 NaOH. Isolated organics are dried over MgS04, filtered and concentrated to give compound 919b.

PREPARATIVE EXAMPLE 103 Compound 918a, was converted to 920a, by reacting with CH2CI2frFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2C12, and washed with 1.0 NaOH. Isolated organics are dried over MgS04, filtered and concentrated to give compounds 920a.

PREPARATIVE EXAMPLE 104 Compound 918b was converted to 920b by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2CI2, and washed with 1.0 NaOH. Isolated organics are dried over MgS04, filtered and concentrated to give compound 920b.

PREPARATIVE EXAMPLE 105 Step A

Compound 921 was reacted in essentially the same manner as in Preparative Example 23, Steps A-D, of WO 02/18368, to get compound 922.

In essentially the same manner as in Preparative Example 42, Step A, of WO 02/18368, using 922 as the starting material, compound 923 is prepared.

PREPARATIVE EXAMPLE 106

Compound 923 from Preparative Example 105 Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get 924a (i. e., isomer 1) and 924b (i. e., isomer 2).

PREPARATIVE EXAMPLE 107

Compound 923 from Preparative Example 105 Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get 925a (i. e., isomer 1) and 925b (i. e., isomer 2).

EXAMPLE 1295 Following essentially the same procedure as Examples 590-603 (wherein the chloroformates are prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula :

were prepared wherein K is defined in Table 91 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 91 Example R Isomer 1 Isomer 2 1295 H NMR (400MHz, CDCI3, TMS) S 1. 417 (s, 9H), 1. 454 (d, ° OX J=1. 6Hz, 1H), 1. 857 (s, 3H), 2. 20- 2. 05 (m, 4H), 3. 205 (broad, 1 H), mp= 3. 432 (s, 1 H), 3. 612 (s, 1 H), 3. 731 (d, 184-185 °C J=6. 4Hz, 1 H), 3. 853 (s, 3H), 4. 575 (s, 1 H), 6. 538 (s, 1H), 7. 086 (s, 1H), 7. 114 (s, 1H), 7. 262 (d, 2H), 7. 540 (s, 1 H), 8. 530 (d, J=2. 0Hz, 1 H), 8. 876 (d, J=2. 0Hz, 1H).

EXAMPLE 1314 Following essentially the same procedure as Examples 590-603 (wherein the chloroformates are prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula :

were prepared wherein R is defined in Table 93 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 93 Example R Isomer 1 Isomer 2 1314)/'HNMR (400MHz. CD03. TMS) mp= 8 1. 418 (s, 9H), 1. 456 (s, 1 H), 183-184 °C 1. 859 (s, 3H), 2. 20-2. 05 (m, 4H), 3. 205 (broad, 1H), 3. 612 (s, 1 H), 3. 692 (s, 1H), 3. 740 (s, 1 H), 3. 854 (s, 3H), 4. 576 (s, 1 H), 6. 541 (s, 1H), 7. 090 (s, 1H), 7. 116 (s, 1H), 7. 262 (d, 2H), 7. 548 (s, 1H), 8. 530 (d, J=2. 0Hz, 1 H), 8. 864 (d, J=2. 0Hz, 1H) PREPARATIVE EXAMPLE 108 Step A

926 In essentially the same manner as in Preparative Example 23, Steps A-D, of WO 02/18368, use compound 234a (from Step B) to prepare 926.

StepB

In essentially the same manner as in Preparative Example 42, Step A, of WO 02/18368, use 926 to prepare 927.

Step C

Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 928a and 928b.

Step D

Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 929a and 929b.

EXAMPLE 1573

Step A React 882, from Preparative Example 73 Step B, with ethylmagnesium bromide following the procedure described in Preparative Example 73 Step C.

Step B React 365a with 931 (from Step A) following essentially the same procedure as in Preparative Example 73, Step D, to give the 930 as a white solid, mp-163-165°C EXAMPLE 1574

Step A 880 Dissolve 880 (1. 4g, 10 mol), CF3TMS (1.46g, 10.25 mol), and CsF (15.2 mg, 0. 1mmol) in 15 ml THF. Stir at room temperature overnight, then concentrate under vacuum. Flash chromatograph the residue on silica gel using 0. 5%-1% methanol in methylene chloride to obtain 933.

Step B

React 365a with the 933 (from Step A) following essentially the same procedure as in Preparative Example 73, Step D, to give 932, mp = 189.9-190. 1°C.

EXAMPLE 1575

934 React 372 (Example 167 of WO 02/18368) (0.06g, 0. 097mmol) with 5 equivalents (0.019g, 0. 48mmol) of NaH (60% in oil) in 2ml of dry THF at 0°C for 5 min.

Add 0. 027g (0. 11mmol) of 4- (bromomethyl) pyridine. Raise temperature to 60-65°C and continue to add NaH and 4- (bromomethyl) pyridine until reaction is complete by TLC (5% CH30H in CH2CI2 containing NH40H. Partition between ethyl acetate and

brine. Dry organic layer over Na2SO4, concentrate and chromatograph on silica gel, eluting with 1 %-4% CH30H in CH2CI2 containing NH40H, to give 934 as a light yellow solid.

EXAMPLE 1576 Following essentially the same procedure as in Example 1575, compound 372 was reacted with 2- (bromomethyl) pyridine. HBr to afford compound 935 identified in Table 105 below.

EXAMPLE 1577 Following essentially the same procedure as in Example 1575, compound 372 was reacted with 3- (bromomethyl) pyridine. HBr to afford compound 936 identified in Table 105 below.

EXAMPLE 1578 Following essentially the same procedure as in Example 1575, compound 372 was reacted with benzyl bromide to afford compound 937 identified in Table 105 below.

EXAMPLE 1579 Following essentially the same procedure as in Example 1575, compound 372 was reacted with CH31 to afford compound 938 identified in Table 105 below.

Table 105 Example R= Compound PHYS. DATA MH+ = 641 1575 934 c MH+ = 641 1576 N 935 Nô/ N MH+ = 641 1577 936 ZON mi + = 640 1578 937 Mu+-564 1579 CHs 938 EXAMPLE 1580 Step A

941 To a 125 ml flask, was added 4-hydroxymethyl piperidine (940) (1 g, 8. 68mmol) and 20 ml of MeOH, cool to 0°C, then added Boc-anhydride (2.84g, 13. 02mmol, 1.5 eq.), and adjust to pH 8. 5-9. 5 over 1 hour with 13m1, 13.0 mmol, 1.5eq. of 1.0 N NaOH.

Reaction was allowed to warm to room temperature and stirred for 1 hour. TLC with 20% EtoAc/CH2CI2. Removed most MeOH via evaporation. Added CH2CI2 and washed with H2O, brine and filtered through Na2SO4. The solvent was evaporated to give 1. 82g of a clear oil. Oily product crystallized upon standing to give a white solid product 941.

Step B 941 (0.3g, 1. 395mmol) was transferred into a flask and dissolved in anhydrous CH2CI2. Cool to 0°C. Added 129ul, 1.67 mmol, 1.2eq., of methanesulfonyl chloride and triethylamine 129ul, 2.09 mrnoi, 1. 5eq. ). Allowed to warm to room temperature while stirring for 1 hour. TLC with 20% EtoAc/CH2CI2. Added saturated NaHCO3, and stir 3-4 minutes, separated the CH2CI2 layer, washed with H20, brine and filtered through Na2SO4. Solvent was evaporated to give 0. 423g of a clear oil, compound 942.

Step C

942 (0 1 g, 3. 413mmol) was transferred into a reaction flask and added anhydrous CH2CI2 (1 ml), followed by addition of (1) 4-aminobenzonitrile (0. 040g, 3.4 mmol) and triethylamine (61ul, 4.4 mmol, 1.3 eq. ) and stir at room temperature for 10 minutes. TLC with 10% EtoAc/CH2CI2, reaction still did not complete. Stir for 11/2 hour, TLC again, reaction stopped. Removed solvent to dryness. Added to residue, (1 ml) of anhydrous THF at room temperature, then added 0. 0136g, 3.4 mmol of NaH (60% in oil Disp. ). Let stir for ½ hour, followed reaction progress by TLC. Added to reaction mixture additional NaH (0.0136g, 3.4 mmol), stirred for ½ hour, monitored reaction by TLC, then heated reaction mixture to 60°C in an oil bath for 45 minutes then overnight. Removed solvent in rotary evaporator under vacuum. Residue was dissolved in CH2CI2 and washed with H20, then brine. Filtered through Na2SO4, removed solvent to dryness to give 0. 125g of crude product. Crude was purified by flash chromatography using (silica gel) and eluting with CH2CI2 then with 1-5% EtoAc/ CH2CI2. Isolated 0. 035g of product, 943.

Step D N --N Nu nu ci cri H N (N) N (N) N 2) 1 CNJ 371a N CN CH Cl N 2 2 H. 2HCL 0 N TEA N CI 3) TEA olo p 20% o/ ( N Cl Cl inToluene. oXO 939 939

943 (0.034g, 0.11 mmol) was transferred into a reaction flask and dissolved in CH2CI2 (3 mi) and cooled to 0°C. TEA (60ul, 0.43 mmol, 4 eq. ) was added, followed by (213ul, 0.0427g, 0.43 mmol, 4 eq. ) of a 20% phosgene/toluene solution. Reaction was allowed to stir at 0°C for 11/2 hours. After 11/2 hours, N2 was bubbled into the reaction for-10 minutes, then added 0.056g, 0.12 mmol, 1.1 eq. , of starting material <BR> <BR> <BR> (2) -compound 371 a (Preparative Example 42, Step F, of WO 02/18368) followed by triethylamine (33ul, 0.24 mmol, 2.2 eq. ) in 1 ml of CH2CI2. Allowed to stir at 0°C for 11/2 hours. Reaction mixture was washed with NaHCO3, then H20, then brine and organic layer was filtered through Na2SO4. Removed solvent to dryness to give 0.083g of crude product. Purified on flash silica gel column eluting with 2,4, 6, 8% (10% NH40H/CH30H)/CH2CI2). Isolated product gave 0. 039g of 939, MH+ = 747.

EXAMPLE 1581

939 was reacted in the same manner as Compound 360a (Preparative Example 40, Step G, of WO 02/02/18368), using (0. 118g, 0.25 mmol) of 939 and (5 ml) of 4N HO in dioxane to give 0.252g of 944, MH+ = 647.

EXAMPLE 1582

In a 100 ml flask was added 944 (0. 073g, 0. 067024mmol) and 5 ml of anhydrous CH2CI2 and stirred followed by addition of TEA (37ul, 4 eq. ) and trimethylsilyl isocyanate (90ul, 0.07 mmol, 10eq.). Reaction was allowed to stir at room temperature for 1 hour. TLC with 7% (10% NH40H/CH30H)/CH2CI2. Stir 11/2 hours, then added saturated NaHC03 and stirred for 10 minutes, separated CH2CI2 layer, and washed with H20, brine and dried over Na2SO4, filtered and concentrated filtrate to dryness to give 0.056g of crude product. Purified on Flash silica gel column eluting with CH2CI2, then with 1-7 % (10% NH40H/CH30H)/CH2CI2. Isolated 0. 038g of the desired product, 945, MH+ = 690.

EXAMPLE 1583

In a 50ml reaction flask was added (0. 0092g, 0. 0882mmol, 1.05 eq. ) of 2- hydroxy isobutyric acid [CAS 594-61-6] in 1 ml of anhydrous DMF and 1 ml of anhydrous CH2CI2followed by addition of NMM (46ul, 0.42 mmol, 5 eq. ) ; HOBT (0.0178g, 0.11 mmol, 1. 3 eq.), DEC (0. 024g, 0. 13mmol, 1. 5 eq.). Reaction mixture was allowed to stir at room temperature for-10 minutes, then added 944 (0.084g, 0.08 mmol, 1 eq. ) in 1 ml of DMF and 1 ml of CH2CI2. Reaction was allowed to stir at room temperature overnight. Removed solvent in rotary evaporator, added EtoAc and washed with saturated NaHC03, then 3 (X) with H20, then with Brine. Organic layer was filtered through NazS04, evaporated filtrate to dryness to give 0.087g of crude product. Purified crude on a Flash silica gel column eluting with CH2CI2-1-5% (10% NH40H/CH30H)/CH2CI2, to give 0. 048g of a white solid Compound 946, MH = 733.

EXAMPLE 1584

In a 50 ml flask was transferred (0.084g, 0. 084mmol) of 944 and 2 ml of anhydrous CH2CI2followed by addition of triethylamine (50ul, 4. 2mmol, 5 eq. ) and methanesulfonylchloride (7. 8ul, 0.10 mmol, 1.2eq.). Reaction was allowed to stir at room temperature overnight. Tlc with 5% (10% NH40H/CH30H)/CH2CI2. Added saturated NaHC03 and stirred vigorously 5-10 minutes. Separated CH2CI2 layer and washed with H20, Brine and filtered through Na2SO4. Filtrate was evaporated to dryness to give 0.080g of crude product. Purified crude on a Flash silica gel column eluting with CH2CI2-1-4% (10%NH4OH/CH3OH)/ CH2Cl2, to give 0. 041g - compound 947, MH+= 725.

EXAMPLE 1585

In a 50 ml flask was transferred (0.084g, 0. 084mmol) of 944 and 2 ml of anhydrous CHzCl2followed by addition of triethylamine (58ul, 4. 2mmol, 5 eq. ) and triflic anhydride (16. 9ul, 0. 1008mol, 1.2eq.). Reaction was allowed to stir at room temperature overnight. TLC with 5% (10% NH40H/CH30H)/CH2CI2. Added saturated NaHC03 and stirred vigorously 5-10 minutes. Separated CH2Clz layer and washed with H20, brine and filtered through Na2SO4. Filtrate was evaporated to dryness to give 0.065g of crude product. Purified crude on a Flash silica gel column eluting with CH2Cl2- 1-4% (10% NH4OH/CH3OH)/ CH2Cl2. to give 0.028g-compound 948, MH+=779.

EXAMPLE 1586

Step A 4-aminobenzonitrile (0. 1g, 0.85 mmol) was dissolved in (5ml) of CH2Cl2. To this solution was added isobutylene oxide (61mg, 0. 85mmol) and 1g of silica gel.

Reaction mixture was stirred at room temperature for 16 hours. Isobutylene oxide (0. 75ul, 8mmol) was added and reaction was heated to 60°C for 16 hours. 4- aminobenzonitrile (200mg, 1. 6mmol) and isobutylene oxide (0. 75ul, 8mmol) was added and reaction refluxed for another 7 hours. Volatile solvents evaporated and material chromatographed on silica gel column, eluting with 1-9% ethyl acetate/ CH2Cf2, to give 295mg of the desired product-951.

Step B Compound 951 from Step A was N-protected with a Boc group using standard conditions to give 952.

STEP C

Compound 952 from Step B was 0-protected using tetrabutyldimethyl- silyl (TBDMS) to give 953.

Step D

953 954 The Boc group of 953 Step C was deprotected using HCI-Dioxane to give 954.

Step E

Compound 954 from Step D was treated in a similar way to compound of Example 1580, Step D, to give 955.

Step F

Compound 955 from Step E, was deprotected by treatment with tetrabutylammoniumfluoride (TBAF) to give the title compound 949.

EXAMPLE 1587

956 957 956 and 957 were prepared in a similar manner to 949 using the appropriate substituted starting epoxide.

PREPARATIVE EXAMPLE 109 Step A

To a stirred solution of 1, 2-dimethylimidazole, compound 958 (1.92g, 1eq. 20 mmol) in 50 ml of Et20, was added BuLi (2.5 M in Hexanes, 1 eq. 20 mmol, 8 ml) and stirred at room temperature, a yellow suspension results. Stirred for 1. 5 hr, more precipitate forms. Reaction mixture was treated with 3.5 mi of DMF, stirred for 2-5 hours or until reaction was complete. Quench reaction with NH4CI solution and extract with CH2CI2, wash organic 3x with brine. Isolate organic and evaporate to dryness to obtain product as a crude. Purification from Prep Plate Chromatography 10: 1 CH2CI2 : MeOH : 2N NH3 afforded 0.52 g of compound 959, #21%.

Step B

Following essentially the same procedures as in Example 510 (Step A), but using compound 959 (0. 25g, 2mmol) as the intermediate, compound 960 was prepared. Yellow solid (0.54g), 50% yield.

Step C

Following essentially the same procedures as in Example 510 (Step B) but using Compound 960 (0.45g, 0. 84mmol) as the starting material, compound 961 was prepared. Light yellow solid (0.372).

Step D

Following essentially the same procedures as in Example 510 (Step C) but using Compound 961 (0. 267g, 0. 5mmol) as the starting material, compound 962 was prepared.

Step E

Following essentially the same procedures as in Example 510 (Step D) but using Compound 962 (0. 5mmol) as the starting material, compound 963 was prepared. (0.18g). steP F

\ \,HO HO N HO N N /2 - N OD COLUMN-1 N-2 i r N + N N N OO 963a963a 963b 963

Following essentially the same procedures as in Example 510 (Step E), Compound 963 was separated by Chiral HPLC to give compounds 963a and 963b.

Chiral OD Prep HPLC Column, eluting with 1PA (10%) hexanes (80%) + 0.2% DEA Isomer 1, compound 963a : retention time = 7. 61 min isomer 2, compound 963b: retention time = 10. 56 min PREPARATIVE EXAMPLE 110 Step A

0 H 0 zozo Acétone N in K2CO3 N 964 965 To a stirred solution of 964 (Ethyl 4-methyl-5-imidazole carboxylate, 7.7g, 50mmol) in 100ml of acetone at room temperature, was added K2CO3 (6. 9g, 50 mmol) portionwise. Stirred at room temperature for 25 minutes, added in Mel (5 ml, 80mmol) stirred for 21/2 h, (monitored reaction by TLC). Additional K2CO3 (3. 09g, 22mmol) and Mel (3ml) were added. Stirred reaction for 16h, then filtered reaction mixture and rinsed with acetone (80mut). A clear filtrate obtained. Filtrate was evaporated and the residue was chromatographed (eluent methylene chloride/methanol (60: 1) to afford 1. 8g of solid. This solid was purified by Prep Plate chromatography ( (20 : 1) CH2CI2 : MeOH NH3), compound still impure. Another column chromatography ( (50 : 1) CH2Cl2:MeOH#NH3) was done to afford 383 mg of the desired product, compound 965.

Step B 965 966 To a stirred solution of compound 965 (680mg) in 10 ml THF at-78°C was added dropwise 1. OM LAH in THF (5. 0ml). Reaction was stirred and allowed to warm to room temperature overnight. Cooled reaction mixture to 0°C then added 5ml of H20 dropwise. Allowed reaction to warm to room temperature while stirring for 1 hr.

Filtered through celite and rinsed with 20ml THF/40m1 H2O. A clear filtrate obtained.

Filtrate afforded compound 966.

Step C

966 967 To a stirred solution of compound 966 (-4mol) at room temperature was added (3. 0g) of Mon02, a suspension resulted. Heated reaction mixture to a gentle reflux for 18hr. Additional MnO2/THF was added (6. 0g/20m1). Stirred at reflux for 24hr. Cooled to room temperature, filtered through celite and rinsed with 50ml MeOH.

Solvent was evaporated and azeotroped residue with toluene to afford crude product.

Crude was purified by column chromatography (20: 1 CH2CI2/MeOH), then (8: 1 CH2CI2 : MeOH) to elute out desired product as a white solid, compound 967.

Step D

If one were to follow essentially the same procedures as in Example 510 (Step A), but using compound 967 as the intermediate, then one could prepare compound 968.

Step E

If one were to follow essentially the same procedures as in Example 510 (Step B), but using compound 968 as the starting material, then one could prepare compound 969.

Step F

If one were to follow essentially the same procedures as in Example 510 (Step C), but using compound 969 as the starting material, then one could prepare compound 970.

Step G

If one were to follow essentially the same procedures as in Example 510 (Step D, but using Compound 970 as the starting material, then one could prepare compound 971.

Step H

If one were to follow essentially the same procedures as in Example 510 (Step E), then compound 971 could be separated by Chiral HPLC to give compounds 971 a and 971 b.

PREPARATIVE EXAMPLE 111 Step A

To a stirred solution of 972 (ethyl 4-methyl-5-imidazole carboxylate, 3. 08g, 20mmol) in 30ml of THF, at room temperature, was added NaH (0. 8g, 20 mmol) portionwise. Stirred at room temperature for 10 minutes, then cooled to 0°C. Added in Mel (1.5 ml, 24 mmol) stirred for 2 h, quenched with saturated NH4CI, extracted with ethyl acetate (2x), and washed with brine. Purified crude by column chromatography using a 20: 1 CH2CI2 : MeOH, to afford product, compound 973.

Step B To a stirred solution of compound 973 (0.9g) in 15 ml THF, was added 3m1 of a 10% LiOH solution and stirred reaction for 2 days. Evaporated solvent, azeotroped once with toluene, evaporated solvent to afford product, compound 974.

Step C To a stirred solution of compound 974 (-5. 4 mmol) in 40ml of anhydrous DMF at room temperature under N2, was added, 1. 05g, 10.8 mmol of (1); 2.07g, 10.8 mmol of (2); 0.729g, 5.4 mmol of (3); and 5.5 ml, 50mmol of (4). Reaction mixture was stirred

at room temperature for 5 hours. Reaction progress was monitored by TLC. Added 1 N HCI until pH < 5, extracted with diethyl ether (2x), cooled to 0°C then basified with saturated NaHCOs. extracted with CH2CI2, dry with MgS04, evaporated the solvent to afford 0. 6g of compound 975, brown oil.

Step D

To compound 975 (0. 590g, 3.2 mmol) in 5 ml of toluene at-70°C, was added (3. 6ml, 3. 6mmol of LAH (1 M in THF) ) dropwise. Reaction mixture was stirred at temperatures ranging from-70°C to-50°C for 30 minutes. Quenched reaction with 4ml brine, and stirred at room temperature for 20 minutes. Reaction was eluted through a cake of celite with ethyl acetate/CH2CI2. Dried filtrate, evaporated solvent to afford 0. 162g of product (yellow oil), compound 976.

Step E

Following essentially the same procedures as in Example 510 (Step A), reacting compound 365a (0.612g, 1.25 mmol) but using compound 976 (0. 152g) as the intermediate, compound 977 was prepared. (Yellow solid, 0.408g).

Step F

If one were to follow essentially the same procedures as in Example 510 (Step B), but using Compound 977 as the starting material, then one could prepare compound 978.

Step G

If one were to follow essentially the same procedures as in Example 510 (Step C), but using compound 978 as the starting material, then compound 979 could be prepared.

Step H

If one were to follow essentially the same procedures as in Example 510 (Step D), but using Compound 979 as the starting material, then one could prepare compound 980.

Step I N=\ t\ N==-\ HO N OH N HO \ \ 2 \ k OD COLUMN N N N N N N CN C N 00 0A0T 00 980 98osa

If one were to follow essentially the same procedures as in Example 510 (Step E), compound 980 could be separated by Chiral HPLC using a Chiral OD Prep HPLC column to give compounds 980a and 980b.

PREPARATIVE EXAMPLE 112 Step A

o non EtMgBr Ho - *% DMF N Tr 4-lodo-1-Trityl-1 H-lmidazole 981 Rep. Org. Prep. Proceed Int. (1996) 28 (6), 709-710.

To a stirred solution of 4-iodo-1-trityl-1H-imidazole (4. 36g, 10mmol) in THF (100ml) was added EtMgBr (4moi, 12 mmol) and let stir for 30 minutes. DMF (0. 93mut, 12mmol) was added and let stir for 1 hour. The reaction was poured into saturated ammonium chloride and extracted with EtOAc. The organic layer was dried with MgS04, filtered, and concentrated under vacuo to yield 3.5g of light yellow solid.

Step B

Following essentially the same procedures as in Example 510 (Step A), but using compound 981 (0. 72g) as the intermediate and MgBr. Et2O (2. 58g in 50moi THF, 7. 5moi), crude compound 982 was obtained. The crude material was purified via preparative plate chromatography (1-3% MeOH with NH3/CH2CI2) to obtain pure product, compound 982 (0. 29, 39%).

Following essentially the same procedures as in Example 510 (Step B), but using compound 982 (0.29g) as the starting material, compound 983 was prepared (0.29g). The crude material was purified via preparative plate chromatography (2% MeOH with NH3/CH2CI2) to yield 0. 237g of pure product, compound 983.

Step D

Following essentially the same procedures as in Example 510 (Step C), but using compound 983 (230mg) as the starting material, compound 984 was prepared (222mg).

Step E

Following essentially the same procedures as in Example 510 (Step D), but using compound 984 (0.2g) as the starting material, crude isomers 985a and 985b were prepared. The isomers were purified and separated via preparative plate chromatography (5% MeOH with NH3/CH2CI2) to obtain 0.16g of pure 985a and 0. 06g of pure 985b.

PREPARATIVE EXAMPLE 113

To compound 982 (390mg) dissolved in THF (3ml) was added NaH (60% in mineral oil, 28mg). After 5 minutes, iodomethane was added and let stir for several hours. The reaction was concentrated under vacuo and carried on crude to the next reaction.

PREPARATIVE EXAMPLE 114 Step A woo 987 To a stirred solution of 987 (2-methyl-1 H-imidazole-4-carboxaldehyde, 1 g, 9. 09mmol) in 10 ml of DMF at 0°C was added NaH (60% in mineral oil (0.36g)) portionwise. Stirred mixture for 1/2 hr, then added SEM-CI (2. 02ml, 9. 9mmol). Stirred reaction until completed. Added reaction mixture to brine and extracted with CH2CI2 (3x). Evaporated solvent to get an oil. Column chromatography (CH2Cl2 (100%-2% MeOH NH3/CH2CI2) afforded 1. 68g of product, compound 988 (77%).

Step B

Following essentially the same procedures as in Example 510 (Step A), reacting compound 365a (0. 12g, 0. 25mmol) but using compound 988 (0. 1g) as the intermediate, compound 989 was prepared (96mg, 56%).

Step C

Following essentially the same procedures as in Example 510 (Step B), but using Compound 989 (0. 52g, 0. 79mmol) as the starting material, compound 990 was prepared.

Step D

Following essentially the same procedures as in Example 510 (Step C), but using compound 990 (0. 51 g, 0. 79mmol) as the starting material, compound 991 was prepared.

Steppe

Following essentially the same procedures as in Example 510 (Step D), but using Compound 991 (0. 79mmol) as the starting material, compound 992 was prepared.

Step F

To compound 992 (0.1g) dissolved in THF (5ml) at room temperature under N2, was added 0. 2m1 of tetrabutylammonium fluoride 1 M solution in THF (TBAF). Stirred reaction for 2hr. Additional TBAF was added (0. 2moi), monitored reaction by TLC. No reaction after 4 hours. Reaction was treated with 0. 5m ! of TBAF and heated to 85°C.

After 2hr, reaction completed. Cooled reaction and added to brine and extracted with CH2CI2 (3x), dried organic over MgS04, filter and evaporated solvent to give crude product. Purification by Prep Plate Chromatography using 95% CH2CI2/MeOH NH3 (5%) afforded 0.12g of product, compound 993.

Step G NH NH NH HO OH HO - N 1 N 2 N N I N 2 N N N N N zN>, N N N N 0 O''O p 993 993a 993b

If one were to follow essentially the same procedures as in Example 510 (Step E), then compound 993 could be separated by Chiral HPLC to give compounds 993a and 993b, using a Chiral OD Prep HPLC Column.

PREPARATIVE EXAMPLE 115 Step A To a stirred solution of 994 (3. 08g, 20mmol) in 15 mi of DMF at 0°C was added NaH (60% in mineral oil, 0. 80g) portionwise. After stirring for several minutes, SEM-CI (3. 54ml, 20mmol) was added and let the reaction stir overnight. Brine was added to the reaction and extracted with EtOAc. The organic layer was washed with water and brine, dried with MgSO4, filtered and concentrated under vacuum. Purified by flash elute column chromatography (CH2CI2/MeOH, 50: 1 to 20: 1) to afford 4. 54g of yellow oil, compound 995.

Step B To a stirred solution of compound 995 (3.5g) in THF (50mi) was added a LiOH solution (1 M, 24ml) and stirred for 2 days. The reaction was not complete ; therefore, 25ml of MeOH and another 10ml of the LiOH solution was added and the reaction was heated to 40°C for 2 hours. The reaction was concentrated under vacuo, azeotroped once with toluene, and evaporated to dryness to afford compound 996, which was carried on directly without further purification.

Step C

4) NMM Following a similar procedure to that described in Preparative Example 111 Step C, but using compound 996, compound 997 was prepared (5.37g crude).

Step D

Following a similar procedure to that described in Preparative Example 111 Step D, but using compound 997 (4. 2g), compound 998 was prepared.

PREPARATIVE EXAMPLE 116 Step A

If one were to follow a similar procedure as described in Example 510 (Step A), but using compound 998 as the intermediate, then compound 999 could be prepared.

Step B

If one were to follow a similar procedure as described in Example 510 (Step B), but use Compound 999, then compound 1000 could be obtained.

Step C

If one were to follow a similar procedure as described in Example 510 (Step C), but using compound 1000 as the starting material, then compound 1001 could be prepared.

Step D

If one were to follow a similar procedure as described in Example 510 (Step D), but using compound 1001, then one could obtain compound 1002.

Step E

If one were to follow a similar procedure as described in Preparative Example 114 (Step F), but using compound 1002, then one could obtain compound 1003.

Step F Nu HO NH HO NH HO NH 1 2 I Ñ rNA non + N = N N N N N O 1003 1003a 1003b

If one were to follow a similar procedure as described in Example 510 (Step E), then compound 1003 could be separated by Chiral HPLC to give compounds 1003a and 1003b.

EXAMPLE 1588 Compound 963a (Isomer 1) and compound 963b (Isomer 2) were converted to compound 1004a and compound 1004b by following a similar procedure as described in Example 507.

EXAMPLE 1589 Compound 971 a (Isomer 1) and compound 971 b (Isomer 2) were converted to compound 1005a and compound 1005b by following a similar procedure as described in Example 507.

EXAMPLE 1590 Compound 980a (Isomer 1) and compound 980b (Isomer 2) were converted to compound 1006a and compound 1006b by following a similar procedure as described in Example 507.

EXAMPLE 1591 Isomers 985a and 985b were converted to compound 1007a and compound 1007b by following a similar procedure as described in Example 507.

EXAMPLE 1592 To the product from Preparative Example 113 dissolved in CH2CI2 (5ml) was added trifluoroacetic acid (1 ml) and let stir for 1 hour. The reaction was concentrated under vacuo and carried on crude to the next reaction.

EXAMPLE 1593 Compound 993a (Isomer 1) and compound 993b (Isomer 2) were converted to compound 1009a and compound 1009b by following a similar procedure as in Example 507.

EXAMPLE 1594 If one were to follow a similar procedure as described in Example 507, then compound 1003a (Isomer 1) and compound 1003b (Isomer 2) can be converted to compound 1010a and compound 1010b.

PREPARATIVE EXAMPLE 117 Step A

Following the same procedure as described in Example 510 Step C, but using compound 795 (3g) from Example 489 of WO 02/18368, the desired crude product was obtained (3.3g).

Step B ° o 0 /1 cri Flash Column ci ci N 00 N-+- Chromatography N N N N O''O' O O O O 1011 1011 1011a 1011b (Isomer A) (Isomer B)

The crude material above (1011) was separated by flash column chromatography (40% EtOAc/Hex) to yield pure isomer A (1011 a) (1. 23g) and an impure isomer B (1011 b) (1. 64g). Impure isomer B was triterated in CH2CI2/MeOH and filtered to give pure isomer 1011 b (0.7g). steP C

2-Methylimidazole (1.1g) was dissolved in dry DMF (15ml) followed by the addition of NaH (60% in mineral oil, 300mg). After stirring for 20 minutes, compound 1011 b (1.2g) was added and the solution was heated to 90°C for 4 hours. The reaction was concentrated under vacuo, dissolved in CH2CI2 and washed with brine.

The organic layer was dried, concentrated under vacuo and purified via flash column chromatography (6% MeOH/CH2CI2+ NH40H) to give the desired product (1. 47g).

Step D

Compound 1012 (1.4g) was converted to compound 1013 (1.09g) by following the procedure set forth in Example 507.

PREPARATIVE EXAMPLE 118 Step A

Following the same procedure as described in Preparative Example 117 Step C, but using compound 1011 a (696mg), the desired compound was obtained (903mg).

Steo B

Compound 1014 (0.9g) was converted to compound 1015 (0. 58g) by following the procedure set forth in Example 507. EXAMPLES 3157-3162 Compound 1015

1015 from Preparative Example 118 Step B was reacted in essentially the same manner as in Example 511-513 to afford the compounds in Table 134.

Table 134 Example Compound 3157 \ N HO 2 H CI - 2 cri N ce N '0' H 3158 \ /N N) HO S 9X - 2 ci N (N) N N"I0 H 3159 N N HO 2 ci H XCI N ci C Ouzo Neo 3160 \ zon Zon ho H \ CI cri N = (N) N Ñ 3161 ZON Nez ho cri CI (N) N Cl -0-H H 3162 ZON Gaz ZEN ci ci r N N ce N N"-o H EXAMPLES 3163-3168 Compound 1013

from Preparative Example 117 Step D was reacted in essentially the same manner as in Examples 511-513 to afford the compounds in Table 135.

Table 135 Exam le Compound 3163 zon N' HO XN - I cl I . 1 N C N NC N H 3164 3164 H N) >N N N ho 1 \ ce N cri CNg N N-'O H 3165 nit /N HO Cl 1 cri N N C N 0 H 3166 \ M-N N ci N cl sNX N HOBT N c) ZON neo H N N N HO 1 Ñ Cl - 1 ci N-= tN) N H2NXO _ 3168 _ _. ZON N HO 1 CI cri N = (N) C N N-O u H EXAMPLE 3256 1016 1018

1019a/1019b To a THF (freshly distilled, 10 mL) solution of 1016 (980 mg, 2 mmol) kept at -78 °C, BuLi (1. 6 mL, 2.5 M hexanes solution, 4 mmol) was added in dropwise. After 15 min, THF (6 mL) solution of 1017 (676 mg, 2 mmol) was added in. After stirring at - 78 °C for 1.5 hrs, the reaction mixture was participated between ethyl acetate and brine at room temperature. The aqueous layer was extracted with ethyl acetate once.

The combined ethyl acetate layers was dried and concentrated in vacuo. The resulting crude was purified with silica gel column eluting with methanol/methylene chloride (2%-5%). Compound 1018 (834 mg) was obtained as a light yellow solid.

Compound 1018 (390 mg, 0.52 mmol) was dissolved in THF (3 mL) at room temperature. NaH (28 mg, 60% in mineral oil, 0.7 mmol) was added in followed by Mel (1.0 mL) 5 min later. After stirring for 20 hrs, the mixture was evaporated to dryness in vacuo. The resulting crude was taken up in CH2CI2 (5 mL) and TFA (1 mL) was added. One hour later, the mixture was evaporated to dryness. The crude was

retaken up in COz and made to PH>8 by addition of triethyl amine (ca. 0. 6 mL).

(Boc) 20 (320 mg, 1.5 mmol) was then added. After stirring for 30 mins, the solvents were removed in vacuo and the residue was participated between CH2Cl2 and H2O.

The organic layer was dried and concentrated. The crude was purified with prep TLC plates using 10% methanol (2M NH3)/CH2CI2 to yield a light yellow solid (121 mg).

The product was separated by a semi-prep OD HPLC column eluting with 30% IPA/Hexane/0. 2% DEA to give pure isomers 1019a (44.8 mg, isomer 1, Mu+ = 536) and 1019b (53.6 mg, isomer2, MH+ = 536).

EXAMPLE 3257 O N 0 N 1 \ IN 1 \ i N N , 0 0 CH2CI2 N N obi N N N N ° ° 1 020a 1019a , _N _N 2 N 11 2 N I HCI/dioxane I CH2CI2 N N I --k H ouzo 1020b 1019b

Compound 1019b (isomer 2) was converted to 1020b by reacting it with 20% 4M HCI (dioxane)/CH2CI2 at room temperature under N2 overnight.

The same procedure was used to prepare 1020a (isomer 1) from 1019a.

EXAMPLES 3258-3260 Each isomer, 1020a and 1020b from Example 3257 was dissolved in CH2C12.

TEA was added in till PH >8 and followed by the corresponding isocyanates. Once TLC indicated the complete consumption of starting material, the solvent was concentrated in vacuo. The residue was purified by silica gel preparative thin layer chromatography or silica gel chromatography to afford compounds of the formulas:

wherein R is defined in Table 140 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 140

EXAMPLE R Isomer 1 Isomer 2 Data Data I 3258 oN MH+ 535 MH+ 535 H 3259 ONtO MH+ 561 MH+ 561 H 3260-t _CN MH+ 580 MH 580 H-

EXAMPLES 3261-3263 Isomer 1020a from Example 3257 was dissolved in CH2CI2 at room temperature under nitrogen, followed by addition of the corresponding carboxylic acid, and the appropriate reagents: EDC, HOBt and NMM. Reaction was then stirred overnight and added in 1 N HCI till pH = 2. After stirring for 5 min, it was then basicified with sat. NaHC03 followed by extraction of CH2CI2. The organic solvent was concentrated in vacuo and the residue was then purified by silica gel column to give compounds of the formula :

wherein R is defined in Table 141 and the number 1 in the formula represents isomer 1.

Table 141 EXAMPLE R Isomer 1 Data I 3261 | Data 32ì1, MH 5ZZ 3262 OH MH'584 OH 3263 S Ph MH+ 584 Oh e

EXAMPLE 3264 Isomer 1020b from Example 3257 was dissolved in CH2CI2at room temperature under nitrogen, followed by addition of diisopropylethyl amine to pH>8.

Reaction was then treated with the corresponding sulfonyl chloride and stirred at room temperature till TLC indicated the completion of reaction. Quench reaction with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give a compound of the formula :

wherein R is defined in Table 142 and the number 2 in the formula represents isomer 2.

Table 142 EXAMPLE Isomer 2 Data I 3264 o-s o MH+ 514 1

EXAMPLES 3265-3267 Isomer 1020b from Example 3257 was dissolved in CH2CI2 at room temperature under nitrogen, followed by addition of TEA. Reactions were then treated with the respective chloroformates (made from the corresponding alcohols according to Preparative Example 74) and stirred at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2- Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formula :

wherein R is defined in Table 142 and the number 2 in the formula represents isomer 2.

Table 142 EXAMPLE R Isomer 2 Data 3265 Mu+ 522 3266 ofOe MH+ 562 32fi7 3267 Mu+ 564 EXAMPLE 3268 791 791a 791b (Preparative Example 65) of WO 02/18368

Compound 791 was separated by AD HPLC column eluting with 15%-30% IPA/Hexanes/0. 2% DEA to give pure isomers 791a (isomer 1, MH+ = 547. 1) and 791b (isomer 2. MH+ = 547. 1).

EXAMPLE 3269 N3 N N3 N 1 \ IN 1 \ IN ce HCI/dioxane CH2CI2 N AOXO H I N N I H 1021a 791a Na N N3 N 2 \ IN 2 IN CI \ CI HCI/dioxane CHzCIz N N N , H 1021b 791 b

Compound 791 b (isomer 2) was converted to 1021 b by reacting it with 20% 4M HCI (dioxane)/CH2CI2 at room temperature under N2 overnight.

The same procedure was used to prepare 1021 a (isomer 1) from 791 a.

EXAMPLE 3270 Each isomer, 1021 a and 1021 b from Example 3269 was dissolved in CH2CI2,.

TEA was added in till PH >8 and followed by the corresponding isocyanate. Once TLC indicated the complete consumption of starting material, the solvent was concentrated in vacuo. The residue was purified by silica gel preparative thin layer chromatography or silica gel chromatography to afford compounds of the formulas

wherein R is defined in Table 144 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 144 EXAMPLE R Isomer 1 Isomer 2 Data Data I 3270 AeCN | MH+ 591 | MH+ 591 H

EXAMPLE 3271 Each isomer, 1021 a and 1021 b from Example 3269 was dissolved in CH2CI2 at room temperature under nitrogen, followed by addition of the corresponding carboxylic acid, and the appropriate reagents : EDC, HOBt and NMM. Reaction was then stirred overnight and added in 1 N HCI till pH = 2. After stirring for 5 min, it was then basicified with sat. NaHC03 followed by extraction of CH2CI2. The organic solvent was concentrated in vacuo and the residue was then purified by silica get column to give compounds of the formulas :

wherein R is defined in Table 145 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 145 EXAMPLE R Isomer 1 Isomer 2 Data Data I 3271 o MH+ 533 MH+ 533 /"OH

EXAMPLE 3272 Each isomer, 1021 a and 1021 b from Example 3269 was dissolved in CH2CI2 at room temperature under nitrogen, followed by addition of diisopropylethyl amine to PH>8. Reactions were then treated with the corresponding sulfonyl chloride and stirred at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formulas :

wherein R is defined in Table 146 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 146 EXAMPLE Isomer 1 Isomer 2 Data Data l- 3272 O=S=O MH''S25 MH+ 525 1

EXAMPLE 3273 Each isomer, 1021 a and 1021 b from Example 3269 was dissolved in CH2CI2at room temperature under nitrogen, followed by addition of TEA. Reactions were then treated with the respective chloroformate (made from the corresponding alcohols according to Preparative Example 74) and stirred at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formulas :

wherein R is defined in Table 147 and the number 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 147 EXAMPLE R Isomer 1 Isomer 2 Data Data 3273 o, c=o MH+ 533 MH+ 533 EXAMPLES 3274-3277

Each isomer from Examples 3268 and 3270-3273 was dissolved in MeOH at room temperature under nitrogen, followed by addition of excess SnCI2. Reactions were stirred at room temperature overnight and then concentrated in vacuo. The residue was stirred in a mixture of 1 N NaOH and ethyl acetate for 30 mins. Extract with ethyl acetate several times and wash the organic layer with brine. Organic layer was dried and evaporated to dryness. The crude was purified by silica gel column to give compounds of the formulas :

wherein R is defined in Table 148 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

Table 148 EXAMPLE R Isomer 1 Isomer 2 Data Data 3274 MH* 521 MH+ 521 1 3274r < -/\-CM 3275 He MH+ 565 MHç 565 0-11- 3276 o=s=o MH+ 499 MH+ 499 I 3277 p----* MH+ 507 /OH *Isomer 1 of Example 3277 was not made.

EXAMPLES 3278-3279 Following a procedure similar to that of Example 3270 the azide compound

is prepared wherein R is and the number 2 in the formula represents isomer 2.

Then, following a procedure similar to that of Examples 3274 to 3278 the amino compounds of formula :

is prepared from the azide compound wherein R is defined in Table 149 and the number 2 in the formula represenst isomer 2.

Table 149 EXAMPLE Isomer 2 Data r-X MH+ 547 3278 0--l-N-0 H MH+ 521 3279/--NH 0 EXAMPLE 3280 N3 N N3 N N3 N N3 N 2 zu ci 1. TFA, CH2CI2 ei 2. isopropyl chloroformate, TEA, CH2CI2 N N O O O O 791 Isomer 2 1032

1032 1033 Isomer 2 of Compound 791 (70 mg, 0.13 mmol) was dissolved in CH2CI2 (5 mL) at room temperature. TFA (1 mL) was added in. After the reaction mixture was stirred under N2 for 1 hour, it was evaporated to dryness with CH3Ph. The residue was retaken up in CH2CI2 (5 mL) and the solution was made to pH>8 by addition of triethyl amine (ca. 0.2 mL). Isopropyl chloroformate (0.13 mL, 1.0 M in CH3Ph) was then added in dropwise. After stirring for 1 hr, the reaction was quenched with water and the mixture was extracted with CH2CI2 twice. The organic layer was dried and concentrated. The crude was purified with prep TLC plates using 10% methanol (2M NH3)/CH2CI2 to give Compound 1032 as a light yellow solid (50 mg). MS Mol 533.

Compound 1032 (160 mg, 0.3 mmol) was dissolved in MeOH (5 mL) at room temperature and SnCI2 (150 mg, 0.79 mmol) was added in. After 3 hrs, majority of solvent was removed in vacuo. To the residue was added 30 mL 1 N NaOH and 20 mL ethyl acetate. The turbid solution became clear after stirring for 20 min. Extract the aqueous layer once with ethyl acetate. The combined organic layer was dried and concentrated. The crude was purified by prep TLC plates using 10% methanol (2M NH3)/CH2CI2 to give compound 1033 as a light yellow solid (90.0 mg).

M. P. 132-135°C. MS M+1 507.

EXAMPLE 3281

To a solution of compound 792 (Example 486 of WO 02/18368) (0.052 gm, 0.1 mmole) in 5 ml of dry dichloromethane was added 0.02 gm of triethylamine and 0. 01g of methyl-chloroformate. After stirring for two hours under dry nitrogen the reaction mixture was washed with brine and the organic phase separated, dried over Magnesium sulfate, filtered and evaporated to obtain a crude mixture. The crude mixture was chromatographed on silica gel using 10% methanol/dichloromethane as the eluent to obtain 0.019 gm of final product. MH+ 579 (Isomer 1) and MH+ 579 (Isomer 2).

EXAMPLES 3282-3287f Following a procedure similar to that in Example 3281, but using the corresponding sulfonyl chloride, isocyanate, chloroformate or acid chloride of the R9b substituent, compounds of the formulas :

were prepared wherein R9b is defined in Table 150 and the numbers 1 and 2 in the formulas represent Isomers 1 and 2, respectively.

Table 150 Example R Isomer 1 Isomer 2 Data Data 3282 MH+ 563 MH+ 563 0 3283 H2N MH+ 564 MH+ 564 ... _ 3284 \ MH+ 592 Ml 1+ 592 HN ou 3285 MH+ 599 MH+ 599 0 0 3286 MH+ 607 MH+ 607 0 0 3287 0 MH+620 MH+620 nu 3287a I l MH+ 593. 1 ., \K 3287b MH+ 606. 1 H 3287c Mu+ 589. 1 3287d MH+ 591. 3 Y 3287e o MH+ 605. 1 3287f MH+ 593. 3 OMe EXAMPLE 3288

4001 To a solution of the compound of Example 3282 (Isomer 2) (150 mg) was added 10 mi of dichloromethane and 2 mi of trifluoroacetic acid. The mixture was stirred for 1.5 hrs and then evaporated to dryness. The mixture was azeotroped with dichloromethane two times and re-dissolved in 15 ml of dichloromethane and 0.5 ml of triethyl amine. To 0.08 mmol of the resulting compound was added 15 mg of 4- cyanophenylisocyanate. The reaction was stirred for 1 hr and then concentrated. The

residue was chromatographed on silica gel using 10% methanol/dichloromethane to obtain 0.033 gm of product. MH+ 607 (Isomer 2).

EXAMPLES 3289-3291 Following a procedure similar to that in Example 3288 compounds of the formula:

were prepared using the corresponding chloroformate or isocyanate for substituent R, wherein R is defined in Table 151, and the number 2 in the formula represents Isomer 2.

Table 151 Isomer 2 Data 3289 MH+ 549 0 3290 MH+ 562 _ H 3291 0 MH+ 591 'o 0

EXAMPLES 3292-3297 Using the compound of Example 3287 (Isomer 2) and following a procedure similar to that in Example 3288 compounds of the formula :

were prepared using the corresponding isocyanate, sulfonyl chloride, or chloroformate for substituent R, wherein R is defined in Table 152, and the number 2 in the formula represents Isomer 2.

Table 152 Example R Isomer 2 Data 3292 NCA, MH 664 LEZ H 3293 MH+598 0 3294 oa0lo MH+648 CL. 3295 I r MH+619 N' H 3296 aN'O MH+645 ZOZO H 3297 MH+606 oxo EXAMPLES 3298-3302 Using the compound of Example 3285 (Isomer 2) and following a procedure similar to that in Example 3288 compounds of the formula:

were prepared using the corresponding isocyanate, sulfonyl chloride, or chloroformate for substituent R, wherein R is defined in Table 153, and the number 2 in the formula represents Isomer 2.

Table 153 Example Isomer 2 Data I 3298 Mu+ 598 /NO H 3299 M H+ 542 H, Nô 3300 MH+ 585 1, 3301 t lXO MHt 627 solo 3302 MH+ 577 0= in 0

EXAMPLES 514-3255 If one were to follow procedures similar to those of Examples 511-513, or 536, or 566-567 or 590-603, then one would obtain compounds of the formulas described below, wherein R is defined in Table 153A, and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively : (1) Examples 514-535, 537-544, 546-565, 568, 570-573,575-589, and 604- 614, the compounds of these examples would have the formulas :

(2) From isomers 897a and 897b: Examples 615-639, 715-732 (see Preparative Example 74 for preparation of chloroformates), 787-814,899, 900,902- 905,907-913, and 915-922, the compounds of these examples would have the formulas:

(3) From isomers 898a and 898b : Examples 640-664, 733-750 (see Preparative Example 74 for preparation of chloroformates), 815-842,923, 924,926- 929, 931-937, and 939-94, the compounds of these examples would have the formulas :

(4) From isomers 899a and 899b: Examples 665-689,751-768 (see Preparative Example 74 for preparation of chloroformates), 843-870,947, 948,950- 953,955-961, and 963-, the compounds of these examples would have the formulas :

(5) From isomers 900a and 900b: Examples 690-714,769-786 (see Preparative Example 74 for preparation of chloroformates), 871-898,971, 973-977, 979-985, 987, and 989-995, the compounds of these examples would have the formulas :

(6) From isomers 919a and 919b: Examples 996-1020,1046-1073, 1103- 1121 (see Preparative Example 74 for preparation of chloroformates), 1140, 1141, 1143,1144-1146, 1148-1154, and 1156-1163, the compounds of these examples would have the formulas :

(7) From isomers 920a and 920b: Examples 1021-1045,1075-1102, 1122- 1139 (see Preparative Example 74 for preparation of chloroformates), 1164-1165, 1167-1170, 1172-1178, and 1180-1187, the compounds of these examples would have the formulas :

(8) From isomers 924a and 924b: Examples 1188-1212, 1239-1266, 1296- 1313 (see Preparative Example 74 for preparation of chloroformates), 1333-1334, 1336-1339,1341-1347, and 1349-1356, the compounds of these examples would have the formulas :

(9) From isomers 925a and 925b: Examples 1213-1221,1223-1238, 1267- 1294,1315-1332 (see Preparative Example 74 for preparation of chloroformates), 1357-1358, 1360-1363, 1365-1371, and 1373-1380, the compounds of these examples would have the formulas :

(10) From isomers 928a and 928b : Examples 1381-1405,1432-1459, 1432- 1459,1488-1505 (see Preparative Example 74 for preparation of chloroformates), 1525-1529,1531, 1533-1539, and 1541-1548, the compounds of these examples would have the formulas :

(11) From isomers 929a and 929b: Examples 1406-1409, and 1411-1431, 1460-1487, 1506-1524 (see Preparative Example 74 for preparation of chloroformates), 1549-1550,1552-1555, 1557-1563, and 1565-1572, the compounds of these examples would have the formulas :

(12) From isomers 1004a and 1004b: Examples 1595-1619, 1620-1647, 1648,1650-1654, 1656-1660, 1662-1671, and 1672-1690 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(13) From isomers 1005a and 1005b: Examples 1691-1715, 1716-1743, 1744-1745, 1747-1750, 1752-1758,1760-1767, and 1768-1786 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(14) From isomers 1006a and 1006b: Examples 1787, and 1788-1811,1812- 1839, 1840-1845, 1847-1861, and 1862-1880 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(15) From isomers 1007a and 1007b : Examples 1881-1905,1906-1933, 1935-1940, 1942-1956, and 1957-1975 (see Preparative Example 74 for preparation of chloroformate), the compounds of these examples would have the formulas :

(16) From isomers 1009a and 1009b: Examples 1976-2000, 2001-2028, 2028a, 2029-2033, 2035-2049, and 2050-2068 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(17) From isomers 1010a and 1010b : Examples 2069-2093, 2094-2099, 3000-3021, 3022-3027, 3029-3043, and 3044-3062 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(18) From compound 1008 : Examples 3063-3087, 3088-3115, 3116-3121, 3123-3137, 3138-3156 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

(19) From compounds 1013 and 1015: Examples 3169-3187,3188-3215, 3216-3221, 3223-3237, 3237a, and 3238-3255 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas :

TABLE 153A Examples Isomer 1 and Isomer 2 514, 615, 640, 665, 690, 996, 1021, 1188, 1213, 1381, 1406, 1595, 1691, 1787, 1881, 1976, 2069, 3063, NH 515, 616, 641, 666, 691, 997, 1022, 1189, 1214, 1382, 1407, 1596, 1692, 1788, 1882, 1977, 2070, 3064, 3169 0-N H 516, 617, 642, 667, 692, 998, 1023, 1190, 1215, 1383. 1408, 1597, 1693, 1789, 1883, 1978, 2071, 3065, 3170 p N H 517, 618, 643, 668, 693, 999, 1024, 1191, 1216, 1384, 1409, 1598, 1694, 1790, 1884, 1979, 2072, 3066, 3171 orGL_N- H 619, 644, 669, 694, 1000, 1025, 1192, 1217, 1385, 1411, 1599, 1695, 1791,'/ 1885, 1980. 2073, 3067 O'N H 518, 620, 645, 670, 695, 1001, 1026, 1193, 1218, 1386, 1412, 1600, 1696, 1792, 1886, 1981, 2074, 3068, 3172 0 N H 519, 621, 646, 671, 696, 1002, 1027, 1194, 1219, 1387, 1413, 1601, 1697', 1793, 1887, 1982, 2075, 3069, 3173 o=L_HX H 520, 622, 647, 672, 697, 1003, 1028, 1195, 1220, 1388, 1414, 1602, 1698, l 1794, 1888, 1983, 2076, 3070, 3174 p N H 521, 623, 648, 673, 698, 1004, 1029, 1196, 1221, 1389, 1415, 1603, 1699, 1795, 1889, 1984, 2077, 3071, 3175 O N H 624, 649, 674, 699, 1005, 1030, 1197, 1223, 1390, 1416, 1604, 1700, 1796, 1890, 1985, 2078, 3072 ozon H 522, 625, 650, 675, 700, 1006, 1031, 1198, 1224, 1391, 1417, 1605, 1701, 1797, 1891, 1986, 2079, 3073, 3176 in O'''N H 626, 651, 676, 701, 1007, 1032, 1199, 1225, 1392, 1418, 1606, 1702, 1798,) CN 1892, 1987, 2080, 3074,", O-N H 523, 627, 652, 677, 702, 1008, 1033, 1200, 1226, 1393, 1419, 1607, 1703, 1799, 1893, 1988, 2081, 3075 < wu N H H 524, 628, 653, 678, 703, 1009, 1034, 1201, 1227, 1394, 1420, 1608, 1704, Br 1800, 1894, 1989, 2082, 3076, 3177 OZON H 525, 629, 654, 679, 704, 1010, 1035, 1202, 1228, 1395, 1421, 1609, 1705, 1801, 1895, 1990, 2083, 3077, 3178 t H H 526, 630, 655, 680, 705, 1011, 1036, 1203, 1229, 1396, 1422, 1610, 1706, F 1802, 1896, 1991, 2084, 3078, 3179 1 W H H 527, 631, 656, 681, 706, 1012, 1037, 1204, 1230, 1397, 1423, 1611, 1707, OCH3 1803, 1897, 1992, 2085, 3079, 3180 OZON H 528, 632, 657, 682, 707, 1013, 1038, 1205, 1231, 1398, 1424, 1612, 1708, 0 1804, 1898, 1993, 2086, 3080, 3181 ON H 529, 633, 658, 683, 708, 1014, 1039, 1206, 1232, 1399, 1425, 1613, 1709, F 1805, 1899, 1994, 2087, 3081 F F ON H H 530, 634, 659, 684, 709, 1015, 1040, 1207, 1233, 1400, 1426, 1614, 1710, 1806, 1900, 1995, 2088, 3082, 3182 \ O^ N H 531, 635, 660, 685, 710, 1016, 1041, 1208, 1234, 1401, 1427, 1615, 1711, 1807, 1901, 1996, 2089, 3083, 3183 N OZON H 532, 636, 661, 686, 711, 1017, 1042, 1209, 1235, 1402, 1428, 1616, 1712,. O 1808, 1902, 1997, 2090, 3084, 3184 OZON 'u 533, 637, 662, 687, 712, 1018, 1043, 1210, 1236, 1403, 1429, 1617, 1713, 1809, 1903, 1998, 2091, 3085, 3185 O ; N X H 534, 638, 663, 688, 713, 1019, 1044, 1211, 1237, 1404, 1430, 1618, 1714,, 1810, 1904, 1999, 2092, 3086, 3186 0 N'ON H 535, 639, 664, 689, 714, 1020, 1045, 1212, 1238, 1405, 1431, 1619, 1715,'/=\ 1811, 1905, 2000, 2093, 3087, 3187 p N \/ H 537, 787, 815, 843, 871, 1046, 1075, 1239, 1267, 1432, 1460, 1620, 1716, 1812, 1906, 2001, 2094, 3088, 3188 0 538, 788, 816, 844, 872, 1047, 1076, 1240, 1268, 1433, 1461, 1621, 1717, 1813, 1907, 2002, 2095, 3089, 3189 0"-" 539, 789, 817, 845, 873, 1048, 1077, 1241, 1269, 1434, 1462, 1622, 1718, 1814, 1908, 2003, 2096, 3090, 3190 0 :- 540, 790, 818, 846, 874, 1049, 1078, 1242, 1270, 1435, 1463il623, 1719, 1815, 1909, 2004, 2097, 3091, 3191 O 541, 791, 819, 847, 875, 1050, 1079, 1243, 1271, 1436, 1464, 1624, 1720, 1816, 1910, 2005, 2098, 3092, 3192 oK 542, 792, 820, 848, 876, 1051, 1080, 1244, 1272, 1437, 1465, 1625, 1721, 1817, 1911, 2006, 2099, 3093, 3193 0 543, 793, 821, 849, 877, 1052, 1081, 1245, 1273, 1438, 1466, 1626, 1722, 1818, 1912, 2007, 3000, 3094, 3194 _ 544, 794, 822, 850, 878, 1053, 1082, 1246, 1274, 1439, 1467, 1627, 1723, 1819, 1913, 2008, 3001, 3095, 3195 0/0 546, 795, 823, 851, 879, 1054, 1083, 1247, 1275, 1440, 1468, 1628, 1724, 1820, 1914, 2009, 3002, 3096, 3196 O 547, 796, 824, 852, 880, 1055, 1084, 1248, 1276, 1441, 1469, 1629, 1725, 1821, 1915, 2010, 3003, 3097, 3197 0 °\) 548, 797, 825, 853, 881, 1056, 1085, 1249, 1277, 1442, 1470, 1630, 1726, 1822, 1916, 2011, 3004, 3098, 3198 o 549, 798, 826, 854, 882, 1057, 1086, 1250, 1278, 1443, 1471, 1631, 1727, 1823, 1917, 2012, 3005, 3099, 3199 0 O vi 550, 799, 827, 855, 883, 1058, 1087, 1251, 1279, 1444, 1472, 1632, 1728, 1824, 1918, 2013, 3006, 3100, 3200 4 N ON 551, 800, 828, 856, 884, 1059, 1088, 1252, 1280, 1445, 1473, 1633, 1729, 1825, 1919, 2014, 3007, 3101, 3201 0 552, 801, 829, 857, 885, 1060, 1089, 1253, 1281, 1446, 1474, 1634, 1730, 1826, 1920, 2015, 3008, 3102, 3202 O 553, 802, 830, 858, 886, 1061, 1090, 1254, 1282, 1447, 1475, 1635, 1731, 1827, 1921, 2016, 3009, 3103, 3203 O 554, 803, 831, 859, 887, 1062, 1091, 1255, 1283, 1448, 1476, 1636, 1732, 0 1828, 1922, 2017, 3010, 3104, 3204 0 1 2 555, 804, 832, 860, 888, 1063, 1092, 1256, 1284, 1449, 1477, 1637, 1733, 1829, 1923, 2018, 3011, 3105, 3205 '))) 556, 805, 833, 861, 889, 1064, 1093, 1257, 1285, 1450, 1478, 1638, 1734, 1830, 1924, 2019, 3012, 3106, 3206 out cri cl 557, 806, 834, 862, 890, 1065, 1094, 1258, 1286, 1451, 1479, 1639, 1735, 1831, 1925, 2020, 3013, 3107, 3207 Br Br 558, 807, 835, 863, 891, 1066, 1095, 1259, 1287, 1452, 1480, 1640, 1736, 1832, 1926, 2021, 3014, 3108, 3208 0"ruz F 559, 808, 836, 864, 892, 1067, 1096, 1260, 1288, 1453, 1481, 1641, 1737, 1833, 1927, 2022, 3015, 3109, 3209 out CON CN 560, 809, 837, 865, 893, 1068, 1097, 1261, 1289, 1454, 1482, 1642, 1738, 1834, 1928, 2023, 3016, 3110, 3210 CL3 CH3 561, 810, 838, 866, 894, 1069, 1098, 1262, 1290, 1455, 1483, 1643, 1739, 1835, 1929, 2024, 3017, 3111, 3211 0 OCH3 OCH3 562, 811, 839, 867, 895, 1070, 1099, 1263, 1291, 1456, 1484, 1644, 1740, 1836, 1930, 2025, 3018, 3112, 3212 0 N 563, 812, 840, 868, 896, 1071, 1100, 1264, 1292, 1457, 1485, 1645, 1741,-« 1837, 1931, 2026, 3019, 3113, 3213 0 + 564, 813, 841, 869, 897, 1072, 1101, 1265, 1293, 1458, 1486, 1646, 1742, 1838, 1932, 2027, 3020, 3114, 3214 zon N 565, 814, 842, 870, 898, 1073, 1102, 1266, 1294, 1459, 1487, 1647, 1743, O 1839, 1933, 2028, 3021, 3115, 3215 o- 899, 923, 947, 971, 1140, 1164, 1333, 1357, 1525, 1549, 1648, 1744, 1840,. 1935, 2028a, 3022, 3116, 3216 O 0 568, 900, 924, 948, 973, 1141, 1165, 1334, 1358, 1526, 1550, 1650, 1745,. 1841, 1936, 2029, 3023, 3117, 3217 -S O \ 570, 902, 926, 950, 974, 1143, 1167, 1360, 1528, 1552, 1651, 1747, 1842, 1937, 2030, 3024, 3118, 3218 O_Ss s O 571, 903, 927, 951, 975, 1144, 1168, 1336, 1337, 1361, 1529, 1553, 1652, 1748, 1843, 1938, 2031, 3025, 3119, S, O 572, 904, 928, 952, 976, 1145, 1169, 1338, 1362, 1527, 1554, 1653, 1749, 1844, 1939, 2032, 3026, 3120, 3220 0 573, 905, 929, 953, 977, 1146, 1170, 1339, 1363, 1531, 1555, 1654, 1750,, F 1845, 1940, 2033, 3027, 3121, 3221 O=S+F 0 F 575, 907, 931, 955, 978, 1148, 1172, 1341, 1365, 1533, 1557, 1656, 1752, 1847, 1942, 2035, 3029, 3123, 3223 ÓsV 0 V 576, 908, 932, 956, 980, 1149, 1173, 1342, 1366, 1534, 1558, 1657, 1753, /==\ 1848, 1943, 2036, 3030, 3124, 3224 S v O 0 577, 909, 933, 957, 981, 1150, 1174, 1343, 1367, 1535, 1559, 1658, 1754,'/=\ 1849, 1944, 2037, 3031, 3125, 3225 °s39 ri 0 578, 910, 934, 958, 982, 1151, 1175, 1344, 1368, 1536, 1560, 1659, 1755,'/=\</ 1850, 1945, 2038, 3032, 3126, 3226 ou , is 0 579, 911, 935, 959, 983, 1152, 1176, 1345, 1369, 1537, 1561, 1660, 1756, 1851, 1946, 2039, 3033, 3127, 3227, Sv O 0 580, 913, 937, 961, 985, 1154, 1178, 1346, 1371, 1539, 1563, 1662, 1758,,/=\ F 1852, 1947, 2040, 3034, 3128, 3228 F ils F 581, 912, 936, 960, 984, 1153, 1177, 1347, 1370, 1538, 1562, 1663, 1757, 1853, 1948, 2041, 3035, 3129, 3229 O 582, 915, 939, 963, 987, 1156, 1180, 1349, 1373, 1541, 1565, 1664, 1760, 1854, 1949, 2042, 3036, 3130, 3230 O 583, 916, 940, 964, 989, 1157, 1181, 1350, 1374, 1542, 1566, 1665, 1761, 1855, 1950, 2043, 3037, 3131, 3231 C F 0 0 584, 917, 941, 965, 990, 1158, 1182, 1351, 1375, 1543, 1567, 1666, 1762,'/=\ 1856, 1951, 2044, 3038, 3132, 3232 OS--O-CN n O 585, 918, 942, 966, 991, 1159, 1183, 1352, 1376, 1544, 1568, 1667, 1763, 1857, 1952, 2045, 3039, 3133, 3233 Ó 0 O 586, 919, 943, 967, 992, 1160, 1184, 1353, 1377, 1545, 1569, 1668, 1764, 1858, 1953, 2046, 3040, 3134, 3234 ßSt O Q 587, 920, 944, 968, 993, 1161, 1185, 1354, 1378, 1546, 1570, 1669, 1765, 1859, 1954, 2047, 3041, 3135, 3235 S > O W 588, 921, 945, 969, 994, 1162, 1186, 1355, 1379, 1547, 1571, 1670, 1766, S, 1860, 1955, 2048, 3042, 3136, 3236 Õ 0 589, 922, 946, 970, 995, 1163, 1187, 1356, 1380, 1548, 1572, 1671, 1767, 1861, 1956, 2049, 3043, 3137, 3237 / o w O 0 604, 715, 733, 751, 769, 1103, 1122, 1296, 1315, 1488, 1506, 1673, 1769, 1863, 1958, 2051, 3045, 3139, 3238 o o 716, 734, 752, 770, 1104, 1123, 1297, 1316, 1489, 1507, 1674, 1770, 1864, 1959, 2052, 3046, 3140, 3239 0 0 605, 717, 735, 753, 771, 1105, 1124, 1298, 1317, 1490, 1508, 1675, 1771, 1865, 1960, 2053, 3047, 3141, 3240 0 718, 736, 754, 772, 1106, 1125, 1299, 1318, 1491, 1509, 1676, 1772, 1866, 1961, 2054, 3048, 3142, 3241 719, 737, 755, 773, 1107, 1126, 1300, 1319, 1492, 1511, 1677, 1773, 1867, 1962, 2055, 3049, 3143, 3242 OtoX 720, 738, 756, 774, 1108, 1127, 1301, 1320, 1493, 1512, 1678, 1774, 1868, 1963, 2056, 3050, 3144, 3243 1109, 1510, 1672, 1768, 1862, 1957, 2050, 3044, 3138, 3237a 721, 739, 757, 775, 1111, 1128, 1303, 1321, 1494, 1513, 1679, 1775, 1869, 1964, 2057, 3051, 3145, 3244 OTO--- 606, 722, 740, 758, 776, 1110, 1129, 1302, 1322, 1495, 1514, 1680, 1776, 1870, 1965, 2058, 3052, 3146, 3245 o oX 723, 741, 759, 777, 1112, 1130, 1304, 1323, 1496, 1515, 1681, 1777, 1871, 1966, 2059, 3053, 3147, 3246 °mo > 724, 742, 760, 778, 1113, 1131, 1305, 1324, 1497, 1516, 1682, 1778, 1872, 0 1967, 2060, 3054, 3148, 3247 607, 725, 743, 761, 779, 1120, 1132, w \ 1306, 1331, 1498, 1517, 1683, 1779, 1873, 1968, 2061, 3055, 3149, 3248 know 0 608, 726, 744, 762, 780, 1114, 1133, w 1307, 1325, 1499, 1518, 1684, 1780, 1874, 1969, 2062, 3056, 3150, 3249 °to93 / 609, 727, 745, 763, 7819-1115, 1134, 1308, 1326, 1500, 1519, 1685, 1781, 1875, 1970, 2063, 3057, 3151, 3250 0-' 610, 728, 746, 764, 782, 1116, 1135, Os 1309, 1327, 1501, 1520, 1686, 1782, 1876, 1971, 2064, 3058, 3152, 3251 WO _. 611, 729, 747, 766, 783, 1117, 1136, CI 1310, 1328, 1502, 1521, 1687, 1783, 1877, 1972, 2065, 3059, 3153, 3252 0 0- 612, 730, 749, 765, 784, 1119, 1137, Br 1311, 1329, 1503, 1522, 1688, 1784, S 1878, 1973, 2066, 3060, 3154, 3253 oAOw 0 613, 731, 748, 767, 785, 1118, 1138, F 1312, 1330, 1504, 1523, 1689, 1785, * S 1879, 1974, 2067, 3061, 3155, 3254 oAOw 0 614, 732, 750, 768, 786, 1121, 1139, 1313, 1332, 1505, 1524, 1690, 1786, 1880, 1975, 2068, 3062, 3156, 3255 bzw . oWOw 0

EXAMPLES 3303-4618 If one were to follow the procedures of Examples 3258-3267, 3270-3302, using the corresponding isocyanates, acid chlorides, sulfonyl chlorides or chloroformates of substituent R defined in Table 154, then one would obtain compounds of the formulas :

1024a 1024b 1025a 1025b 1026a 1026b

1027a 1027b 1028a 1028b 1029a 1029b

1030a 1030b

1031a 1031b wherein R is defined in Table 154 and the numbers 1 and 2 in the formulas represent Isomers 1 and 2, respectively."Ex."represents"Example"and"Compd."represents "Compound"in the table.

Table 154 Ex. Compd. Ex. Compd. Ex. Compd R 3303 1022a 3309 1025a 3316 1028b 3304 1022b 3310 1025b 3317 1029a 3305 1023a 3311 1026a 3318 1030a o'NH2 3306 1023b 3312 1026b 3319 1030b 3307 1024a 3313 1027a 3320 1031a 3308 1024b 3314 1027b 3321 1031b 3315 1028a 3322 1022a 3328 1025a 3335 1028b 3323 1022b 3329 1025b 3336 1 029a 0g N 3324 1023a 3330 1026a 3337 1029b H 3325 1023b 3331 1026b 3338 1030a 3326 1024a 3332 1027a 3339 1030b 3327 1024b 3333 1027b 3340 1031a 3334 1028a 3341 1031b 3342 1022a 3348 1025a 3355 1028b 3343 1022b 3349 1025b 3356 1029a 3344 1023a 3350 1026a 3357 1029b H 3345 1023b 3351 1026b 3358 1030a 3346 1024a 3352 1027a 3359 1030b 3347 1024b 3353 1027b 3360 1031a 3354 1028a 3361 1031b 3362 1022a 3368 1025a 3375 1028b 3363 1022b 3369 1025b 3376 1029a OAN 3364 1023a 3370 1026a 3377 1029b H 3365 1023b 3371 1026b 3378 1030a 3366 1024a 3372 1027a 3379 1030b 3367 1024b 3373 1027b 3380 1031a 3374 1028a 3381 1031b 3382 1023a 3386 1026a 1028b'/ 3383 1023b 3387 1027a 3392 1029a p N 3384 1025a 3388 1027b 3393 1030a H 3385 1025b 3389 1028a 3394 1030b 3390 1028b 3395 1031a 3396 1022a 3402 1025a 3409 1028b 3397 1022b 3403 1025b 3410 1029a 3398 1023a 3404 1026a 3411 1029b H 3399 1023b 3405 1026b 3412 1030a 3400 1024a 3406 1027a 3413 1030b 3401 1024b 3407 1027b 3414 1031a 3408 1028a 3415 1031b 3416 1022a 3422 1025a 3429 1028b 3417 1022b 3423 1025b 3430 1029a 1 OAN/ 3418 1023a 3424 1026a 3431 1029b 1030a 3419 1023b 3425 1026b 3432 1030a 3420 1024a 1 3426 1027a 3433 1030b 3421 1024b 3427 1027b 3434 1031a 3428 1028a 3435 1031b 3436 1022a 3442 1025a 3449 1028b 3437 1022b 3443 1025b 3450 1029a Oa N w 3438 1023a 3444 1026a 3451 1029b H 3439 1023b 3445 1026b 3452 1030a 3440 1024a 3446 1027a 3453 1030b 3441 1024b 3447 1027b 3454 1031a 3448 1028a 3455 1031b 3456 1022a 3462 1025a 3469 1028b 3457 1022b 3463 1025b 3470 1029a 3458 1023a 3464 1026a 3471 1029b 0--i-N 3459 1023b 3465 1026b 3472 1030a 3460 1024a 3466 1027a 3473 1030b 3461 1024b 3467 1027b 3474 1031a 3468 1028a 3475 1031b b 3476 1022a 3482 1025a 3489 1028b 3477 1022b 3483 1025b 3490 1029a 3478 1023a 3484 1026a 3491 1029b p N 3479 1023b 3485 1026b 3492 1030a H 3480 1024a 3486 1027a 3493 1030b 3481 1024b 3487 1027b 3494 1031a 3488 1028a 3495 1022a 3501 1025a 3508 1028b z 3496 1022b 3502 1025b 3509 1029a 3497 1023a 3503 1026a 3510 1029b p N 3498 1023b 3504 1026b 3511 1030a H 3499 1024a 3505 1027a 3512 1030b 3500 1024b 3506 1027b 3513 1031a 3507 1028a 3514 1031b 3515 1022a 3521 1025a 3527 1028b t"CN 3516 1022b 3522 1025b 3528 1029a 3517 1023a 3523 1026a 3529 1029b o 3518 1023b 3524 1027a 3530 1030a H 3519 1024a 3525 1027b 3531 1030b 3520 1024b 3526 1028a 3532 1031a 3533 1022a 3539 1025a 3546 1028b 3534 1022b 3540 1025b 3547a 1029a 3535 1023a 3541 1026a 3547 1029b 3536 1023b 3542 1026b 3548 1030a 3537 1024a 3543 1027a 3549 1030b N 3538 1024b 3544 1027b 3550 1031a 3545 1028a 3551 1031b 3552 1022a 3558 1025a 3565 1028b Br 3553 1022b 3559 1025b 3566 1029a 3554 1023a 3560 1026a 3567 1029b 3555 1023b 3561 1026b 3568 1030a H 3556 1024a 3562 1027a 3569 1030b 3557 1024b 3563 1027b 3570 1031a 3664 1028a 3571 1031b 3572 1022a 3578 1025a 3585 1028b i 3573 1022b 3579 1025b 3586 1029a 3574 1023a 3580 1026a 3587 1029b p N 3575 1023b 3581 1026b 3588 1030a H 3576 1024a 3582 1027a 3589 1030b 3577 1024b 3583 1027b 3590 1031a 3584 1028a 3591 1031b 3592 1022a 3598 1025a 3605 1028b F 1025b 3606 1029a 3594 1023a 3600 1026a 3607 1029b 0 N ior 3595 1023b 3601 1026b 3608 1030a H 3596 1024a 3602 1027a 3609 1030b 3597 1024b 3603 1027b 3610 1031a 3604 1028a 3611 1031b 3612 1022a 3618 1025a 3625 1028b 3613 1022b 3619 1025b 3626 1029a 3614 1023a 3620 1026a 3627 1029b OA N ~ 3615 1023b 3621 1026b 3628 1030a H 3616 1024a 3622 1027a 3629 1030b 3617 1024b 3623 1027b 3630 1031a 3624 1028a 3631 1031b 3632 1022a 3638 1025a 3645 1028b 3633 1022b 3639 1025b 3646 1029a 3634 1023a 3640 1026a 3647 1029b 0 N 3635 1023b 3641 1026b 3648 1030a H 3636 1024a 3642 1027a 3649 1030b 3637 1024b 3643 1027b 3650 1031a 3644 1028a 3651 1031b 3652 1022a 3658 1025a 3665 1028b F 3653 1022b 3659 1025b 3666 1029a F 3654 1023a 3660 1026a 3667 1029b, 3655 1023b 3661 1026b 3668 1030a ^ otv 3656 1024a 3662 1027a 3669 1030b 0 N 3657 1024b 3663 1027b 3670 1031a 3664 1028a 3671 1031b 3672 1022a 3678 1025a 3685 1028b 3673 1022b 3679 1025b 3686 1029a 3674 1023a 3680 1026a 3687 1029b vs/ j H 3675 1023b 3681 1026b 3688 1030a 3676 1024a 3682 1027a 3689 1030b N 3677 1024b 3683 1027b 3690 1031a 3684 1028a 3691 1031b 3692 1022a 3698 1025a 3705 1028b 3693 1022b 3699 1025b 3706 1029a 3694 1023a 3700 1026a 3707 1029b 3695 1023b 3701 1026b 3708 1030a 3696 1024a 3702 1027a 3709 1030b OA N w 3697 1024b 3703 1027b 3710 1031a H 3704 1028a 3711 1031b 3712 1022a 3718 1025a 3725 1028b. O 3713 1022b 3719 1025b 3726 1029a 3714 1023a 3720 1026a 3727 1029b 3715 1023b 3721 1026b 3728 1030a 3716 1024a 3722 1027a 3729 1030b 3717 1024b 3723 1027b 3730 1031a 3724 1028a 3731 1031b 3732 1022a 3738 1025a 3745 1028b 3733 1022b 3739 1025b 3746 1029a OA N 3734 1023a 3740 1026a 3747 1029b H 3735 1023b 3741 1026b 3748 1030a 3736 1024a 3742 1027a 3749 1030b 3737 1024b 3743 1027b 3750 1031a 3744 1028a 3751 1031b 3752 1022a 3758 1025a 3765 1028b 3753 1022b 3759 1025b 3766 1029a 3754 1023a 3760 1026a 3767 1029b O N N-N 3755 1023b 3761 1026b 3768 1030a H 3756 1024a 3762 1027a 3769 1030b 3757 1024b 3763 1027b 3770 1031a 3764 1028a 3771 1031b 3772 1022a 3778 1025a | 3785 1028b l 3773 1022b 3779 1025b 3786 1029a 3774 1023a 3780 1026a 3787 1029b H 3775 1023b 3781 1026b 3788 1030a 3776 1024a 3782 1027a 3789 1030b 3777 1024b 3783 1027b 3790 1031a 3784 1028a 3791 1031b 3792 1022a 3798 1025a 3805 1028b 3793 1022b 3799 1025b'3806 1029a 3794 1023a 3800 1026a 3807 1029b 3795 1023b 3801 1026b 3808 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3876. 1 1028a 3883. 1 1031 b 3884. 1 1022a 3890. 1 1025a 3897. 1 1028b 3885. 1 1022b 3891. 1 1025b 3898. 1 1029a 3886. 1 1023a 3892. 1 1026a 3899. 1 1029b 3887. 1 1023b 3893. 1 1026b 3900. 1 1030a 3888. 1 1024a 3894. 1 1027a 3901. 1 1030b 3889. 1 1024b 3895. 1 1027b 3902. 1 1031 a 3896. 1 1028a 3903. 1 1031 b 3904. 1 1022a 3910. 1 1025a 3917. 1 1028b F 3905. 1 1022b 3911. 1 1025b 3918. 1 1029a SS F 3906. 1 1023a 3912. 1 1026a 3919. 1 1029b ó F 3907. 1 1023b 3913. 1 1026b 3920. 1 1030a 3908. 1 1024a 3914. 1 1027a 3921. 1 1030b 3909. 1 3914. 1 1027b 3922. 1 1031 a | 3916. 1 1028a 3923. 1 1031 b 3944. 1 1022a 3950. 1 1025a 3957. 1 1028b 3945 1 1022b 3951. 1 1025b 3958. 1 1029a 3946. 1 1023a 3952. 1 1026a 3959. 1 1029b 3947. 1 1023b 3953. 1 1026b 3960. 1 1030a 3948. 1 1024a 3953. 1 1027a 3961. 1 1030b 3949_1 1024b 3g55. 1 1027b 3962. 1 1031a 3956. 1 1028a 3963. 1 1031 b 3964. 1 1022a 3970. 1 1025a 3977. 1 1028b 3965. 1 1022b 3971. 1 1025b 3978. 1 1029a ors 3966. 1 1023a 3972. 1 1026a 3979. 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1030a" 4048 1024a 4054 1027a 4061 1030b 4049 1024b 4055 1027b 4062 1031a 4056 1028a 4063 1031b 4064 1022a 4070 1025a 4077 1028b 4065 1022b 4071 1025b 4078 1029a 0 ci 4066 1023a 4072 1026a 4079 1029b 4067 1023b 4073 1026b | 4080 1030a O 4068 1024a 4074 1027a 4081 1030b 4069 1024b 4075 1027b 4082 1031a 4076 1 028a 4083 1031b 4084 1022a 4090 1025a 4097 1028b 4085 1022b 4091 1025b 4098 1029a S Br 4086 1023a 4092 1026a 4099 1029b 4087 1023b 4093 1026b 4100 1030a 4088 1024a 4094 1027a 4101 1030b 4089 1024b 4095 1027b 4102 1031a 4096 1028a 4103 1031b 4104 1022a 4110 1025a 4117 1028b 4105 1022b 4111 1025b 4118 1029a O S F 4106 1023a 4112 1026a 4119 1029b 4107 1023b 4113 1026b 4120 1030a 4108 1024a 4114 1027a 4121 1030b 4109 1024b 4115 1027b 4122 1031a 4116 1028a 4123 1031b 4124 1022a 4130 1025a 4137 1028b 4125 1022b 4131 1025b 4138 1029a CN 4126 1023a 4132 1026a 4139 1029b 4127 1023b 4133 1026b 4140 1 030a O 4128 1024a 4134 1027a 4141 1030b 4129 1024b 4135 1027b 4142 1031a 4136 1028a 4143 1031b 4144 1022a 4150 1025a 4157 1028b 4145 1022b 4151 1025b 4158 1029a 0 4146 1023a 4152 1026a 4159 1029b 4147 1023b 4153 1026b 4160 1030a 4148 1024a 4154 1027a 4161 1030b 4149 1024b 4155 1027b 4162 1031a 4156_ 1028a 4163 1031b 4164 1022a 4170 1025a 4177 1028b 4165 1022b 4171 1025b 4178 1029a 4166 1023a 4172 1026a 4179 1029b 4167 1023b 4173 1026b 4180 1030a 4168 1024a 4174 1027a 4181 1030b 4169 1024b 4175 1027b 4182 1031a 4176 1028a 4183 1031b 4184 1022a 4190 1025a 4197 1028b 4185 1022b 4191 1025b 4198 1029a 4186 1023a 4192 1026a 4199 1029b 4187 1023b 4193 1026b 4200 1030a 4188 1024a 4194 1027a 4201 1030b 4189 1024b 4195 1027b 4202 1031a 4196 1028a 4203 1031b 4204 1022a 4210 1025a 4217 1028b 4205 1022b 4211 1025b 4218 1029a 4206 1023a 4212 1026a 4219 4207 1023b 4213 1026b 4220 1030a 4208 1024a 4214 1027a 4221 1030b 4209 1024b 4215 1027b 4222 1031a 4216 1028a 4223 1031b 4224 1022a 4230 1025a 4237 1028b 4225 1022b 4231 1025b 4238 1029a 4226 1023a 4232 1026a 4239 1029b 4227 1023b 4233 1026b 4240 1030a 4228 1024a 4234 1027a 4241 1030b = S 4229 1024b 4235 1027b 4242 1031aï 4236 1028a 4243 1031b 4244 1022a 4250 1025a 4257 1028b 4245 1022b 4251 1025b 4258 1029a 4246 1023a 4252 1026a 4259 1029b O 4247 1023b 4253 1026b 4260 1030a 4248 1024a 4254 1027a 4261 1030b 4249 1024b 4255 1027b 4262 1031a 4256 1028a 4263 1031b 4264 1022a 4270 1025a 4277 1028b 4265 1022b 4271 1025b 4278 1029a 4266 1023a 4272 1026a 4279 1029b 4267 1023b 4273 1026b 4280 1030a 4268 1024a 4274 1027a 4281 1030b 4269 1024b 4275 1027b 4282 1031a 4276 1028a 4283 1031b 4284 1022a 4290 1025a 4297 1028b 4285 1022b 4291 1025b 4298 1029a 4286 1023a 4292 1026a 4299 1029b 4287 1023b 4293 1026b 4300 1030a 4288 1024a 4294 1027a 4301 1030b 4289 1024b 4295 1027b 4302 1031a 4296 1028a 4303 1031b 4304 1022a 4310 1025a 4316 1028b 4305 1022b 4311 1025b 4317 1029a 4306 1023a 4312 1026a 4317a 1030a 4307 1023b 4313 1027a 4320 1031a 4308 1024a 4314 1027b 4309 1024b 4315 1028a 4321 1022a 4327 1025a 1 4334 1028b 4322 1022b 4328 1025b 4335 1029a 4323 1023a 4329 1026a 4336 1029b 4324 1023b 4330 1026b 4337 1030a 4325 1024a 4331 1027a 4338 1030b 4326 1024b 4332 1027b 4339 1031a 4333 1028a 4340 1031b 4341 1022a 4347 1025a 4354 1028b 4342 1022b 4348 1025b 4355 1029a 4343 1023a 4349 1026a 4356 1029b 4344 1023b 4350 1026b 4357 1030a 4345 1024a 4351 1027a 4358 1030b 4346 1024b 4352 1027b 4359 1031a 4353 1028a i 4360 1031 b 4353 1028a 4367 1025a 4374 1028b 4362 1022b 4368 1025b 4375 4375 1029a A ~ 4363 1023a 4369 1026a 4376 1029b 4364 1023b 4370 1026b 4377 1030a 4365 1024a 4371 1027a 4378 1030b 4366 1024b 4372 1027b 4379 1031a 4373 1028a 4380 1031b 4381 1022a 4387 1025a 4394 1028b 4382 1022b 4388 1025b 4395 1029a 4383 1023a 4389 1026a 4396 1029b 4384 1023b 4390 1026b 4397 1030a 4385 1024a 4391 1027a 4398 1030b 4386 1024b 4392 1027b 4399 1031a 4393 1028a 4400 1031b 4401 1022a 4407 1025a 4414 1028b 4402 1022b 4408 1025b 4415 1029a 4403 1023a 4409 1026a 4416 1029b 4404 1023b 4410 1026b 4417 1030a 4405 1024a 4411 1027a 4418 1030b 4406 1024b 4412 1027b 4419 1031a 4413 1028a 4420 1031b 4421 1022a 4427 1025a 4434 1028b 4422 1022b 4428 1025b 4435 1029a 4423 1023a 4429 1026a 4436 1029b 4424 1023b 4430 1026b 4437 1030a 4425 1024a 4431 1027a 4438 1030b 4426 1024b 4432 1027b 4439 1031a 4433 1028a 444p 1031b l l 4441 1022a 4447 1025a 4454 1028b 4442 1022b 4448 1025b 4455 1029a 4443 1023a 4449 1026a 4456 1029b 4444 1023b 4450 1026b 4457 1030a 4445 1024a 4451 1027a 4458 1030b 4446 1024b 4452 1027b 4459 1031a 4453 1028a 4460 1031b 4461 1022a 4467 1025a 4474 1028b 4462 1022b 4468 1025b 4475 1029a 4463 1023a 4469 1026a 4476 1029b 4464 1023b 4470 1026b 4477 1030a 4465 1024a 4471 1027a 4478 1030b 4466 1024b 4472 1027b 4479 1031a 4473 1028a 4480 1031b 4481 1022a 4487 1025a 4494 1028b 4482 1022b 4488 1025b 4495 1029a 4483 1023a 4489 1026a 4496 1029b 4484 1023b 4490 1026b 4497 1030a 4485 1024a 4491 1027a 4498 1030b 4486 1024b 4492 1027b 4499 1031a 4493 1028a 4500 1031b 4501 1022a 4507 1025a 4514 102$b/O 4502 1022b 4508 1025b 4515 1029a 4503 1023a 4509 1026a 4516 1029b 4504 1023b 4510 1026b 4517 1030a 4505 1024a 4511 1027a 4518 1030b 4506 1024b 4512 1027b 4519 1031a 4513 1028a 4520 1031b _ l F 4521 1022a 4527 1025a 4534 1028b ci 4522 1022b 4528 1025b 4535 1029a 4523 1023a 4529 1026a 4536 1029b 4524 1023b 4530 1026b 4537 1030a 0 4525 1024a 4531 1027a 4538 1030b 4526 1024b 4532 1027b 4539 1031a 4533 1028a 4540 1031b 4541 1022a 4547 1025a 4554 1028b Br 4542 1022b 4548 1025b 4555 1029a 4543 1023a 4549 1026a 4556 1029b 4544 1023b 4550 1026b 4557 1030a 4545 1024a 4551 1027a 4558 1030b 4546 1024b 4552 1027b 4559 1031a 4553 1028a 4560 1031b 4561 1022a 4567 1025a 4574 1028b F 4562 1022b 4568 1025b 4575 1029a 4563 1023a 4569 1026a 4576 1029b WOw 4564 1023b 4570 1026b 4577 1030a 4565 1024a 4571 1027a 4578 1030b 4566 1024b 4572 1027b 4579 1031a 4573 1028a 4580 1031b 4581 1022a 4587 1025a 4594 1028b 4582 1022b 4588 1025b 4595 1029a 4583 1023a 4589 1026a 4596 1029b 4584 1023b 4590 1026b 4597 1030a 4585 1024a 4591 1027a 4598 1030b 4586 1024b 4592 1027b 4599 1031a 4593 1028a 4600 1031b 4601 1022a 4607 1025a 4613 1028b 4602 1022b 4608 1025b 4614 1029a 4603 1023a 4609 1026a 4615 1030a 4604 1023b 4610 1027a 4616 1030b 4605 1024a 4611 1027b 4617 1031a 4606 1024b 4612 1028a 4618 1031b EXAMPLE 4619

To a CH2CI2 (5 mL) solution of compound 1033 (Example 3280) (35 mg, 0.07 mmol) was added 0. 03 mL of triethyl amine followed by isopropyl chloroformate (0.084 mL, 1. 0 M in CH3Ph, 0.084 mmol). The reaction was stirred at room temperature under N2 for 1 hr. It was then quenched with saturated NaHC03 solution and extracted with CH2CI2 several times. The combined organic solution was dried (MgS04) and evaporated to dryness. The residue was purified by prep TLC plates using 10%

methanol (2M NH3)/CH2CI2 to give compound 5001 as an off white solid (15.0 mg).

M. P. 152-155 °C (dec). MS M+1 593.

ASSAYS FPT activity was determined by measuring the transfer of [3H] farnesyl from [3H] farnesyl pyrophosphate to a biotinylated peptide derived from the C-terminus of H-ras (biotin-CVLS). The reaction mixture contains: 50 mM Tris pH7. 7. 5 mM MgCtz, 5 zM Zon4, 5 mM DTT, 0. 1% Triton-X, 0.05 M peptide, 0.03 nM purified human farnesyl protein transferase, 0. 180 uM [3H] famesyl pyrophosphate, plus the indicated concentration of tricyclic compound or vehicle control in a total volume of 100 pI. The reaction was incubated in a Vortemp shaking incubator at 37°C, 45 RPM for 60 minutes and stopped with 150 pl of 0.25 M EDTA containing 0.5% BSA and 1.3 mg/ml Streptavidin SPA beads. Radioactivity was measured in a Wallach 1450 Microbeta liquid scintillation counter. Percent inhibition was calculated relative to the vehicle control.

COS Cell IC50 (Cell-Based Assay) were determined following the assay procedures described in WO 95/10516, published April 20,1995. GGPT IC50 (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), Cell Mat Biochemical assay and anti-tumor activity (in vivo anti-tumor studies) could be determined by the assay procedures described in WO 95/10516. The disclosure of WO 95/10516 is incorporated herein by reference thereto.

Various tumor cells (5 x 105 to 8 x 106) were innoculated subcutaneously into the flank of 5-6 week old athymic nu/nu female mice. Three tumor cell models were used: mouse fibroblasts transformed with H-Ras; HTB-177 human non small cell lung cancer cells or LOX human melanoma cells. Animals were treated with beta cyclodextran vehicle only or compounds in vehicle twice a day (BID) or once a day (QD) for 7 days per week for 1 (x1), 2 (x2) or 3 (x3) weeks. The percent inhibition of tumor growth relative to vehicle controls were determined by tumor measurements.

The results are reported in Table 155.

Table 155 Compound No. Tumor Dose Route and Average (MPK) Schdule % Tumor Inhibition (372) H-Ras fibroblasts 40 po, BID, x2 92 "H-Ras fibroblasts 10 po, BID, x2 70 ,. H-Ras fibroblasts 80 po, QD, x2 91 "H-Ras fibroblasts 20 po, QD, x2 55 " H-Ras fibroblasts 60 po, BID, x2 98 H-Ras fibroblasts 20 po, BID, x2 59 H-Ras fibroblasts 6. 6 po, BID, x2 19 " HTB-177 60 po, BID, x3 87 HTB-177 20 po, BID, x3 43 "HTB-177 120 po, QD, x3 54 " HTB-177 40 po, QD, x3 11 " HTB-177 80 po, BID, x3 96 " HTB-177 40 po, BID, x3 79 HTB-177 20 po, BID, x3 47 LOX 15 po, BID, xl 20. 9 " LOX 30 po, BID, x1 54.8 " LOX 60 po, BID, x1 90.3 (The schedule"po, BID, x3", for example, means orally, twice a day for 7 days (14

times per week) for 3 weeks).

Soft Agar Assay : Anchorage-independent growth is a characteristic of tumorigenic cell lines.

Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37°C under 5% C02 to allow colony outgrowth. After incubation, the colonies can be stained by overlaying the agar

with a solution of MTT (3- [4, 5-dimethyl-thiazol-2-yl]-2, 5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the ICso's can be determined.

There are compounds of this invention have an FPT lC5o in the range of 0.05 nM to 100 nM and a Soft Agar ICso in the range of <0. 5 nM to 50 nM.

The compound of Example 4916 had an FPT IC50 of 1.2 nM, and a Soft Agar IC50 of <0. 5 nM.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutical acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e. g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutical acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20 Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical acceptable carrier, such as an inert compressed gas, e. g. nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or

emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e. g. , an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutical acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

The chemotherapeutic agent and/or radiation therapy can be administered in association with the compounds of the present invention according to the dosage and administration schedule listed in the product information sheet of the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art. Dosages and dosage regimens are exemplified in the embodiments of this invention. Additional examples of dosages and dosage regimens of chemotherapeutic agents useful in this invention are given in Table 156.

TABLE 156 Examplary Chemotherapeutic Agents Dosage and Dosage Regimens Cisplatin : 50-100 mg/m2 every 4 weeks (IV) * Carboplatin : 300-360 mg/m2 every 4 weeks (IV) Taxotere: 60-100 mg/m2 every 3 weeks (IV) * (IV)-intravenously It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e. g. , dosage amounts and times of administration) can be varied in view of the observed effects of the administered chemotherapeutic agents (i. e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

In an example of combination therapy in the treatment of pancreatic cancer, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, gemcitabine, which is administered at a dosage of from 750 to 1350 mg/m2 weekly for three out of four weeks during the course of treatment.

In an example of combination therapy in the treatment of lung cancer, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, paclitaxel, which is administered at a dosage of from 65 to 175 mg/m2 once every three weeks.

In an example of combination therapy in the treatment of gliomas, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1. 0)) is administered orally in a range of from 50 to 400 mg/day, in two

divided doses; in association with the antineoplastic agent, temozolomide, which is administered at a dosage of from 100 to 250 mg/m2.

In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, cisplatin, which is administered intravenously in a range of from 50 to 100 mg/m2 once every four weeks.

In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, carboplatin, which is administered intravenously in a range of from 300-360 mg/m2 once every four weeks.

In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i. e., a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the chemotherapeutic agent, carboplatin, which is administered intravenously in a range of from 300 to 360 mg/m2 once every four weeks and the chemotherapeutic agent, paclitaxel, which is administered at a dosage of from 65 to 175 mg/m2 once every three weeks.

In another example of combination therapy in the treatment of cancer an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the chemotherapeutic agent, Cisplatin, which is administered intravenously in a range of from 50 to 100 mg/m2 once every four weeks and the chemotherapeutic agent, Gemcitabine, which is administered at a dosage of from 65 to 175 mg/m2 once every three weeks.

The signal transduction inhibition therapy can be administered according to the dosage and administration schedule listed in the product information sheet of the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art. Examples of ranges of dosage and dosage regimens of some signal transduction inhibitors are given Table 157.

TABLE 157 Examplarv Slqnal Transduction Inhibitors Dosage and Dosage Regimens Iressa (ZD1839)-EGF receptor kinase inhibitor: 150-700 mg/day (oral) OSI-774-EGF receptor kinase inhibitor : 100-1000 mg/day (oral) Herceptin-HER-2/neu antibody: 100-250 mg/m2/week (IV) * C225-EGF receptor antibody: 200-500 mg/m2/week (IV) ABX-EGF-EGF receptor antibody: 0.2-2 mg/kg every 2 weeks (IV) Gleevec (STI-571)-bcr/abl kinase inhibitor: 300-1000 mg/day (oral) * (lV » intravenously It will be apparent to those skilled in the art that the administration of the signal tranduction inhibitor can be varied depending on the disease being treated and the known effects of the signal transduction inhibitor therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e. g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered signal transduction inhibitors on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses in association with the signal tranduction inhibitor, EGF receptor kinase inhibitor, Iressa (ZD1839), which is administered orally in the range of 150-700 mg/day.

The FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)), the chemotherapeutic agent, signal transduction inhibitor

and/or radiation can be administered by different routes. For example, the FPT inhibitor can be administered orally, while the chemotherapeutic agent may be administered intravenously. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

The particular choice of the chemotherapeutic agent, signal transduction inhibitor and/or radiation to use with the FPT inhibitor of this invention will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.

The FPT inhibitor of this invention (i. e. , a compound of this invention, e g., a compound of Formula (1.0)), chemotherapeutic agent, signal transduction inhibitor and/or radiation may be administered concurrently (e. g., simultaneously, just prior to or after, or within the same treatment protocol) or sequentiallyl. Determination of the sequence of administration can be determined by the skilled clinician. Some factors that the skilled clinician can use to determine the treatment protocol are the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent, signal transduction inhibitor and/or radiation to be administered in conjunction (i. e. , within a single treatment protocol) with the FPT inhibitor.

If the FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1.0)), chemotherapeutic agent, signal transduction inhibitor and/or radiation are not administered simultaneously then the FPT inhibitor may be administered first followed by the administration of the chemotherapeutic agent, signal transduction inhibitor and/or radiation, or the chemotherapeutic agent, signal transduction inhibitor and/or radiation can be administered first followed by the administration of the FPT inhibitor. This alternate administration may be repeated during a single treatment protocol until the treatment protocol is completed. The determination of the order of administration, and the number of repititions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

Thus, in accordance with experience and knowledge, the practising physician can modify each protocol for the administration of a component (therapeutic agent- i. e. , FPT inhibitor of this invention (i. e. , a compound of this invention, e. g. , a compound of Formula (1. 0)), chemotherapeutic agent, signal transduction inhibitor or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radio-logical studies, e. g., CAT or MRI scan, and successive measure-ments can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

Additional pharmaceutical and method of treating embodiments of this invention are set forth below.

An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a compound of this invention in combination with a pharmaceutically acceptable carrier.

An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a compound of formula 1.0 in combination with a pharmaceutical acceptable carrier.

An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of compound of formula 1.4 in combination with a pharmaceutical acceptable carrier.

An embodiment of this invention is directed to a method for treating the abnormal growth of cells in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e. g. , a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors expressing an activated ras oncogene in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of thisinvention (e. g. , a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment wherein said tumors are selected from the group consisting of: pancreatictumors, lung tumors, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck tumors, melanomas, breast tumor, prostate tumors, ovarian tumors, bladder tumors, glioma tumors, epidermal tumors and colon tumors, comprising administering to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0).

An embodiment of this invention is directed to a method of inhibiting ras farnesyl protein transferase in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors, wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e. g. , a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of thisinvention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said tumors are selected from the group consisting of : pancreatic tumors, lung tumors, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck tumors, melanomas,

breast tumor, prostate tumors, ovarian tumors, bladder tumors, glioma tumors, epidermal tumors and colon tumors.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said tumors are selected from the group consisting of lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is an antineoplastic agent selected from: Uracil mustard, Chtormethine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Temozolomide, Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Gemcitabine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Taxol, Taxotere, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide, Teniposide 17a- Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, and Hexamethylmelamine.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g.,

a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is a microtubule affecting agent selected from allocolchicine, Halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, Taxotere, thiocolchicine, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothilone A, epothilone, discodermolide, estramustine, nocodazole and MAP4.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is selected from Gemcitabine, Cisplatin, Carboplatin, paclitaxel, paclitaxel derivatives, and Taxotere.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of formula 1.0 is selected from the group consisting

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of the invention is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of formula 1.0 is selected from the group consisting of :

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of formula 1.0 is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of formula 1.0 is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the tumors treated are selected from the group consisting of: lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias ; wherein the chemotherapeutic agent is selected from the group consisting of : paclitaxel, a paclitaxel derivative, taxotere, cyclophosphamide, 5-fluorouracil, temozolomide, vincristine, cisplatin, carboplatin, and gemcitabine.

An embodiment of this invention is directed to a method of lung cancer in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the chemotherapeutic agent is selected from the group consisting of: carboplatin, taxol and taxotere.

An embodiment of this invention is directed to a method of lung cancer in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the chemotherapeutic agent is selected from the group consisting of : gemcitabine and cisplatin.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e. g., a compound of fornula 1.0) in combination with an effective amount taxol and/or radiation, wherein the tumors treated are selected from the group consisting of : lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the tumors are selected from the group consisting of: pancreatic tumors, lung tumors, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck tumors, melanomas, breast tumors, prostate tumors, ovarian tumors, bladder tumors, gliomas and colon tumors.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the signal tranduction inhibitor is selected from the group consisting of: a bcr/abl kinase inhibitor, an epidermal growth factor receptor inhibitor, and a HER-2/neu receptor inhibitor.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the signal tranduction inhibitor is selected from

the group consisting of : Gleevec, Iressa, OSI-774, Imclone C225, Abgenix ABX-EGF, and Herceptin.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e. g., a compound of formula 1. 0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the tumors treated are selected from the group conisting of : lung tumors, head and neck tumors, bladder tumors, breast tumors, prostate tumors and myeloid leukemias ; and the signal transduction inhibitor is selected from the group consisting of : Gleevec, Iressa, OSI-774, Imclone C225, Abgenix ABX-EGF ; and Herceptin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of : (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of aVß3 integrins; or (13) small molecule inhibitors of aV3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors; (16) anthracyclines ; (17) biologics ;

(18) Thalidomide (or related Imid) ; and (19) Gleevec.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators; (8) anti-tumor nucleoside derivatives; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of avß3 integrins ; or (13) small molecule inhibitors of aVp3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors ; (16) anthracyclines ; (17) biologics ; and (18) Thalidomide (or related Imid).

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ;

(5) VEGF inhibitors that are antibodies ; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators ; (8) anti-tumor nucleoside derivatives ; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloids ; (12) antibodies that are inhibitors of aV3 integrins; or (13) small molecule inhibitors of avß3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors ; (16) anthracyclines ; and (17) biologics.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules ; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules ; (7) estrogen receptor antagonists or selective estrogen receptor modulators; (8) anti-tumor nucleoside derivatives; (9) epothilones ; (10) topoisomerase inhibitors; (11) vinca alkaloid ; (12) antibodies that are inhibitors of avß3 integrins ; and (13) small molecule inhibitors of aV03 integrins.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is selected from paclitaxel or docetaxel, and said platinum coordinator compound is selected from carboplatin or cisplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel and said platinum coordinator compound is carboplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel and said platinum coordinator compound is cisplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel and said platinum coordinator compound is cisplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and

two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel and said platinum coordinator compound is carboplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1. 4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel administered in an amount of about 150 mg to about 250 mg/m2 once every three weeks per cycle, and said platinum coordinator compound is carboplatin administered once every three weeks per cycle in amount of to provide an AUC of about 5 to about 8.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1. 4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel administered in an amount of about 50 mg to about 100 mg/m2 once every three weeks per cycle, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 100 mg/m2 once every three weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of this invention and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is selected from the group consisting of :

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of this invention and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is selected from the group consisting of:

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is:

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is:

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor is :

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein the treatment is given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein non small cell lung cancer is treated.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody, wherein said taxane is paclitaxel and said EGF inhibitor is Herceptin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is an antinucleoside derivative, and the other antineoplastic agent is a platinum coordinator compound.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is an antinucleoside derivative, and the other antineoplastic agent is a platinum coordinator compound, wherein said antinucleoside derivative is gemcitabine and said platinum coordinator compound is cisplatin.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g. , 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is an antinucleoside

derivative, and the other antineoplastic agent is a platinum coordinator compound, wherein said antinucleoside derivative is gemcitabine and said platinum coordinator compound is carboplatin.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1. 4F wherein X is N) ; and (b) carboplatin ; and (c) paclitaxel.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of : (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) ; and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered twice a day, said carboplatin is administered once every three weeks per cycle, and said paclitaxel is administered once every three weeks per cycle, said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paclitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m2, wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1. 4F wherein X is N) ; and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paclitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m, said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paclitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m2, wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paclitaxel is administered once every three

weeks per cycle in an amount of about 175 to about 225 mg/m2, wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of : (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) ; and (b) carboplatin ; and (c) paclitaxel, wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 6, said paclitaxel is administered once every three weeks per cycle in an amount of about 175 mg/m2, wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and: (b) cisplatin ; and (c) gemcitabine.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and: (b) cisplatin ; and (c) gemcitabine wherein said FPT inhibitor is administered twice a day, said cisplatin is administered once every three or four weeks per cycle, and said gemcitabine is administered once a week per cycle, said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

(a) an FPT inhibitor of formula 1. 4F (e. g., 1.4F wherein X is N) ; and : (b) cisplatin ; and (c) gemcitabine wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 to about 100 mg/m2, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1.4F wherein X is N) ; and: (b) cisplatin ; and (c) gemcitabine wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 to about 100 mg/m2, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and: (b) cisplatin ; and (c) gemcitabine wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 to about 100 mg/m2, and said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of :

(a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) gemcitabine.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) gemcitabine, wherein said FPT inhibitor is administered twice a day, said carboplatin is administered once every three weeks per cycle, and said gemcitabine is administered once a week per cycle, said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) ; and (b) carboplatin ; and (c) gemcitabine, wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) gemcitabine, said treatment being given for one to seven weeks per cycle, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, and said gemcitabine is administered once a

week per cycle in an amount of about 750 to about 1250 mg2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); and (b) carboplatin ; and (c) gemcitabine, wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, and said treatment being given for one to seven weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies ; or (4) VEGF kinase inhibitors that are small molecules.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416, and SU6688.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:

(1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies; or (4) VEGF kinase inhibitors that are small molecules, wherein the FPT inhibitor is administered twice a day, said antineoplastic agent that is an antibody is administered once a week per cycle and said antineoplastic agent that is a small molecule is administered daily, said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutical effective amounts of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies; or (4) VEGF kinase inhibitors that are small molecules, wherein said FPT inhibitor is administered in an amount of about SO mg to about 200 mg twice a day, and said antineoplastic agent that is an antibody is administered once a week per cycle in an amount of about 2 to about 10 mg/m2, and said antineoplastic agent that is a small molecule is administered daily in an amount of about 50 to about 2400 mg/m2, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutical effective amounts of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies; or (4) VEGF kinase inhibitors that are small molecules, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, and said antineoplastic agent that is an antibody is administered once

a week per cycle in an amount of about 2 to about 10 mg/m2, and said antineoplastic agent that is a small molecule is administered daily in an amount of about 50 to about 2400 mg/m2, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1. 4F (e. g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules ; (3) VEGF inhibitors that are antibodies; or (4) VEGF kinase inhibitors that are small molecules, said treatment being given for one to four weeks per cycle, wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, and said antineoplastic agent that is an antibody is administered once a week per cycle in an amount of about 2 to about 10 mg/m2, and said antineoplastic agent that is a small molecule is administered daily in an amount of about 50 to about 2400 mg/m2, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel administered in an amount of about 150 mg to about 250 mg/m2 once a week per cycle, and said platinum coordinator compound is carboplatin administered once a week per cycle in an amount to provide an AUC of about 5 to about 8.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e. g., 1. 4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel administered in an amount of about 50 mg to about 100 mg/m2 once a week

per cycle, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 100 mg/m2 once a week per cycle.

An embodiment of this invention is directed to a method of treating of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of: (a) an FPT inhibitor of formula 1. 4F (e. g. , 1.4F wherein X is N) ; and (b) carboplatin ; and (c) docetaxel.

An embodiment of this invention is directed to a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1. 4F (e. g., 1. 4F wherein X is N); and (b) one or more antineoplastic agents selected from the group consisting of: (1) taxanes; and (2) platinum coordinator compounds.

An embodiment of this invention is directed to a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); (b) at least two different antineoplastic agents selected from the group consisting of: (1) taxanes; (2) platinum coordinator compounds; and (3) anti-tumor nucleoside derivatives (e. g., 5-Fluorouracil).

An embodiment of this invention is directed to a method of treating CML in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); (b) Gleevec ; and (c) interferon (e. g., Intron-A).

An embodiment of this invention is directed to a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) ; (b) Gleevec ; and (c) pegylated interferon (e. g., Peg-Intron, and Pegasys).

An embodiment of this invention is directed to a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) ; (b) an anti-tumor nucleoside derivative (e. g. , Cytarabine (i. e. , Ara- C)).

An embodiment of this invention is directed to a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); (b) an anti-tumor nucleoside derivative (e. g. , Cytarabine (i. e. , Ara- C) ); and (c) an anthracycline.

An embodiment of this invention is directed to a method of treating non- Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1. 4F wherein X is N) ; (b) Rituximab (Rituxan).

An embodiment of this invention is directed to a method of treating non- Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutical effective amounts of : (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); (b) Rituximab (Rituxan); and (c) an anti-tumor nucleoside derivative (e. g., Fludarabine (i. e. , F-ara- A).

An embodiment of this invention is directed to a method of treating non- Hodgkin's lymphom in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N); (b) Genasense (antisense to BCL-2).

An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1.4F wherein X is N); (b) a proteosome inhibitor (e. g. , PS-341 (Millenium)).

An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1.4F wherein X is N); (b) Thalidomide or related imid.

An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutical effective amounts of: (a) an FPT inhibitor of formula 1.4F (e. g., 1. 4F wherein X is N); (b) Thalidomide.

Other embodiments of this invention are directed to the embodiments described above using an FPT inhibitor of formula 1.4F (e. g. , 1.4F wherein X is N) wherein in addition to the administration of the FPT inhibitor and antineoplastic agents radiation therapy is also administered prior to, during, or after the treatment cycle.

For the embodiments of this invention using compounds of formula 1.4F (e. g., 1.4F wherein X is N), the compounds of formula 1.4F are preferably selected from the group consisting of:

more preferably selected from the group consisting of:

most preferably :

even more preferably In other embodiments of this invention, compounds of this invention other than those of formula 1. 4F, are used in the same manner as was described for the use of the compounds of formula 1. 4F, in these other embodiments the compounds are preferably selected from the group consisting of:

more preferably selected from the group consisting of :

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.