Novel farnesyl protein transferase inhibitors as antitumor agents

BACKGROUND

[0002] WO 95/10516, published Apr. 20, 1995 and WO 97/23478, published Jul. 3, 1997 disclose tricyclic compounds useful for inhibiting farnesyl protein transferase.

[0003] WO 98/54966 published Dec. 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).

[0004] Farnesyl Protein Transferase (FPT) Inhibitors are known in the art, see for example U.S. Pat. No. 5,874,442 issued Feb. 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. Pat. No. 6,096,757 issued Aug. 1, 2000.

[0005] 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.

[0006] WO 01/45740 published Jun. 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.

[0007] The WEB site http://www.osip.com/press/pr/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 (Paraplatin®) and Paclitaxel (Taxol®) for the treatment of Non Small Cell Lung Cancer.

[0008] The WEB site http://cancertrials.nci.nih.gov/types/lung/iressa 12100.html in a disclosure posted Dec. 14, 2000 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:

[0009] (1) phase III Randomized Study of ZD 1839 (IRESSA, an epidermal growth factor inhibitor) combined with gemcitabine and cisplatin in chemotherapy-naïve patients with Stage IIIB or IV non-small cell lung cancer; and

[0010] (2) phase III Randomized Study of ZD 1839 (IRESSA, an epidermal growth factor inhibitor) combined with paclitaxel and carboplatin in chemotherapy-naïve patients with Stage IIIB or IV non-small cell lung cancer.

[0011] WO 01/56552 published Aug. 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).

[0012] WO 01/62234 published Aug. 30, 2001 discloses a method of treatment and dosing regimen for treating mammalian tumors by the discontinuous administration of a farnesyl 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 farnesyl 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).

[0013] WO 01/64199 published Sep. 7, 2001 discloses a combination of particular FPT inhibitors with taxane compounds (e.g., paclitaxel or docetaxel) useful in the treatment of cancer.

[0014] 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

[0015] 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:

[0016] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0017] 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

[0018] each of a, b, c, and d is carbon, wherein each carbon has an R1 or R2 group bound to said carbon;

[0019] the dotted line () represents optional bonds;

[0020] X represents N or CH when the optional bond (to C11) is absent, and represents C when the optional bond (to C11) is present;

[0021] 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;

[0022] 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);

[0023] A and B are independently selected from the group consisting of:

[0024] (1) —H;

[0025] (2) —R9;

[0026] (3) —R9—C(O)—R9;

[0027] (4) —R9—CO2—R9a;

[0028] (5) —(CH2)pR26;

[0029] (6) —C(O)N(R9)2, wherein each R9 is the same or different;

[0030] (7) —C(O)NHR9;

[0031] (8) —C(O)NH—CH2—C(O)—NH2;

[0032] (9) —C(O)NHR26;

[0033] (10) —(CH2)pC(R9)—O—R9a;

[0034] (11) —(CH2)p(R9)2, wherein each R9 is the same or different;

[0035] (12) —(CH2)pC(O)R9;

[0036] (13) —(CH2)pC(O)R27;

[0037] (14) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[0038] (15) —(CH2)pC(O)NH(R9);

[0039] (16) —(CH2)pC(O)N(R26)2, wherein each R26 is the same or different;

[0040] (17) —(CH2)pN(R9)—R9a, (e.g. —CH2—N(CH2-pyridine)-CH2-imidazole);

[0041] (18) —(CH2)pN(R26)2, wherein R26 is the same or different (e.g., —(CH2)p—NH—CH2—CH3);

[0042] (19) —(CH2)pNHC(O)R50;

[0043] (20) —(CH2)pNHC(O)2R5;

[0044] (21) —(CH2)pN(C(O)R27a)2 wherein each R27, is the same or different;

[0045] (22) —(CH2)pNR51C(O)R27;

[0046] (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;

[0047] (24) —(CH2)pNR51C(O)NR27;

[0048] (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;

[0049] (26) —(CH2)pNR51C(O)N(R27a)2, wherein each R27, is the same or different;

[0050] (27) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;

[0051] (28) —(CH2)pNHCO2R50;

[0052] (29) —(CH2)pNC(O)NHR51;

[0053] (30) —(CH2)pCO2R51;

[0054] (31) —NHR9;

[0055] (32)

[0056] wherein R30 and R31 are the same or different, and each p is independently selected; provided that for each

[0057] group when one of R30 or R31 is selected from the group consisting of: —OH, ═O, —OR9a, —NH2, —NHR9a, —N(R9)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);

[0058] (33)

[0059] 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);

[0060] (34) -alkenyl-CO2R9a;

[0061] (35) -alkenyl-C(O)R9a;

[0062] (36) -alkenyl-CO2R51;

[0063] (37) -alkenyl-C(O)—R27a;

[0064] (38) (CH2)p-alkenyl-CO2—R51;

[0065] (37) —(CH2)pC═NOR51; and

[0066] (39) —(CH2)p-phthalimid;

[0067] p is 0, 1, 2, 3 or 4;

[0068] each R1 and R2 is independently selected from the group consisting of:

[0069] (1) H;

[0070] (2) Halo;

[0071] (3) —CF3,

[0072] (5) —COR10,

[0073] (6) —SR10;

[0074] (7) —S(O)tR15 wherein t is 0, 1 or 2;

[0075] (8) —N(R10)2;

[0076] (9) —NO2;

[0077] (10) —OC(O)R10;

[0078] (11) —CO2R10;

[0079] (12) —OCO2R15;

[0080] (13) —CN;

[0081] (14) —NR10COOR15;

[0082] (15) —SR15C(O)OR15;

[0083] (16) —SR15N(R13)2 provided that R15 in —SR15N(R13)2 is not —CH2 and wherein each R13 is independently selected from the group consisting of: H and —C(O)OR15;

[0084] (17) benzotriazol-1-yloxy;

[0085] (18) tetrazol-5-ylthio;

[0086] (19) substituted tetrazol-5-ylthio;

[0087] (20) alkynyl;

[0088] (21) alkenyl; and

[0089] (22) alkyl,

[0090] said alkyl or alkenyl group optionally being substituted with halogen, —OR10 or —CO2R10;

[0091] R3 and R4 are the same or different and each independently represent H, and any of the substituents of R1 and R2;

[0092] 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 —CO2R10, or R5 is combined with R6 to represent ═O or ═S;

[0093] R8 is selected from the group consisting of:

[0094] R9 is selected from the group consisting of:

[0095] (1) unsubstituted heteroaryl;

[0096] (2) substituted heteroaryl;

[0097] (3) arylalkoxy;

[0098] (4) substituted arylalkoxy;

[0099] (5) heterocycloalkyl;

[0100] (6) substituted heterocycloalkyl;

[0101] (7) heterocycloalkylalkyl;

[0102] (8) substituted heterocycloalkylalkyl;

[0103] (9) unsubstituted heteroarylalkyl;

[0104] (10) substituted heteroarylalkyl;

[0105] (11) unsubstituted heteroarylalkenyl;

[0106] (12) substituted heteroarylalkenyl;

[0107] (13) unsubstituted heteroarylalkynyl; and

[0108] (14) substituted heteroarylalkynyl;

[0109] wherein said substituted R9 groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:

[0110] (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);

[0111] (2) —CO2R14;

[0112] (3) —CH2OR14,

[0113] (4) halogen (e.g. Br, Cl or F),

[0114] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0115] (6) amino;

[0116] (7) trityl;

[0117] (8) heterocycloalkyl;

[0118] (9) cycloalkyl, (e.g., cyclopropyl or cyclohexyl);

[0119] (10) arylalkyl;

[0120] (11) heteroaryl;

[0121] (12) heteroarylalkyl and

[0122] (13)

[0123] wherein R14 is independently selected from: H; alkyl; aryl, arylalkyl, heteroaryl and heteroarylalkyl;

[0124] R9a is selected from the group consisting of: alky and arylalkyl;

[0125] R9b is selected from the group consisting of:

[0126] (1) —C(O)R9a;

[0127] (2) —SO2R9a;

[0128] (3) —C(O)NHR9a;

[0129] (4) —C(O)OR9a; and

[0130] (5) —C(O)N(R9c)2;

[0131] Each R9c is independently selected from the group consisting of: H, alkyl and arylalkyl;

[0132] R10 is selected from the group consisting of: H; alkyl; aryl and arylalkyl;

[0133] R11 is selected from the group consisting of:

[0134] (1) alkyl;

[0135] (2) substituted alkyl;

[0136] (3) unsubstituted aryl;

[0137] (4) substituted aryl;

[0138] (5) unsubstituted cycloalkyl;

[0139] (6) substituted cycloalkyl;

[0140] (7) unsubstituted heteroaryl;

[0141] (8) substituted heteroaryl;

[0142] (9) heterocycloalkyl; and

[0143] (10) substituted heterocycloalkyl;

[0144] wherein said substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl R11 groups are substituted with one or more (e.g. 1, 2 or 3) substituents, provided that selected from the group consisting of:

[0145] (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);

[0146] (2) fluoro; and

[0147] (3) alkyl; and

[0148] wherein said substituted aryl and substituted heteroaryl R11 groups are substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:

[0149] (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);

[0150] (2) halogen (e.g. Br, Cl or F); and

[0151] (3) alkyl;

[0152] R11a is selected from the group consisting of:

[0153] (1) H;

[0154] (2) OH;

[0155] (3) alkyl;

[0156] (4) substituted alkyl;

[0157] (5) aryl;

[0158] (6) substituted aryl;

[0159] (7) unsubstituted cycloalkyl:

[0160] (8) substituted cycloalkyl;

[0161] (9) unsubstituted heteroaryl;

[0162] (10) substituted heteroaryl;

[0163] (11) heterocycloalkyl;

[0164] (12) substituted heterocycloalkyl; and

[0165] (13) —OR9a;

[0166] wherein said substituted alkyl, 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:

[0167] (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);

[0168] (2) —CN;

[0169] (3) —CF3;

[0170] (4) fluoro;

[0171] (5) alkyl;

[0172] (6) cycloalkyl;

[0173] (7) heterocycloalkyl;

[0174] (8) arylalkyl;

[0175] (9) heteroarylalkyl;

[0176] (10) alkenyl and

[0177] (11) heteroalkenyl; and

[0178] wherein said substituted aryl and substituted heteroaryl R11a groups have one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:

[0179] (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);

[0180] (2) —CN;

[0181] (3) —CF3;

[0182] (4) halogen (e.g Br, Cl or F);

[0183] (5) alkyl;

[0184] (6) cycloalkyl;

[0185] (7) heterocycloalkyl;

[0186] (8) arylalkyl;

[0187] (9) heteroarylalkyl;

[0188] (10) alkenyl; and

[0189] (11) heteroalkenyl;

[0190] R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and -alkyl-(piperidine Ring V);

[0191] R15 is selected from the group consisting of: alkyl and aryl;

[0192] R21, R22 and R46 are independently selected from the group consisting of:

[0193] (1) —H;

[0194] (2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0195] (3) unsubstituted aryl, (e.g. phenyl);

[0196] (4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0197] (5) unsubstituted cycloalkyl, (e.g. cyclohexyl);

[0198] (6) substituted cycloalkyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0199] (7) heteroaryl of the formula,

[0200] (8) heterocycloalkyl of the formula:

[0201] (i.e., piperidine Ring V) wherein R44 is selected from the group consisting of:

[0202] (a) —H,

[0203] (b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0204] (c) alkylcarbonyl (e.g., CH3C(O)—);

[0205] (d) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and —C(O)OCH3);

[0206] (e) haloalkyl (e.g., trifluoromethyl); and

[0207] (f) —C(O)NH(R51);

[0208] (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 —NH2 then the remaining groups are not —OH;

[0209] (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

[0210] (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; or

[0211] (12) R21 and R22 taken together with the carbon to which they are bound form a cyclic ring selected from the group consisting of:

[0212] (a) unsubstituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl);

[0213] (b) cycloalkyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0214] (c) unsubstituted cycloalkenyl

[0215] (d) cycloalkenyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0216] (e) heterocycloalkyl, e.g., a piperidyl ring of the formula:

[0217] wherein R44 is selected from the group consisting of:

[0218] (1) —H,

[0219] (2) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0220] (3) alkylcarbonyl (e.g., CH3C(O)—);

[0221] (4) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and —C(O)OCH3);

[0222] (5) haloalkyl (e.g., trifluoromethyl); and

[0223] (6) —C(O)NH(R5);

[0224] (f) unsubstituted aryl (e.g., phenyl);

[0225] (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

[0226] (i) heteroaryl selected from the group consisting of:

[0227] R26 is selected from the group consisting of:

[0228] (1) —H;

[0229] (2) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0230] (3) alkoxy (e.g. methoxy, ethoxy, propoxy);

[0231] (4) —CH2—CN;

[0232] (5) R9;

[0233] (6) —CH2CO2H;

[0234] (7) —C(O)alkyl; and

[0235] (8) CH2CO2alkyl;

[0236] R27 is selected from the group consisting of:

[0237] (1) —H;

[0238] (2) —OH;

[0239] (3) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0240] (4) alkoxy;

[0241] R27a is selected from the group consisting of:

[0242] (1) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0243] (2) alkoxy;

[0244] R30, R31, R32 and R33 are independently selected from the group consisting of:

[0245] (1) —H;

[0246] (2) —OH;

[0247] (3) ═O;

[0248] (4) alkyl;

[0249] (5) aryl (e.g. phenyl);

[0250] (6) arylalkyl (e.g. benzyl);

[0251] (7) —OR9a;

[0252] (8) —NH2;

[0253] (9) —NHR9a;

[0254] (10) —N(R9a)2 wherein each R9a is independently selected;

[0255] (11) —N3;

[0256] (12) —NHR9b; and

[0257] (13) —N(R9a)R9b;

[0258] R50 is selected from the group consisting of:

[0259] (1) alkyl;

[0260] (2) unsubstituted heteroaryl;

[0261] (3) substituted heteroary; and

[0262] (4) amino;

[0263] wherein said substituents on said substituted R50 groups 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;

[0264] R51 is selected from the group consisting of: H, and alkyl (e.g., methyl, ethyl, propyl, butyl and t-butyl); and

[0265] provided that 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

[0266] provided that 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

[0267] provided that 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

[0268] provided that a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and

[0269] provided that a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and

[0270] provided that the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms.

[0271] This invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula 1.0 and a pharmaceutically acceptable carrier.

[0272] This invention also provides a method of inhibiting farnesyl 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 formula 1.0.

[0273] 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 formula 1.0.

[0274] 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 formula 1.0 in combination with at least one chemotherapeutic agent (also know in the art as antineoplastic agent or anticancer agent).

[0275] 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 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.

[0276] 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 formula 1.0 in combination with at least one signal transduction inhibitor.

[0277] In the methods of this invention the compounds 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

[0278] 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.

[0279] As used herein, the following terms have the following meanings unless otherwise described:

[0280] AD HPLC is a HPLC column from Chiral Technologies;

[0281] AUC-represents “Area Under the Curve”;

[0282] BOC-represents tert-butyloxycarbonyl;

[0283] CBZ-represents —C(O)OCH2C6H5 (i.e., benzyloxycarbonyl);

[0284] CH2Cl2-represents dichloromethane;

[0285] CIMS-represents chemical ionization mass spectrum;

[0286] Cmpd-represents Compound;

[0287] DBU-represents 1,8-Diazabicyclo[5.4.0]undec-7-ene;

[0288] DEAD-represents diethylazodicarboxylate;

[0289] DEC-represents EDCI which represents 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride;

[0290] DMF-represents N,N-dimethylformamide;

[0291] DPPA-represents diphenylphosphoryl azide

[0292] Et-represents ethyl;

[0293] Et3N-represents TEA which represents triethylamine;

[0294] EtOAc-represents ethyl acetate;

[0295] EtOH-represents ethanol;

[0296] FAB-represents FABMS which represents fast atom bombardment mass spectroscopy;

[0297] HOBT-represents 1-hydroxybenzotriazole hydrate;

[0298] HRMS-represents high resolution mass spectroscopy;

[0299] IPA-represents isopropanol;

[0300] i-PrOH-represents isopropanol;

[0301] Me-represents methyl;

[0302] MeOH-represents methanol;

[0303] MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;

[0304] MS-represents mass spectroscopy;

[0305] NMM-represents N-methylmorpholine;

[0306] OD HPLC is a HPLC column from Chiral Technologies;

[0307] PPh3-represents triphenyl phosphine;

[0308] Ph-represents phenyl;

[0309] Pr-represents propyl;

[0310] SEM-represents 2,2-(Trimethylsilyl)ethoxymethyl;

[0311] TBDMS-represents tert-butyldimethylsilyl;

[0312] t-BUTYL-represents —C—(CH3)3;

[0313] TFA-represents trifluoroacetic acid;

[0314] THF-represents tetrahydrofuran;

[0315] Tr-represents trityl;

[0316] Tf-represents SO2CF3;

[0317] at least one-represents one or more-(e.g. 1-6), more preferrably 1-4 with 1, 2 or 3 being most preferred;

[0318] 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;

[0319] 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;

[0320] 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;

[0321] alkylcarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (—CO—), for example, —COCH3;

[0322] alkyloxycarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (—CO—) through an oxygen atom, for example, —C(O)—OC2H5;

[0323] 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;

[0324] amino-represents an —NH2 moiety;

[0325] antineoplastic agent-represents a chemotherapeutic agent effective against cancer;

[0326] 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, —COOR 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 R is selected from the group consisting of: alkyl and aryl;

[0327] arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined above;

[0328] arylheteroalkyl-represents a heteroalkyl group, as defined below, substituted with an aryl group, as defined above;

[0329] aryloxy-represents an aryl moiety, as defined above, covalently bonded to an adjacent structural element through an oxygen atom, for example, —O-phenyl (i.e., phenoxy);

[0330] compound-with reference to the antineoplastic agents, includes the agents that are antibodies;

[0331] 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;

[0332] consecutively-means one following the other;

[0333] 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;

[0334] 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,

[0335] wherein said alkyl is generally a C1-C6 alkyl group, usually a C1-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:

[0336] cycloalkylalkyl-represents an alkyl group, as defined above, substituted with a cycloalkyl group, as defined above;

[0337] 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;

[0338] 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 farnesylation 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;

[0339] halo (or halogen)-represents fluoro, chloro, bromo or iodo;

[0340] haloalkyl-represents an alkyl group, as defined above, substituted with a halo group;

[0341] heteroatom-represents a O, N or S atom;

[0342] 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;

[0343] 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;

[0344] 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: —O—, —S— and —N-provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another;

[0345] 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-furyl, 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:

[0346] heteroarylalkenyl-represents an alkenyl group, as defined above, substituted with a heteroaryl group, as defined below;

[0347] heteroarylalkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined above;

[0348] heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as defined below;

[0349] 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(R18)2 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

[0350] heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as above;

[0351] “in association with”-means, in reference to the combination therapies of the invention, that the agents or components are adminstered concurrently or sequentially;

[0352] patient-represents a mammal, such as a human;

[0353] 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.

[0354] The positions in the tricyclic ring system are:

[0355] A “+” or a “−” in Ring II in the compounds below indicates the “(+)-isomer” or “(−)-isomer”, respectively.

[0356] 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:

[0357] Those skilled in the art will appreciate that the numbers “1” and “2” in a formula, e.g.,

[0358] represent Isomers 1 and 2, respectively. One of the isomers is

[0359] and one of the isomers is:

[0360] For example, for the isomers

[0361] one isomers is

[0362] and one isomer is:

[0363] 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.

[0364] Those skilled in the art will appreciate that the compounds of formula 1.0 are also represented by compounds of formula 1.1:

[0365] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0366] (A) one of a, b, c and d represents N or N+O−, and the remaining a, b, c, and d groups represent CR1 (i.e., carbon with an R1 group) wherein each R1 group on each carbon is the same or different; or

[0367] (B) each a, b, c, and d group represents CR1 (i.e., carbon with an R1 group) wherein each R1 group on each carbon is the same or different;

[0368] (C) the dotted lines ( - - - ) represent optional bonds;

[0369] (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;

[0370] (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;

[0371] (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:

[0372] (1) there are two A substituents bound to C-5 wherein each A substituent is independently selected; and

[0373] (2) there are two B substituents bound to C-6 wherein each B substituent is independently selected; and

[0374] (3) at least one of the two A substituents or one of the two B substituents is H; and

[0375] (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;

[0376] (G) A and B is independently selected from the group consisting of:

[0377] (1) —H;

[0378] (2) —R9;

[0379] (3) —R9—C(O)—R9;

[0380] (4) —R9—CO2—R9a;

[0381] (5) —(CH2)pR26;

[0382] (6) —C(O)N(R9)2, wherein each R9 is the same or different;

[0383] (7) —C(O)NHR9;

[0384] (8) —C(O)NH—CH2—C(O)—NH2;

[0385] (9) —C(O)NHR26;

[0386] (10) —(CH2)pC(R9)—O—R9a;

[0387] (11) —(CH2)p-1CH(R9)2, provided that p is not 0, and wherein each R9 is the same or different;

[0388] (12) —(CH2)pC(O)R9;

[0389] (13) —(CH2)pC(O)R27a;

[0390] (14) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[0391] (15) —(CH2)pC(O)NH(R9);

[0392] (16) —(CH2)pC(O)N(R26)2, wherein each R26 is the same or different;

[0393] (17) —(CH2)pN(R9)—R9a (e.g. —CH2—N(CH2-pyridine)-CH2-imidazole);

[0394] (18) —(CH2)pN(R26)2, wherein each R26 is the same or different (e.g., —(CH2)p—N H—CH2—CH3);

[0395] (19) —(CH2)pNHC(O)R50;

[0396] (20) —(CH2)pNHC(O)2R50;

[0397] (21) —(CH2)pN(C(O)R27a)2 wherein each R27a is the same or different;

[0398] (22) —(CH2)pNR51C(O)R27,

[0399] (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;

[0400] (24) —(CH2)pNR51C(O)NR27,

[0401] (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;

[0402] (26) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;

[0403] (27) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;

[0404] (28) —(CH2)pNHCO2R5;

[0405] (29) —(CH2)pNC(O)NHR51;

[0406] (30) —(CH2)pCO2R51;

[0407] (31) —NHR9;

[0408] (32)

[0409] wherein R30 and R31 are the same or different, and each p is independently selected; provided that for each

[0410] group when one of R30 or R31 is selected from the group consisting of: —OH, ═O, —OR9, —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);

[0411] (33)

[0412] 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(R9)2, —N3, —NHR9b, and —N(R9a)R9b, then the remaining R30 or R3 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);

[0413] (34) -alkenyl-CO2R9a;

[0414] (35) -alkenyl-C(O)R9a;

[0415] (36) -alkenyl-CO2R51;

[0416] (37) -alkenyl-C(O)—R27a;

[0417] (38) (CH2)p-alkenyl-CO2—R51;

[0418] (39) —(CH2)pC═NOR51; and

[0419] (40) —(CH2)p-Phthalimid;

[0420] (H) p is 0, 1, 2, 3 or 4;

[0421] (I) R1 is selected from the group consisting of:

[0422] (1) H;

[0423] (2) halo;

[0424] (3) —CF3;

[0425] (4) —OR

[0426] (5) COR10;

[0427] (6) —SR10;

[0428] (7) —S(O)tR15;

[0429] (8) —N(R10)2;

[0430] (9) —NO2;

[0431] (10) —OC(O)R10;

[0432] (11) CO2R10;

[0433] (12) —OCO2R15;

[0434] (13) —CN;

[0435] (14) —NR10COOR15;

[0436] (15) —SR5C(O)OR15;

[0437] (16) —SR15N(R13)2 wherein each R13 is independently selected from the group consisting of: H and —C(O)OR15, and provided that R15 in —SR15N(R13)2 is not —CH2;

[0438] (17) benzotriazol-1-yloxy;

[0439] (18) tetrazol-5-ylthio;

[0440] (19) substituted tetrazol-5-ylthio;

[0441] (20) alkynyl;

[0442] (21) alkenyl;

[0443] (22) alkyl;

[0444] (23) alkyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, —OR and —CO2R10;

[0445] (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;

[0446] (J) Each R3A is independently selected from the group consisting of:

[0447] (1) halo;

[0448] (2) —CF3;

[0449] (3) —OR10;

[0450] (4) COR10;

[0451] (5) —SR10;

[0452] (6) —S(O)tR15;

[0453] (7) —N(R10)2;

[0454] (8) —NO2;

[0455] (9) —OC(O)R10;

[0456] (10) CO2R10;

[0457] (11) —OCO2R15;

[0458] (12) —CN;

[0459] (13) —NR10COOR15;

[0460] (14) —SR C(O)OR15;

[0461] (15) —SR15N(R13)2 wherein each R13 is independently selected from the group consisting of: H and —C(O)OR15, and provided that R15 in —SR15N(R13)2 is not —CH2;

[0462] (16) benzotriazol-1-yloxy;

[0463] (17) tetrazol-5-ylthio;

[0464] (18) substituted tetrazol-5-ylthio;

[0465] (19) alkynyl;

[0466] (20) alkenyl;

[0467] (21) alkyl;

[0468] (22) alkyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, —OR10 and —CO2R10; and

[0469] (23) alkenyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, —OR10 and —CO2R10;

[0470] (K) m is 0, 1 or 2;

[0471] (L) t is 0, 1 or 2

[0472] (M) R5, R6, R7 and R7a are each independently selected from the group consisting of:

[0473] (1) H;

[0474] (2) —CF3;

[0475] (3) —COR10;

[0476] (4) alkyl;

[0477] (5) unsubstituted aryl;

[0478] (6) alkyl substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of: —S(O)tR15, —NR COOR10, —C(O)R15, and —CO2R10; and

[0479] (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

[0480] (N) R together with R represents ═O or ═S;

[0481] (O) R8 is selected from the group consisting of:

[0482] (P) R9 is selected from the group consisting of:

[0483] (1) unsubstituted heteroaryl;

[0484] (2) substituted heteroaryl;

[0485] (3) unsubstituted arylalkoxy;

[0486] (4) substituted arylalkoxy;

[0487] (5) heterocycloalkyl;

[0488] (6) substituted heterocycloalkyl;

[0489] (7) heterocycloalkylalkyl;

[0490] (8) substituted heterocycloalkylalkyl;

[0491] (9) unsubstituted heteroarylalkyl;

[0492] (10) substituted heteroarylalkyl;

[0493] (11) unsubstituted heteroarylalkenyl;

[0494] (12) substituted heteroarylalkenyl;

[0495] (13) unsubstituted heteroarylalkynyl and

[0496] (14) substituted heteroarylalkynyl;

[0497] 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:

[0498] (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);

[0499] (2) —CO2R14;

[0500] (3) —CH2OR14,

[0501] (4) halogen (e.g. Br, Cl or F),

[0502] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0503] (6) amino;

[0504] (7) trityl;

[0505] (8) heterocycloalkyl;

[0506] (9) cycloalkyl, (e.g. cyclopropyl or cyclohexyl);

[0507] (10) arylalkyl;

[0508] (11) heteroaryl;

[0509] (12) heteroarylalkyl and

[0510] (13)

[0511] wherein R14 is independently selected from the group consisting of: H; alkyl; aryl, arylalkyl, heteroaryl and heteroarylalkyl;

[0512] (Q) R9a is selected from the group consisting of: alky and arylalkyl;

[0513] (R) R9b is selected from the group consisting of:

[0514] (1) —C(O)R9a;

[0515] (2) —SO2R9a;

[0516] (3) —C(O)NHR9a;

[0517] (4) —C(O)OR9a; and

[0518] (5) —C(O)N(R9c)2;

[0519] (S) Each R9c is independently selected from the group consisting of: H, alkyl and arylalkyl;

[0520] (T) R10 is selected from the group consisting of: H; alkyl; aryl and arylalkyl;

[0521] (U) R11 is selected from the group consisting of:

[0522] (1) alkyl;

[0523] (2) substituted alkyl;

[0524] (3) unsubstituted aryl;

[0525] (4) substituted aryl;

[0526] (5) unsubstituted cycloalkyl;

[0527] (6) substituted cycloalkyl;

[0528] (7) unsubstituted heteroaryl;

[0529] (8) substituted heteroaryl;

[0530] (9) heterocycloalkyl; and

[0531] (10) substituted heterocycloalkyl;

[0532] wherein said substituted alkyl, 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:

[0533] (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);

[0534] (2) fluoro; and

[0535] (3) alkyl; and wherein said substituted aryl and substituted heteroaryl R11 groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:

[0536] (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);

[0537] (2) halogen (e.g. Br, Cl or F); and

[0538] (3) alkyl;

[0539] (V) R11a is selected from the group consisting of:

[0540] (1) H;

[0541] (2) OH;

[0542] (3) alkyl;

[0543] (4) substituted alkyl;

[0544] (5) unsubstituted aryl;

[0545] (6) substituted aryl;

[0546] (7) unsubstituted cycloalkyl;

[0547] (8) substituted cycloalkyl;

[0548] (9) unsubstituted heteroaryl;

[0549] (10) substituted heteroaryl;

[0550] (11) heterocycloalkyl;

[0551] (12) substituted heterocycloalkyl; and

[0552] (13) OR9a;

[0553] wherein said substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl R11a groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:

[0554] (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);

[0555] (2) —CN;

[0556] (3) —CF3;

[0557] (4) fluoro;

[0558] (5) alkyl;

[0559] (6) cycloalkyl;

[0560] (7) heterocycloalkyl;

[0561] (8) arylalkyl;

[0562] (9) heteroarylalkyl;

[0563] (10) alkenyl and

[0564] (11) heteroalkenyl; and

[0565] wherein said substituted aryl and substituted heteroaryl R11a groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:

[0566] (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);

[0567] (2) —CN;

[0568] (3) —CF3;

[0569] (4) halogen (e.g Br, Cl or F);

[0570] (5) alkyl;

[0571] (6) cycloalkyl;

[0572] (7) heterocycloalkyl;

[0573] (8) arylalkyl;

[0574] (9) heteroarylalkyl;

[0575] (10) alkenyl and

[0576] (11) heteroalkenyl;

[0577] (W) R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and -alkyl-(piperidine Ring V);

[0578] (X) R15 is selected from the group consisting of: alkyl and aryl;

[0579] (Y) R21, R22 and R46 are independently selected from the group consisting of:

[0580] (1) H;

[0581] (2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0582] (3) unsubstituted aryl (e.g. phenyl);

[0583] (4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0584] (5) unsubstituted cycloalkyl, (e.g. cyclohexyl);

[0585] (6) substituted cycloalkyl substituted with one or more substituents independently selected from: alkyl, halogen, CF3 or OH;

[0586] (7) heteroaryl of the formula,

[0587] (8) piperidine Ring V:

[0588] wherein R44 is selected from the group consisting of:

[0589] (a) H,

[0590] (b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl),

[0591] (c) alkylcarbonyl (e.g., CH3C(O)—);

[0592] (d) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and —C(O)OCH3);

[0593] (e) haloalkyl (e.g., trifluoromethyl) and

[0594] (f) —C(O)NH(R51);

[0595] (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 —NH2 then the remaining groups are not —OH;

[0596] (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

[0597] (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; or

[0598] (12) R21 and R22 taken together with the carbon to which they are bound form a cyclic ring selected from the group consisting of:

[0599] (a) unsubstituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl);

[0600] (b) cycloalkyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0601] (c) unsubstituted cycloalkenyl

[0602] (d) cycloalkenyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0603] (e) heterocycloalkyl, e.g., a piperidyl ring of the formula:

[0604] wherein R44 is selected from the group consisting of:

[0605] (1) —H,

[0606] (2) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0607] (3) alkylcarbonyl (e.g., CH3C(O)—);

[0608] (4) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and-C(O)OCH3);

[0609] (5) haloalkyl (e.g., trifluoromethyl); and

[0610] (6) —C(O)NH(R51);

[0611] (f) unsubstituted aryl (e.g., phenyl);

[0612] (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

[0613] (i) heteroaryl selected from the group consisting of:

[0614] (Z) R26 is selected from the group consisting of:

[0615] (1) H;

[0616] (2) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0617] (3) alkoxy (e.g. methoxy, ethoxy, propoxy);

[0618] (4) —CH2—CN;

[0619] (5) R9;

[0620] (6) —CH2CO2H;

[0621] (7) —C(O)alkyl and

[0622] (8) CH2CO2alkyl;

[0623] (AA) R27 is selected from the group consisting of:

[0624] (1) H;

[0625] (2) —OH;

[0626] (3) alkyl (e.g. methyl, ethyl, propyl, or butyl), and

[0627] (4) alkoxy;

[0628] (AB) R27, is selected from the group consisting of:

[0629] (1) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0630] (2) alkoxy;

[0631] (AC) R30, R31, R32 and R33 are independently selected from the group consisting of:

[0632] (1) —H;

[0633] (2) —OH;

[0634] (3) ═O;

[0635] (4) alkyl;

[0636] (5) aryl (e.g. phenyl);

[0637] (6) arylalkyl (e.g. benzyl);

[0638] (7) —OR9a;

[0639] (8) —NH2;

[0640] (9) —NHR9a;

[0641] (10) —N(R9a)2 wherein each R9a is independently selected;

[0642] (11) —N3;

[0643] (12) —NHR9b; and

[0644] (13) —N(R9a)R9b;

[0645] (AD) R50 is selected from the group consisting of:

[0646] (1) alkyl;

[0647] (2) unsubstituted heteroaryl;

[0648] (3) substituted heteroaryl; and

[0649] (4) amino;

[0650] 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;

[0651] (AE) R51 is selected from the group consisting of: —H and alkyl (e.g., methyl, ethyl, propyl, butyl and t-butyl); and

[0652] (AF) provided that 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

[0653] (AG) provided that 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

[0654] (AH) provided that 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

[0655] (AI) provided that a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and

[0656] (AJ) provided that a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and

[0657] (AK) provided that the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms.

[0658] 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

[0659] 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).

[0660] 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.

[0661] Piperidine Ring V includes the rings:

[0662] Examples of Ring V include, but are not limited to:

[0663] 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:

[0664] wherein p of the —(CH2)p— moiety of said B group is 0, and wherein p of the

[0665] 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

[0666] 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 R31 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, C1-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, C1-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, C1-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 R1 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 R1 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 alkyl (e.g., C1 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 15A, 1.6A or 1.7A.

[0667] One embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0668] wherein:

[0669] (1) a, b, c, d, R3A, R5, R6, R7, R7a, R8 and X are as defined for formula 1.1;

[0670] (2) B is the group:

[0671] (3) in said B group:

[0672] (a) p of the —(CH2)p— moiety is 0;

[0673] (b) p of the

[0674] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0675] (c) when p is 1 for the moiety

[0676] then R30 is selected from the group consisting of: —OH, or —NH2 (preferably —OH), and R31 is alkyl, most preferably C1-C6 alkyl, more preferably C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl;

[0677] (d) when p is 2 or 3 for the moiety

[0678] 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 C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0679] (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.

[0680] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0681] wherein:

[0682] (1) R8 and X are as defined for formula 1.0;

[0683] (2) B is the group:

[0684] (3) in said B group:

[0685] (a) p of the —(CH2)p— moiety is 0;

[0686] (b) p of the

[0687] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0688] (c) when p is 1 for the moiety

[0689] then R30 is selected from the group consisting of: —OH or —NH2, and R31 is alkyl, most preferably C1-C6 alkyl, more preferably C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl;

[0690] (d) when p is 2 or 3 for the moiety

[0691] 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 C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0692] (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;

[0693] (4) a is N;

[0694] (5) b, c and d are CR1 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;

[0695] (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); and

[0696] (7) R5, R6, R7, and R7a are H.

[0697] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0698] wherein:

[0699] (1) R8 is as defined for formula 1.0;

[0700] (2) B is the group:

[0701] (3) in said B group:

[0702] (a) p of the —(CH2)p— moiety is 0;

[0703] (b) p of the

[0704] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0705] (c) when p is 1 for the moiety

[0706] then R30 is selected from the group consisting of: —OH or —NH2, and R31 is alkyl, most preferably C1-C6 alkyl, more preferably C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl;

[0707] (d) when p is 2 or 3 for the moiety

[0708] 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 C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0709] (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;

[0710] (4) a is N;

[0711] (5) b, c and d are CR1 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;

[0712] (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);

[0713] (7) X is N or CH; and

[0714] (8) R5, R6, R7, and R7a are H.

[0715] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0716] wherein:

[0717] (1) a, b, c, d, R3A, R5, R6, R7, R7a, R8 and X are as defined for formula 1.1;

[0718] (2) B is the group:

[0719] (3) in said B group:

[0720] (a) p of the —(CH2)p— moiety is 0;

[0721] (b) p of the

[0722] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0723] (c) when p is 1 for the moiety

[0724] then

[0725] (i) R30 is —OH, and R31 is H; or

[0726] (ii) R30 is —NH2, and R31 is H; or

[0727] (iii) R30 is selected from the group consisting of:

[0728] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0729] (2) —N3;

[0730] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0731] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0732] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl);

[0733] (d) when p is 2 or 3 for the moiety

[0734] then:

[0735] (i) for one —CR30R31— moiety

[0736] (1) R30 is —OH, and R31 is H; or

[0737] (2) R30 is —NH2, and R31 is H; or

[0738] (3) R30 is selected from the group consisting of:

[0739] (a) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0740] (b) —N3;

[0741] (c) —NHR9b wherein R9b is as defined for formula 1.1; and

[0742] (d) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0743] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C2 alkyl, and methyl); and

[0744] (ii) for the remaining —CR30R31— moieties R30 and R3 are hydrogen; and

[0745] (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.

[0746] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0747] wherein:

[0748] (1) R8 and X are as defined for formula 1.0;

[0749] (2) B is the group:

[0750] (3) in said B group:

[0751] (a) p of the —(CH2)p— moiety is 0;

[0752] (b) p of the

[0753] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0754] (c) when p is 1 for the moiety

[0755] then

[0756] (i) R30 is —OH, and R31 is H; or

[0757] (ii) R30 is —NH2, and R31 is H; or

[0758] (iii) R30 is selected from the group consisting of:

[0759] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0760] (2) —N3;

[0761] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0762] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0763] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl);

[0764] (d) when p is 2 or 3 for the moiety

[0765] then:

[0766] (i) for one —CR30R31— moiety

[0767] (1) R30 is —OH, and R31 is H; or

[0768] (2) R30 is —NH2, and R31 is H; or

[0769] (3) R30 is selected from the group consisting of:

[0770] (a) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0771] (b) —N3;

[0772] (c) —NHR9b wherein R9b is as defined for formula 1.1; and

[0773] (d) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0774] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C2 alkyl, and methyl); and

[0775] (ii) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0776] (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;

[0777] (4) a is N;

[0778] (5) b, c and d are CR1 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;

[0779] (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); and

[0780] (7) R5, R6, R7, and R7a are H.

[0781] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0782] wherein:

[0783] (1) R8 is as defined for formula 1.0;

[0784] (2) B is the group:

[0785] (3) in said B group:

[0786] (a) p of the —(CH2)p— moiety is 0;

[0787] (b) p of the

[0788] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0789] (c) when p is 1 for the moiety

[0790] then

[0791] (i) R30 is —OH, and R31 is H; or

[0792] (ii) R30 is —NH2, and R31 is H; or

[0793] (iii) R30 is selected from the group consisting of:

[0794] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0795] (2) —N3;

[0796] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0797] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0798] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl);

[0799] (d) when p is 2 or 3 for the moiety

[0800] then:

[0801] (i) for one —CR30R31— moiety

[0802] (1) R30 is —OH, and R31 is H; or

[0803] (2) R30 is —NH2, and R31 is H; or

[0804] (3) R30 is selected from the group consisting of:

[0805] (a) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., —OR9a is —OCH3;

[0806] (b) —N3;

[0807] (c) —NHR9b wherein R9b is as defined for formula 1.1; and

[0808] (d) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0809] R31 is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C1-C2 alkyl, and methyl); and

[0810] (ii) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0811] (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;

[0812] (4) a is N;

[0813] (5) b, c and d are CR1 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;

[0814] (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);

[0815] (7) X is N or CH; and

[0816] (8) R5, R6, R7, and R7a are H.

[0817] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0818] wherein:

[0819] (1) a, b, c, d, R3A, R5, R6, R7, R8 R and X are as defined for formula 1.1;

[0820] (2) B is the group:

[0821] (3) in said B group:

[0822] (a) p of the —(CH2)p— moiety is 0;

[0823] (b) p of the

[0824] moiety is 1;

[0825] (c)

[0826] (i) R30 is —OH, and R31 is H; or

[0827] (ii) R30 is —NH2, and R3 is H; or

[0828] (iii) R30 is selected from the group consisting of:

[0829] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0830] (2) —N3;

[0831] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0832] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0833] 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

[0834] (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.

[0835] Another embodiment of this invention is directed to compounds of formula 1.4E having the formula:

[0836] wherein:

[0837] (1) R8 and X are as defined for formula 1.0;

[0838] (2) B is the group:

[0839] (3) in said B group:

[0840] (a) p of the —(CH2)p— moiety is 0;

[0841] (b) p of the

[0842] moiety is 1;

[0843] (c)

[0844] (i) R30 is —OH, and R31 is H; or

[0845] (ii) R30 is —NH2, and R31 is H; or

[0846] (iii) R30 is selected from the group consisting of:

[0847] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0848] (2) —N3;

[0849] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0850] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0851] 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

[0852] (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;

[0853] (4) a is N;

[0854] (5) b, c and d are CR1 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;

[0855] (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); and

[0856] (7) R5, R6, R7, and R7a are H.

[0857] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0858] wherein:

[0859] (1) R8 is as defined for formula 1.0;

[0860] (2) B is the group:

[0861] (3) in said B group:

[0862] (a) p of the —(CH2)p— moiety is 0;

[0863] (b) p of the

[0864] moiety is 1;

[0865] (c)

[0866] (i) R30 is —OH, and R31 is H; or

[0867] (ii) R30 is —NH2, and R31 is H; or

[0868] (iii) R30 is selected from the group consisting of:

[0869] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0870] (2) —N3;

[0871] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0872] (4) —N(R9a)R9b wherein R9a and R9b is as defined for formula 1.1; and

[0873] 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

[0874] (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;

[0875] (4) a is N;

[0876] (5) b, c and d are CR1 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;

[0877] (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);

[0878] (7) X is N or CH; and

[0879] (8) R5, R6, R7, and R7a are H.

[0880] 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.

[0881] 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).

[0882] 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.

[0883] 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).

[0884] Another embodiment of this invention is directed to a compound of formula 1.4 wherein p is 1 for the moiety

[0885] and R30 is —NH2.

[0886] Another embodiment of this invention is directed to a compound of formula 1.4 wherein p is 1 for the moiety

[0887] R30 is —NH2, and X is N.

[0888] Another embodiment of this invention is directed to a compound of formula 1.4D wherein p is 1 for the moiety

[0889] 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).

[0890] 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.

[0891] 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, R31 is H, and X is N.

[0892] 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 25-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).

[0893] 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.

[0894] 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.

[0895] 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, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0896] 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:

[0897] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0898] (2) —N3;

[0899] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0900] (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).

[0901] 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:

[0902] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0903] (2) —N3;

[0904] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0905] (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, C0-C2 alkyl, and methyl), and X is N.

[0906] 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:

[0907] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0908] (2) —N3;

[0909] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0910] (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, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0911] Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is —OH, and R31 is H.

[0912] 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.

[0913] Another embodiment of this invention is directed to a compound of formula 1.4D 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).

[0914] Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is —NH2, and R31 is H.

[0915] 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.

[0916] 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).

[0917] Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is selected from the group consisting of:

[0918] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0919] (2) —N3;

[0920] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0921] (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).

[0922] Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is selected from the group consisting of:

[0923] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0924] (2) —N3;

[0925] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0926] (4) —NR9aR9b 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.

[0927] Another embodiment of this invention is directed to a compound of formula 1.4D wherein R30 is selected from the group consisting of:

[0928] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0929] (2) —N3;

[0930] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0931] (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, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0932] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is —OH, and R31 is H.

[0933] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is —OH, R31 is H, and X is N.

[0934] 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).

[0935] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is —NH2, and R31 is H.

[0936] 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.

[0937] 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).

[0938] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of:

[0939] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0940] (2) —N3;

[0941] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0942] (4) —NR9aR9b 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., C0-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl).

[0943] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of:

[0944] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0945] (2) —N3;

[0946] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0947] (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.

[0948] Another embodiment of this invention is directed to a compound of formula 1.4E wherein R30 is selected from the group consisting of:

[0949] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0950] (2) —N3;

[0951] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0952] (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, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0953] Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is —OH, and R31 is H.

[0954] 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.

[0955] 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).

[0956] Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is —NH2, and R31 is H.

[0957] 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.

[0958] 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).

[0959] Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of:

[0960] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0961] (2) —N3;

[0962] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0963] (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).

[0964] Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of:

[0965] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0966] (2) —N3;

[0967] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0968] (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.

[0969] Another embodiment of this invention is directed to a compound of formula 1.4F wherein R30 is selected from the group consisting of:

[0970] (1) —OR9a wherein R9a is C1 to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., —OR9a is —OCH3);

[0971] (2) —N3;

[0972] (3) —NHR9b wherein R9b is as defined for formula 1.1; and

[0973] (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, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0974] 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.

[0975] Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is —OR9′, R31 is H, and X is N.

[0976] 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).

[0977] 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.

[0978] 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.

[0979] 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, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0980] 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.

[0981] 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.

[0982] 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, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0983] 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 H.

[0984] 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.

[0985] 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).

[0986] 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 alkyl (e.g., methyl).

[0987] Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R30 is —OR9′, R31 is alkyl (e.g., methyl), and X is N.

[0988] 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).

[0989] 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 alkyl (e.g., methyl).

[0990] 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.

[0991] 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), X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).

[0992] 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).

[0993] 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), and X is N.

[0994] 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).

[0995] 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).

[0996] 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), and X is N.

[0997] 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).

[0998] 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.

[0999] 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.

[1000] 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.

[1001] 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.

[1002] 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.

[1003] 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.

[1004] 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 alkyl (e.g., isopropyl or t-butyl).

[1005] 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 alkyl (e.g., isopropyl or t-butyl, and preferably isopropyl), R30 is —NH2 and R31 is H.

[1006] 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).

[1007] 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 R11 is alkyl (e.g., isopropyl or t-butyl).

[1008] 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 CR1 groups, and all of said R1 substituents are H.

[1009] 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 CR1 groups, and said R1 substituent at C-3 is halo and said R1 substituents at C-2 and C-4 are hydrogen.

[1010] 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.

[1011] 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.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] 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.

[1016] 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.

[1017] 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.

[1018] 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.

[1019] 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.

[1020] 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 C1 to C2 alkyl), and preferably said substituent is methyl.

[1021] 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.

[1022] In another embodiment, R8 is 2.0 in formula 1.2 wherein R11 is as defined for formula 1.0.

[1023] In another embodiment, R8 is 3.0 in formula 1.2 wherein R11 is as defined for formula 1.0.

[1024] In another embodiment, R8 is 4.0 in formula 1.2 wherein R11a and R12 are as defined for formula 1.0.

[1025] In another embodiment, R8 is 5.0 in formula 1.2 wherein R21, R22, and R46 are as defined for formula 1.0.

[1026] In another embodiment, R8 is 2.0 in formula 1.3 wherein R11 is as defined for formula 1.0.

[1027] In another embodiment, R8 is 3.0 in formula 1.3 wherein R11 is as defined for formula 1.0.

[1028] In another embodiment, R8 is 4.0 in formula 1.3 wherein R11a and R12 are as defined for formula 1.0.

[1029] In another embodiment, R8 is 5.0 in formula 1.3 wherein R21, R22, and R46 are as defined for formula 1.0.

[1030] In another embodiment, R8 is 2.0 in formula 1.4 wherein R11 is as defined for formula 1.0.

[1031] In another embodiment, R8 is 3.0 in formula 1.4 wherein R11 is as defined for formula 1.0.

[1032] In another embodiment, R8 is 4.0 in formula 1.4 wherein R11a and R12 are as defined for formula 1.0.

[1033] In another embodiment, R8 is 5.0 in formula 1.4 wherein R21, R22, and R46 are as defined for formula 1.0.

[1034] Preferably, in formulas 1.3 and 1.4, all R1 substituents are H, or R1 at C-3 is halo and R1 at C-2 and C-4 is hydrogen, most preferably all R1 substituents are hydrogen.

[1035] Preferably, in formulas 1.3 and 1.4, when m is 1 then R3A is preferably Cl at the C-8 position.

[1036] In formulas 1.3 and 1.4, when m is 2, then the substitution is 7,8-dihalo, or 8,10-dihalo.

[1037] 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.

[1038] Preferably, in formulas 1.2 and 1.3 X is N.

[1039] Preferably, in formula 1.4 X is N.

[1040] Another embodiment of this invention is directed to compounds of formula 1.4 having the formula:

[1041] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl.

[1042] Another embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[1043] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl.

[1044] Thus, one embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[1045] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl.

[1046] Another embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[1047] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl.

[1048] In formulas 1.2, 1.3, 1.4, 1.5, 1.6, and 1.7, R9 is preferably:

[1049] Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F having the formula:

[1050] 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., C1 to C4, such as, isopropy or t-butyl). Preferably R8 is 2.0, R11 is isopropyl, R30 is —NH2, and R31 is H.

[1051] Another embodiment of the invention is directed to compounds of formula 1.5A having the formula:

[1052] wherein all substituents are as defined for formulas 1.4D, 1.4E or 1.4F. Compounds of formula 1.5A include compounds wherein R3 is 2.0, and include compounds wherein R8 is 2.0 wherein R11 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.

[1053] Thus, one embodiment of the invention is directed to compounds of formula 1.5A having the formula:

[1054] 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., C1 to C4, such as, isopropy or t-butyl). Preferably R8 is 2.0, R11 is isopropyl, R30 is —NH2, and R31 is H.

[1055] Another embodiment of the invention is directed to compounds of formula 1.5A having the formula:

[1056] 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., C1 to C4, such as, isopropy or t-butyl). Preferably R8 is 2.0, R11 is isopropyl, R30 is —NH2, and R31 is H.

[1057] In formulas 1.4D, 1.4E, 1.4F, 1.5A, 1.6A, and 1.7A, R9 is preferably:

[1058] The compounds of formula 1.0 include the R isomer:

[1059] wherein:

[1060] X is N or CH;

[1061] a is N or C(N or CR1 in 1.1A); and

[1062] 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.

[1063] The compounds of formula 1.0 also include the S isomer:

[1064] wherein:

[1065] X is N or CH (preferably N);

[1066] a is N or C (a is N or CR1 in 1.1B); and

[1067] 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).

[1068] In one embodiment of the compounds of formula 1.0, R1, 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-fluoro, (f) 8-chloro or (g) 8-bromo.

[1069] 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-fluoro, (f) 8-chloro or (g) 8-bromo.

[1070] 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 CR1 or N, with N being preferred.

[1071] In one embodiment of the invention, R8 in compounds of formula 1.0 is selected from the group consisting of:

[1072] 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.

[1073] In one embodiment of the invention, for compounds of formula 1.0, R11a is selected from the group consisting of: alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, heteroaryl, substituted heteroaryl, unsubstituted cyloalkyl and substituted cycloalkyl, wherein:

[1074] (1) said substituted aryl and substituted heteroaryl R11a 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 Cl), cyano, —CF3, and alkyl;

[1075] (2) said substituted cycloalkyl R11a 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

[1076] (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.

[1077] 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:

[1078] (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 Cl), —CN and CF3; and

[1079] (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.

[1080] 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, R11a is selected from the group consisting of: t-butyl, cyanophenyl, chlorophenyl, fluorophenyl and cyclohexyl. In another embodiment, R11a is cyanophenyl (e.g., p-cyanophenyl).

[1081] In one embodiment of the invention, for compounds of formula 1.0, R11 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 R11 groups include: methyl, ethyl, propyl, isopropyl, t-butyl, cyclohexyl or substituted cyclohexyl. In one embodiment of the invention, R11 is selected from the group consisting of: methyl, isopropyl, t-butyl, cyclohexyl and fluorocyclohexyl (preferably p-fluorocyclohexyl). In one embodiment of the invention, R11 is selected from the group consisting of: methyl, isopropyl, t-butyl, and cyclohexyl. In one embodiment of the invention R11 is t-butyl or cyclohexyl. In one embodiment of the invention R11 is t-butyl for 2.0, and R11 is methyl for 3.0. In one embodiment of this invention R11 is isopropyl.

[1082] 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.

[1083] In one embodiment of the invention, for compounds of formula 1.0, R5, R6, R7 and R7a are H.

[1084] In one embodiment of the invention, for compounds of formula 1-0, R9 is selected from the group consisting of:

[1085] (1) unsubstituted heteroaryl;

[1086] (2) substituted heteroaryl;

[1087] (3) arylalkoxy;

[1088] (4) substituted arylalkoxy;

[1089] (5) heterocycloalkyl;

[1090] (6) substituted heterocycloalkyl;

[1091] (7) heterocycloalkylalkyl;

[1092] (8) substituted heterocycloalkylalkyl;

[1093] (9) heteroarylalkyl;

[1094] (10) substituted heteroarylalkyl;

[1095] (11) heteroarylalkenyl and

[1096] (12) substituted heteroarylalkenyl;

[1097] 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:

[1098] (1) —OH;

[1099] (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;

[1100] (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;

[1101] (4) halo (e.g., Br, F, 1, or Cl);

[1102] (5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alky! (e.g., methyl, ethyl, propyl, isopropyl, t-butyl or butyl, preferably isopropyl, or t-butyl);

[1103] (6) amino;

[1104] (7) trityl;

[1105] (8) heterocycloalkyl;

[1106] (9) arylalkyl (e.g. benzyl);

[1107] (10) heteroaryl (e.g. pyridyl) and

[1108] (11) heteroarylalkyl;

[1109] In one embodiment of the invention, for the compounds of formula 1.0, R9 is selected from the group consisting of:

[1110] (1) heterocycloalkyl;

[1111] (2) substituted heterocycloalkyl;

[1112] (3) heterocycloalkylalkyl;

[1113] (4) substituted heterocycloalkylalkyl;

[1114] (5) unsubstituted heteroarylalkyl;

[1115] (6) substituted heteroarylalkyl;

[1116] (7) unsubstituted heteroarylalkenyl and

[1117] (8) substituted heteroarylalkenyl;

[1118] 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:

[1119] (1) —OH;

[1120] (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;

[1121] (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.

[1122] (4) halo (e.g., Br or Cl);

[1123] (5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl);

[1124] (6) amino;

[1125] (7) trityl;

[1126] (8) heterocycloalkyl,

[1127] (9) arylalkyl;

[1128] (10) heteroaryl and

[1129] (11) heteroaryalkyl;

[1130] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[1131] (1) heterocycloalkyl;

[1132] (2) substituted heterocycloalkyl;

[1133] (3) heterocycloalkylalkyl;

[1134] (4) substituted heterocycloalkylalkyl;

[1135] (5) unsubstituted heteroarylalkyl;

[1136] (6) substituted heteroarylalkyl;

[1137] (7) unsubstituted heteroarylalkenyl and

[1138] (8) substituted heteroarylalkenyl;

[1139] 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:

[1140] (1) halo (e.g., Br, or Cl);

[1141] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl);

[1142] (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).

[1143] (4) amino;

[1144] (5) trityl;

[1145] (6) arylalkyl, and

[1146] (7) heteroarylalkyl.

[1147] In one embodiment of the invention, R9 is selected from the group consisting of:

[1148] (1) heterocycloalkylalkyl;

[1149] (2) substituted heterocycloalkylalkyl;

[1150] (3) unsubstituted heteroarylalkyl and

[1151] (4) substituted heteroarylalkyl;

[1152] 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:

[1153] (1) halo (e.g., Br, or Cl);

[1154] (2) alkyl usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and t-butyl, most preferably t-butyl);

[1155] (3) amino; and

[1156] (4) trityl.

[1157] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[1158] (1) heterocycloalkylalkyl;

[1159] (2) substituted heterocycloalkylalkyl;

[1160] (3) unsubstituted heteroarylalkyl and

[1161] (4) substituted heteroarylalkyl;

[1162] 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:

[1163] (1) halo (e.g., Br, or Cl); and

[1164] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl).

[1165] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[1166] (1) piperidinyl;

[1167] (2) piperizinyl;

[1168] (3) —(CH2)p-piperidinyl;

[1169] (4) —(CH2)p-piperizinyl;

[1170] (5) —(CH2)p-morpholinyl and

[1171] (6) —(CH2)p-imidazolyl;

[1172] wherein p is 0 to 1, and wherein the ring moiety of each R9 group is optionally 1o substituted with one, two or three substituents independently selected from the group consisting of:

[1173] (1) halo (e.g., Br, or Cl); and

[1174] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl).

[1175] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[1176] (1) -piperizinyl;

[1177] (2) —(CH2)p-piperidinyl;

[1178] (3) —(CH2)p-imidazolyl; and

[1179] (4) —(CH2)p-morpholinyl,

[1180] 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.

[1181] 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.

[1182] In one embodiment of the invention, for formula 1.0, R9 is —(CH2)-(2-methyl)-imidazolyl.

[1183] 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, R21 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.

[1184] 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 R21, R22 or R46 is 4-pyridyl-N-Oxide.

[1185] 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:

[1186] wherein R44 is —C(O)NHR51. In one embodiment of the invention, R51 is —C(O)NH2. In one embodiment of the invention, piperidine Ring V is:

100

[1187] and in one embodiment of the invention Ring V is:

101

[1188] Thus, in one embodiment of the invention, for formula 1.0, R21, R22 and R46 are independently selected from the group consisting of:

[1189] (1) H;

[1190] (2) aryl (most preferably phenyl);

[1191] (3) heteroaryl and

[1192] (4) heterocycloalkyl (i.e., Piperidine Ring V)

[1193] wherein at least one of R2′, 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 R21 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.

[1194] In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of:

[1195] (1) —H;

[1196] (2) —R9;

[1197] (3) —R9—C(O)—R9;

[1198] (4) —R9—CO2—R9a;

[1199] (5) —C(O)NHR9;

[1200] (6) —C(O)NH—CH2—C(O)—NH2;

[1201] (7) —C(O)NHR26;

[1202] (8) —(CH2)p(R9)2 wherein each R9 is the same or different;

[1203] (9) —(CH2)pC(O)R9;

[1204] (10) —(CH2)pC(O)R27a;

[1205] (11) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[1206] (12) —(CH2)pC(O)NH(R9);

[1207] (13) —(CH2)pNHC(O)R50;

[1208] (14) —(CH2)pNHC(O)2R50;

[1209] (15) —(CH2)pN(C(O)R27a)2 wherein each R27, is the same or different;

[1210] (16) —(CH2)pNR51C(O)R27;

[1211] (17) —(CH2)pNR5 C(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;

[1212] (18) —(CH2)pNR5 C(O)NR27;

[1213] (19) —(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;

[1214] (20) —(CH2)pNR5 C(O)N(R27a)2, wherein each R27a is the same or different;

[1215] (21) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;

[1216] (22) —(CH2)pNHCO2R50;

[1217] (23) —(CH2)pCO2R51;

[1218] (24) —NHR9;

[1219] (25)

102

[1220] wherein R30 and R31 are the same or different and

[1221] (26)

103

[1222] wherein R30, R31, R32 and R33 are the same or different.

[1223] In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of:

[1224] (1) —H;

[1225] (2) —R9;

[1226] (3) —R9—C(O)—R9;

[1227] (4) —R9—CO2—R9a;

[1228] (5) —C(O)NHR9;

[1229] (6) —(CH2)p(R9)2, wherein each R9 is the same or different;

[1230] (7) —(CH2)pC(O)R9;

[1231] (8) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[1232] (9) —(CH2)pC(O)NH(R9);

[1233] (10) —(CH2)pNR50C(O)R27;

[1234] (11) —(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;

[1235] (12) —(CH2)pNR51C(O)NR27;

[1236] (13) —(CH2)pNR51C(O)NR27 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;

[1237] (14) —NHR9; and

[1238] (15)

104

[1239] wherein R30 and R31 are the same or different.

[1240] Examples of A and B include but are not limited to:

105

[1241] wherein p is 0, 1, 2, 3 or 4.

[1242] Examples of A and B also include but are not limited to:

106

[1243] Examples of A and B also include but are not limited to:

107

108

[1244] Thus, examples of B include but are not limited to:

109

110

[1245] Preferred examples of B include:

111

[1246] More preferred examples of B include:

112

[1247] A most preferred example of B is:

113

[1248] Examples of R8 groups include, but are not limited to:

114

115

116

[1249] Examples of R8 also include, but are not limited to:

117

118

[1250] Examples of R8 also include, but are not limited to:

119

[1251] Examples of R8 also include, but are not limited to:

120

121

[1252] 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:

[1253] (1) heteroaryl;

[1254] (2) substituted heteroaryl;

[1255] (3) arylalkyl;

[1256] (4) substituted arylalkyl;

[1257] (5) arylalkoxy;

[1258] (6) substituted arylalkoxy;

[1259] (7) heterocycloalkyl;

[1260] (8) substituted heterocycloalkyl;

[1261] (9) heterocycloalkylalkyl;

[1262] (10) substituted heterocycloalkylalkyl;

[1263] (11) unsubstituted heteroarylalkyl;

[1264] (12) substituted heteroarylalkyl;

[1265] (13) alkenyl;

[1266] (14) substituted alkenyl;

[1267] (15) unsubstituted heteroarylalkenyl; and

[1268] (16) substituted heteroarylalkenyl,

[1269] 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:

[1270] (1) —OH;

[1271] (2) —CO2R14;

[1272] (3) —CH2OR14,

[1273] (4) halo,

[1274] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[1275] (6) amino;

[1276] (7) trityl;

[1277] (8) heterocycloalkyl;

[1278] (9) arylalkyl;

[1279] (10) heteroaryl and

[1280] (11) heteroarylalkyl,

[1281] wherein R14 is independently selected from the group consisting of: H; and alkyl, preferably methyl and ethyl.

[1282] In one embodiment of the invention, for formula 10., 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:

[1283] (1) arylalkyl;

[1284] (2) substituted arylalkyl;

[1285] (3) arylalkoxy;

[1286] (4) substituted arylalkoxy;

[1287] (5) heterocycloalkyl;

[1288] (6) substituted heterocycloalkyl;

[1289] (7) heterocycloalkylalkyl;

[1290] (8) substituted heterocycloalkylalkyl;

[1291] (9) unsubstituted heteroarylalkyl;

[1292] (10) substituted heteroarylalkyl;

[1293] (11) alkenyl;

[1294] (12) substituted alkenyl;

[1295] (13) unsubstituted heteroarylalkenyl; and

[1296] (14) substituted heteroarylalkenyl,

[1297] 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:

[1298] (1) —OH;

[1299] (2) halo, (preferably Br);

[1300] (3) alkyl (e.g. methyl, ethyl, propyl, butyl, or t-butyl);

[1301] (4) amino; and

[1302] (5) trityl.

[1303] 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:

[1304] (1) heterocycloalkylalkyl;

[1305] (2) substituted heterocycloalkylalkyl;

[1306] (3) unsubstituted heteroarylalkyl; and

[1307] (4) substituted heteroarylalkyl;

[1308] wherein said substituents for said substituted R9 groups are the same or different alkyl groups (e.g., C1-C4 alkyl).

[1309] 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:

[1310] (1) unsubstituted heteroaryl(C1-C3)alkyl; and

[1311] (2) substituted heteroaryl (C1-C3)alkyl;

[1312] wherein the substituents for said substituted R9 group are as defined above.

[1313] 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:

[1314] (1) unsubstituted heteroaryl(C1-C3)alkyl, with unsubstituted heteroaryl-CH2— being preferred; and

[1315] (2) substituted heteroaryl(C1-C3)alkyl, with substituted heteroaryl-CH2— being preferred;

[1316] 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).

[1317] 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:

[1318] (1) —CH2-imidazolyl;

[1319] (2) substituted imidazolyl-CH2—;

[1320] (3) —(CH2)2-imidazolyl;

[1321] (4) substituted imidazolyl-(CH2)2—;

[1322] (5) —(CH2)3-imidazolyl;

[1323] (6) substituted imidazolyl-(CH2)3—;

[1324] (7) —CH2-piperazinyl and

[1325] (8) —CH2-morpholinyl;

[1326] 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:

122

[1327] with the substituted imidazolyl:

123

[1328] being most preferred.

[1329] 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

124

[1330] being preferred.

[1331] 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.

[1332] 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).

[1333] In one embodiment of the invention, for compounds of formula 1.0, there is a double bond between C-5 and C-6.

[1334] Compounds of formula 1.0, having C-11 R- and S-stereochemistry include:

125

126

127

128

129

[1335] wherein:

[1336] X is N or C;

[1337] Q is Br or Cl; and

[1338] Y is alkyl, arylalkyl, or heteroarylalkyl.

[1339] Representative compounds of this invention include but are not limited to:

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

[1340] Preferred compounds of the invention are:

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

[1341] More preferred compounds of the invention are:

193

194

195

196

197

198

199

200

201

202

203

[1342] Most preferred compounds of the invention are:

204

205

206

[1343] Compounds of the formula:

207

208

209

210

211

212

[1344] 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.

[1345] Compounds of the formula:

213

214

[1346] 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.

[1347] Another embodiment of this invention is directed to compounds selected from the group consisting of:

215

216

[1348] Another embodiment of this invention is directed to compounds selected from the group consisting of:

217

[1349] Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

[1350] 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.

[1351] 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.

[1352] 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.

[1353] All such acid and base salts are intended to be pharmaceutically 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.

[1354] The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

[1355] The compounds of this invention: (i) potently inhibit farnesyl 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 farnesyl 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.

[1356] The compounds of this invention inhibit farnesyl 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 farnesyl protein transferase, is useful in the treatment of the cancers described below.

[1357] 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 regulatory 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.

[1358] This invention also provides a method for inhibiting or treating tumor (i.e., cancer) growth by administering an effective amount (e.g., a therapeutically 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 therapeutically effective amount) of the above described compounds.

[1359] 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.

[1360] 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.

[1361] Examples of proliferative diseases (tumors, i.e., cancers) which may be inhibited or treated include, but are not limited to:

[1362] (A) lung cancer (e.g., lung adenocarcinoma and non small cell lung cancer);

[1363] (B) pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma);

[1364] (C) colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma);

[1365] (D) myeloid leukemias (for example, acute myelogenous leukemia (AML), CML, and CMML);

[1366] (E) thyroid follicular cancer;

[1367] (F) myelodysplastic syndrome (MDS);

[1368] (G) bladder carcinoma;

[1369] (H) epidermal carcinoma;

[1370] (I) melanoma;

[1371] (J) breast cancer;

[1372] (K) prostate cancer;

[1373] (L) head and neck cancers (e.g., squamous cell cancer of the head and neck);

[1374] (M) ovarian cancer;

[1375] (N) gliomas;

[1376] (O) cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas);

[1377] (P) sarcomas;

[1378] (Q) tetracarcinomas;

[1379] (R) nuroblastomas;

[1380] (S) kidney carcinomas;

[1381] (T) hepatomas;

[1382] (U) non-Hodgkin's lymphoma;

[1383] (V) multiple myeloma; and

[1384] (W) anaplastic thyroid carcinoma.

[1385] 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 claim 1

[1386] 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 lymphoma and multiple myeloma.

[1387] 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 alkaloids, (12) antibodies that are inhibitors of αvβ3 integrins, (13) small molecules that are inhibitors of αvβ3 integrins, (14) folate antagonists, (15) ribonucleotide reductase inhibitors, (16) anthracyclines, (17) biologics; (18) thalidomide (or related imid), and (19) Gleevec.

[1388] This invention also provides a method of treating cancer 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 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.

[1389] 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 therapeutically 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.

[1390] This invention also provides a method of treating non-Hodgkin's lymphoma 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).

[1391] This invention also provides a method of treating multiple myeloma 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 proteosome inhibitor (e.g., PS-341 from Millenium); or (2) Thalidomide (or related imid).

[1392] This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

[1393] (a) an FPT inhibitor of formula 1.0;

[1394] (b) at least two different antineoplastic agents selected from the group consisting of:

[1395] (1) taxanes;

[1396] (2) platinum coordinator compounds;

[1397] (3) EGF inhibitors that are antibodies;

[1398] (4) EGF inhibitors that are small molecules;

[1399] (5) VEGF inhibitors that are antibodies;

[1400] (6) VEGF kinase inhibitors that are small molecules;

[1401] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1402] (8) anti-tumor nucleoside derivatives;

[1403] (9) epothilones;

[1404] (10) topoisomerase inhibitors;

[1405] (11) vinca alkaloids;

[1406] (12) antibodies that are inhibitors of αVβ3 integrins;

[1407] (13) small molecule inhibitors of αVβ3 integrins

[1408] (14) folate antagonists;

[1409] (15) ribonucleotide reductase inhibitors;

[1410] (16) anthracyclines;

[1411] (17) biologics;

[1412] (18) Thalidomide (or related Imid); and

[1413] (19) Gleevec.

[1414] This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

[1415] (a) an FPT inhibitor of formula 1.0;

[1416] (b) at least two different antineoplastic agents selected from the group consisting of

[1417] (1) taxanes;

[1418] (2) platinum coordinator compounds;

[1419] (3) EGF inhibitors that are antibodies;

[1420] (4) EGF inhibitors that are small molecules;

[1421] (5) VEGF inhibitors that are antibodies;

[1422] (6) VEGF kinase inhibitors that are small molecules;

[1423] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1424] (8) antitumor nucleoside derivatives;

[1425] (9) epothilones;

[1426] (10) topoisomerase inhibitors;

[1427] (11) vinca alkaloids;

[1428] (12) antibodies that are inhibitors of αVβ3 integrins; or

[1429] (13) small molecule inhibitors of αvβ3 integrins

[1430] (14) folate antagonists;

[1431] (15) ribonucleotide reductase inhibitors;

[1432] (16) anthracyclines;

[1433] (17) biologics; and

[1434] (18) Thalidomide (or related Imid).

[1435] This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

[1436] (a) an FPT inhibitor of formula 1.0;

[1437] (b) at least two different antineoplastic agents selected from the group consisting of:

[1438] (1) taxanes;

[1439] (2) platinum coordinator compounds;

[1440] (3) EGF inhibitors that are antibodies;

[1441] (4) EGF inhibitors that are small molecules;

[1442] (5) VEGF inhibitors that are antibodies;

[1443] (6) VEGF kinase inhibitors that are small molecules;

[1444] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1445] (8) anti-tumor nucleoside derivatives;

[1446] (9) epothilones;

[1447] (10) topoisomerase inhibitors;

[1448] (11) vinca alkaloids;

[1449] (12) antibodies that are inhibitors of αVβ3 integrins; or

[1450] (13) small molecule inhibitors of αVβ3 integrins

[1451] (14) folate antagonists;

[1452] (15) ribonucleotide reductase inhibitors;

[1453] (16) anthracyclines; and

[1454] (17) biologics.

[1455] This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

[1456] (a) an FPT inhibitor of formula 1.0;

[1457] (b) at least two different antineoplastic agents selected from the group consisting of:

[1458] (1) taxanes;

[1459] (2) platinum coordinator compounds;

[1460] (3) EGF inhibitors that are antibodies;

[1461] (4) EGF inhibitors that are small molecules;

[1462] (5) VEGF inhibitors that are antibodies;

[1463] (6) VEGF kinase inhibitors that are small molecules;

[1464] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1465] (8) anti-tumor nucleoside derivatives;

[1466] (9) epothilones;

[1467] (10) topoisomerase inhibitors;

[1468] (11) vinca alkaloids;

[1469] (12) antibodies that are inhibitors of αVβ3 integrins; and

[1470] (13) small molecule inhibitors of αVβ3 integrins.

[1471] 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:

[1472] (a) an FPT inhibitor of formula 1.0;

[1473] (b) at least two different antineoplastic agents selected from the group consisting of:

[1474] (1) taxanes;

[1475] (2) platinum coordinator compounds;

[1476] (3) EGF inhibitors that are antibodies;

[1477] (4) EGF inhibitors that are small molecules;

[1478] (5) VEGF inhibitors that are antibodies;

[1479] (6) VEGF kinase inhibitors that are small molecules;

[1480] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1481] (8) anti-tumor nucleoside derivatives;

[1482] (9) epothilones;

[1483] (10) topoisomerase inhibitors;

[1484] (11) vinca alkaloids;

[1485] (12) antibodies that are inhibitors of αVβ3 integrins; and

[1486] (13) small molecule inhibitors of αVβ3 integrins.

[1487] 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:

[1488] (a) an FPT inhibitor of formula 1.0;

[1489] (b) at least two different antineoplastic agents selected from the group consisting of:

[1490] (1) taxanes;

[1491] (2) platinum coordinator compounds;

[1492] (3) anti-tumor nucleoside derivatives;

[1493] (4) topoisomerase inhibitors; and

[1494] (5) vinca alkaloids.

[1495] 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:

[1496] (a) an FPT inhibitor of formula 1.0;

[1497] (b) carboplatin; and

[1498] (c) paclitaxel.

[1499] 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:

[1500] (a) an FPT inhibitor of formula 1.0;

[1501] (b) cisplatin; and

[1502] (c) gemcitabine.

[1503] 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:

[1504] (a) an FPT inhibitor of formula 1.0;

[1505] (b) carboplatin; and

[1506] (c) gemcitabine.

[1507] 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:

[1508] (a) an FPT inhibitor of formula 1.0;

[1509] (b) Carboplatin; and

[1510] (c) Docetaxel.

[1511] This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1512] (a) an FPT inhibitor of formula 1.0;

[1513] (b) an antineoplastic agent selected from the group consisting of:

[1514] (1) EGF inhibitors that are antibodies;

[1515] (2) EGF inhibitors that are small molecules;

[1516] (3) VEGF inhibitors that are antibodies; and

[1517] (4) VEGF kinase inhibitors that are small molecules.

[1518] 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:

[1519] (a) an FPT inhibitor of formula 1.0; and

[1520] (b) one or more antineoplastic agents selected from the group consisting of:

[1521] (1) taxanes; and

[1522] (2) platinum coordinator compounds.

[1523] 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:

[1524] (a) an FPT inhibitor of formula 1.0;

[1525] (b) at least two different antineoplastic agents selected from the group consisting of:

[1526] (1) taxanes:

[1527] (2) platinum coordinator compounds; and

[1528] (3) anti-tumor nucleoside derivatives (e.g., 5-Fluorouracil).

[1529] This invention also provides a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1530] (a) an FPT inhibitor of formula 1.0;

[1531] (b) Gleevec; and

[1532] (c) interferon (e.g., Intron-A).

[1533] This invention also provides a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1534] (a) an FPT inhibitor of formula 1.0;

[1535] (b) Gleevec; and

[1536] (c) pegylated interferon (e.g., Peg-Intron, and Pegasys).

[1537] This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1538] (a) an FPT inhibitor of formula 1.0;

[1539] (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)).

[1540] This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1541] (a) an FPT inhibitor of formula 1.0;

[1542] (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)); and

[1543] (c) an anthracycline.

[1544] This invention also provides a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1545] (a) an FPT inhibitor of formula 1.0;

[1546] (b) Rituximab (Rituxan).

[1547] This invention also provides a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1548] (a) an FPT inhibitor of formula 1.0;

[1549] (b) Rituximab (Rituxan); and

[1550] (c) an anti-tumor nucleoside derivative (e.g., Fludarabine (i.e., F-ara-A).

[1551] This invention also provides a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1552] (a) an FPT inhibitor of formula 1.0;

[1553] (b) Genasense (antisense to BCL-2).

[1554] This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1555] (a) an FPT inhibitor of formula 1.0;

[1556] (b) a proteosome inhibitor (e.g., PS-341 (Millenium)).

[1557] This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1558] (a) an FPT inhibitor of formula 1.0;

[1559] (b) Thalidomide or related imid.

[1560] This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1561] (a) an FPT inhibitor of formula 1.0;

[1562] (b) Thalidomide.

[1563] 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.

[1564] It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein R2s 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, Ick, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

[1565] 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 farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.

[1566] 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.

[1567] 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.

[1568] 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).

[1569] For radiation therapy, γ-radiation is preferred.

[1570] 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.

[1571] Typical signal transduction inhibitors include but are not limited to:

[1572] (i) Bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec);

[1573] (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

[1574] (iii) HER-2/neu receptor inhibitors such as, for example, Herceptin® (trastuzumab).

[1575] 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.

[1576] 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, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, N.J. 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).

[1577] 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.

[1578] 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.

[1579] 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., Taxol®) or Docetaxel (e.g., Taxotere®)) can be administered once a week or once every three weeks.

[1580] 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.

[1581] 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.

[1582] The FPT inhibitor can be administered orally, preferably as a solid dosage form, more preferably a capsule, and while the total therapeutically 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.

[1583] 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 200 mg 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).

[1584] 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; (1) for the anti-tumor nucleoside Cytarabine (Ara-C) 100-200 mg/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) 10-25 mg/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 alkaloids; (q) for the fol ate 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 250-1000 mg/m2 IV given with leucovorin every 3 to 4 weeks; (r) for the fol ate 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 lymphoma) 200-400 mg/m2 IV weekly over 4-8 weeks for 6 months.

[1585] Gleevec can be used orally in an amount of about 200 to about 800 mg/day.

[1586] 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 releapse or toxicity. See for example Mitsiades et al., “Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells; therapeutic implications”, Blood, 99(12):4525-30, Jun. 15, 2002, the disclosure of which is incorporated herein by reference thereto.

[1587] For example, Paclitaxel (e.g., Taxol® 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., Taxol® 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.

[1588] 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.

[1589] 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.

[1590] 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.

[1591] Thus, in one example (e.g., treating non small cell lung cancer):

[1592] (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;

[1593] (2) Paclitaxel (e.g., Taxol®) 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

[1594] (3) Carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

[1595] In another example (e.g., treating non small cell lung cancer):

[1596] (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;

[1597] (2) Paclitaxel (e.g., Taxol®) 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

[1598] (3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

[1599] In another example (e.g., treating non small cell lung cancer):

[1600] (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;

[1601] (2) Docetaxel (e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m2; and

[1602] (3) Carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

[1603] In another example (e.g., treating non small cell lung cancer):

[1604] (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;

[1605] (2) Docetaxel (e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m2; and

[1606] (3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

[1607] Thus, in one example (e.g., treating non small cell lung cancer):

[1608] (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 1.25 mg administered twice a day, and most preferably about 100 mg administered twice a day;

[1609] (2) Paclitaxel (e.g., Taxol®) 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

[1610] (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8, and preferably 6.

[1611] In a preferred example of treating non small cell lung cancer:

[1612] (1) the FPT inhibitor is administered in an amount of 100 mg administered twice a day;

[1613] (2) Paclitaxel (e.g., Taxol®) is administered once every three weeks in an amount of 175 mg/m2; and

[1614] (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of 6.

[1615] In another example (e.g., treating non small cell lung cancer):

[1616] (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;

[1617] (2) Paclitaxel (e.g., Taxol®) 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

[1618] (3) Cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

[1619] In another example (e.g., treating non small cell lung cancer):

[1620] (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;

[1621] (2) Docetaxel (e.g., Taxotere®) is administered once every three weeks in an amount of about 50 to about 100 mg/m2; and

[1622] (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

[1623] In another example (e.g., treating non small cell lung cancer):

[1624] (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;

[1625] (2) Docetaxel (e.g., Taxotere®) is administered once every three weeks in an amount of about 50 to about 100 mg/m2; and

[1626] (3) Cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

[1627] In a preferred example for treating non small cell lung cancer using the FPT inhibitor, Docetaxel and Carboplatin:

[1628] (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;

[1629] (2) Docetaxel (e.g., Taxotere®) is administered once every three weeks in an amount of about 75 mg/m2; and

[1630] (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 6.

[1631] In the above examples the Docetaxel (e.g., Taxotere®) and Cisplatin, the Docetaxel (e.g., Taxotere®) and Carboplatin, the Paclitaxel (e.g., Taxol®) and Carboplatin, or the Paclitaxel (e.g., Taxol®) and Cisplatin are preferably administered on the same day.

[1632] In another example (e.g., CML):

[1633] (1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day;

[1634] (2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally; and

[1635] (3) interferon (Intron-A) is administered in an amount of about 5 to about 20 million IU three times per week.

[1636] In another example (e.g., CML):

[1637] (1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day;

[1638] (2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally; and

[1639] (3) pegylated interferon (Peg-Intron or Pegasys) is administered in an amount of about 3 to about 6 micrograms/kg/day.

[1640] In another example (e.g., non-Hodgkin's lymphoma):

[1641] (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

[1642] (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.

[1643] In another example (e.g., multiple myeloma):

[1644] (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

[1645] (2) the proteosome inhibitor (e.g., PS-341-Millenium) is administered in an amount of about 1.5 mg/m2 twice weekly for two consecutive weeks with a one week rest period.

[1646] In another example (e.g., multiple myeloma):

[1647] (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

[1648] (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.

[1649] 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.

[1650] Antineoplastic agents that can be used in combination with the FPT inhibitor are:

[1651] (1) taxanes such as paclitaxel (TAXOL®) and/or docetaxel (Taxotere®);

[1652] (2) platinum coordinator compounds, such as, for example, carboplatin, cisplatin and oxaliplatin;

[1653] (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), monocional antibody ICR-62 (ICR, Sufton, 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);

[1654] (4) EGF inhibitors that are small molecules, such as, Tarceva (TM) (OSI-774, OSI Pharmaceuticals, Inc.), and Iressa (ZD 1839, Astra Zeneca);

[1655] (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);

[1656] (6) VEGF kinase inhibitors that are small molecules such as SU 5416 and SU 6688 (both from Sugen, Inc.);

[1657] (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.);

[1658] (8) anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine;

[1659] (9) epothilones such as BMS-247550 (Bristol-Myers Squibb), and EP0906 (Novartis Pharmaceuticals);

[1660] (10) topoisomerase inhibitors such as topotecan (Glaxo SmithKline), and Camptosar (Pharmacia);

[1661] (11) vinca alkaloids, such as, navelbine (Anvar and Fabre, France), vincristine and vinblastine; and

[1662] (12) antibodies that are inhibitors of αVβ3 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).

[1663] Preferred antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin, gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, navelbine, IMC-1 C11, SU5416 or SU6688. Most preferred antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin, navelbine, gemcitabine, or Herceptin.

[1664] 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% NaCl) or dextrose solution (e.g., 5% dextrose)).

[1665] 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

[1666] 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.

[1667] 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, 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.

[1668] 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, 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.

[1669] 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 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.

[1670] 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.

[1671] Preferably, non small cell lung cancer is treated in the methods described in the above embodiments.

[1672] 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 therapeutically 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.

[1673] 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 paclitaxeronce 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.

[1674] 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 100 mg/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.

[1675] 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.

[1676] 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 (Taxotere®) 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.

[1677] 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.

[1678] 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:

[1679] (1) the FPT inhibitor;

[1680] (2) a taxane; and

[1681] (3) an antineoplastic agent selected from:

[1682] (a) an EGF inhibitor that is a small molecule;

[1683] (b) a VEGF inhibitor that is an antibody; or

[1684] (c) a VEGF kinase inhibitor that is a small molecule.

[1685] 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.

[1686] 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.

[1687] 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 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.

[1688] 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.

[1689] 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, 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.

[1690] 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, 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.

[1691] 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, 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.

[1692] 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, 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.

[1693] Preferably, non small cell lung cancer is treated in the methods using gemcitabine in the embodiments described above.

[1694] 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.

[1695] 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-IC11, SU5416 or SU6688. Preferably non small cell lung cancer is treated.

[1696] 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.

[1697] 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.

[1698] Another embodiment of this invention is directed to a pharmaceutical composition comprising at least two different antineoplastic agents and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCl) or a dextrose solution (e.g., 5% dextrose).

[1699] Another embodiment of this invention is directed to a pharmaceutical composition comprising the FPT inhibitor and at least two different antineoplastic agents and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCl) or a dextrose solution (e.g., 5% dextrose).

[1700] 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% NaCl) or a dextrose solution (e.g., 5% dextrose).

[1701] 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.

[1702] 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 therapeutically 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.

[1703] 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.

[1704] 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.

[1705] 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.

[1706] 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.

[1707] 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.

[1708] 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.

[1709] 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.

[1710] 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

[1711] 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.

[1712] Alkylating agents (including nitrogen mustards, 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.

[1713] 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.

[1714] Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commercially available as Taxol® 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.

[1715] Hormones and steroids (including synthetic analogs): 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.

[1716] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

[1717] Other chemotherapeutics include Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabinbe, Reloxafine, and Droloxafine.

[1718] 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.

[1719] 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, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

Microtubule Affecting Agents

[1720] 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.

[1721] 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.

[1722] 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. Pat. 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).

[1723] More specifically, the term “paclitaxel” as used herein refers to the drug commercially available as Taxol (NSC number: 125973). Taxol® 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, oaclitaxel 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).

[1724] 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. 41:3747).

[1725] 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.).

[1726] 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.

[1727] 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. Pat. No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.

[1728] 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).

[1729] General Preparative Schemes

[1730] The following processes may be employed to produce compounds of the invention.

Pyridyl Tricyclic Compounds

[1731] 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:

218

[1732] The synthesis of 5-bromo tricyclic compound 1b 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. Y1 represents —CH2—, —O— 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 HCl(aq) at the appropriate temperatures results in the formation of the 5 and 6 azaketones, if and 1e respectively.

219

[1733] (wherein Rx represents R9)

[1734] 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.

220

[1735] (wherein R″ represents H or alkyl (e.g., methly and ethyl).

[1736] Synthesis of 3-carbon spaced analogs can be prepared as outlined in Scheme 3. Thus, subjecting tricyclic vinyl bromide 1b to a Heck type reaction using ethyl acrylate and catalyzed by Pd0 gives the α-β 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 HCl-dioxane gave the hydrochloride salts of amines. Using standard chemistry, these amines were converted to ureas, carbamates, sulfonamides and amides.

[1737] 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.

221

[1738] (wherein R″ represents H or alkyl (e.g., methly and ethyl).

[1739] Preparation of 6-substituted 3-carbon spaced imidazole compounds was carried out as outlined in scheme 4. A mixture of ketones 1f and 1i 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.

222

[1740] (wherein R′ represents H or alkyl (e.g., methly and ethyl).

[1741] 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 Pd0 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 funtionaiization was carried out as previously described Suberane compounds were prepared in a similar way

223

[1742] 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.

224

[1743] Lactams 7a can be prepared from amine 6b by reacting with bromo butanonyl acid chloride as outlined in Scheme 7.

225

[1744] 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.

226

227

[1745] 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.

228

229

[1746] 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.

[1747] Mesylate aa is prepared by first carbonylating compound H from Scheme 14 using Pd0, 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.

230

231

232

[1748] 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.

[1749] 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).

233

234

235

236

[1750] 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.

237

238

[1751] 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.

[1752] Scheme 14: Preparation of One-Methylene Piperazines

[1753] 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.

239

[1754] 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.

240

[1755] 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.

241

[1756] The resulting alcohols functions of E and F are converted to a leaving group, such as a halide, with reagents such as SOCl2 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.

242

[1757] 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 PdCl2 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.

243

[1758] 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 HCl-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 Is reduced, such as a mixed anhydride or an acylimidazole. This is done by reacting the resulting carbocylic acids with a chloroformate to form the mixed anhydride or with carbonydiimidazole to form the acylimidazole (Synlett. (1995), 839). The resulting activated carboxylic acids are reduced with NaBH4 in solvents such as methanol, ethanol or aqueous THF.

244

[1759] The hydroxy functions of K and L are converted into leaving groups such as a methanesulfonate or an arylsulfonate such as a tosylate, 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.

245

246

[1760] The vinylhalide or vinyltriflate intermediates A1 and B1 (Scheme 10) are carbonylated with CO gas under a pressure of about 100 ps; and a temperature of 80° C. to 100° C. using a palladium catalyst such as PdCl2 and triphenyl phosphine in toluene and containing DBU and an alcohol such as methanol. If methanol is used, methyl esters C1 and D1 are obtained. Intermediates C1 and D1 are reacted as are intermediates I1 and J1 (see Scheme 15a below) following essentially the same procedure as in Scheme 14 to yield compounds of Formula 1.0 of this invention.

247

[1761] 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 F1 and G1 to stand until aldehyde is visible by NMR (at least two weeks) and then reacting with Hg(OAc)2, KI followed by NaBH4, as described in J. Chem. Soc., Perkin Trans., (1984), 1069 and Tet. Left., (1988), 6331, yields mixtures H1, I1 and J1, and K1. Intermediates H1 and J1 are separated and reacted, as are intermediates K1 and L1, following essentially the same procedure as in Scheme 14 to yield compounds of Formula 1.0, of this invention.

248

[1762] Those skilled in the a rt will appreciate that Schemes 11, 12, 12a, 13, 14, 15 and 15a using reactants having the moieties

249

[1763] (related to formula 1.0), for example, are also representative of reactants having the moieties:

250

[1764] (related to compounds of formula 1.1).

251

[1765] (wherein R represents R8, and R11 represents R10)

[1766] 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.

252

[1767] (wherein R represents R8)

[1768] In Scheme 17, the synthesis of the C-linked imidazoleb proceeds through the Heck reaction of the appropriately substituted vinylimidazole 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-alkylimidazole derivatives.

Suberyl Compounds

[1769] 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 CR1 in formula 1.1) can be prepared according to Scheme 18:

253

[1770] 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.

254

255

256

257

258

259

260

261

262

263

264

[1771] 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 isocyarate 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.

265

266

267

268

269

270

271

272

273

274

[1772] 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 R8 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 R8 substituent.

275

276

277

[1773] wherein “IM” represents imidazolyl in the compound CO(IM)2.

278

279

[1774] 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.

[1775] 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.

PREPARATIVE EXAMPLE 1

[1776]

280

[1777] Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCl (1.4 L conc. HCl in 600 ml H2O) for 12 h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2Cl2 (1×4L, and 2×2.5L). The organic phase was washed with brine, dried over Na2SO4 and MgSO4 and then filtered. All the volatiles were then removed to give 368 g of the title compound (2). MH+=311

281

[1778] To the title compound from Preparative Example 1, Step A (363 g, 1.17 mol) was added trifuromethane sulfonic acid (1.8 Kg) under N2. The reaction mixture was refluxed at 170° C. The progress of the reaction was monitored by 1H NMR. After 4 days the reaction was only 63% complete. After 8 days the reaction was found to be 80% complete according to 1H NMR; thus another 130 mL of CF3SO3H were added and refuxing continued for another 24 h. It was then poured into ice and basified with 800 mL of NaOH (50%) and extracted twice with CH2Cl2(1×8L then 1×7L). The organic phase was combined, washed with H2O and filtered through celite. It was then dried over MgSO4 and Na2SO4 and again filtered through celite. The filtrate was concentrated to give a black brown semi-solid that was pre adsorbed on 600 g of silica gel and then chromatographed on 2.3 Kg of silica gel eluting first with 5% CH3OH—CH2Cl2 (saturated with ammonia) and then with 10% CH3OH—CH2Cl2 (saturated with ammonia) to give 102 g of the title compound (3) as a solid. mp=73-75; MS (FAB) m/z 483 (MH+).

282

[1779] To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1 L of CH2Cl2 at 0° C. was added ethylchloroformate (55 mL), dropwise. The reaction mixture was stirred at room temperature overnight. It was further diluted with 1 L CH2Cl2 and stirred with 2L of dilute NaHCO3, pH˜7-8. The organic layer was separated and dried over MgSO4 and Na2SO4, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).

283

[1780] The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2Cl2 and dibromo dimethylhydantoin, (132 g, 0.462 mol) was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0° C. under N2 atmosphere and 174 mL of CF3SO3H were added over 37 min. while keeping temperatures between −1 to 1° C. The reaction mixture was stirred for 3 h, cooled to −10° C. and basified with 50% NaOH (170 mL), keeping the temperature below 1° C. The aqueous phase was extracted with CH2Cl2 and then dried over MgSO4, dried and concentrated to give 354 g of yellow foam that was chromatographed on silica gel eluting with 10-50% of ethyl acetate-hexanes gradient to give 50 g of compound (5) (14% yield) and 147 grams of the desired title compound (6) (49% yield). Compound (6) MS m/z (rel intens) 462 (MH+); Compound (5) MS m/z (rel intens) 542 (MH+).

284

[1781] To a solution of piperazine 0.186 g (2.2 mmol, 5 equiv.) in 5 mL of THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH4OH)—CH2Cl2 to give a mixture of title compounds (7) and (8). FAB m/z 467 (MH+).

285

[1782] The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of conc. HCl was stirred at room temperature for 16 h. The reaction mixture was pored into ice and with conc. NH4OH and then extracted with CH2Cl2 to give a mixture of compounds (9) and (10). MS (FAB) m/z 399 (MH+).

PREPARATIVE EXAMPLE 2

[1783]

286

[1784] Compound 6 from Preparative Example 1, Step D (10 g, 21.7 mmol) was hydrolyzed in the same manner as described in Preparative Example 1, Step A, to give the title compound (11). MH+=389.

287

[1785] 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, 6 mL, 0.77 mol). After stirring at room temperature overnight, the solution was diluted with dichloromethane, washed with saturated NaHCO3 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% CH3OH(saturated with ammonia)-CH2Cl2 to give the title compound (12). MS (FAB) m/z 469 (MH+).

288

[1786] 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, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH+).

289

[1787] The product from Preparative Example 2, Step C (22.5 g) was dissolved in 150 mL of conc. HCl and stirred for 16 h. The reaction mixture was poured into ice, basified with conc. NH4OH and then extracted with CH2Cl2 to give a mixture of compounds (15) and (16). MS (FAB) m/z 405 (MH+).

Preparative Example 2A

[1788]

290

[1789] 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).

[1790] Compound 17: mp=118-119; [α]D22=+136.9° (9.00 mg/2 mL, MeOH); MS (FAB) m/z 469 (MH+).

[1791] Compound 18: mp=119-120; [α]D22=−178.2° (9.90 mg/2 mL, MeOH); MS (FAB) m/z 469 (MH+).

291

[1792] 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, to give 22.2 g of a mixture of compounds (31) and (32). MS (473) (MH+).

PREPARATIVE EXAMPLE 3

[1793]

292

[1794] To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100° C., and stirred for 4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2Cl2 and water and the mixture was then extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH+).

293

[1795] To a solution of the title compound from Preparative Example 3, Step A (6.4 g, 13 mmole) in ethanol (500 ml), was added copper chloride (0.96 g, 9.7 mmole). The reaction was cooled to 0° C. Portionwise, added sodium borohydride (4.97 g, 131 mmole). The reaction stirred overnight at room temperature. Another portion of sodium borohydride (2.46 g, 65 mmole) was added and the reaction stirred for 2 more hours, then the solvent was removed. To the residue was added saturated sodium bicarbonate and the mixture was extracted with CH2Cl2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the reduced ester (20) and the alcohol (21) title compounds. This crude mixture was taken on to the next step without purification.

294

[1796] To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2Cl2 (100 ml) was added triethyl amine (2.4 ml). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting with 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH+). (recovered unreacted ester (20))

PREPARATIVE EXAMPLE 4

[1797]

295

[1798] To a solution of title compound (11) from Preparative Example 2, Step A (20 g, 51.32 mmole) in CH3OH/H2O (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 CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness affording the title compound (23). MS 491 (MH+).

296

[1799] Following a similar procedure as in Preparative Example 3, Step A, the title compound (24) was prepared. MS 509 (MH+).

297

[1800] 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+).

298

[1801] 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+).

299

[1802] Following a similar procedure described in Preparative Example 3, Step C, the title compound (27) was prepared. MS 549 (MH+).

300

[1803] 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 CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography eluting with 2% CH3OH: saturated with ammonia-CH2Cl2, to afford the title compound (28). MS 519 (MH+).

301

[1804] Dissolved the product from Preparative Example 4, Step F (0.55 g, 1.08 mmole) in 4 N dioxane/HCl (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+).

PREPARATIVE EXAMPLE 5

[1805]

302

[1806] Compound (20) from Preparative Example 3, Step B (0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixtre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2Cl2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid. mp 122.7-123.4° C.; MS 461 (MH+).

EXAMPLE 1

[1807]

303

[1808] Compound (17) from Preparative Example 2, Step E 0.31 g (0.66 mmol) was treated in the same manner as described in Preparative Example 1, Step E to give a mixture of compounds (31) and (32) that were further separated on a HPLC Chiralpack AD column eluting with 30% isopropanol-70% hexane-0.2% diethylamine to give 0.04 g of target compound (31) and 0.07 g of target compound (32).

[1809] Compound 31: mp=174-175; [α]D22=+96.0° (3.6 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

[1810] Compound 32: mp=173-174; [α]D22=+21.7° (8.4 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

EXAMPLE 2

[1811]

304

[1812] As described for preparation of Example 1 above, 0.31 g of compound (18) from Preparative Example 2 Step E was converted to a mixture of compounds (33) and (34) that were subsequently separated on a Chiralpack AD column HPLC eluting with and 30% isopropanol-70% hexane-0.2% diethylamine as eluent to give 0.12 g of target compound (33) and 0.04 g of target compound (34).

[1813] Compound 33: mp=178-179; [α]D22=−30.5° (9.5 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

[1814] Compound 34: mp=172-173; [α]D22=−84° (3.5 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

EXAMPLE 3

[1815]

305

[1816] Product from Preparative Example 2, Step B (0.4 g, 0.86 mmol) was treated in the same manner as described in Preparative Example 1 Step E, substituting homopiperazine (Aldrich), to give of a mixture of compounds 35 and 36 that were further separated by flash chromatography, eluting with 10% CH3OH:saturated with NH3/CH2Cl2 as eluent to give 0.13 g of target compound (35) and 0.17 g of target compound (36).

[1817] Compound (35): mp=116-117; MS (FAB) m/z 487 (MH+).

[1818] Compound (36): mp=111-112; MS (FAB) m/z 487 (MH+).

EXAMPLE 4

[1819]

306

[1820] The ketones of Preparative Example 2, Step D (0.50 g, 1.23 mmol), Histamine® (0.21 g, 1.8 mmol) and p-toluene sulfonic acid (monohydrate) were dissolved in anhydrous toluene (40 mL) and refluxed in a Dean Stark trap apparatus for 24 h. The reaction mixture was then cooled, diluted with ethyl acetate and extracted with NaHCO3. The organic layer was then dried over MgSO4 and concentrated to dryness. Purification by flash chromatography on silica gel, eluting with 3% CH3OH(saturated with NH3)—CH2Cl2, afforded 0.17 g (28% yield) 5-substituted histamine adduct (38) as the first eluting product and 0.08 g (13% yield) of the 6-substituted histamine adduct (37) as the second eluting product.

[1821] Compound (37): mp=124-125; MS (FAB) m/z 498 (MH+).

[1822] Compound (38): mp=119-120; MS (FAB) m/z 498 (MH+).

EXAMPLES (5) AND (6)

[1823] By using the same procedure as above and substituting the appropriate amines, compounds of the formula:

307

[1824] were prepared wherein R is as defined in Table 1 below. In the “Compound #” column, one compound # represents the C5 substitued compound and the other compound # represents the C6 substituted compound.

1TABLE 1ExR =Compound #5

308

(39) AND (40).6

309

(41) AND (42).

EXAMPLE 7

[1825]

310

[1826] To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). The reaction mixture was heated to 90° C. for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2Cl2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH+)

EXAMPLE 8

[1827]

311

[1828] 2-methylimidazole was dissolved in DMF (10 ml). To this was added one equivalent of NaH and the reaction was allowed to stir at room temperature for 1 h.

312

[1829] Following a similar procedure as described in Example 7, substituting 2-methyl imidazoyl sodium (45) for imidazoyl sodium, the racemic mixture of the title compound (46) was prepared. MS 511 (MH+).

EXAMPLE 9

[1830]

313

[1831] Compound (22) was reacted in the same the same manner as Example 8, substituting 4-methylimidazole in Step A, affording a mixture of 4 and 5-methyl substituted imidazole derivatives (47) and (48).

EXAMPLE 10

[1832]

314

[1833] To SEM protected methylimidazole (30 g, 0.141 mole) prepared according to literature procedure, Whiften, J. P., J. Org. Chem. 1986, 51, 1891-1894, in THF (250 ml) at −78° C. was added 2.5 M n-butyl lithium (74 ml, 0.184 mole) over 1 h. The solution was stirred for 1 h at −78° C., then a solution of diphenyl disulfide (34.27 g, 0.155 mole) in THF (125 ml) was added over 1/2 h. The mixture was stirred and warmed to room temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH (5×50 ml) and then brine (50 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCl (100 ml) and stirred for 12 h. at 60° C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2SO4, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes:Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

315

[1834] Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methyl-2-phenylsulfanyl-1H-imidazole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH+).

EXAMPLE 11

[1835]

316

[1836] Compound (27) from PREPARATIVE EXAMPLE 4, STEP E, was treated in the same manner as in Example 9 above to afford a mixture of the 4 and 5-substituted imidazol title compounds (51) and (52).

317

[1837] The compounds from Step A above were further seperated into a mixture of (4 and 5) (+) enantiomers and (4 and 5) (−) enantiomers using preparatory HPLC Chiral AD column, eluting with 20% Isopropanol-Hexane: 0.2% Diethyl amine. MS 532 (MH+). The pure (+) and (−) enantiomeric pairs were then reacted with triphenyl methyl chloride (Aldrich) in CH2Cl2 starting at 0° C. and warming to room temperature over 3 h. The crude product was purified by column chromatography eluting with 50% ethyl acetate-acetone, affording the pure (+) and (−) 4-methyl substituted enantiomers (53A) and (53B); MS 533 (MH+). The column was then flushed with 100% methanol, the fraction was concentrated and the residue was treated with methanol saturated with ammonia, overnight at reflux temperature. The product was purified by column chromatography eluting with 50% ethyl acetate-acetone, affording the pure (+) and (−) 5-methyl substituted enantiomers (54A) and (54B); MS 533 (MH+).

EXAMPLE 12

[1838]

318

[1839] Compound (28) from PREPARATIVE EXAMPLE 4, STEP F, was separated into pure enatiomers by preparatory HPLC using a chiral AD column eluting with 20% Isopropanol:Hexane: 0.2% Diethyl amine to give pure title compounds (55) and (56). MS 519 (MH+).

EXAMPLE 13

[1840]

319

[1841] Compound (29) from PREPARATIVE EXAMPLE 4, STEP G (0.20 g, 0.48 mmole) was dissolved in CH2Cl2 (10 ml). Added triethyl amine (0.30 ml, 1.92 mmole) followed by trimethylsilyl isocyanate (Aldrich) (1.3 ml, 9.6 mmole) and stirred at room temperature over night. Quenched reaction with 1.0 N NaOH and extracted with CH2Cl2. Dried organic layer over MgSO4, filtered and concentrated. Purified by column chromatography eluting with 3-5% Methanol saturated with Ammonia-CH2Cl2, affording the title compound (57) as a white solid. MS 464 (MH+).

EXAMPLES 14 AND 15

[1842] By substituting the appropriate isocyanates, and following the procedure described in EXAMPLE 13 above, compounds of the formula:

320

[1843] were prepared wherein R is defined in Table 2.

2TABLE 2ExR =Compound #:14

321

(58). MS 518 (MH+).15

322

(59). MS 544 (MH+).

EXAMPLE 16

[1844]

323

[1845] Compound (55) was deprotected following the procedure described in PREPARATIVE EXAMPLE 4, STEP G, to give the (+) enantiomer of the starting amine which was then reacted with 4-Chlorophenyl isocyanate (Aldrich) (0.05 g, 0.34 mmole) in the same manner as Example 13 above, affording the title compound (60) as a white solid. MS 572 (MH+).

EXAMPLE 17

[1846]

324

[1847] Compound (56) was deprotected following the procedure described in PREPARATIVE EXAMPLE 4, STEP G to give the (−) enantiomer of the starting amine. Reacting in the same fashion as Example 16 above, afforded the title compound (61) as a white solid. MS 572 (MH+).

EXAMPLE 18

[1848]

325

[1849] Following the procedure described in Example 16, substituting cyclohexyl chloroformate (BASF) in place of the isocyanate, afforded the title compound (62) as a white solid. MS 545 (MH+).

EXAMPLE 19

[1850]

326

[1851] Following the same procedure as described in Example 18 above, substituting the (−) enatiomer of the starting amine from Example 17, afforded the title compound (63) as a white solid. MS 545 (MH+).

PREPARATIVE EXAMPLE 6

[1852]

327

[1853] In a sealed tube, was added ethoxy ethyne (Fluka) followed by tributyltin hydride (Aldrich) and heated to 55° C. for two days. The reaction mixture was then concentrated to a brown red liquid. Purification via distillation afforded the title compound (64) as an off-white liquid. BP range 98°-115° C., (0.35 to 0.2 mmHg).

328

[1854] To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(triphenylphosphine) palladium(II) (Alrich) (0.373 g, 0.53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVE EXAMPLE 6, STEP A. The reaction: stirred over night at 75-80° C. under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (0.93 g, 15.94 mM) in H2O (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2Cl2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2Cl2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3%-1:1% ethyl acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90° C.

329

[1855] To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H2O (33.7 ml/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated KI solution (70-80 ml) and was stirred for five minutes. Added CH2Cl2 and stirred for 1 h. The reaction was extracted with CH2Cl2 (2×100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH+).

330

[1856] To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130° C.; MS 455 (MH+).

331

[1857] Compound (67) from Preparative Example 6, Step D was reacted in the same manner as described in Preparative Example 3, Step C, to afford the title compound (68) as a peach solid.

332

[1858] Compound (68) from Preparative Example 6, Step D (0.1 g, 0.19 mM) was dissolved in THF (2.5 ml). To the mixture was added Lil (Aldrich) (0.064 g, 0.48 mM) and stirred over night at room temperature. The reaction mixture was concentrated, taken up in CH2Cl2 and washed with brine (25 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (69) as a yellow-brown solid.

EXAMPLE 20

[1859]

333

[1860] Compound (68) from Preparative Example 6, Step E, was reacted in the same manner as described in Example 8, Step B, resulting in the title compound (70) as a white solid, mp 94-101° C.

EXAMPLE 21

[1861]

334

[1862] To compound (69) from Preparative Example 6, Step F (0.3 g, 0.05 mM) in CH3CN (1 ml) was added imidazole (Aldrich) (0.014 g, 0.2 mM). The reaction was heated to 52° C. and stirred over night. The reaction was cooled, concentrated, then diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by silica gel column chromatography eluting with 0-5% methanol/saturated with ammonia:CH2Cl2 to afford the title compound (71)as a white solid. mp 95-104° C.; MS 505 (MH+).

EXAMPLE 22

[1863]

335

[1864] Substituting 2-methylimidazole for imidazole and reacting in essentially the same manner as Example 21, the title compound (72) was afforded as a light tan solid. mp 93-104° C.

EXAMPLE 23

[1865]

336

[1866] Compound (71) (0.31 g, 0.06 mM) from Example 21 was dissolved in 4M HCl/Dioxane (0.5 ml) and stirred for 1 h. Concentration of the reaction mixture afforded the title compound (73) as a light yellow solid. mp 195-205° C.

EXAMPLE 24

[1867]

337

[1868] To a solution of compound (73) from Example 23 (0.026 g, 0.05 mM) in CH2Cl2, was added, triethyl amine (Aldrich) (0.046 ml, 0.33 mM) followed by methane sulfonyl chloride (Aldrich) (0.01 ml, 0.1 mM). The reaction stirred at room temperature for 36 h. The reaction was quenched with saturated sodium bicarbonate (50 ml) and extracted with ethyl acetate (2×75 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by preparatory thin layer chromatography eluting with 90:10 CH2Cl2: methanol saturated with ammonia to afford the title compound (74), mp 105-116° C.

EXAMPLE 25

[1869]

338

[1870] Compound (72) from Example 22 was stirred with 4M HCl/Dioxane over 2 h Concentration of reaction mixture afforded the title compound (75) as an off-white solid, mp 185-203° C.

EXAMPLE 26-29

[1871] Reacting compound (75) from Example 25, in the same manner as described in Example 13, and substituting the appropriate isocyanate, compounds of the formula:

339

[1872] were prepared wherein R is defined in Table 3.

3TABLE 3ExR =Compound #:26

340

(76). mp 133-144° C.27

341

(77). mp 131-140° C.28

342

(78). mp 125-132° C.29

343

(79). mp 160-172° C.

EXAMPLE 30

[1873]

344

[1874] A solution of cyclohexanol (Aldrich) (25 ml, 0.2 mol) in CH2Cl2 (50 ml) was added dropwise over 1 h to a solution of phosgene in toluene (262 ml of a 1.93 M solution, 0.5 mol) at 0° C. The reaction was warmed to room temperature over 3 h. and stirred over night. The volatiles were removed to afford the title compound (80) as a colorless liquid.

345

[1875] Reacting compound (75) from Example 25 in the same manner as described in Example 13, substituting the acid chloride (80) from Example 30, Step A in place of the isocyanate, afforded the title compound (81) as an off-white semi-solid. mp 89-98° C.

EXAMPLE 31

[1876]

346

[1877] Reacting compound (75) from Example 25 in the same manner as described in Example 13 but substituting methanesulfonyl chloride in place of the isocyanate, afforded the title compound (82) as a tan semi-solid mp 120-129° C.

EXAMPLE 32

[1878]

347

[1879] Compound (75) was seperated into pure (+) and (−) enantiomers using preparatory chiralpak-AD column chromatography, eluting with 85:15:0.2% 2-propanol:hexane/diethyl amine affording the title compounds (83) and (84) respectively.

EXAMPLE 33

[1880]

348

[1881] Compound (83) was reacted in the same manner as in Example 27 affording the title compound (85) as a white solid. mp 122-129° C.

EXAMPLE 34

[1882]

349

[1883] Compound (84) was reacted in the same manner as in Example 27 affording the title compound (86) as a white solid mp 118-133° C.

EXAMPLE 35

[1884]

350

[1885] Compound (69) from Example 19 was reacted in the same manner as described in Example 21 substituting 4-methylimidazole for imidazole, to afford a mixture of the 4 and 5 substituted imidazole derivatives. The mixture (0.234 g, 0.45 mM) was subsequently treated with trityl chloride (Aldrich) (0.047 g, 0.17 mM) and separated by preparatory thin layer chromatography, eluting with 1:6% ethyl acetate-acetone affording the pure isomers (87) and (88) mp (87) 97-107° C. (white solid).

EXAMPLE 36

[1886]

351

[1887] Compound (87) from Example 35 (0.085 g, 0.16 mM) was reacted in the same manner as described in Example 25. The resulting enantiomeric mixture was then separated by Preparatory Chiralpak-AD column chromatography eluting with 15-85% Isopropanol-Hexane, 0.2% diethylamine, affording enantiomers 1 and 2 as off-white solids.

EXAMPLE 37

[1888]

352

[1889] Enantiomerically pure compound (89) from Example 36 (0.02 g, 0.049 mM) was reacted in a similar manner as in Example 27 to afford the title compound (91) as a white solid. mp 130-142° C.

EXAMPLE 38

[1890]

353

[1891] Enantiomerically pure compound (90) from Example 36 (0.023 g, 0.054 mM) was reacted in a similar manner as in Example 27 to afford the title compound (92). mp 125-135° C.

PREPARATIVE EXAMPLE 7

[1892]

354

[1893] A mixture of piperizinyl compounds (9) and (10) from PREPARATIVE EXAMPLE 1, STEP F in THF at −78° C. was reacted with LDA (1.1 eq.) and stirred for 1.5 h. The mixture was warmed to −20° C. and then N-phenyl trifluoromethane sulfonimide (1.1 eq.) was added. Stirred over night at room temperature then extracted mixture with EtOAc and washed with H2O. Dried over Na2SO4 and concentrated. Purification and separation by flash silica gel column chromatography afforded pure Compounds (93A & 93B).

355

[1894] Compound (93A) from above was dissolved in DMF. Successively added, Et3N (29 eq.), Ethyl acrylate (5.4 eq.), K2CO3 (5 eq.), Bu4NBr (2 eq.) and Palladuim (II) acetate (0.13 eq.). The mixture stirred and heated to 100° C. for 4 h. After cooling, the mixture was concentrated and the residue was taken up in CH2Cl2 and extracted with CH2Cl2/H2O. The organic layer was dried over Na2SO4 then concentrated and the residue purfied by flash silica column chromatography to afford the title compound (94).

356

357

[1895] Compound (94) was dissolved in EtOH cooled in an ice bath and reacted with NaBH4 (15 eq.) for 3 min. Then added CuCl (2 eq) and stirred for 2 h. at room temperature. The mixture was filtered, concentrated and extracted with CH2Cl2. Washed with water then brine, dried over Na2SO4 and concentrated to a mixture of the title compound (95) and the hydroxy compound (96).

358

[1896] Compound (95), was then further reacted with LiBH4(3 eq.) in THF at reflux temperature for 4 h. EtOAc was added and the mixture was washed with Na2CO3 then dried over Na2SO4 and concentrated to afford the title compound (96).

359

[1897] Dissolved compound (96) in CH2Cl2, added Et3N (3 eq.) followed by methane sulfonylchloride (1.5 eq.). The mixture stirred at room temperature over night then diluted with CH2Cl2 and washed with Na2CO3. Dried over NaSO4 and concentrated to afford the title compound (97).

360

361

[1898] To a solution of sodium imidazole (Aldrich) in DMF was added, NaH (2 eq.). 1o Stirred for 15 min. then added compound (97) (from above) (1 eq.) and stirred over night at room temperature. The reaction mixture was concentrated and then extracted with ethyl acetate. Washed with Na2CO3, dried over NaSO4, filtered then concentrated. Crude product was purified by flash silica column chromatography. Further seperation of pure (+) enantiomers and pure (−) enantiomers was accomplished on a chiracel AD column affording the title compounds (98) and (99).

362

363

[1899] Compounds (98) and (99) were individually hydrolyzed to their free amines by refluxing in conc. HCl for 5 h. The reaction mixtures were seperately poured into ice and basified with NH4OH. The solutions were then extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to afford the title compounds (100) and (101).

PREPARATIVE EXAMPLE 8

[1900]

364

[1901] In a similar manner as described in Preparative Example 7, Steps A-G, substituting 2-methylimidazole for sodium imidazole, in Step F, the title compounds (102) and (103) were prepared.

PREPARATIVE EXAMPLE 9

[1902]

365

[1903] Compound (23) from Preparative Example 4 was reacted with piperazine in the same manner as described in Preparative Example 1, Step E, affording the title compound (104).

366

[1904] Compound (104) from above was hydrolyzed with 6N HCl over night at reflux temperature. The cooled reaction mixture was basified with 50% w/w NaOH and then extracted with 80% THF-EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to dryness, affording the title compound (105).

367

[1905] Compound (105) was dissolved in 50:1 MeOH:H2O then added di-tert-butyl dicarbonate (2 eq.). Adjusted pH to 9 and stirred for 4 h at room temperature. The reaction mixture was concentrated and extracted with CH2Cl2. The organic layer was washed with Na2CO3, dried, filtered and concentrated to dryness affording a mixture of title compounds (106) and (107).

368

[1906] To the mixture of compounds (106) and (107) from Step C above, in 80% MeOH/H2O at room temperature was added, cesium carbonate (2 eq.). The reaction stirred overnight. The mixture was then concentrated, extracted with CH2Cl2, washed with H2O, dried over MgSO4, filtered and concentrated to dryness affording the title compound (107).

369

[1907] Compound (107) was reacted with N-phenyl trifluoromethane sulfonimide in a similar manner as described in Preparative Example 7, Step A, affording the title compound (108A & 108B).

370

[1908] Compound (108A) was reacted with ethyl acrylate in a similar manner as described in Preparative Example 7, Step B affording the title compound (109).

371

[1909] Compound (109) was reacted with NaBH4 and CuCl in a similar manner as described in Preparative Example 7, Step C affording the title compound (110).

372

[1910] Dissolved compound (110) in THF and then added 1 M LiAlH4/THF (1 eq.) and stirred for 1.5 h at room temperature. To the mixture was added H2O and 15% NaOH then extracted with EtOAc. The reaction was washed with brine, dried over MgSO4, filtered and concentrated. Purification by flash silica column chromatography eluting with 20% EtOAc/CH2Cl2 afforded the hydroxy title compound (111).

373

[1911] Compound (111) was reacted with methane sulfonyl chloride in a similar manner as described in Preparative Example 7, Step E affording the title compound (112).

374

[1912] Compound (112) was reacted in a similar manner as Preparative Example 7, Step F substituting 4-methylimidazole for sodium imidazole. A mixture of (+,−)4 and (+,−)5-methylimidazoles resulted. The mixture was treated in the same manner as described in Example 11 affording pure stereoisomers (113), (114), (115) and (116).

375

376

[1913] Compounds (113) and (114) were hydrolyzed to their free amines by stirring in HCl/Dioxane for 4 h. The mixtures were then concentrated to dryness affording the title compounds (117) and (118).

PREPARATIVE EXAMPLE 10

[1914]

377

[1915] In a similar manner as described in Preparative Example 9, Steps A-K, substituting 4,5-dimethylimidazole in Step J, the title compounds (119) and (120) were prepared.

EXAMPLE 39-45

[1916] Reacting compounds (100) or (101) from Preparative Example 7, in the same manner as described in Example 13, substituting the appropriate isocyanate or chloroformate, compounds of the formula:

378

[1917] were prepared wherein R is defined in Table 4. In the column “Compound #” one compound # is the (+) isomer and the other compound # is the (−) isomer.

4TABLE 4ExR =Compound #:39

379

(121) AND (122)40

380

(123) and (124)41

381

(125) AND (126).42

382

(127) AND (128).43

383

(129) AND (130).44

384

(131) AND (132).45

385

(133) AND (134).

EXAMPLE 46-51

[1918] Reacting compounds (102) or (103) from Preparative Example 8, in the same manner as described in Example 13, substituting the appropriate isocyanate or chloroformate, compounds of the formula:

386

[1919] were prepared wherein R is as defined in Table 5. In the column “Compound #” one compound # is the (+) isomer and the other compound # is the (−) isomer.

5TABLE 5ExR =Compound #:46

387

(135) AND (136).47

388

(137) AND (138).48

389

(139) AND (140).49

390

(141) AND (142)50

391

(143) AND (144).51

392

(145) AND (146).

EXAMPLE 52-59

[1920] Reacting compounds (117) or (118) from Preparative Example 9, in the same manner as described in Example 13, substituting the appropriate isocyanate, chloroformate or sulfonyl chloride, compounds of the formula:

393

[1921] were prepared wherein R is defined in Table 6. In the column “Compound #” one compound # is the (+) isomer and the other compound # is the (−) isomer.

6TABLE 6ExR =Compound #:52

394

(147) AND (148)53

395

(149) and (150)54

396

(151) AND (152).55

397

(153) AND (154).56

398

(155) AND (156)57

399

(157) AND (158).58

400

(159) AND (160).59

401

(161) AND (162).

EXAMPLE 60-69

[1922] Reacting compounds (119) or (120) from Preparative Example 10, in the same manner as described in Example 13, substituting the appropriate isocyanate, chloroformate or sulfonyl chloride, compounds of the formula.

402

[1923] were prepared wherein R is defined in Table 7. In the column “Compound #” when there are two compounds listed for one example, one compound # is the (+) isomer and the other compound # is the (−) isomer.

7TABLE 7ExR =Compound #:60

403

(163) AND (164)61

404

(165) and (166)62

405

(167) AND (168)63

406

(169) AND (170)64

407

(171) (−)-isomer65

408

(172) AND (173)66

409

(174) AND (175)67

410

(176) AND (177)68

411

(178) AND (179)69

412

(180) AND (181)

PREPARATIVE EXAMPLE 11

[1924]

413

[1925] Ethyl 2,2-dimethyl acrylate (50.0 g, 2.0 eq.) was stirred with imidazole (13.28 g, 200 mmol) at 90° for 48 hours. The resulting solution was cooled, diluted with 300 mL H2O—CH2Cl2 (1:1) and separated. The aqueous layer was extracted with CH2Cl2 (2×75 mL) and the combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by flash chromatography using a 10% MeOH in CH2Cl2 solution as eluent to give pure product as a clear oil. CIMS: MH+=197.

414

[1926] A solution of the title compound from Preparative Example 11, Step A, (10.0 g, 50.96 mmol) was treated with LiAlH4 (51 mL, 1 M solution in ether, 1.0 eq.). The reaction mixture was stirred one hour before quenching by the dropwise additon of saturated Na2SO4 (˜3.0 mL). The resulting slurry was dried with Na2SO4 (solid), diluted with EtOAc (100 mL) and filtered through a plug of Celite. The filtrate was concentrated to give crude product which was used without further purification. CIMS: MH+=155.

415

[1927] Iodine (3.83 g, 1.2 eq.) was added to a solution of Ph3P (3.95 g, 1.2 eq.) and imidazole (1.02 g, 1.2 eq.) in CH2Cl2 (30 mL) portionwise over 15 minutes followed by a solution of the title compound from Preparative Example 11, Step B, (3.83 g, 12.56 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred one hour before concentrating in vacuo. The residue was dissolved in THF (100 mL), treated with KOt-Bu (4.51 g, 3.2 eq.) and stirred at room temperature over night. The reaction mixture was diluted with water (100 mL) and CH2Cl2 (100 mL), separated, and the aqueous layer extracted with CH2Cl2 (2×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography using neat EtOAc then 5% MeOH in EtOAc as eluent to give a pale yellow oil (184).

[1928] CIMS: MH+=137.

416

[1929] Pd(OAc)2 (0.023 g, 10 mol %) was added to a solution of the title compound (184) from Preparative Example 11, Step C, (0.30 g, 2.0 eq.), compound (23)(0.50 g, 1.02 mmol), Bu4NBr (0.66 g, 2.0 eq.), TEA (2.84 mL, 20.eq.) and K2CO3 (0.70 g, 5.0 eq) in DMF (10 mL). The resulting solution was heated to 100° C. for 48 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and CH2Cl2 (50 mL), separated, and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography using an 8% MeOH in CH2Cl2 solution as eluent to yield a 4:1 mixture of the compound (184) and coupled product (185). This mixture (0.27 g) was stirred in CH2Cl2: TFA (7.0 mL, 5:2) for 1.5 hours. The crude product was concentrated under reduced pressure, neutralized with NaOH (1N), and extracted with CH2Cl2 (3×20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography using a 15% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give the title compound (185) as a tan solid. LCMS: MH+=445.

EXAMPLE 70

[1930]

417

[1931] Methanesulfonyl chloride (0.005 mL, 1.3 eq) was added to a solution of Compound (185) from Preparative Example 11, Step D (0.02 g, 0.045 mmol) and TEA (0.010 mL, 1.5 eq.) in CH2Cl2 (1 mL). The resulting solution was stirred 12 hours at room temperature and diluted with saturated NaHCO3 (5 mL), separated, and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using an 8% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give the title compound (186) as a tan solid mp 124-129° C.; LCMS: MH+=523.

EXAMPLE 71

[1932]

418

[1933] pTosNHNH2 (0.085 g, 3 eq) was added to a solution of compound (186) from Example 70 (0.08 g, 0.0153 mmol) and DBU (0.11 mL, 5.0 eq.) in toluene (5 mL) and the resulting solution was heated to reflux. Subsequently, every 2 hours over 6 hours the solution was cooled and additional pTosNHNH2 (3.0 eq) added and the solution heated to reflux. After heating at reflux 2 hours following the final addition the solution was cooled, diluted with CH2Cl2 (25 mL) and washed with saturated NaHCO3 (3×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give the title compound (187) as a tan solid. mp 112-116° C.; LCMS: MH+=525.

PREPARATIVE EXAMPLE 12

[1934]

419

[1935] Literature compound 1H-imidazole-4-carbaldehyde was tritylated according to the literature procedure Kelley, et al.; J. Med. Chem 20(5), (1977), 721 affording the title compound (188).

420

[1936] nBuLi (2.00 mL, 2.2 eq; 1.7M in hexanes) was added dropwise to Ph3PCH3Br (1.4 g, 2.3 eq) in THF (10 mL). The resulting orange solution was stirred 30 minutes at room temperature before cooling to −78° C. and adding the trityl protected 1(3)H-imidazole-4-carbaldehyde (0.50 g, 1.48 mmol) in THF (7.0 mL). The resulting solution was warmed slowly to room temperature and stirred overnight. The reaction was quenched by the addition of water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a 45% hexanes in EtOAc solution as eluent to yield the title compound (189) as a white solid.

421

[1937] Pd(OAc)2 (0.021 g, 0.10 eq.) was added to a solution of compound (12) from Preparative Example 2, Step B (0.44 g, 0.95 mmol), compound (189) from Preparative Example 12, Step B (0.32 g, 1.0 eq.), Bu4NBr (0.61 g, 2.0 eq.), and K2CO3 (0.66 g, 5.0 eq.) in DMF (8.0 mL). The resulting solution was heated to 100° C. over night, cooled, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and CH2Cl2 (50 mL), serparated, and the aqueous layer extracted with CH2Cl2 (2×50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using 100% EtOAc as eluent. LCMS: 723 (MH+).

EXAMPLE 72

[1938]

422

[1939] To a solution of the title compound from Preparative Example 12, Step C (1.43 g, 1.97 mmol) in water (70 mL) was added AcOH (70 mL). The resulting solution was heated at reflux two hours, cooled to room temperature and neutralized by the dropwise addition of 50% (w/w) NaOH. The solution was then extracted with CH2Cl2 (3×200 mL) and the combine organics were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent. mp=190° C. (dec.); LCMS: MH+=483.

EXAMPLE 73

[1940]

423

[1941] The title compound (191) from Example 72 was separated into individual (+)- and (−)-enantiomers by preparative HPLC using a ChiralPak AD column eluting with 70:30 hexanes: iPrOH containing 0.2% diethylamine as eluent. Compound (192): FABMS: MH+=481; mp=109-112° C.; [α]20D=+398° (2.0 mg in 2.0 mL MeOH).

[1942] Compound (193): FABMS: MH+=481; mp=126-129° C.; [α]20D=−3670 (2.0 mg in 2.0 mL MeOH).

EXAMPLE 74

[1943]

424

[1944] The title compound (191) from Example 72 was dissolved in toluene (50 mL) and DBU (0.26 mL, 5.0 eq.) and pTosNHNH2 (0.33 g, 3.3 eq.) were added. The resulting solution was heated to reflux 2.5 hours before cooling to room temperature and adding additional pTosNHNH2 (0.33 g, 3.3 eq.). The reaction mixture was heated at reflux for an additional 2 hours and cooling to room temperature. The resulting solution was diluted with saturated NaHCO3 (100 mL) and extracted with CH2Cl2 (3×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give pure product (194). mp=158-162; LCMS: MH+=483.

EXAMPLE 75

[1945]

425

[1946] In a similar manner as described in Example 73 above, the following enantiomers were separated:

[1947] Compound (195): LCMS: MH+=483; mp=129-131° C.; [α]20D=+1340 (2.0 mg in 2.0 mL MeOH).

[1948] Compound (196): LCMS: MH+=483; mp=125-126° C.; [α]20D=−1050 (2.0 mg in 2.0 mL MeOH).

PREPARATIVE EXAMPLE 13

[1949]

426

[1950] Imidazole (2.50 g, 36.72 mmol) and basic alumina (15 g) were combined and shaken 15 minutes before adding propargyl chloride (2.66 mL, 1.0 eq.). The resulting mixture was stirred 84 hours and suspended in EtOAc. The slurry was filtered and the filtrate was washed with H2O and brine and dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give a clear oil.

EXAMPLE 76

[1951]

427

[1952] A solution of compound (23) (0.50 g, 1.02 mmol) and compound (197) from Preparative Example 13 (0.22 g, 2.0 eq.) in TEA (3.0 mL) and pyridine (0.5 mL) was deoxygenated 15 minutes before adding PdCl2(PPh3)2 (0.018 g, 2.5 mol %) and CuI (0.002 g, 1.0 mol %). The resulting solution was heated for 48 hours. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using an 8% MeOH in CH2Cl2 solution as eluent. mp 109-112° C.; LCMS: 515 (MH+).

PREPARATIVE EXAMPLE 14

[1953]

428

[1954] Compound (21) from Preparative Example 3, Step C, (2.83 g, 6.37 mmol) was dissolved in 120 ml of dichloromethane and 0.16 ml of de-ionized water. Dess-Martin periodinane (3.85 g, 9 mmol) was added as a solid at ambient temperature and the reaction mixture stirred for 4 hours. Then added a 20% Na2S2O3 solution (50 ml) and stirred for 15 minutes. The layers were separated and the dichloromethane layer washed with saturated NaHCO3, dried over magnesium sulfate, filtered and evaporated to obtain the title product (199). FABMS: 445 (MH+).

429

[1955] 4-Iodo-1-trityl-imidazole (prepared according to the literature procedure Kirk, Kenneth L.; J. Heterocycl. Chem.; EN; 22; 1985; 57-59) (0.48 g, 1.1 mmol) was dissolved in 5 ml of dichloromethane under a dry nitrogen atmosphere. Ethylmagnesium bromide (0.36 ml). was added and the reaction mixture stirred. After 30 minutes compound (199) (0.44 g, 1 mmol) was dissolved in 5 ml of dichloromethane and added to the reaction mixture while stirring. After stirring 4 hours at ambient temperature, the mixture was washed with saturated ammonium chloride solution, dried over magnesium sulfate, filtered, and evaporated to give a solid residue. The product was chromatographed on a flash silica gel column using ethyl acetate as the eluent to obtain the title compound (200). FABMS: 756 (MH+).

EXAMPLE 77

[1956]

430

[1957] Compound (200) (0.6 gm) was dissolved in 10 ml of trifluoroacetic acid and stirred at ambient temperature. After 7 hours the reaction mixture was evaporated to dryness under vacuum and chromatographed on silica gel using 5% 2N methanol:ammonia/dichloromethane to obtain title compound (201). FABMS: 514 (MH+).

PREPARATIVE EXAMPLE 15

[1958]

431

[1959] Compound (200) (0.5 g, 0.66 mmol) was dissolved in 5 ml of dichloromethane. Triethylamine (0.14 ml, 0.99 mmol) and methanesulfonyl chloride (0.062 ml, 0.79 mmol) were added and the reaction mixture stirred for 18 hours. The reaction mixture was added to brine and extracted with dichloromethane three times. Dried over magnesium sulfate, filtered and concentrated to dryness under vacuum to give a residue which was chromatographed on silica gel using ethyl acetate as the eluent to obtain the title compound (202). FABMS: 537 (MH+).

432

[1960] Compound (202) was detritylated in the same manner as EXAMPLE 77 affording the title compound (203). FABMS: 495 (MH+).

EXAMPLE 78

[1961]

433

[1962] Compound (203) (77 mg) was hydrogenated over PtO2 in ethanol at atmospheric hydrogen for 24 hours. After filtration of the catalyst followed by evaporation of the ethanol and chromatography on a Chiral Technologies® AD HPLC column the title product was obtained as two pure enantiomers (205) and (206). FABMS: 497 (MH+).

PREPARATIVE EXAMPLE 16

[1963]

434

[1964] Compound (200) (0.15 g, 0.198 mmol) was dissolved in 4 ml of dichloromethane and 5 uL of de-ionized water. Dess-Martin periodinane (0.12 g, 0.3 mmol) was added and the reaction mixture stirred for 4 h. 5 ml of a 20% Na2S2O3 solution was added and the reaction mixture stirred for another 15 minutes. The layers were separated and the dichloromethane layer was washed with saturated NaHCO3, dried over magnesium sulfate, filtered and evaporated to obtain the title compound (207). FABMS: 753 (MH+).

EXAMPLE 79

[1965]

435

[1966] Compound (207) was detritylated in the same manner as Example 77 affording the title compound (208). FABMS: 511 (MH+).

PREPARATIVE EXAMPLE 17

[1967]

436

[1968] Compound (207) (0.15 g, 0.2 mmol) was dissolved in 5 ml of tetrahydrofuran. Ethylmagnesium bromide (0.1 ml, 3 M in ether) was added at ambient temperature and stirred under a dry nitrogen atmosphere. After 2 hours, added another portion of ethylmagnesium bromide (0.1 ml, 3 M in ether). After 4 hours the reaction mixture was washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and evaporated to obtain the title compound (209). The product was further purified by flash silica column chromatography eluting with 50% ethylacetate/hexanes. FABMS: 783 (MH+).

EXAMPLE 80

[1969]

437

[1970] Compound (209) was detritylated in the same manner as Example 77 affording the title compound (210). FABMS: 541 (MH+).

PREPARATIVE EXAMPLE 18

[1971]

438

[1972] Compound (211) (14 g, 29 mmol) prepared by NaOH hydrolysis of Compound (20) from Preparative Example 3, Step B, was dissolved in 400 ml of DMF. 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (8.3 g,-43 mmol), 1-hydroxybenzotriazole (5.9 g, 43 mmol), triethylamine (40 ml), and N,O-dimethylhydroxylamine hydrochloride(3.8 g, 40 mmol) were added and the reaction mixture stirred at room temperature under a dry nitrogen atmosphere. After 24 hours the reaction mixture was poured into brine and the product extracted with ethylacetate two times. After drying over magnesium sulfate, filtration, and chromatography on silica gel using 10% ethyl acetate/hexanes the title compound (212) was obtained.

439

[1973] Compound (212) (0.53 g, 1.01 mmol) was treated as in PREPARATIVE Example 14, Step B to obtain the title compound (213) after silica gel chromatography.

EXAMPLE 81

[1974]

440

[1975] Compound (213) (300 mg, 0.387 mmol) was dissolved in methanol and sodium borohydride (50 mg) was added portionwise while stirring. After 1 hour the mixture was added to 1N HCl followed by the addition of 1N NaOH and extracted with ethylacetate to obtain a crude product which was treated with neat trifluoroacetic acid for 5 hrs, and evaporated to dryness. The mixture was dissolved in methanol and reacted with di-tert.butyldicarbonate (0.2 gm) while maintaining the pH at 10 with 1N NaOH for 1 hour. The mixture was then treated with 2N Methanolic ammonia for 15 minutes followed by evaporation of the solvents and chromatography on silica gel. Further seperation of isomers was accomplished on a Chiral Technologies® AD HPLC column obtaining the pure isomers. (214) and (215). FABMS M+1=535

EXAMPLE 82

[1976]

441

[1977] Compound (23) from Preparative Example 4, Step A (25.47 gm, 52 mmol) was dissolved in 300 ml of dry toluene and 39.5 ml of methanol. Palladium chloride (0.92 gm), triphenylphosphine (6.887 gm) and DBU (10.5 ml) were added and the reaction mixture transferred to a pressure reaction vessel. The reaction vessel was purged with carbon monoxide and then pressurized to 100 psi with carbon monoxide and the mixture stirred at 80° C. for 5 hours. The reaction was cooled in an ice bath and purged with nitrogen 34 times. The reaction mixture was transferred to a separatory funnel and 500 ml of ethylacetate was added. The mixture was washed with water three times, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give a dark brown gum. The gum was purified by column chromatography on silica gel using 12.5%-25% ethylacetate/hexanes to obtain 12.58 gm of pure title product (216) FABMS: 469 (MH+) and 9.16 gm of a mixture of two compounds.

PREPARATIVE EXAMPLE 19

[1978]

442

[1979] Compound (216) from Example 82 (5.16 gm, 11 mmol) was dissolved in methanol (150 ml). 10% lithium hydroxide (2.9 ml) was added along with dioxane (50 ml) and the reaction stirred for 4 hours. Added an additional portion of 10% lithium hydroxide (5.7 ml) and the reaction stirred for 18 hours. The reaction mixture was concentrated to s small volume and diluted with 50 ml of water The mixture was acidified to pH=3 with 10% citric acid and the product extracted with dichloromethane to obtain the title compound (217). FABMS: 455 (MH+)

PREPARATIVE EXAMPLE 20

[1980]

443

[1981] Compound (65) from Preparative Example (6), Step B, was let stand for approximately two weeks at room temperature, after which time the pressence of some aldehyde was observed by NMR of the crude material. This material was then treated as in Preparative Example 6, Steps C and D to afford a mixture of Compounds (218) and (67). The crude mixture was separated on flash silica column chromatography eluting with 1:1-3:1 ethyl acetate:hexanes to afford pure Compound (218).

444

[1982] Compound (218) from Step A above, was combined with triethylamine (64.4 ml; 0.462 mmol) in CH2Cl2 (4 ml) treated with methyl sulfonyl chloride (17.93 ml; 0.231 mmol) and let stir over night at room temperature. The reaction mixture was diluted with CH2Cl2 (70 ml), quenched with brine (25 ml) and extracted. The organic layer was dried over MgSO4, filtered and concentrated to give an off-white solid (219) (93 mg; 100%).

445

[1983] Compound (219) from Step B above, was taken up in DMF. To this solution was added a previously reacted solution of 2-methylimidazole (145.27 mg; 1.734 mmol) and NaH (60%) (69.4 mg; 1.734 mmol) in DMF. The reaction mixture was allowed to stir at room temperature for two hours. The DMF was removed and the. residue taken up in CH2Cl2 quenched with sat. aqueous NaHCO3 and extracted with 2×100 ml CH2Cl2. The organic layers were combined and purified by preparative TLC plates to give an off-white solid. (220)

446

[1984] Compound (220) from Step C above, was dissolved in 1,4-Dioxane (3 ml). To this solution was then added 4M HCl in Dioxane (5 ml) and the reaction stirred for 3 hours at room temperature. The mixture was then concentrated and dried over night under high vacuum to afford the hydrochloride salt as an off-white solid. (221)

EXAMPLE 83

[1985]

447

[1986] To a solution of compound (221) from Preparative Example 20, Step D (51 mg;

[1987] 0.126 mmol) and triethylamine (61.47 ml; 0.441 mmol) in CH2Cl2 (2 ml) was added 4-trifluoromethylphenyl isocyanate (20.26 ml; 0.139 mmol) at 0° C. The reaction stirred for 2-3 hours under N2 atmosphere. The CH2Cl2 and excess triethylamine were removed under vacuo and the resultant product was purified by preparatory thin layer chromatography eluting with 98:2 CH2Cl2/(sat.)MeOH/NH3) affording the title compound as a white solid (222).

PREPARATIVE EXAMPLE 21

[1988]

448

[1989] Commercially available Ethyl 4-Pyridyl Acetate (4.5 g; 27.2 mmol), EtOH (70 ml) and 10% Palladium on Charcoal (catalytic) was shaken under 55 psi hydrogen at room temperature for 94 hrs. The mixture was filtered through Celite and the cake was washed with (4×40 ml) of EtOH. The filtrate was concentrated and purified by flash silica column chromatography eluting with 3% (10% NH4OH:MeOH)/CH2Cl2.

449

[1990] 4-Pyridyl Acetic Acid (2.362 g) from Step A above, was taken up in CH2Cl2 (118 ml). To this was added trimethylsilyl isocyanate (27.87 ml). The reaction stirred for 67 hr then was diluted with CH2Cl2 (700 ml) and washed with saturated aqueous NaHCO3 (150 ml). The aqueous layer was extracted with 2×200 ml CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by flash silica column chromatography eluting with 2% (10% NH4OH:MeOH)/CH2Cl2.

450

[1991] Product from Step B above (40.63 mg; 0.1896 mmol) was taken up in EtOH (2 ml) and CH2Cl2 (2 ml) and treated with 1 M LiOH (0.5 ml; 0.455 mmol). The reaction mixture was heated to 50° C. and stirred for 5 hr. The reaction was cooled to room temperature treated with 1N HCl (0.57 ml; 0.531 mmol) and stirred for 5 minutes. The resultant mixture was concentrated and dried under high vacuum for 4 days affording the title compound as a white solid. (223)

EXAMPLE 84

[1992]

451

[1993] To a solution of Compound (221) from Preparative Example 20, Step D (51 mg; 126 mmol), 4-methylmorpholine (69.3 ml; 0.630 mmol), DEC (31.44 mg; 0.164 mmol), and HOBT (22.2 mg; 0.164 mmol) in DMF (2 ml) was added, 4-Pyridylacetic Acid 1-N-Oxide (disclosed in U.S. Pat. No. 5,719,148; Feb. 17, 1998). The reaction stirred for 3 hours at room temperature. The reaction was diluted with CH2Cl2 and washed two times with saturated aqueous NaHCO3. The organic layers were combined, concentrated and purified by preparative thin layer chromatography eluting with 95:5 CH2Cl2: sat. MeOH/NH3 affording the title compound as a white solid (224).

EXAMPLE 85

[1994]

452

[1995] Compound (221) from Preparative Example 20, Step D (51 mg; 0.126 mmol) was combined with compound (223) from Preparative Example 21, Step C and reacted in the same manner as Example 84 to afford the title compound as a white solid. (145-155° C. dec.) MH+ 573.(225)

EXAMPLE 86

[1996]

453

[1997] Compound (221) from Preparative Example 20, Step D (51 mg; 0.126 mmol) was combined with 4-Fluorophenylacetic acid (Acros) (29.29 mg; 0.190 mmol) and reacted in the same manner as Example 84 to afford the title compound as an off-white solid. (108-125° C. dec.) MH+ 541.(226)

PREPARATIVE EXAMPLE 22

[1998]

454

[1999] Compound (220) from Preparative Example 20, Step C, (150 mg; 0.289 mmol) was treated with 4M HCl in Dioxane and allowed to stir for 2-3 hr at room temperature under a N2 atmosphere. The crude mixture was separated into pure (+) isomer (227) and (−) isomer (228) by preparative chiral HPLC using an AD column, eluting with 85:15:2 Hexanes:IPA:DEA.

EXAMPLES 87-90

[2000] The appropriate (+) compound (227) or (−) compound (228) isomer from Preparative Example 22 above, was taken up in CH2Cl2 treated with the corresponding isocyanate and stirred at room temperature over night. Crude product was purified directly by preparative thin layer chromatography to afford compounds (229-232):

455

[2001] wherein R is as defined in Table 8.

8TABLE 8Ex.RCompound #87

456

(229)(+)(148-156° C. dec.) MH+ 556.88

457

(230)(+)(155-166° C. dec.) MH+ 563.89

458

(231)(−)(145-153° C. dec.) MH+ 556.90

459

(232)(−)(159-168° C. dec.) MH+ 563.

PREPARATIVE EXAMPLE 23

[2002]

460

[2003] The tricyclic keto-compound (disclosed in U.S. Pat. No. 5,151,423) (30.0 g; 123.2 mmol) was combined with NBS (48.2 g; 271.0 mmol) and benzoyl peroxide (0.42 g) in CCl4 (210 ml). The reaction was heated to 80° C. for 10 hr. The mixture was cooled and let stand for 8 hr. The resulting precipitate was filtered. Added MeOH (200 ml) and stirred the mixture over 2 days. The solid was filtered and dried under vacuum to a constant weight.

461

[2004] The dibromo compound (233) from Step A (35.72 g; 88.97 mmol) above was dissolved in CH2Cl2 (1.5 L) and cooled to 0° C. Dropwise, DBU (15.96 ml) was added and the suspension stirred for 3 hr. The reaction mixture was concentrated redissolved in CH2Cl2 (1.5 L) filtered through a bed of silica gel and rinsed with 5% EtOAc/CH2Cl2 (4 L). The combined rinses were concentrated and purified by flash silica gel column chromatography into pure 5 and 6 mono-bromo substituted compounds eluting with 10-30% EtOAc/Hex then 3%EtOAc/CH2Cl2.

462

[2005] The 5-bromo substituted compound (234a) from Step B above (4.0 g; 12.45 mmol) was taken up in MeOH and cooled to 0° C. NaBH4 (916.4 mg; 24.2 mmol) was added and the reaction mixture stirred for 5.5 hr. The solvent was removed and the resulting residue was used directly.

463

[2006] The alcohol compound (235) from Step C above (3.98 g; 12 mmol) was dissolved in CH2Cl2 cooled to 0° C. and treated with 2,6-Lutidine (5.73 ml; 49 mmol). SOCl2 (1.8 ml; 24.6 mmol) was added and the reaction was allowed to stir and come to room temperature over 3 hr. The reaction mixture was poured into 0.5 N NaOH (80 ml) extracted and concentrated in vacuo. The crude product was taken up in CH3CN and treated with 1,2,2,6,6-Pentamethylpiperidine (4.45 ml; 24.6 mmol) (Aldrich). The reaction was heated to 60-65° C. treated with tert-butyl 1-piperazinecarboxylate (2.32 g; 12 mmol) (Aldrich) and stirred over night under N2 atmosphere. The reaction mixture was concentrated to dryness, redissolved in CH2Cl2 and washed with sat. aqueous NaCO3. The organic layer was dried over Na2SO4, filtered and purified by flash silica gel column chromatography eluting with 1:4-1:2 EtOAc/Hexanes to afford the product as a white solid.

464

[2007] The BOC-protected bromo-compound (236) from Step D above (2 g; 4 mmol), triphenyl phosphine (0.54 g; 2 mmol), and palladium chloride (0.0723 g; 0.4 mmol) were combined in MeOH (10 ml) and toluene (30 ml). To this mixture was added DBU (0.835 ml; 5.5 mmol) and the mixture was sealed in a Parr bomb. The reaction mixture was stirred and subjected to 90 psi of CO at 80° C. for 5 hr. The reaction was diluted with EtOAc (200 ml) and washed with 2×80 ml H2O. The organic layer was dried over MgSO4, filtered and purified by flash silica column chromatography eluting with 1:3 EtOAc/Hexanes.

465

[2008] Compound (237) from Step E above (1.73 g; 3.681 mmol) was treated with 4 M HCl in Dioxane (35 ml) and allowed to stir at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the resulting tan solid was further dried under high vaccuum.

466

[2009] The HCl salt (238) from Step F above (1.36 g; 3.68 mmol) was dissolved in THF, cooled to 0° C., treated with 1 M DIBAL in cyclohexane (18.41 ml; 18 mmol) and stirred over night at room temperature. The mixture was concentrated to dryness and used directly in the next step.

467

[2010] The alcohol (239) from Step G above was taken up in MeOH (50 ml) and H2O (5 ml) and treated with Boc anhydride (1.56 g; 7.14 mmol). The pH was adjusted to approximately 10 with 1N NaOH. The reaction mixture was concentrated, taken up in CH2Cl2 and washed with H2O (2×). The organic layer was dried over MgSO4, filtered and concentrated to a tan solid containing both product and an impurity.

[2011] Alternatively, compound (237) was converted to compound (240) by first preparing the acylimidazole followed by NaBH4 reduction using the following procedure:

[2012] Compound (237) from Step E above (7.0 mmol) was dissolved in a mixture of 15 mL methanol, 60 mL dioxane and 6 mL water containing 25 mL of 10% aqueous LiOH. The mixture was heated at 60° C. for 4 hr, then it was concentrated under vacuum and the pH adjusted to 5.2 with 10% aqueous citric acid. The residue was dissolved in CH2Cl2, washed with brine, dried over MgSO4 and concentrated under vacuum to give the carboxylic acid. The acid was then dissolved in 20 mL THF containing 14 mmol of 1,1′-carbonyl diimidazole and heated at 38° C. for 18 hr. The mixture was then concentrated under vacuum to give the acylimidazole. The residue was dissolved in a mixture of 21.2 mL of THF and 5.3 mL water and cooled to 0° C. To the solution was added 35 mmol of NaBH4 and it was stirred for 1.5 hr. 5 mL brine and 25 mL CH2Cl2 was then added. The organic layer was dried over MgSO4 and concentrated under vacuum to give compound (240) in essentially a quantitative yield.

468

[2013] The crude product (240) from Step H above (200 mg; 0.45 mmol) was taken up in CH2Cl2 (2 ml) and treated with triethyl amine (126 ml; 0.91 mmol) followed by methanesulfonyl chloride (35 ml; 0.45 mmol). The reaction stirred over night at room temperature. The mixture was diluted with CH2Cl2 and quenched with sat. aqueous NaCl. The organic layer was dried over MgSO4, filtered and concentrated to afford compound (241).

EXAMPLE 91

[2014]

469

[2015] The mesylate compound (241) from Preparative Example 23, Step I above (230 mg; 0.442 mmol) was reacted in the same manner as Preparative Example 20,

[2016] Step C. Purification of the crude product was accomplished by preparative TLC plates eluting with 95:5 CH2Cl2/MeOH(NH3) followed by 1:1 EtOAc:Hexanes to afford the title compound as a light tan solid (242) 105-116° C. (dec) MH+ 506.

PREPARATIVE EXAMPLE 24

[2017]

470

[2018] NaCN and 3-Phenylpropionaldehyde (ACROS) were dried overnight under vacuum. The aldehyde was then passed through activated Al2O3. Tosylmethyl isocyanide (5 g, 25.6 mmol) (ACROS) and dry 3-Phenylpropionaldehyde (3.36 g; 25.1 mmol) were combined in EtOH (42 ml) and stirred for 5 minutes. To the turbid mixture was added the dry NaCN (1.23 g; 25.1 mmol). An exothermic reaction was observed and after 5 minutes TLC showed consumption of starting material. The reaction was transferred to a sealed tube and used directly in the next experiment.

471

[2019] The crude product (243) from Step A above (25 mmol), was diluted up to 65 ml total volume with EtOH. To this mixture was added 7N NH3 in MeOH (100 ml) and the reaction was heated to 90° C. over night (20 hr). The reaction was allowed to cool to room temperature and stirred for 2 hr then concentrated to dryness. The crude product was purified by flash silica column chromatoghraphy eluting with a gradient of 1-5% MeOH(sat. NH3)/CH2Cl2 (244).

PREPARATIVE EXAMPLE 25

[2020]

472

[2021] Propionaldehyde (1.5 g; 25.11 mmol) (ACROS) and tosylmethyl isocyanide (5 g; 25.6 mmol) were reacted in the same manner as Preparative Example 24 above to afford the title compound (245).

PREPARATIVE EXAMPLE 26

[2022]

473

[2023] The (+) isomer of compound (67) from Preparative Example 6 isolated by chiral AD column chromatography was further reacted as in Preparative Example 6 to obtain compound (246).

EXAMPLE 92 AND 93

[2024]

474

[2025] Compound (246) from Preparative Example 26 above was reacted in the same manner as Examples (22), (25) and (29) using the appropriate imidazole or isocyanate respectively to afford the title compounds (247) and (248).

EXAMPLES 94-96

[2026] In a similar manner as Preparative Example 26 above, the (+) isomer of the carbamate was obtained and reacted in essentially the same manner as Examples 92 and 93 substituting with the appropriate imidazoles, to provide compounds (249)-(251) of the formula:

475

[2027] wherein R is defined in Table 9. In Table 9, “Cmp.#” represents “Compound #”.

9TABLE 9Ex.R =Cmp. #Phys. Data94

476

249mp 133.2-144.3° C. dec. MH(+) 577.1495

477

250mp 132.1-143.8° C. dec. MH(+) 591.1696

478

251mp 134.1-144.9° C. dec. MH(+) 563.10

EXAMPLES 97-101

[2028] In essentially the same manner as in Preparative Example (20) and Example (29), compounds of the formula:

479

[2029] were prepared wherein R is as defined in Table 10. In Table 10, “Cmp.#” represents “Compound #”.

10TABLE 10EX.R =Cmp #PHYS. DATA97

480

252mp 148-159° C. dec. MH(+) 577.98

481

253mp 134-142° C. dec. MH(+) 563.99

482

254mp 90-102° C. dec. MH(+) 625.100

483

255mp 126-139° C. dec. MH(+) 577.101

484

256mp 151-164° C. dec. MH(+) 535.

EXAMPLE 102

[2030]

485

[2031] The (+) isomer of compound (218) obtained in essentially the same manner as Preparative Example (22), was further reacted in the same manner as in Preparative Example (6), Steps E and F, Examples (21), (23) and (29) sustituting with 2-Ethyl imidazole in Ex. (21) to afford the title compound (257). (146-157° C. dec.), MH+ 564

PREPARATIVE EXAMPLE 27

[2032]

486

[2033] In essentially the same manner as Preparative Example (20), substituting 4-methylimidazole, compound (258) was prepared as a mixture of 4 and 5 substituted imidazole derivatives. This mixture was then reacted in a similar manner as Example 35 and the isomers separated (258A) and (258B).

EXAMPLE 103

[2034]

487

[2035] The pure 4-methylimidazole isomer (258A) was reacted as in Preparative Example 20, Step D, and Example (29) to afford the title compound as a white solid (259). (128-138° C. dec.) MH+ 549

EXAMPLE 104

[2036]

488

[2037] Step A

[2038] Compound (108) from Preparative Example 9, Step E, was reacted with compound (64) from Preparative Example 6, Step A in essentially the same manner as in Preparative Example 6, Steps B-F, to afford a mixture of one and two methylene spaced iodo intermediates.

[2039] Step B

[2040] The mixture of intermediates from Step A above was reacted in essentially the same manner as in Example 22 to afford a mixture of one and two methylene spaced imidazole derivatives.

[2041] Step C

[2042] The mixture from Step B above was reacted in the same manner as Preparative Example 20, Step D, followed by a reaction with phenyl isocyante in the same manner as Example 15 to afford the title compound as a 1:1 mixture (260a) and (260b) (133-145° C. dec.); MH+ 544

PREPARATIVE EXAMPLE 28

[2043]

489

[2044] Ref: Gazz. Chim. Ital. (1972) 102, 189-195; J. Org. Chem. (1991) 56, 1166-1170.

[2045] Ethyl nipecotate (70.16 g, 0.446 mmol) and D-tartaric acid (67 g, 1.0 eq) were dissolved in hot 95% EtOH (350 mL). The resulting solution was cooled to room temperature and filtered and the crystals washed with ice-cold 95% EtOH. The crystals were then recrystallized from 95% EtOH (550 mL) to give the tartrate salt (38.5 g, 56% yield). The salt (38.5 g) was dissolved in water (300 mL) and cooled to 0° C. before neutralizing with 3M NaOH. The solution was extracted with CH2Cl2 (5×100 mL) and the combined organics dried over Na2SO4 and concentrated under reduced pressure to give a clear oil (19.0 g, 89% yield). CIMS: MH+=158.

490

[2046] LAH (118 mL, 1.0 M in Et2O, 1.0 eq.) was added to a solution of the product from Step A (18.5 g, 0.125 mmol) in THF (250 mL) at 0° C. over 20 minutes. The resulting solution was warmed slowly to room temperature and then heated at reflux 2 hours. The reaction was cooled to room temperature and quenched by the slow addition of saturated Na2SO4. The resulting slurry was dried by the addition of Na2SO4, filtered through Celite and concentrated to give a colorless oil (13.7 g, 98% crude yield). CIMS: MH+=116; [α]20D=−8.4° (5.0 mg in 2 mL MeOH).

491

[2047] The product of Step B (13.6 g, 0.104 mmol) was dissolved in MeOH (100 mL) and H2O (100 mL) di-tert-butyl dicarbonate (27.24,1.2 eq.) was then added portionwise keeping the pH>10.5 by the addition of 50% NaOH. The reaction mixture was stirred at room temperature an additional 2.5 hours and concentrated in vacuo. The residue was diluted with H2O (350 mL) and extracted with CH2Cl2 (3×150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50% EtOAc in hexanes solution as eluent to give a white solid (12.13 g, 48% yield). FABMS: MH+=216; [α]20D=+15.2 (5.0 mg in MeOH).

492

[2048] p-Toluenesulfonyl chloride (12.75 g, 1.2 eq.) was added portionwise to a solution of the product from Step C (12.00 g, 55.74 mmol) in nvridine (120 mL) at 0° C. The resulting solution was stirred at 0° C. overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with cold 1N HCl (5×300 mL), saturated NaHCO3 (2×150 mL), H2O (1×100 mL), and brine (1×100 mL), dried over Na2SO4 and concentrated in vacuo to give a pale yellow solid (21.0 g, 100% crude yield). FABMS: MH+=370.

493

[2049] The product of Step D (21.0 g, 55.74 mmol) in DMF (300 mL) was treated with sodium imidazole (8.37 g, 1.5 eq.) and the resulting solution heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with H2O (300 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 7% MeOH in CH2Cl2 solution as eluent to give a pale yellow solid (7.25 g, 49% yield). FABMS: MH+=266; [α]20D=+8.0 (5.0 mg in MeOH).

494

[2050] The product of Step E (5.50 g, 20.73 mmol) was stirred at room temperature in 4M HCl in dioxane (50 mL) overnight. The resulting solution was concentrated and the residue triturated with Et2O to give Compound (261) as a yellow solid (4.90 g, 99% yield). CIMS: MH+=166.

PREPARATIVE EXAMPLE 29

[2051]

495

[2052] By essentially the same procedure set forth in Preparative Example 28 above, using L-tartaric acid instead of D-tartaric acid in Step A, Compound (262) was prepared.

PREPARATIVE EXAMPLE 30

Preparation of Compounds (263) and (264)

[2053]

496

[2054] 3(R)-(3-Methanesulfonyloxymethyl)pyrrolidine (J. Med. Chem. 1990, 33, 77-77) (0.993 g, 3.56 mmoles) was dissolved in anhydrous DMF (25 mL) and sodium imidazole (0.6 g, 10 mmoles) was added. The mixture was heated at 60° C. for 2 h and then evaporated to dryness. The product was extracted with CH2C;2 and washed with brine. The CH2Cl2 extract was evaporated to dryness to give the titled compound (263) (1.1409 g, 100%), ESMS: FABMS (M+1)=252; 1HNMR (CDCl3) 1.45 (s, 9H), 1.5-1.7 (m, 1H), 1.9-2.1 (m, 1H), 2.5-2.7 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.6 (m, 2H), 3.9 (dd, 2H), 6.9 (s, 1H), 7.1(s, 1H), 7.45 (s, 1H)

[2055] In a similar manner, the (S) isomer was prepared from 3(S)-(3-methanesulfonyloxymethyl)pyrrolidine (0.993 g, 3.56 mmol) to give the title compound (1.14 g, 100%).

497

[2056] The (R) product (0.48 g, 1.91 mmoles) from Step A was stirred in 4N HCl in dioxane (10 mL) for 2 h and then evaporated to dryness to give the title compound (263) as the HCl salt.

[2057] In a similar manner the (S) isomer was prepared to give compound (264) as the HCl salt.

PREPARATIVE EXAMPLE 31

[2058]

498

[2059] 1N-Benzyl-3(R)-hydroxy-pyrrolidines (5 g, 28.21 mmol) and triethylamine (7.86 mL, 56.35 mmol) were dissolved in CH2Cl2 (50 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (2.62 mL, 33.87 mmol) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the (R) title compound (7.2 g, 96.4%). FABMS (M+1)=256; 1HNMR (CDCl3) 2.2 (m, 1H), 2.3 (m, 1H), 2.52 (m, 1H), 2.7-2.85 (m, 3H), 2.95 (s, 3H), 3.65 (q, 2H), 5.16 (m, 1H), 7.3 (s, 5H).

[2060] In a similar way the (S) isomer was prepared from 1N-Benzyl-3(S)-hydroxy-pyrrolidines (5 g, 28.21 mmoles) to give the (S) title compound (7.15 g, 98%).

499

[2061] A solution of the (R) product from Step A (2.0 g, 7.84 mmoles) was added to a stirred solution of imidazole (1.1 g, 16.17 mmoles) in DMF (25 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH4OH in methanol)—CH2Cl2 as eluant to give the title compound (0.95 g, 50.56%). FABMS (M+1)=228.

[2062] In a similar fashion the other isomer was prepared.

500

[2063] A mixture of the (S) product (0.95 g) from Step B and 10% Pd on carbon (0.5 g) in EtOH (20 mL) was shaken at 50 psi under an atmosphere of hydrogen for 24 h. The catalyst was filtered and the solvent removed to give the title compound (266) (0.522 g, 99.9%).

[2064] In a similar manner the (R) isomer was prepared from 1.0 g of the starting (R) product from Step B and 10% Pd on carbon (0.6 g) to give compound (265) in 99% yield.

PREPARATIVE EXAMPLE 32

[2065]

501

[2066] By essentially the same procedure set forth in Preparative Example 31 above, beginning with L or D-prolinol, the title compounds (267) and (268) were prepared.

EXAMPLE 105

[2067]

502

[2068] Compound (217) from Preparative Example 19 (0.227 g, 0.499 mmol) was added to a solution of Compound (262) from Preparative Example 29 (0.131 g, 0.649 mmol), DEC (0.249 g, 1.3 mmol), HOBT (0.175 g, 1.3 mmol) and NMM (0.5 mL) in DMF (25 mL). The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with H2O until precipitation ceased and slurry was filtered. The precipitate was diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give the title compound (269) (0.184 g, 62% yield).

EXAMPLES 106-111

[2069] Using the appropriate amine from the Preparative Examples 28-32, and following essentially the same procedure as in Example 105 above, compounds of the formula:

503

[2070] were prepared wherein R is defined in Table 11

11TABLE 11EX.R =Compound #PHYS. DATA106

504

270MH+ = 603107

505

271MH+ = 589108

506

272MH+ = 589109

507

273MH+ = 589110

508

274MH+ = 603111

509

275MH+ = 603

EXAMPLE 112

[2071]

510

[2072] Compound (274) from Example 110 above (0.125 g, 0.213 mmoles) in CH2Cl2 (50 mL) was stirred with TFA (10 mL) at room temperature overnight. The reaction mixture was evaporated to give the TFA salt (0.28 g) which was redissolved in CH2Cl2 (50 mL) and cooled (ice water bath). Triethyl amine (0.1 mL) followed by methane sulfonyl chloride (0.038 g, 0.319 mmoles) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with sodium bicarbonate and water. The organic layer was dried over MgSO4 and evaporated to dryness to give the title compound (276) (0.05 g, MH+=567)

EXAMPLE 113

[2073]

511

[2074] Starting with Compound (273) from Example 109 above and following essentially the same procedure as in Example 112 above, Compound (277) was prepared (MH+=567).

PREPARATIVE EXAMPLE 33

[2075]

512

[2076] To a stirred solution of bromine (33.0 g, 210 mmol) in CCl4 (100 ml) was added a solution of dibenzosuberenone (37.0 g, 179 mmol) in CCl4 (200 ml) at room temperature. The resulting solution was stirred at room temperature for 1.5 hours. The white crystals were collected by filtration to give the product (278) (60.12 g, 92% yield, M+H=367).

513

[2077] A solution of the di-bromo compound (278) from step A (60.0 g, 163 mmol) and NaOH (20.0 g, 491 mmol) in MeOH (500 ml) was stirred and heated to reflux for 1.5 hours. The reaction mixture was then cooled to room temperature and stirred overnight. The mixture was evaporated to dryness then extracted with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered and evaporated to dryness to give a yellow solid (279) (46.34 g, 100% yield, M=285)

514

[2078] To a stirred solution of the mono-bromo compound (279) from step B (10.0 g, 35.07 mmol) in MeOH (200 ml) under nitrogen at 0° C. was added NaBH4 (1.94 g, 51.2 mmol). The resulting solution was stirred at 0° C. for 1.5 hours, then evaporated, followed by extraction with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered, and evaporated to dryness to give a white solid (280) (10.3 g, 100%, M=287).

515

[2079] To a stirred solution of the alcohol (280) from Step C (10.0 g, 34.8 mmol) in CH2Cl2 (200 ml) at 0° C. was added 2,6-lutidine (14.9 g, 139.3 mmol) and thionyl chloride (8.28 g, 69.66 mmol). The resulting solution was warmed to room temperature and stirred overnight. The solution was then poured onto 0.5N NaOH solution, followed by extraction with CH2Cl2. The combined aqueous layer was dried over Na2SO4, filtered, and concentrated to dryness to give a crude brown oil (15.5 g). To a solution of this crude oil (15.5 g) in acetonitrile (200 ml) was added 2,6-Bis (dimethyl)-1-methyl piperidine (10.81 g, 69.66 mmol) and N-Boc piperidine (6.49 g, 34.83 mmol). The resulting mixture was warmed to 65° C. overnight. The mixture was evaporated to dryness, followed by extraction with CH2Cl2/saturated NaHCO3. The combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography on silica gel, eluting with 5% EtOAc/95% Hexane to give the protected N-Boc compound (281) (5.68 g, 36% yield, MH+=455).

516

[2080] To a solution of the N-Boc compound (281) from Step D (4.0 g, 8.78 mmol) in anhydrous toluene (100 ml) and methanol (20 ml) was added triphenylphosphine (1.15 g, 4.39 mmol), DBU (1.81 g, 11.9 mmol) and palladium (II) chloride (0.15 g, 0.88 mmol). The resulting mixture was purged with carbon oxide at 80 psi to 100 psi and heated to 78° C.-82° C. for 5 hours, followed by stirring at room temperature for overnight. The solution was then extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered, evaporated and the crude product was purified by column chromatography on silica gel, eluting with 10% EtOAc/90% Hexane to give the ester compound (282) (2.1 g, 55% yield, MH+=435).

517

[2081] To a stirred solution of the ester compound (282) from Step E (1.2 g, 2.77 mmol) in THF (15 ml) at 0° C. was added a 1 M solution of DIBAL (16.62 ml, 16.62 mmol). The resulting solution was stirred at room temperature for 4 hours. To the solution was then added 10% potassium sodium tartarate, followed by extraction with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and evaporated to give a solid (283) (1.1 g, 100% yield, MH+=406).

518

[2082] To a solution of the alcohol (283) from Step F (0.62 g, 1.52 mmol) in CH2Cl2 (15 ml) under nitrogen was added triethyl amine (0.64 ml, 4.56 mmol) and methane sulfonyl chloride (0.26 g, 2.29 mmol). The resulting solution was stirred at room temperature overnight. The mixture was washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to give the mesylate compound (284) (0.53 g, 76% yield, M-CH3SO3H=389.1).

519

[2083] To a stirred solution of 1-methyl-imidazole (1.04 g, 12.7 mmol) in DMF (10 ml) under nitrogen, was added NaH (0.305 g, 12.7 mmol). The resulting solution was stirred at room temperature for 15 minutes, followed by the addition of the mesylate compound (284) from step G (2.05 g, 4.23 mmol). The reaction mixture was stirred at room temperature overnight, then evaporated to dryness, and extracted with an EtOAc-NaHCO3 solution. The combined organic layer was dried over Na2SO4, concentrated and the crude product purified by silica gel column chromatography eluting with 2% MeOH/98% NH3—CH2Cl2 to give the product (285) (0.775 g, 39% yield, MH+=471).

520

[2084] A solution of the product (285) from step H (0.3 g, 0.64 mmol) in 4M HC! in dioxane (40 ml) was stirred at room temperature for 3 hours and then concentrated to dryness to give the hydrochloride salt of the title product (286) (0.42 g, 100% yield, MH+=371).

EXAMPLES 114 AND 115

[2085] The racemic mixture of Preparative Example 33, Step H above was seperated into its pure isomers by HPLC, using a Chiral AD column eluting with 15% IPA/75% Hexane/0.2% DEA to afford the compounds in Table 12.

12TABLE 12EX. #CMPD #PHYS. DATA114287 isomer 1MS M+ = 471115288 isomer 2MS M+ = 471

EXAMPLES 116-119

[2086] Starting with the piperazine compound (286) from Preparative Example 33 Step I, and reacting it with the appropriate isocyanate or sulfonyl chloride, following essentially the same procedure as indicated in Table 13, compounds of the formula:

521

[2087] were prepared wherein R is defined in Table 13.

13TABLE 13EX. #PROCEDURER =CMPD #PHYS. DATA116Example 13

522

289 isomer 1MS M+ = 515117Example 13

523

290 isomer 2MS M+ = 515118Example 24

524

291a isomer 1MS M+ = 449119Example 24

525

291b isomer 2MS M+ = 449

PREPARATIVE EXAMPLE 34

[2088]

526

[2089] To a stirred solution of alcohol (280) from Preparative Example 33, Step C (30.0 g, 104.5 mmol) in CH2Cl2 (500 mL) under nitrogen at −20° C. was added thionyl chloride (106.7 mL, 1,46 mmol). The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The crude mixtue was diluted with toluene (50 mL), followed by the addition of more SOCl2 (106.7 mL) at room temperature. The resulting solution was heated to reflux for 2 hours until the reaction went to completion. The reaction mixture was then cooled to room temperature and concentrated to dryness to give a light brown solid (292) (35.67 g, 100% yield, M-BrCl=191).

527

[2090] To a suspension of Mg (3.63 g) in anhydrous THF (95 mL) under nitrogen at room temperature was added 4-chloro-1-methyl piperidine (3 mL, 10% of the total amount) and one small crystal of iodine. The resulting solution was heated to reflux, followed by the addition of iodomethane (0.5 mL) and the remainder of the 4-chloro-1-methyl piperidine (27 mL). The reaction was stirred for one hour and then concentrated to dryness to give the crude Grignard reagent (0.8M).

[2091] To a stirred solution of the chloro compound (292) from Preparative Example 34, Step A (35.67 g, 116.7 mmol) in anhydrous THF (200 mL) under nitrogen at room temperature, was added dropwise the Grignard reagent (as obtained above) (0.8M, 146 mL, 116.7 mmol). The resulting solution was stirred at room temperature for 3 hours, followed by the extraction with EtOAc-H2O. The combined organic layer was dried over MgSO4, filtered and evaporated to dryness to give the product (293) (49.25 g, 100% yield, MH+=368).

528

[2092] To a stirred solution of Compound (293) from Step B above (42.9 g, 116.5 Is mmol) in toluene (400 mL) under nitrogen was added triethylamine (49 mL, 349.5 mmol). The resulting solution was heated to refux, followed by the dropwise addition of ethyl chloroformate (126 g, 1165 mmol). Continued to heat the solution at the reflux temperature for 2 hours. The reaction was then stirred at room temperature overnight, followed by extraction with an EtOAc-1N NaOH solution. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and the crude product purified by column chromatography on normal phase silica gel, eluting with 30% EtOAc/70% Hexane to give a light yellow solid (294) (2.99 g, 12% yield, MH+=426.3).

529

[2093] A solution of the ester (294) from step C above (3.34 g, 7.83 mmol) in 6N HCl (20 mL) was heated to reflux overnight. The reaction was cooled to room temperature and basified with NH4OH solution, followed by extraction with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and evaporated to dryness to give a crude free piperidine (2.80 g, 100% yield, MH+=534)

[2094] To the crude material (as obtained above) (2.77 g, 7.82 mmol) in 50% MeOH/1% H2O (200 mL) was added Di-tert-butyl dicarbonate (3.41 g, 15.64 mmol). The reaction mixture was adjusted to pH=9 and stirred at room temperature for 4 hours, evaporated to dryness then extracted with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by HPLC, using chiral AD column, eluting with 15% IPA/75% Hexane/0.2% DEA to give the pure isomers of the N-Boc compounds (295a) and (295b) (3.42 g, 96% yield, MH+=454).

530

[2095] To a stirred solution of the pure (+) or (−) isomer of the N-Boc compound from Step D above (4.0 g, 8.78 mmol) in anhydrous toluene (100 mL) and methanol (20 mL) was added triphenyl phosphine (1.15 g, 4.39 mmol), DBU (1.81 g, 11.9 mmol) and palladium (II) chloride (0.15 g, 0.88 mmol). The resulting mixture was purged with carbon monooxide at 80 psi to 100 psi and heated to 78° C.-82° C. for 5 hours, followed by stirring at room temperature overnight. The solution was then extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered, evaporated and purified by column chromatography on silica gel, eluting with 10% EtOAc/90% Hexane to give the ester (296a) or (296b) (2.1 g, 55% yield, MH+=435).

531

[2096] To a stirred solution of the (+) or (−) isomer of the ester from Step E above, (1.2 g, 2.77 mmol) in THF (15 mL) at 0° C. was added 1M solution of DIBAL (16.62 mL, 16.62 mmol). The resulting solution was stirred at room temperature for 4 hours. To the solution was then added 10% potential sodium tartarate, followed by extraction with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and evaporated to give a solid (297a) or (297b) (1.1 g, 100% yield, MH+=406).

532

[2097] To a stirred solution of the (+) or (−) isomer of the alcohol from Step F, above (0.62 g, 1.52 mmol) in CH2Cl2 (15 mL) under nitrogen was added triethyl amine (0.64 mL, 4.56 mmol) and methane sulfonyl chloride (0.26 g; 2.29 mmol). The resulting solution was stirred at room temperature for overnight. The mixture was washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to give the mesylate compound (298a) or (298b) (0.53 g, 76% yield, M-CH3SO3H=389.1).

533

[2098] To a stirred solution of 1-methyl-imidazole (1.04 g, 12.7 mmol) in DMF (10 mL) under nitrogen, was added NaH (0.305 g, 12.7 mmol). The resulting solution was stirred at room temperature for 15 minutes, followed by the addition of the (+) or (−) isomer of the mesylate compound (299) from Step G above (2.05 g, 4.23 mmol). The reaction mixture was stirred at room temperature overnight then evaporated to dryness, followed by extraction with an EtOAc-NaHCO3 solution. The combined organic layer was dried over Na2SO4, concentrated and the crude product was purified by silica gel column chromatography, eluting with 2% MeOH/98% NH3—CH2Cl2 to give the product (299a) or (299b) (0.775 g, 39% yield, MH+=471).

534

[2099] A solution of the (+) or (−) isomer of the product from Step I above (0.3 g, 0.64 mmol) in 4M HCl in dioxane (40 mL) was stirred at room temperature for 3 hours and then concentrated to dryness to give the HCl salt of the product (300a) or (300b) (0.42 g, 100% yield, MH+=371).

EXAMPLES 120 AND 121

[2100] Starting with the appropriate (+) or (−) isomer of Compound (300) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate, compounds of the formula:

535

[2101] were prepared wherein R is defined in Table 14.

14TABLE 14EX. #PROCEDURER =CMPD #PHYS. DATA120Example 13

536

301 isomer 1MS MH+ = 514121Example 13

537

302 isomer 2MS MH+ = 514

PREPARATIVE EXAMPLE 35

[2102]

538

[2103] To a stirred solution of the bomo-compound (295a) from Preparative Example 34, Step D, (0.5 g, 1.10 mmol) in 1-methyl-2-pyrrolidinone (4.3 mL) under nitrogen, was added lithium chloride (0.14 g, 3.3 mmol), tri-2-furylphosphine (0.013 g, 0.04 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (0.02 g, 0.02 mmol). The resulting solution was stirred at room temperature for 5 minutes, followed by the addition of tributyl (vinyl) tin (0.39 g, 1.24 mmol). The reaction was then heated to 85° C. for 2 hours, followed by extraction with EtOAc-H2O. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on normal phase silica gel, eluted with 10% EtOAc/90% CH2Cl2 to give a light yellow liquid (303a) (0.06 g, 15% yield, MH+=390).

539

[2104] To a stirred solution of 1-methylimidazole (0.377 g, 4.6 mmol) in anhydrous THF (4 mL) under nitrogen at −78° C., was added 2.5M n-BuLi/Hexane (0.33 mL). The resulting solution was stirred at −78° C. for 30 minutes and then allowed to warm at room temperature. To this stirred solution was added the alkene compound (303a) from step A above,(0.78 g, 2.1 mmol) in THF. The resulting solution was then heated to 120° C. overnight then cooled to room temperature, and extracted with EtOAc—H2O. The combined organic layer was dried over MgSO4, filtered, evaporated and purified by column chromatography on normal phase silica gel, eluted with 3% MeOH/97% NH3—CH2Cl2 to give a light yellow solid (304a) (0.09 g, 10% yield, MH+=456.1).

540

[2105] A solution of the product (304a) from Step B above (0.18 g, 3.72 mmol) in 4M HCl/dioxane (5 mL) was stirred at room temperature for 2 hours, then concentrated to dryness to give a crude off white solid (305a) (0.22 g, 100% yield. MH+=384.2).

[2106] Using the same procedure as defined in Preparative Example 35 above starting with the Boc-protected Bromo compound (295b), compound (305b) was prepared (MH+=384.2).

EXAMPLES 122-125

[2107] Starting with the appropriate (+) or (−) isomer of Compound (305) (i.e., 305a and 305b) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate, compounds of the formula:

541

[2108] were prepared wherein R is defined in Table 15.

15TABLE 15EX. #PROCEDURER =CMPD #PHYS. DATA122Example 13

542

306 isomer 1MS MH+ = 537.1 m.p. = 118.1-119.0° C.123Example 13

543

307 isomer 2MS MH+ = 537.1 m.p. = 107.8-108.4° C.124Example 13

544

308 isomer 1MS MH+ = 528.2 m.p. = 119.6-120.2° C.125Example 13

545

309 isomer 2MS MH+ = 528.2 m.p. = 120.5-121.3° C.

PREPARATIVE EXAMPLE 36

[2109]

546

[2110] To a solution of Compound (93A) from Example 7, Step A (5.0 g, 10.02 mmol) in 1-methyl-2-pyrrolidinone (40 mL) under nitrogen at room temperature, was added LiCl (1.27 g, 30.06 mmol), Tri-2-furrylphosphine (0.093 g, 0.4 mmol) and tris(dibenzylidene acetone)dipalladium(0) (0.18 g, 0.2 mmol). The resulting solution was stirred at room temperature for 5 minutes, followed by the addition of tributyl(vinyl) tin (3.3 mL, 11.3 mmol) and stirred overnight at 80° C.-85° C. The solution was cooled to room temperature, followed by extraction with EtOAc-H2O. The organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluted with 20% EtOAc/80% CH2Cl2 to give the product (310) (3.88 g, 95% yield, MH+=409.1)

547

[2111] To a stirred solution of 4,5-dimethylimidazole (25.8 mg, 0.268 mmol) in anhydrous THF (0.2 mL) at −78° C. under Argon, was added 2.5M n-BuLi (0.032 mL, 0.08 mmol). The resulting solution was warmed to room temperature, followed by the addition of the alkene compound (310) from Step A above (0.1 g, 0.24 mmol) in anhydrous THF (0.2 mL). The solution was then heated in an oil bath to 120° C. for 25 hours, followed by extraction with CH2Cl2—H2O. The combined organic layer was then washed with brine, dried over Na2SO4, filtered and purified by column chromatography on silica gel, eluting with 5% MeOH/95% CH2Cl2 to give the product (311) (0.046 g, 100% yield, MH+=505).

548

[2112] A solution of Compound (311) from Step B above (0.57 g, 1.28 mmol) in 6N HCl (20 mL) was heated to reflux for 24 hours then concentrated to dryness. To the residue was then added saturated NaHCO3 and NaCl. The solution was extracted twice with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated to dryness to give the crude product (0.52 g, 93% yield). The crude material was then dissolved in 20% EtOH/80% Hexane/0.2% DEA and purified by HPLC on a preparative AD column, eluting with 20%-50% IPA/Hexane/0.2% DEA (UV=254 nm, Attn=1024, ABS=2) to give pure isomers of the product (312a) and (312b) (0.225 g, MH+=433).

EXAMPLES 126-133

[2113] Starting with the appropriate (+) or (−) isomer of Compound (312) (i.e., 312a or 312b) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate or sulfonyl chloride, compounds of the following formula:

549

[2114] prepared wherein R is defined in Table 16.

16TABLE 16PHYS. DATAEX. #PROCEDURER =CMPD #Mass spec126Example 13

550

313 isomer 1M+ = 577127Example 13

551

314 isomer 2M+ = 577128Example 13

552

315 isomer 1M+ = 558129Example 13

553

316 isomer 2M+ = 558130Example 13

554

317 isomer 1M+ = 570131Example 13

555

318 isomer 2M+ = 570132Example 13

556

319 isomer 1M+ = 511133Example 13

557

320 isomer 2M+ = 511

PREPARATIVE EXAMPLE 37

[2115]

558

[2116] To a solution of Compound (310) from Preparative Example 36, Step A (0.66 g, 8.1 mmol) in THF (4.0 mL) under nitrogen at −78° C., was added dropwise 2.5M n-BuLi/Hexane (1.5 mL). The resulting solution was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature, followed by the addition of 1-methylimidazole (3.0 g, 7.3 mmol) in THF (3.0 mL). The solution was then heated to 120° C. over the weekend and then cooled down to room temperature and concentrated to dryness. The mixture was extracted with EtOAc-H2O, dried over MgSO4, filtered and purified by column chromatography on silica gel, eluting with 3% MeOH/97% NH3—CH2Cl2 to give the product (321)(1.64 g, 46% yield, MH+=491.1).

559

[2117] A solution of Compound (321) from Preparative Example 37, Step A above (0.6 g, 1.22 mmol) in 12N HCl (10 mL) was heated to reflux overnight then concentrated to dryness to give the residue as a gum. This residue was dissolved in saturated NaHCO3, stirred for 10 minutes, saturated with NaCl and then stirred with CH2Cl2 for 10 minutes. The solid was filtered and the aqueous layer was extracted twice with CH2Cl2, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the Compound (322) as a light brown solid (566 ma, MH+=419.1).

560

[2118] To a solution of Compound (322) from Step B above (0.566 g, 1.35 mmol) in IS MeOH (20 mL) and H2O (1 mL) at 0° C., was added Boc anhydride (0.44 g, 2.02 mmol). The solution was basified with 1N NaOH solution to maintain pH=8.5-9.5 and concentrated to dryness, followed by extraction with CH2Cl2—H2O. The combined organic layer was washed twice with H2O then brine, dried over Na2SO4, filtered and concentrated to dryness to give a mixture of isomers 1 and 2 (0.63 g, 100% yield). The isomers were separated by HPLC on a prep AD column, eluting with 15%IPA/85%hexane/0.2%DEA (wave length=254 nm, Aftn=64, ABS=1) to give isomer 1 (323a) (0.28 g, MH+=519.2) and isomer 2 (323b) (0.28 g, MH+=519.2)

561

[2119] A solution of Compound (323a) isomer 1 from Step C above (0.24 g, 0.46 mmol) in 4N HCl/Dioxane (20 mL) was stirred at room temperature for 1 hr. CH2Cl2 (7 mL) was added to the solution and the reaction continued to stir for 2 hrs before being concentrated to dryness. The solution was stirred for 5 minutes with saturated NaHCO3, then saturated with NaCl and extracted three times with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and evaporated to dryness to give Compound (322a) isomer 1(0.163 g, 84% yield, MH+=419.2).

[2120] Compound (322b) was prepared in a similar manner as in Step D above, starting with Compound (323b) to give the other isomer (0.193 g, 84% yield, MH+=419.2)

EXAMPLES 134-147

[2121] Starting with compound 322a or 322b and reacting in a similiar manner as in Example 13 using the appropriate chloroformate, isocyanate, or sulfonyl chloride (or in the case of carboxylic acid, using DEC mediated coupling), compounds of the formula:

562

[2122] were prepared wherein R is defined in Table 17.

17TABLE 17EX. #PROCEDURER =CMPD #PHYS. DATA134Example 13

563

324 Isomer 1MS M+ = 545.2135Example 13

564

325 Isomer 2MS M+ = 545.2136Example 13

565

326 Isomer 1MS M+ = 563.2137Example 13

566

327 Isomer 2MS M+ = 563.2138Example 13

567

328 Isomer 1MS M+ = 606.1 m.p. =62.7-63.0° C.139Example 13

568

329 Isomer 2MS M+ = 606.1 m.p. =70.1-71.0° C.140Example 13

569

330 Isomer 1MS M+ = 572.1 m.p. =120.1-121.4° C.141Example 13

570

331 Isomer 2MS M+ = 572.1 m.p. =128.0-129.0°142Example 13

571

332 Isomer 1MS M+ = 544.2143Example 13

572

333 Isomer 2MS M+ = 544.2144Example 13

573

334 Isomer 1MS M+ = 554.1 m.p. =111.9-112.0° C.145Example 13

574

335 Isomer 2MS M+ = 554.1 m.p. =114.3-115°146Example 13

575

336 Isomer 1MS M+ = 497.1 m.p. =52.4-53.3° C.147Example 13

576

337 Isomer 2MS M+ = 497.1 m.p. =47.1-48.0°

PREPARATIVE EXAMPLE 38

[2123]

577

[2124] To a solution of Compound (310) from Preparative Example 36 Step A (3.0 g, 7.34 mmol) in THF (8 mL) under nitrogen at −78° C., was added dropwise 2.5M n-BuLi/Hexane (0.65 mL, 8.07 mmol). The resulting solution was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature, followed by the addition of 4-methylimidazole (0.66 g, 8.07 mmol) in THF. The solution was heated to 120° C. over night cooled down to room temperature and concentrated to dryness The reaction mixture was extracted with EtOAc-H2O, and the organic layer was dried over MgSO4, filtered and concentrated to give a mixture of 4-methyl substituted (338) and 5-methyl substituted (339) products (2.76 g, 76% yield, M+=491.1).

[2125] Step B

[2126] In a similar manner as described in Example 11, the mixture of products from Step A, above were first seperated into a mixture of pure 4 and 5-substitured (+) enantiomers and pure 4 and 5-substituted (−) enantiomers using chiral HPLC column chromatography, then upon treatment with triphenyl methyl chloride following the procedure in Example 11, the compounds were further seperated into the pure isomers of the 4-substituted compound (338a) (MS M+=491; mp=72.1-73.0° C.) and (338b) (MS M+=491; mp=68.9-69.0° C.) and the 5-substituted compound (339a) and (339b).

578

[2127] A solution of Compound (338a) from step B above (0.035 g, 0.071 mmol) in 6N HCl (2.0 mL) was heated to reflux overnight. The solution was cooled to room temperature, basified with NH4OH solution and extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated to give pure isomer 1, Compound (340a) (0.0334 g, 100% yield, MH+=419.1; mp=60.3-61.0° C.).

[2128] In a similar manner as above, starting with Compound (338b) (isomer 2), Compound (340b) (MH+=419.1) was prepared.

EXAMPLES 148-156

[2129] Starting with the appropriate (+) or (−) isomer of Compound (340) (i.e., 340a or 340b) and reacting in a similiar manner using the procedure shown in Table 18 with the appropriate chloroformate, isocyanate or sulfonyl chloide, compounds of the formula:

579

[2130] prepared wherein R is defined in Table 18.

18TABLE 18EX. #PROCEDURER =CMPD #PHYS. DATA148PreparativeBOC341MS MH+ = 519Ex.4; Step Am.p. = 90.2-91.0° C.149Example 13

580

342 isomer 1MS MH+ = 545 m.p. = 58.8-59.6° C.150Example 13

581

343 isomer 2MS MH+ = 545 m.p. = 60.8-61.2° C.151Example 13

582

344 isomer 1MS MH+ = 545 m.p. = 98.7-99.5° C.152Example 13

583

345 isomer 2MS MH+ = 545 m.p. = 111.3-112.0° C.153Example 13

584

346 isomer 1MS MH+ = 544 m.p. = 77.1-77.8° C.154Example 13

585

347 isomer 2MS MH+ = 544 m.p. = 78.9-79.0° C.155Example 13

586

348 isomer 1MS MH+ = 497 m.p. = 87.4-88.0° C.156Example 13

587

349 isomer 2MS MH+ = 497 m.p. = 88.8-89.0° C.

PREPARATIVE EXAMPLE 39

[2131]

588

[2132] Compound (339a) was reacted in a similar manner as in Preparative Example 38, Step C to give Compound (350a) (0.13 g, 76% yield, MH+=419.3).

[2133] Compound (350b) was prepared in the same manner as above.

EXAMPLES 157-160

[2134] Starting with the appropriate (+) or (−) isomer of Compound (350) (i.e., 350a or 350b) and reacting in a similiar manner using the procedure indicated in the table below and the appropriate Boc or isocyanate reagent, compounds of the formula:

589

[2135] prepared wherein R is defined in Table 19.

19TABLE 19EX. #PROCEDURER =CMPD #PHYS. DATA157PreparativeBOC351MSEx.4; Step Aisomer 1MH+ = 519m.p. =87.8-88.2° C.158PreparativeBOC352MSEx.4; Step Aisomer 2MH+ = 519m.p. =89.0-89.9° C.159Example 13

590

353 isomer 1MS MH+ = 563160Example 13

591

354 isomer 2MS MH+ = 563 m.p. =130.1-131.0° C.

PREPARATIVE EXAMPLE 40

[2136]

592

[2137] To a solution of Compound (93A) from Preparative Example 7, Step A (2.92 g, 5.5 mmol) in anhydrous toluene (70 mL) and MeOH (10 mL) was added triphenyl phosphine (0.72 g, 2.75 mmol), DBU (1.11 mL, 7.42 mmol) and PdCl2 (0.097 g, 0.55 mmol). The resulting solution was purged with CO (100 psi), then heated to 80° C. for five hours. The solution was cooled to room temperature, purged with nitrogen and evaporated to dryness to give a brown oil. The product was purified by silica gel column chromatography eluting with 1% MeOH/99% CH2Cl2 to 4% MeOH/96%CH2Cl2 to give Compound (355) (2.22 g, 92.5% yield, MH+=441.1).

593

[2138] A solution of Compound (355) from Preparative Example 40, Step A (2.2 g, 4.99 mmol) in 6N HCl (50 mL) was heated to 100° C.-110° C. overnight. The solution was cooled to room temperature and evaporated to dryness to give the crude product. To a solution of the crude material in MeOH (50 mL) and H2O (1 mL) at 0° C., was added Boc anhydride (1.63 g, 7.48 mmol). The resulting solution was basified with 1N NaOH to pH=8.5-9.5 and stirred for two hours at 0° C., then evaporated to dryness and extracted with EtOAc-5% Citric acid solution. The organic layer was washed with H2O, then brine, dried over Na2SO4, filtered and concentrated to dryness to give Compound (356) as a yellow solid (2.29 g, 100% yield, MH+=455.1).

594

[2139] To a solution of Compound (356) from Preparative Example 40, Step B above(2.26 g, 4.97 mmol) in anhydrous benzene (18.0 mL) and MeOH (2 mL), was added, over five minutes, (trimethylsilyl)diazomethane (3 mL, 5.99 mmol) in 2M 1N Hexane. The resulting solution was stirred at room temperature for one hour then evaporated to dryness to give 2.33 g of crude material (MH+=369).

[2140] A solution of the crude material (obtained above) in 4N HCl in Dioxane (25 mL) was stirred at room temperature for one hour. The reaction was then evaporated to dryness and purified by flash silica gel column chromatography, eluting with 2% MeOH/98% CH2Cl2 to 6% MeOH/94% CH2Cl2 and then with 50% (10% NH4OH/CH3OH/50% CH2Cl2). The collected fractions were evaporated to dryness and diluted with CH2Cl2. The organic solution was then washed with saturated NaHCO3 and brine, dried with Na2SO4, filtered and evaporated to dryness to afford Compound (357) (1.26 g, 68.3% yield, MH+=369).

595

[2141] To a solution of Compound (357) from Preparative Example 40, Step C (0.6 g, 1.62 mmol) in anhydrous THF (6 mL) at 0° C. was added DIBAL (1 M solution in toluene) (9.78 mL, 9.78 mmol). The resulting solution was warmed to room temperature and stirred overnight. The solution was then quenched with MeOH and evaporated to dryness to give a crude product.

[2142] To the crude material (obtained above) in MeOH at 0° C. was added Boc anhydride (1.06 g, 4.9 mmol). The resulting solution was basified with 1N NaOH to pH=8.5-9.5, stirred for 1 hour and evaporated to dryness. The crude material was diluted with CH2Cl2 to give a slurry. The precipitate was then filtered through celite and the CH2Cl2 was washed with H2O, brine, filtered over Na2SO4 and concentrated to dryness. The crude alcohol product (358) (1.27 g, 100% yield) was used in the next step without further purification.

596

[2143] To a cooled solution of the alcohol (358) from Step D above (1.2 g, 2.73 mmol) in anhydrous CH2Cl2 (12 mL) at 0° C. was added triethyl amine (1.14 mL, 8.18 mmol) and methanesulfonyl chloride (0.3 mL, 4.1 mmol). The resulting solution was warmed to room temperature stirred overnight, then quenched with H2O and stirred for 10 minutes. The reaction was washed with water, then brine, dried over Na2SO4, filtered and evaporated to dryness to give Compound (359) (1.22 g, 86% yield).

597

[2144] To a solution of anhydrous DMF (5 mL) at 0° C. was added, NaH (0.19 g, 8.18 mmol) and 2-methylimidazole (0.67 g, 8.18 mmol). The resulting solution was warmed to room temperature and stirred for 20 minutes. To the reaction was added a solution of Compound (359) from Step E above (1.22 g, 2.3 mmol) in anhydrous DMF (5 mL). The resulting of solution was stirred at room temperature overnight, then diluted with EtOAc and washed with water then brine. The organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel column chromatography eluting with 1% MeOH/99% CH2Cl2 to 5%MeOH/CH2Cl2 to give the product as a mixture of isomers (1.18 g, 100% yield, MH+=505.2). Separation of the product mixture by HPLC using a prep AD column, eluting with 25%IPA/75%hexane/0.2%DEA (isocratic 60 ml/min.) afforded pure isomer 1 (360a) (0.251 g, MH+=505.1) and isomer 2 (360b) (0.251 g, MH+=505.1) as light pink solids.

598

[2145] A solution of Compound (360a) (isomer 1) from Step F above (0.2 g, 0.4 mmol) in 4N HCl in Dioxane (10 mL) was stirred at room temperature for 2 hours and then evaporated to dryness to afford Compound (361a) (0.292 g, 100% yield).

[2146] Compound (361b) (isomer 2) was prepared in a similar manner as above beginning with Compound (360b) from Preparative Example 40, Step F.

EXAMPLES 161-166

[2147] Starting with the appropriate (+) or (−) isomer of Compound (361) (i.e., 361a or 361b) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate shown in Table 20, compounds of the formula:

599

[2148] prepared wherein R is defined in Table 20.

20TABLE 20EX. #PROCEDURER =CMPD #PHYS. DATA161Example 13

600

362a isomer 1MS MH+ = 548162Example 13

601

362b isomer 2MS MH+ = 548163Example 13

602

363a isomer 1MS MH+ = 541164Example 13

603

363b isomer 2MS MH+ = 541165Example 13

604

364a isomer 1MS MH+ = 558166Example 13

605

364b isomer 2MS MH+ = 558166.1Example 13

606

364.1Mp 201.5-208.3° C.

PREPARATIVE EXAMPLE 41

[2149]

607

[2150] In essentially the same manner as in Preparative Example 23, Steps A-D, using the 6-Bromo substituted product from Step B, Compound (234b), the product Compound (365) was prepared (76.6 g, 100% yield).

PREPARATIVE EXAMPLE 42

[2151]

608

[2152] To a solution of Compound (365) from Preparative Example 41 (4.0 g, 8.16 mmol) in toluene (75 mL) and MeOH (20 mL), was added triphenyl phosphine (1.099 g, 4.08 mmol), DBU (1.7 g, 11.02 mmol) and palladium chloride (0.145 g, 0.82 mmol). The resulting solution was evacuated with CO at 100 psi and heated at 78° C.-82° C. for 5 hours, followed by the extraction with EtOAc-H2O. The combined organic layer was then washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography, eluting with 30% EtOAc/70% Hexane to give a Compound (366) (3.12 g, 100% yield, MH+=470.1).

609

[2153] A solution of Compound (366) from Step A above (3.1 g, 6.6 mmol) in 4M HCl/Dioxane (120 mL) was stirred for 3 hours and then concentrated to dryness to give the crude salt of Compound (367) (3.89 g, 100% yield, MH+=370.2)

610

[2154] To a solution of Compound (367) from Step B above (3.43 g, 8.45 mmol) in THF (60 mL) at 0° C., was added DIBAL (7.21 g, 50.7 mmol). The resulting solution was warmed to room temperature, stirred overnight and then concentrated to dryness, followed by the addition of Boc anhydride (3.69 g, 16.9 mmol). The reaction was then extracted with CH2Cl2—H2O, filtered over Na2SO4 and concentrated to dryness to afford Compound (368) (3.75 g, 100% yield, MH+=442.4).

[2155] Step C.1 Alternate Preparation of Compound (368)

[2156] A solution of compound 366 from step A above (23.46 g, 50.98 mmol) in CH2Cl2— MeOH—H2O (120 mL, 600 mL, 60 mL respectively) combined with LiOH (12.0 g, 350.88 mmol) was refluxed at 40° C. overnight. Solvent was removed from the reaction mixture and the residue diluted with CH2Cl2 was acidified to pH 6 with 1N HCl. The organic layer was separated and washed with water, dried over Na2SO4 and concentrated. The product was dissolved in THF (285 mL) at 0° C. Triethyl amine (6 mL, 42.97 mmol) and ethyl chloroformate (4.1 mL, 42.97 mmol) were added and stirred at 0° C. for 1 h. The reaction mixture was filtered and the filtrate was cooled to −70° C. To this filtrate was added NaBH4 (3.97 g, 104.94 mmol) and stirred for 1 heat −70° C. after which time 40 mL of MeOH was added dropwise. The solvents were removed and the residue taken up in methylene chloride, washed with sat. (aq) NaHCO3, then brine, dried over Na2SO4 and concentrated to give Compound (368) as a solid.

611

[2157] To a solution of Compound (368) from Step C above (3.74 g, 8.46 mmol) in CH2Cl2 (100 mL) was added triethyl amine (3.5 mL, 25.38 mmol) and methanesulfonyl chloride (1.45 g, 2.7 mmol). The resulting solution was stirred under nitrogen at room temperature for overnight and then washed with saturated NaHCO3, then brine, and dried over Na2SO4 to give the mesylate compound (369) (3.86 g, 88% yield).

612

[2158] To a solution of 2-methylimidazole (2.43 g, 29.68 mmol) in DMF (30 mL) under N2was added NaH (0.53 g, 22.3 mmol) and stirred for 10 min, followed by the addition of Compound (369) from Step D above (3.86 g, 7.42 mmol). The solution was stirred over night. The solution was then concentrated to dryness and extracted with EtOAc-NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography, eluting with 2% MeOH—NH3/98% CH2Cl2 to afford a mixture of isomers. Further separation was accomplished by Preparative HPLC Chiral AD Column chromatography, eluting with 25% IPA/75% hexane/0.2% DEA to give pure Compound (370a) (isomer 1) (0.160 g) and Compound (370b) (isomer 2) (0.140 g) (MH+=506.1)

613

[2159] A solution of Compound (370a) (isomer 1) from Step E above (0.1059, 0.21 mmol) in 4M HCl/Dioxane (10 mL) was stirred at room temperature for 3 hours and concentrated to dryness to afford Compound (371a) (0.147 g, 100% yield)

[2160] Compound (370b) (isomer 2) from Step E was treated in the same manner as isomer 1 above, to afford Compound (371 b) (isomer 2).

EXAMPLE 167

[2161] To a solution of compound 371a (1.3 g, 2.94 mmol) in CH2Cl2 (60 mL) was added triethyl amine (1.3 mL, 9.4 mmol) and p-cyano phenyl isocyanate (0.466 g, 3.24 mmol). The resulting solution was stirred at room temperature overnight, followed by the extraction with CH2Cl2 and saturated NaHCO3. The organic layer was dried over Na2SO4, evaporated and the residue purified by column chromatography, eluting with 1%-2% MeOH—NH3/98% CH2Cl2 to afford compound (372) (0.870 g, 48% yield) see Table 21 below.

EXAMPLE 168

[2162] Compound 371b (isomer 2) was reacted in a similar manner as in Example 13 with p-cyano phenyl isocyanate to afford compound (373) see Table 21 below.

EXAMPLE 169

[2163] Compound 371a (isomer 1) was reacted in a similar manner as in Example 13 with p-chloro phenyl isocyanate to afford compound (374) see Table 21 below.

EXAMPLE 170

[2164] Compound 371b (isomer 2) was reacted in a similar manner as in Example 13 with p-chloro phenyl isocyanate to afford compound (375) see Table 21 below.

EXAMPLES 167-170.1

[2165]

614

[2166] (R is defined in Table 21).

21TABLE 21EX. #PROCEDURER =CMPD #PHYS. DATA167Example 13

615

372 isomer 1 S-isomerMS MH+ = 550168Example 13

616

373 isomer 2 R-isomerMS MH+ = 550169Example 13

617

374 isomer 1 S-isomerMS MH+ = 559170Example 13

618

375 isomer 2 R-isomerMS MH+ = 559170.1Example 13

619

375.1 isomer 1MS MH+ = 525

PREPARATIVE EXAMPLE 43

[2167]

620

[2168] To a solution of 1-ethylimidazole (0.33 g, 3.46 mmol) in DMF (5 mL) under nitrogen was added NaH (0.083 g, 3.46 mmol) and stirred for 10 minutes, followed by the addition of Compound (369) from Preparative Example 42, Step D (0.6 g, 1.15 mmol) and stirred for over night. The solution was then evaporated to dryness, diluted with ethyl acetate, washed with sodium bicarbonate, dried over sodium sulfate and concentrated to dryness. The reaction mixture was purified by column chromatography on silica gel, eluted with 3% MeOH/97% CH2Cl2 to give a mixture of isomers. Further separation was accomplished using prep. HPLC with a chiral AD column to afford pure Compound (376a) (isomer 1) and Compound (376b) (isomer 2) (MH+=520.1).

621

[2169] A solution of Compound (376a) from Step A (0.107 g, 0.2 mmol) in 4M HCl in Dioxane (10 mL) was stirred for two hours at room temperature then concentrated to dryness to afford Compound (377a) (isomer 1) (0.13 g, 100% yield, MH+=420.1).

[2170] Compound (376b) was reacted in a similiar manner as above to afford Compound (377b) (isomer 2) (MH+=420.1).

EXAMPLES 171-174

[2171] Starting with the appropriate (+) or (−) isomer of Compound (377) (i.e., 377a and 377b) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate as shown in Table 22 below, compounds of the formula:

622

[2172] were made wherein R is defined in Table 22.

22TABLE 22EX. #PROCEDURER =CMPD #PHYS. DATA171Example 13

623

378 isomer 1MS MH+ = 504172Example 13

624

379 isomer 2MS MH+ = 504173Example 13

625

380 isomer 1MS MH+ = 573174Example 13

626

381 isomer 1MS MH+ = 573

PREPARATIVE EXAMPLE 44

[2173]

627

[2174] To a solution of Compound (369) from Preparative Example 42, Step D (0.5 g, 0.96 mmol) in CH3CN (80 mL), was added piperazine (0.25 g, 2.88 mmol) and 2,6-bis (dimethyl)-1-methylpiperidine (0.597 g, 3.84 mmol). The resulting solution was stirred at room temperature for 4 hrs, concentrated to dryness and extracted with CH2Cl2—NaHCO3. The combined organic layer was dried over Na2SO4 and purified by column chromatography on silica gel, eluting with 3%MeOH/97%CH2Cl2 to give the product of 2 isomers (0.28 g, 57% yield). These two isomers were seperated by HPLC on chiral AD column to give pure Compound (382a) (isomer 1) (0.136 g, MH+=510.3) and Compound (382b) (isomer 2) (0.14 g, MH+=510.3)

PREPARATIVE EXAMPLE 45

[2175]

628

[2176] To a solution of Compound (369) from Preparative Example 42, Step D (1.2 g, 2.31 mmol) in CH3CN (100 mL), was added morpholine (0.8 g, 9.23 mmol) and 2,6-bis (dimethyl)-1-methylpiperidine (1.9 g, 12.24 mmol). The resulting solution was stirred at room temperature overnight and concentrated to dryness, followed by extraction with CH2Cl2-NaHCO3. The combined organic layer was dried over Na2SO4 and purified by column chromatography on silica gel, eluting with 1%NH3-MeOH/99%CH2Cl2 to give the product of two isomers (1.1 g, 82% yield). These two isomers were separated by HPLC on chiral AD column to give pure Compound (383a) (isomer 1) (0.24 g, MH+=425.1) and Compound (383b) (isomer 2) (0.112 g, MH+=425.1).

629

[2177] A solution of Compound (383a) from Step A (0.19 g, 0.37 mmol) in 4M HCl/Dioxane (25 mL) was stirred at room temperature for 2.5 hrs and concentrated to dryness to give Compound (384a) (0.194 g, MH+=411.1).

[2178] Compound (384b) was prepared in a similar manner as above starting with Compound (383b) from Step A.

EXAMPLE 175

[2179]

630

[2180] To a solution of Compound (384a) from Preparative Example 45, Step B above (0.05 g, 0.11 mmol) in anhydrous CH2Cl2 (5 mL) was added triethyl amine (0.036 g, 0.36 mmol) and 4-cyanophenyl isocyanate (0.018 g, 0.173 mmol). The resulting solution was stirred at room temperature for 4 hrs under nitrogen and concentrated to dryness, followed by extraction with CH2Cl2—NaHCO3. The combined organic layer was dried over Na2SO4 and concentrated to dryness to give Compound (385a) (isomer 1) (0.06 g, 100% yield, MH+=555.4).

[2181] Starting with Compound (384b) from Preparative Example 45, Step B and reacting it in the same manner as above, Compound (385b) (isomer 2) was prepared (MH+=555.4).

PREPARATIVE EXAMPLE 46

[2182]

631

[2183] To a solution of Compound (369) from Preparative Example 42 Step D (3.0 g, 5.77 mmol) in CH3CN (150 mL) was added 2,6-bis (dimethyl)-1 methyl piperidine (7.16 g, 16.16 mmol) and benzyl-1-piperazinecarboxylate (7.61 g, 34.62 mmol). The resulting solution was stirred overnight, concentrated to dryness, followed by extraction with CH2Cl2—NaHCO3. The combined organic layer was dried over Na2SO4, concentrated to dryness and purified by column chromatography on silica gel, eluting with 1% NH3-MeOH/99% CH2Cl2 and then 30%EtOAc/70% hexane to give the title product Compound (386) (1.24 g, 67% yield, MH+=644.2)

632

[2184] A solution of Compound (386) from Step A above (0.5 g, 0.77 mmol) in 4M HCl/Dioxane (50 mL) was stirred at room temperature for 2 hrs. The solution was then poured onto ice and basified with 1N NaOH solution, followed by extraction with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated to dryness to give Compound (387) (0.43 g, 100% yield, MH+=544.5).

633

[2185] Compound (387) from Step B above was reacted in a similar manner to that described in Example 175 to give a mixture of 2 isomers (0.102 g, 55% yield). Further separation by HPLC, using a chiral AD column afforded pure Compound (388a) (isomer 1) (0.05 g, MH+=688.2) and Compound (388b) (isomer 2) (0.048 g, MH+=688.2).

EXAMPLES 176 AND 177

[2186] Reacting Compound (387) from Preparative Example 46, Step B in a similiar manner as in Example 175 using the appropriate isocyanate as shown in Table 23 below, compounds of the formula:

634

[2187] were prepard wherein R is defined in Table 23.

23TABLE 23EX. #PROCEDURER =CMPD #PHYS. DATA176Example 175

635

389 isomer 1MS MH+ = 688177Example 175

636

390 isomer 1MS MH+ = 688

EXAMPLE 178

[2188]

637

[2189] To a solution of Compound (388a) from Preparative Example 46, Step C (0.05 g, 0.086 mmol) in CH3CN (1 mL) at 0° C. was added iodotrimethylsilane (0.05 mL, 0.343 mmol). The resulting solution was stirred at 0° C. for 1 hr and concentrated to dryness. The residue was then poured onto 1N HCl solution, followed by extraction with ether. The aqueous layer was then basified with 10% NH4OH solution and then extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated to dryness affording Compound (391a) (isomer 1) (0.02 g, 42.5% yield, MH+=554.1).

[2190] Starting with Compound (388b) from Preparative Example 46, Step C, and reacting in the same manner as above, Compound (391b) (isomer 2) was prepared (MH+=554.1).

PREPARATIVE EXAMPLE 47

[2191]

638

[2192] To a solution of Compound (392) prepared according to the procedure in, The Journal of Medicinal Chemistry (1998), 41(10), 1563 (5.0 g, 9.24 mmol) in MeOH (20 mL) and toluene (50 mL), at room temperature, was added triphenylphosphine (1.21 g, 4.62 mmol), DBU (1.90 g, 12.48 mmol) and palladium chloride (0.16 g, 0.92 mmol). The resulting solution was stirred at 80° C. for 6 hrs, then stirred at room temperature overnight. The solution was then concentrated to dryness to give two products. The desired product was purified by column chromatography on normal phase silica gel, eluting with 30% EtOAc/70%hexane to give a white solid compound (394) (2.24 g, 47% yield, MH+=521.1)

639

[2193] A solution of Compound (394) from Step A above (2.38 g, 4.58 mmol) in concentrated HCL (40 mL) was heated to reflux over night. The solution was then cooled down at room temperature and basified with NH4OH solution, followed by extraction with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give a white solid Compound (395) (1.03 g, 52% yield, MH+=435.1).

640

[2194] To a solution of Compound (395) from Step B (1.03 g, 2.37 mmol) in EtOH (50 mL, 200 proof) at room temperature, was bubbled in anhydrous CH2Cl2 gas for 5 minutes. The solution was then heated at 60° C. for 30 minutes, cooled down to room temperature and concentrated to dryness to afford Compound (396) (1.1 g, 100% yield, MH+=463.1)

641

[2195] To a solution of Compound (396) from Step C (1.09 g, 2.19 mmol) in THF (10 mL) at 0° C. was added dropwise DIBAL/toluene (11.0 mL, 10.95 mmol). The resulting solution was stirred overnight at room temperature, then quenched with H2O and concentrated to dryness to give a light brown solid Compound (397) (1.2 g, 100% yield, MH+=421.1).

642

[2196] To a solution of Compound (397) from Step D (0.92 g, 2.19 mmol) in 50% MeOH/1% H2O (50 mL) at room temperature, was added Boc anhydride (0.95 g, 4.38 mmol). The resulting solution was adjusted to pH=9 and stirred at room temperature for 4 hrs and concentrated to dryness, followed by extraction with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give a light brown solid Compound (398) (0.91 g, 80% yield, MH+=521.1).

643

[2197] To a solution of Compound (398) from Step E (0.91 g, 1.75 mmol) in CH2Cl2 (10 mL) was added triethyl amine (0.73 mL, 5.25 mmol) and methanesulfonyl chloride (0.3 g, 2.62 mmol). The resulting solution was stirred at room temperature overnight and then washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to give the mesylate as a light yellow solid Compound (399) (0.94 g, 90% yield).

644

[2198] To a solution of Compound (399) from Step F (0.93 g, 1.60 mmol) in DMF (10 mL) under nitrogen, was added 2-methylimidazole (0.19 g, 2.3 mmol) and NaH (0.037 g). The resulting solution was stirred at room temperature for 15 minutes, then at 90° C. for 3 hrs. The solution was then cooled down to room temperature and concentrated to dryness, followed by extraction with CH2Cl2-NaHCO3. The combined organic layer was dried over MgSO4, filtered, concentrated and purified by column chromatography on normal phase silica gel, eluting with 5%MeOH—NH3/95%CH2Cl2 to give mixture of two isomers as a light red solid (0.39 g, 42% yield, MH+=585.1). The 2 isomers were separated by prep HPLC, using a chiral AD column, eluting with 15%IPA/85%hexane/0.2%DEA to give Compound (400a) (isomer 1) as a light brown solid (0.10 g, 11% yield) and Compound (400b) (isomer 2) as a white solid (0.10 g, 11% yield)

645

[2199] A solution of Compound (400a) (isomer 1) from Step G above (0.07 g, 0.12 mmol) in 4M HCl/Dioxane (3 mL) was stirred at room temperature for 3 hrs then concentrated to dryness to give a white solid Compound (401) (0.06 g, 100% yield)

646

[2200] To a solution of Compound (401) from Step H above (0.057 g, 0.12 mmol) in CH2Cl2 (5 mL) under nitrogen, was added triethyl amine (0.026 g, 0.20 mmol) and 4-cyanophenyl isocyanate (0.019 g, 0.13 mmol). The resulting solution was stirred at room temperature overnight and then extracted with CH2Cl2-NaHCO3. The combined organic layer was dried over Na2SO4, filtered, concentrated to dryness to afford Compound (402) (isomer 1) as a white solid (0.053 g, 70% yield, MH+=629.3)

647

[2201] Compound (400b) was reacted in a similar manner as in Steps H and I above to afford Compound (403) (isomer 2) (0.059 g, 79% yield, MH+=629.3)

PREPARATIVE EXAMPLE 48

[2202]

648

[2203] Compound (371a) (isomer 1) from Preparative Example 42, Step F (70 mg, 0.17 mmol) was dissolved in 1 mL of ethanol and 50 uL of triethylamine. Dimethyl-N-cyanimidothiocarbonate (45 mg, 0.29 mmol) was added and the reaction mixture and stirred at 85° C. for 24 hours. The ethanol was evaporated under reduced pressure and the product chromatographed on silica gel using 5% methanolic-ammonia dichloromethane to obtain 47 mg of title product Compound (404) (FABMS M+1=504).

EXAMPLE 179

[2204]

649

[2205] To a solution of para-cyanoanaline (53 mg, 0.45 mmol) in 1 ml N,N-dimethylformamide was added sodium hydride (18 mg, 0.45 mmol). After stirring under a dry nitrogen atmosphere for ½ hour, Compound (404) (isomer 1) from Preparative Example 48 above (40 mg, 0.08 mmol) was added and the reaction mixture stirred at 55° C. for 4 hours. The reaction mixture was cooled to ambient temperature and added to brine. The crude product was extracted with dichloromethane 3 times. The extracts were concentrated and the crude product chromatographed on silica gel using 5% methanolic-ammonia/dichloromethane to otain 17.6 mg of title product.(405) FABMS M+1=574.1

EXAMPLES 180 AND 181

[2206]

650

[2207] Compound (696a) from Preparative Example 59, Step B, was reacted in the same manner as in Preparative Example 48 and Example 179 substituting the appropriate R reagent to afford the compounds in Table 24.

24TABLE 24EX. #R =CMPD #PHYS. DATA180

651

407FABMS MH+ = 601.1181

652

408FABMS MH+ = 531.1

PREPARATIVE EXAMPLE 49

[2208]

653

[2209] Compounds (51) and (52) from Example 11, Step A, were reacted with TFA in CH2Cl2 to afford compounds (51 a) and (52a).

654

[2210] A library of compounds was prepared by solution phase parallel synthesis. A generic structure of these compounds is shown in FIG. 1 above. The R1A group on the imidazole ring can be H or CH3, the R2A on N-1 of the piperidine is varied in the library.

[2211] Library compounds were prepared using compound (29) from Preparative Example 4 or Compounds (51 a) or (52a) from Preparative Example 49 above as templates as shown in Scheme A. Synthesis is initiated in test tubes by reacting compound (29), (51 a) or (52a) with multiple equivalents of a variety of isocyanates, amines, acids, acid chlorides, sulfonyl chlorides and chloroformates in dichloromethane or chloroform. When urea is the desired product, the reaction can be carried out using isocyanates directly, or alternatively, treating an amine with CDI for several hours, then subject the templates to this solution overnight. When acids are used, the reaction is carried out in the presence of a coupling reagent such as PyBrop and a base such as DIEA overnight. When acid chlorides, sulfonyl chlorides or chloroformates are used, the reaction is typically conducted in the presence of triethylamine. After reaction, an excess amount of polystyrene aminomethyl resin is added to the reaction test tubes, and the reaction allowed to stand overnight. At which time each test tube is filtered through a Bio-Rad Poly-Prep chromatography column into another test tube, and the resin is washed with dichloromethane and MeOH. The combined filtrate solution is concentrated by rotovap evaporation. The residue in each test tube is then dissolved in H2O/CH3CN (50/50, containing 1% TFA) and purified by Gilson 215 liquid Handling-HPLC system to give pure product. The product was identified by mass spectroscopy. Library compounds prepared in this fashion are shown in Table 25 and Table 26.

655

EXAMPLES 182-283

[2212]

656

[2213] (R2A is defined in Table 2)

[2214] The R2A groups in Table 25 contain either a —C(O)— or —SO2— moiety. Those skilled in the art will appreciate that the R2A group is bound to the nitrogen in the above formula by a bond to the carbon of the —C(O)— moiety or by a bond to the sulfur of the —SO2— moiety.

25TABLE 25EXAMPLE #.R2ACOMPOUND #PHYSICAL DATA182

657

409Mass spec. MH+ = 552183

658

410Mass spec. MH+ = 556184

659

411Mass spec. MH+ = 571185

660

412Mass spec. MH+ = 538186

661

413Mass spec. MH+ = 568187

662

414Mass spec. MH+ = 557188

663

415Mass spec. MH+ = 544189

664

416Mass spec. MH+ = 572190

665

417Mass spec. MH+ = 606191

666

418Mass spec. MH+ = 574192

667

419Mass spec. MH+ = 574193

668

420Mass spec. MH+ = 573194

669

421Mass spec. MH+ = 519195

670

422Mass spec. MH+ = 563196

671

423Mass spec. MH+ = 539197

672

424Mass spec. MH+ = 566198

673

425Mass spec. MH+ = 505199

674

426Mass spec. MH+ = 539200

675

427Mass spec. MH+ = 544201

676

428Mass spec. MH+ = 580202

677

429Mass spec. MH+ = 556203

678

430Mass spec. MH+ = 606204

679

431Mass spec. MH+ = 518205

680

432Mass spec. MH+ = 568206

681

433Mass spec. MH+ = 574207

682

434Mass spec. MH+ = 538208

683

435Mass spec. MH+ = 580209

684

436Mass spec. MH+ = 572210

685

437Mass spec. MH+ = 553211

686

438Mass spec. MH+ = 581212

687

439Mass spec. MH+ = 538213

688

440Mass spec. MH+ = 553214

689

441Mass spec. MH+ = 497215

690

442Mass spec. MH+ = 555216

691

443Mass spec. MH+ = 538217

692

444Mass spec. MH+ = 606218

693

445Mass spec. MH+ = 556219

694

446Mass spec. MH+ = 606220

695

447Mass spec. MH+ = 519221

696

448Mass spec. MH+ = 640222

697

449Mass spec. MH+ = 630223

698

450Mass spec. MH+ = 604224

699

451Mass spec. MH+ = 610225

700

452Mass spec. MH+ = 553226

701

453Mass spec. MH+ = 568227

702

454Mass spec. M+ = 572228

703

455Mass spec. MH+ = 624229

704

456Mass spec. MH+ = 572230

705

457Mass spec. MH+ = 554231

706

458Mass spec. MH+ = 552232

707

459Mass spec. MH+ = 552233

708

460Mass spec. MH+ = 598234

709

461Mass spec. MH+ = 570235

710

462Mass spec. MH+ = 610236

711

463Mass spec. MH+ = 563237

712

464Mass spec. MH+ = 504238

713

465Mass spec. MH+ = 566239

714

466Mass spec. MH+ = 574240

715

467Mass spec. MH+ = 543241

716

468Mass spec. MH+ = 518242

717

469Mass spec. MH+ = 582243

718

470Mass spec. MH+ = 519244

719

471Mass spec. MH+ = 543245

720

472Mass spec. MH+ = 610246

721

473Mass spec. MH+ = 518247

722

474Mass spec. MH+ = 529248

723

475Mass spec. MH+ = 513249

724

476Mass spec. MH+ = 606250

725

477Mass spec. MH+ = 491251

726

478Mass spec. MH+ = 606252

727

479Mass spec. MH+ = 548253

728

480Mass spec. MH+ = 487254

729

481Mass spec. MH+ = 539255

730

482Mass spec. MH+ = 562256

731

483Mass spec. MH+ = 565257

732

484Mass spec. MH+ = 526258

733

485Mass spec. MH+ = 598259

734

486Mass spec. MH+ = 548260

735

487Mass spec. MH+ = 580261

736

488Mass spec. MH+ = 598262

737

489Mass spec. MH+ = 529263

738

490Mass spec. MH+ = 475264

739

491Mass spec. MH+ = 573265

740

492Mass spec. MH+ = 525266

741

493Mass spec. MH+ = 518267

742

494Mass spec. MH+ = 577268

743

495Mass spec. MH+ = 532269

744

496Mass spec. MH+ = 516270

745

497Mass spec. MH+ = 524271

746

498Mass spec. MH+ = 557272

747

499Mass spec. MH+ = 524273

748

500Mass spec. MH+ = 584274

749

501Mass spec. MH+ = 584275

750

502Mass spec. MH+ = 573276

751

503Mass spec. MH+ = 491277

752

504Mass spec. MH+ = 603278

753

505Mass spec. MH+ = 589279

754

506Mass spec. MH+ = 616280

755

507Mass spec. MH+ = 584281

756

508Mass spec. MH+ = 603282

757

509Mass spec. MH+ = 490283

758

510Mass spec. MH+ = 593

EXAMPLES 284-377

[2215]

759

[2216] (R2A is defined in Table 26).

26TABLE 26EXAMPLE #R2ACOMPOUND #MH+284

760

511571285

761

512552286

762

513587287

763

514558288

764

515577289

765

516570290

766

517588291

767

518558292

768

519586293

769

520588294

770

521594295

771

522570296

772

523588297

773

524559298

774

525620299

775

526569300

776

527582301

777

528585302

778

529570303

779

530552304

780

531588305

781

532562306

782

533594307

783

534620308

784

535587309

785

536586310

786

537595311

787

538620312

788

539532313

789

540586314

790

541547315

791

542638316

792

543533317

793

544586318

794

545577319

795

546532320

796

547582321

797

548553322

798

549566323

799

550567324

800

551519325

801

552543326

802

553557327

803

554584328

804

555620329

805

556624330

806

557612331

807

558624332

808

559505333

809

560540334

810

561644335

811

562539336

812

563624337

813

564579338

814

565517339

815

566582340

816

567620341

817

568501342

818

569598343

819

570543344

820

571518345

821

572580346

822

573546347

823

574596348

824

575565349

825

576575350

826

577555351

827

578598352

828

579532353

829

580504354

830

581527355

831

582489356

832

583531357

833

584562358

834

585562359

835

586630360

836

587538361

837

588530362

838

589591363

839

590612364

840

591603365

841

592620366

842

593598367

843

594587368

844

595538369

845

596607370

846

597538371

847

598571372

848

599612373

849

600533374

850

601505375

851

602617376

852

603617377

853

604605

PREPARATIVE EXAMPLE 50

[2217]

854

[2218] Compound (365) from Preparative Example 41 was reacted in essentially the same manner as in Preparative Example 4, substituting the appropriate imidazole to obtain Compound (605) wherein R1═H or Compounds (606) and (607)/(608) wherein R1=(2 or 4/5)CH3.

855

[2219] Compounds (607) and (608) from Step A above were treated in the same manner as described in Example 11 to afford pure (+,−) 4-methylimidazole, and pure (+,−) 5-methylimidazole enantiomers; Compound (607a),(607b) and Compound (608a), (608b) respectively.

[2220] A library of compounds was prepared by the method described above starting with Compound (605), Compound (606), Compounds (607)/(608), (607a), (607b) or Compounds (608a) or (608b) used as the templates in Scheme A. A generic structure of these compounds is shown in FIG. 2 above. The R1A group on the imidazole ring can be H or CH3, the R2A on N-1 of the piperazine is varied in the library. Library compounds prepared in this fashion are shown in Table 27, Table 28 and Table 29.

EXAMPLES (378)-(396)

[2221]

856

[2222] (R2A is defined in Table 27).

27TABLE 27PHYSICAL DATAEXAMPLE #R2ACOMPOUND #(MH+)378

857

607564379

858

608 1st Enantiomer564380

859

609 2nd Enantiomer564381

860

610575382

861

611553383

862

612564384

863

613564385

864

614520386

865

615 1st Isomer520387

866

616 2nd Isomer520388

867

617558389

868

618557390

869

619545391

870

620 1st Isomer545392

871

621 2nd Isomer545393

872

622573394

873

623555395

874

624567396H6254204 TFA

EXAMPLES 397-401

[2223]

875

[2224] (R2A is defined in Table 28)

28TABLE 28EXAMPLE #R2COMPOUND #PHYSICAL DATA397

876

626 2 IsomersMass spec. MH+ = 578398

877

627 2nd EnantiomerMass spec. MH+ = 578399

878

628 2nd EnantiomerMass spec. MH+ = 578400

879

629 1st EnantiomerMass spec. MH+ = 578401

880

630 2 IsomersMass spec. MH+ = 534

EXAMPLES 402-406

[2225]

881

[2226] (R2A is defined in Table 29).

29TABLE 29EXAMPLE #R2COMPOUND #PHYSICAL DATA402

882

631 Mixture of 4-Me and 5-MeMass spec. MH+ = 578403

883

632 2nd enantiomer of 4-MeMass spec. MH+= 578404

884

633 2nd enantiomer of 5-Me 1st enantiomer of 4-MeMass spec. MH+ = 578405

885

634 1st enantiomer of 5-MeMass spec. MH+ = 578406

886

635 Mixture of 4-Me and 5-MeMass spec. MH+=534

PREPARATIVE EXAMPLE 51

[2227]

887

[2228] Compound (365) from Preparative Example 41, was reacted in essentially the same manner as Preparative Example 35 substituting Imidazole for 1-Methyl Imidazole in Step B to afford Compound (636) (MH+=406). Compound (636) was then reacted in the library fashion as described above following the procedure of Scheme A to afford the compounds in Table 30 below:

888

[2229] (R2A is defined in Table 30).

30TABLE 30EXAMPLE #R2COMPOUND #PHYSICAL DATA407

889

637Mass spec. MH+ = 550408

890

638 2nd EnantiomerMass spec. MH+ = 550409

891

639 1st EnantiomerMass spec. MH+ = 550410

892

640Mass spec. MH+ = 506

PREPARATIVE EXAMPLE 52

[2230]

893

[2231] Compound (365) was reacted as above in Preparative Example 51, substituting 1-Methyl Imidazole for Imidazole to afford Compound (641) (MH+=420). Compound (641) was then further reacted in the Library fashion described above following the procedure in Scheme A to afford the compounds in Table 31 below.

894

[2232] (R2A is defined in Table 31).

31TABLE 31EXAPLE #R2COMPOUND #PHYSICAL DATA411

895

642Mass spec. MH+ = 520412

896

643Mass spec. MH+ = 564413

897

644 1st EnantiomerMass spec. MH+ = 564414

898

645 2nd EnantiomerMass spec. MH+ = 564

EXAMPLE 415

[2233]

899

[2234] In the essentially the same manner as in Preparative Example 52 above, substituting 4-methylimidazole, the intermediate amine template was prepared Compound (646). This was then reacted in essentially the same manner as in Examples 411-414 above to afford the product Compound (647) as a mixture of 4 and 5-methylimidazole isomers (Mass spec. MH+=564).

PREPARATIVE EXAMPLE 53

[2235]

900

[2236] The racemic Compound (242) from Example 91 was separated by preparative chiral chromatography (Chiralpack AD, 5 cm×50 cm column, flow rate 100 mL/min., 20% 2-propanol/hexane+0.2% diethylamine) to afford the two enantiomers (242a) and (242b).

[2237] Compound (242a), [α]D25=+144.8° (3.16 mg/2 mL MeOH)

[2238] Compound (242b), [α]D25=−144.8° (2.93 mg/2 mL MeOH)

PREPARATIVE EXAMPLE 54

[2239]

901

242a
648 (+ enantiomer, A)

242b
649 (− enantiomer, B)

[2240] Compounds (242a) and (242b) from Preparative Example 53 above were reacted separately in essentially the same manner as Preparative Example 19, Step D to obtain the hydrochloride salt of compounds Compound (648) and Compound (649).

[2241] (648) (+ enantiomer, isomer A), MH+=406.1793

[2242] (649) (− enantiomer, isomer B), MH+=406.1789

PREPARATIVE EXAMPLE 55

[2243]

902

[2244] R=BOC

[2245] (650) (+ enantiomer, A)

[2246] (651) (− enantiomer, B)

[2247] R=H

[2248] (652) (+ enantiomer, A)

[2249] (653) (− enantiomer, B)

[2250] 3-bromo-8-chloroazaketone (U.S. Pat. No. 5,977,128, Preparative Example 11, step A, (1999)) was reacted in essentially the same manner as in Preparative Example 23, and Example 91 to obtain the N-BOC derivatives (650) and (651). Compounds (650) and (651) were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (652) (+ enantiomer, isomer A) and (653) (− enantiomer, isomer B).

[2251] Compound (650), BOC derivative, [α]D25=+69.6° (2.5 mg/2 mL MeOH)

[2252] Compound (651), BOC derivative, [α]D25=−90.0° (3.3 mg/2 mL MeOH)

[2253] Compound (652) (+ enantiomer, isomer A), MH+=485

[2254] Compound (653) (− enantiomer, isomer B), MH+=485

PREPARATIVE EXAMPLE 56

[2255]

903

[2256] Compound (654a) (202 g; 0.7 mole) (J. Org. Chem. 1998, 63, 445) was dissolved in ethanol (5 L). To this mixture was added 12 N HCl (80 ml) and iron powder (180 g) and the reaction was refluxed over night. Additional HCl and iron was added to complete the reaction. The reaction mixture was filtered and the precipitate washed with hot methanol (1L). The filtrate was concentrated under vacuum to approximately 600 ml then partitioned between 4 L CH2CL2 and 1.3 L of 1.3 N NaOH. The organic layer was dried over MgSO4 and filtered hot. The filtrate was concentrated under vacuum to give the aminoketone Compound (654) (184 g).

904

[2257] Compound (654) from Step A above (15 g; 57.98 mmol), was dissolved in 750 mL of ethanol containing 3.75 g of 5% Pd/C (50% in water) and 37.69 g (579.82 m mol) of ammonium formate. The mixture was brought to reflux for 2.5 hr then stirred at room temperature overnight. The reaction was filtered concentrated under vacuum and chromatographed on silica gel using 95:5 methylene chloride (saturated with ammonia) and methanol to give 6.15 g of the pure product Compound (655) as a yellow solid.

905

[2258] To a slurry of Compound (655) (4.79 g; 21.37 mmol) from Step A above, in 75 mL of acetonitrile cooled to 0° C. and under nitrogen, was added t-butylnitrite (10.31 g; 32.05 mmol) and CuCl2 (3.45 g; 24.64 mmol). The mixture was warmed to room temp stirrd over night and then concentrated under vacuum. The residue was slurried in 30 mL of 1N HCl, then neutralized with aqueous NH4OH and extracted with 3×100 mL of ethyl acetate. The organic layer was dried over Na2SO4, concentrated under vacuum, and chromatographed on silica gel using hexane:ethyl acetate (70:30) to obtain the pure product Compound (656).

906

R = BOCR = BOC(657) (+ enantiomer, A)(657.1) (+ enantiomer, A)(658) (− enantiomer, B)(658.1) (− enantiomer, B)R = HR = H(659) (+ enantiomer, A)(659.1) (+ enantiomer, A)(660) (− enantiomer, B)(660.1) (− enantiomer, B)

[2259] Compound (656) from Step B above was reacted in essentially the same manner as in Preparative Example 23, and then Example 91 to obtain the N-BOC derivatives (657), (658), (657.1) and (658.1). Compounds (657), (658), (657.1) and (658.1) were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (659) (+ enantiomer, isomer A), (659.1) (+ enantiomer, isomer A), (660) (− enantiomer, isomer B) and (660.1) (− enantiomer, isomer B).

[2260] Compound (657), BOC derivative, [α]D25=+59,9° (3.3 mg/2 mL MeOH)

[2261] Compound (658), BOC derivative, [α]D25=−57.1° (3.3 mg/2 mL MeOH)

[2262] Compound (659), (+ enantiomer, isomer A), MH+=406

[2263] Compound (660), (− enantiomer, isomer B), MH+=406

[2264] Compound (659.1), (+ enantiomer, isomer A), MH+=406

[2265] Compound (660.1), (− enantiomer, isomer B), MH+=406

PREPARATIVE EXAMPLE 57

[2266]

907

R = BOC

(662) (+ enantiomer, A)
(663) (+ enantiomer, A)

(664) (− enantiomer, B)
(665) (− enantiomer, B)

R = H

(666) (+ enantiomer, A)
(667) (+enantiomer, A)

(668) (− enantiomer, B)
(669) (− enantiomer, B)

[2267] Compound (661) was reacted in essentially the same manner as in Preparative Example 23, and then Example 91 to obtain the N-BOC derivatives (662), (663), (664) and (665). Compounds (662), (663), (664) and (665) were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (666) and (667) (+ enantiomer, isomer A) and (668) and (669) (− enantiomer, isomer B). The C5 and C-6 vinyl bromide intermediates were separated by silica gel chromatography using hexane:ethyl acetate (80:20) in essentially the same manner as was described in Preparative Example 23, Step B.

[2268] Compound (662), BOC derivative

[2269] Compound (663), BOC derivative

[2270] Compound (664), BOC derivative

[2271] Compound (665), BOC derivative

[2272] Compound (666) (+ enantiomer, isomer A), MH+=372

[2273] Compound (667) (+ enantiomer, isomer A), MH+=372

[2274] Compound (668) (− enantiomer, isomer B), MH+=372

[2275] Compound (669) (− enantiomer, isomer B), MH+=372

PREPARATIVE EXAMPLE 58

[2276]

908

R = BOC

(670) (+ enantiomer, A)
(671) (+ enantiomer, A)

(672) (− enantiomer, B)
(673) (− enantiomer, B)

R = H

(674) (+ enantiomer, A)
(675) (+ enantiomer, A)

(676) (− enantiomer, B)
(677) (− enantiomer, B)

[2277] Compound (661) was reacted in essentially the same manner as in Preparative Example 23, and Example 91 substituting 2-ethylimidazole for 2-methylimidazole, to obtain the N-BOC derivatives (670), (671), (672) and (673). Compounds (670), (671), (672) and (673) were then reacted separately in essentially the same manner as in Preparative Example 19, Step D, to obtain the enantiomers (674) and (675) (+ enantiomer, isomer A) and (676) and (677) (− enantiomer, isomer B). The C5 and C-6 vinyl bromide intermediates were separated by silica gel chromatography using hexane:ethyl acetate (80:20) as described in Preparative Example 23, Step B.

[2278] Compound (670), BOC derivative, (+ enantiomer, A)

[2279] Compound (671), BOC derivative, (+ enantiomer, A)

[2280] Compound (672), BOC derivative, (− enantiomer, B)

[2281] Compound (673), BOC derivative, (− enantiomer, B)

[2282] Compound (674), (+ enantiomer, isomer A), MH+=386

[2283] Compound (675), (+ enantiomer, isomer A), MH+=386

[2284] Compound (676), (− enantiomer, isomer B), MH+=386

[2285] Compound (677), (− enantiomer, isomer B), MH+=386

EXAMPLES 416-419

[2286]

909

[2287] (R is defined in Table 32).

[2288] The appropriate (+) enantiomer (648) or (−) enantiomer (649) from Preparative Example 54 above, was taken up in CH2Cl2 treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 32 below.

36TABLE 32Example#REnantiomerComp #Phys. Data.416

910

+678Mp = 162.2-165.6° C. [α]D25= +98.2° (3 mg/ 2 mL MeOH)417

911

−679Mp = 158.1-164.5° C. [α]D25= −81.2° (2.6 mg/ 2 mL MeOH)418

912

+680Mp = 161.5-164.8° C. MH+ = 559.1787419

913

+681Mp 157.7-161.7° C. MH+ = 543.2069

EXAMPLES 420 AND 421

[2289]

914

[2290] (R is defined in Table 33).

[2291] The appropriate (+) enantiomer (652) or (−) enantiomer (653) from Preparative Example 55 above, was taken up in CH2Cl2 treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 33 below.

37TABLE 33Example #REnantiomerComp #Phys. Data.420

915

+682Mp = 168.8-172.3° C.421

916

−683Mp = 172.5-177.7° C.421.1

917

+683.1Mp = 157.1-160.5° C. (dec)421.2

918

+683.2Mp = 223.6-229.1° C. (dec)

EXAMPLES 422 AND 423

[2292]

919

[2293] (R is defined in Table 34).

[2294] The appropriate compound (659) (+) enantiomer, (660) (−) enantiomer or (659A) (+) enantiomer from Preparative Example 56 above, was taken up in CH2Cl2 treated with the corresponding isocyanate and stirred at room temperature over night. The Crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 34 below.

38TABLE 34Example #REnantiomerComp #Phys. Data.422

920

+684Mp = 155.9-165.1° C.423

921

−685Mp = 154.2-164.8° C.492

922

+806Mp = 157.1-160.5° C. MH+=689

EXAMPLES 424 AND 425

[2295]

923

[2296] (R is defined in Table 35).

[2297] The appropriate (+) enantiomer (666) or (−) enantiomer (668) from Preparative Example 57 above, was taken up in CH2Cl2, treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 35 below.

39TABLE 35Example #REnantiomerComp #Phys. Data.424

924

+686Mp = 166-170° C. [α]D25= +106.8°(1.45 mg/2 mL MeOH)425

925

−687Mp=170-176° C. [α]D25=−91° (2.78 mg/2 mL MeOH)

EXAMPLES 426 AND 427

[2298]

926

[2299] (R is defined in Table 36).

[2300] The appropriate (+) enantiomer (674) or (−) enantiomer (676) from Preparative Example 58 above, was taken up in CH2Cl2, treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 36 below.

40TABLE 36Example #REnantiomerComp #Phys. Data.426

927

+688Mp = 150-153° C.427

928

−689Mp = 154-158° C.

EXAMPLES 428 AND 429

[2301]

929

[2302] (R is defined in Table 37).

[2303] The appropriate (+) enantiomer (667) or (−) enantiomer (669) from Preparative Example 57 above, was taken up in CH2Cl2, treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 37 below.

41TABLE 37Exam-pleEnan-Phys.#RtiomerComp #Data.428

930

Isomer 1690MH+ =516429

931

Isomer 2691MH+ =516

EXAMPLES 430 AND 431

[2304]

932

[2305] (R is defined in Table 38).

[2306] The appropriate (+) enantiomer (675) or (−) enantiomer (677) from Preparative Example 58 above, was taken up in CH2Cl2, treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford the following compounds in Table 38 below.

42TABLE 38Exam-pleEnan-Phys.#RtiomerComp #Data.430

933

Isomer 1692MH+ =530431

934

Isomer 2693MH+ =530

PREPARATIVE EXAMPLE 59

[2307]

935

936

937

[2308] To a stirred solution of 2-methylimidazole (1.80 g, 21.97 mmol) in anhydrous DMF (40 mL) at room temperature, was added NaH (5.3 g, 21.97 mmol) and Compound (27) from Preparative Example 4, Step E (4.0 g, 7.33 mmol). The resulting solution was stirred at room remperature for 1 hr and concentrated to dryness. followed by extraction with EtOAc-NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the mixture of single bond and double bond compounds. These compounds were further purified by column chromatography on silica gel, eluting with 2%MeOH/NH3/98%CH2Ci2 to yield: Pure Compound (694) (0.450 g) (MH+=533) and a mixture of (694) and Compound (695) (2.55 g)(MH+=535).

[2309] Compounds (694) and (695) were further purified by chiral prep HPLC, eluting with 15%IPA/85%Hexane/0.2%DEA to give: Compound (695a) (isomer 1; 0.58 g, MH+=535.4) and Compound (694a) (isomer 1; 0.61 g, MH+=533) and a mixture of compounds (694b) and (695b) (isomer 2 products; 0.84 g).

938

[2310] The mixture of compounds (694b/695b) from Step A above (0.8 g, 1.5 mmol) in 4N HCl/Dioxane (40 mL) was stirred at room temperature for 3 hrs and concentrated to dryness to give a mixture of deprotected compounds as product. The product was further purified by chiral HPLC, eluting with 15%1PA/85% hexane/0.2%DEA to give the pure compound (696b) (isomer 2; 0.29 g) and pure Compound (697b) (isomer 2, 0.19 g).

939

[2311] Compounds (694a) and (695a) (pure isomer 1) were individually deprotected using 4N HCl/Dioxane in essentially the same method as that of the isomer 2 products described above, to give the corresponding N—H products (696a) (isomer 1) and (697a) (isomer 1).

EXAMPLES 432-437

[2312] Reacting Compound (696a) (isomer 1) in essentially the same manner as in Example 3 with the appropriate chloroformate or isocyanate, the following compounds listed in Table 39 below, were prepared.

940

[2313] (R is defined in Table 39).

43TABLE 39EXAMPLE #RCOMPOUND #PHYSICAL DATA432

941

698MH+ = 519.1433

942

699MH+ = 577.1434

943

700MH+ = 570.1435

944

701MH+ = 585.1436

945

702—437

946

703MH+ = 558.1

EXAMPLES 438-442

[2314] Reacting Compound (697a) (isomer 1) in essentially the same manner as in Example 3 with the appropriate chloroformate or isocyanate, the following compounds listed in Table 40 below were prepared.

947

[2315] (R is defined in Table 40).

44TABLE 40EXAMPLE #RCOMPOUND #PHYSICAL DATA438

948

704MH+ = 521.1439

949

705MH+ = 579.1440

950

706MH+ = 572.1441

951

707MH+ = 587.1442

952

708MH+ = 560.1

PREPARATIVE EXAMPLE 60

[2316]

953

[2317] To a stirred solution of 4,5-Dimethylimidazole (1.08 g, 11.25 mmol) in anhydrous DMF (35 mL) at room temperature, was added NaH (0.27 g, 11.2 mmol) and stirred for 10 minutes, followed by the addition of Compound (27) from Preparative Example 4 Step E (4.0 g, 7.32 mmol). The resulting solution was srirred at room temperature overnight. To this solution was added the solution of 4,5-dimethylimidazole (0.35 g, 3.65 mmol) and NaH (0.088 g, 3.67 mmol) in DMF (5 mL). The resulting solution was heated at 80° C.-90° C. for 4 hrs, then cooled down to room temperature, followed by extraction with EtOAc-H2O. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness and purified by column chromatography on silica gel, eluting with 50%EtOAc/50%hexane to 5%MeOH/CH2Cl2 to give the mixture of products Compound (709) and Compound (710) (1.2 g, MH+=547.3). The products were further purified by prep chiral HPLC, using a chiral AD column, eluting with 15%1PA/85%hexane/0.2%DEA to give 4 seperate compounds:

[2318] Compound (709a) isomer 1, (0.291 g, MH+=547.3), Compound (710a) isomer 1, (0.305 g, MH+=549.3) and

[2319] Compound (709b) isomer 2, (0.280 g, MH+=547.3), Compound (710b) isomer 2, (0.2 g, MH+=549.3)

954

[2320] A solution of Compound (710a), isomer 1 (0.245 g, 0.45 mmol) in 4N HCl/Dioxane (2 mL) was stirred at room temperature for 3 hrs then concentrated to dryness to give Compound (711a) isomer 1, product (0.184 g, 98% yield) (MH+=455.1).

[2321] Compounds (711b), (isomer 2); (712a) (isomer 1) and (712b) (isomer 2) were all prepared in a similar fashion to that of Compound (711a) isomer 1 in Step B above.

[2322] (711b) (0.085 g, 75% yield).

[2323] (712a) (0.141 g, 75% yield).

[2324] (712b) (0.106 g, 59% yield).

EXAMPLES 443-447

[2325] Reacting Compounds (711a) and (711b) seperately following the procedure described in Example 13 with the appropriate chloroformates or isocyanates, the following compounds listed in Table 41 below were prepared.

955

[2326] (R is defined in Table 41).

45TABLE 41EXAMPLE #RCOMPOUND #PHYSICAL DATA443

956

713MH+ = 575.1444

957

714MH+ = 575.1445

958

715MH+ = 593.2446

959

716MH+ = 593.2447

960

717MH+ = 586.1

EXAMPLES 448-454

[2327] Reacting Compounds (712a) and (712b) seperately following the procedure described in Example 13 with the appropriate chloroformates or isocyanates, the compounds listed in Table 42 below were prepared.

961

[2328] (R is defined in Table 42).

46TABLE 42EXAMPLE #RCOMPOUND #PHYSICAL DATA448

962

718MH+ = 573.1449

963

719MH+ = 573.1450

964

720MH+ = 591.1451

965

721MH+ = 591.1452

966

722MH+ = 584.1453

967

723MH+ = 525.1454

968

724MH+ = 525.1

PREPARATIVE EXAMPLE 61

[2329]

969

[2330] Compound (27) from Preparative Example 4, Step E was reacted in essentially the same manner as described in Preparative Example 60, Step A above substituting 4-Methylimidazole for 4,5-Dimethylimidazole to obtain four seperate compounds as products (BOC derivatives).

[2331] Compound (725a) isomer 1, (0.69 g, MH+=533.1).

[2332] Compound (725b) isomer 2, (0.10 g, MH+=533.1).

[2333] Compound (726a) isomer 1, (0.35 g, MH+=535.1).

[2334] Compound (726b) isomer 2, (0.22 g, MH+=535.1).

970

[2335] In essentially the same manner as described in Preparative Example 60, Step B, the —NH derivatives were prepared:

[2336] Compounds:

[2337] (727a) isomer 1 (0.3 g, 100% yield, MH+=435.1);

[2338] (727b) isomer 2;

[2339] (728a) isomer 1; and

[2340] (728b) isomer 2.

EXAMPLES 455-459

[2341] Reacting Compounds (727a) and (727b) seperately following the procedure described in Example 13 with the appropriate chloroformate or isocyanate, the following compounds listed in Table 43 below were prepared.

971

[2342] (R is defined in Table 43).

47TABLE 43EXAM-COM-PLEPOUNDPHYSICAL#R#DATA455

972

729MH+ = 561.1456

973

730MH+ = 581.1457

974

731MH+ = 572.1458

975

732MH+ = 560.1459

976

733MH+ = 513.1

EXAMPLES 460-469

[2343] Reacting Compounds (728a) and (728b) seperately following the procedure described in Example 13 with the appropriate chloroformates and isocyanates, the following compounds listed in Table 44 below were prepared.

977

[2344] (R is defined in Table 44).

48TABLE 44EXAM-COM-PLEPOUNDPHYSICAL#R#DATA460

978

734MH+ = 559.1461

979

735MH+ = 559.1462

980

736MH+ = 579.1463

981

737MH+ = 579.1464

982

738MH+ = 570.1465

983

739MH+ = 570.1466

984

740MH+ = 558.1467

985

741MH+ = 558.1468

986

742MH+ = 511.1469

987

743MH+ = 511.1

EXAMPLE 470

[2345]

988

[2346] To a stirred solution of Compound (24) from Preparative Example 4, Step D (4.0 g, 8.2 mmol) under nitrogen at room temperature, was added CuCl (0.7 g, 8.2 mmol). The solution was then cooled to 0° C., followed by portion wise addition of NaBH4 (4.66 g, 123,2 mmol). The resulting solution was stirred at 0° C. for 6 h., concentrated to dryness, then extracted with CH2Cl2-sat.NaHCO3. The combined organic layer was dried over MgSO4, filtered, concentrated and purified by column chromatography on 200 mL of normal phase silica gel, eluting with 20%EtOAc/CH2Cl2 to give Compound (744) (3.62 g, 99% yield, MH+=447).

989

[2347] To a stirred solution of Compound (744) from Step A above (3.0 g, 5.7 mmol) in CH2Cl2 (100 mL) under nitrogen at room temperature, was added triethyl amine (2.4 mL, 17.1 mmol) and methanesulfonyl chloride (0.98 g, 8.7 mmol). The resulting solution was stirred at room temperature over night, then washed with saturated NaHCO3. The combined organic layer was dried over Na2SO4, filtered, concentrated to dryness and purified by Biotage column chromatography, eluting with 30%EtOAc/70%CH2Cl2 to give Compound (745) as a white solid (1.19 g, MH+=525.1) and Compound (20) (1.31 g, MH+=489.1)

990

[2348] To a stirred solution of Compound (745) from Step B above (2.17 g, 4.3 mmol) in DMF (50 mL) under nitrogen at room temperature was added phthalimide potassium derivative (1.20 g, 0.5 mmol). The resulting solution was heated to 90° C. for 4 h., cooled down to room temperature, concentrated to dryness and extracted with CH2Cl2-sat.NaHCO3. The combined organic layer was dried over Na2SO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 50%-70%EtOAc/hexane to give Compound (746) as a white solid (1.76 g, 71% yield, MH+=577.0).

991

[2349] To a stirred solution of Compound (746) from Step C above (1.67 g, 2.9 mmol) in EtOH (50 mL) at room temperature, was added hydrazine monohydrate (0.29 g, 5.8 mmol). The resulting solution was heated to reflux for 4 h. cooled down to room temperature, concentrated to dryness and extracted with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give Compound (747) as a white solid (1.23 g, 95% yield, MH+=446.1)

992

[2350] To a stirred solution of Compound (747) from Step D (0.1 g, 0.22 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature, was added TEA (0.06 mL, 0.45 mmol) and methanesulfonyl chloride (0.038 g, 0.34 mmol). The resulting solution was stirred at room temperature over night, then washed with sat. NaHCO3. The combined organic layer was dried over Na2SO4, filtered and purified by column chromatography on silica gel, eluting with 3% MeOH—NH3/CH2Cl2 to give Compound (748) as a white solid (0.087 g, 76% yield, MH+=524.0)

EXAMPLE 471

[2351]

993

[2352] Reacting Compound (747) from Example 470 Step D above in essentially the same manner as in Step E of Example 470 substituting acetylchloride, Compound (749) was prepared.(0.048 g, 45% yield, MH+=488.2).

EXAMPLE 472

[2353]

994

[2354] Reacting Compound (747) from Example 470 Step D above in essentially the same manner as in Step E of Example 470 substituting 4-Chlorobutyryl chloride (ACROS), Compound (750) was prepared (0.67 g, 100% yiled, MH+=514.1).

995

[2355] To a stirred solution of Compound (750) from Step A (0.575 g, 1.11 mmol) in toluene (15 mL) under nitrogen at room temperature, was added K2CO3 (0.55 g, 4.01 mmol). The resulting solution was stirred at room temperature over the weekend then heated to 55° C. for 7 h. The solution was then cooled down to room temperature, filtered, concentrated to dryness and purified by column chromatography, eluting with 1.5%MeOH—NH3/98.5%CH2Cl2 to give Compound (751) as a white solid (0.15 g, 26% yield, MH+=524.1)

EXAMPLE 473

[2356]

996

[2357] To a stirred solution of Compound (20) from Example 470, Step B (0.67 g, 1.37 mmol) in THF (5 mL), was added 1N NaOH solution (6.9 mL, 6.88 mmol). The resulting solution was stirred at room temperature overnight arid concentrated to dryness. The solution was then acidified with 10% citric acid and then extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give Compound (752) as a light yellow product (0.33 g, 52% yield, MH+=461.1)

997

[2358] To a stirred solution of Compound (752) from Step A above (0.1 g, 0.23 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature, was added oxalyl chloride (0.97 g, 7.62 mmol) and diethyl amine (0.47 g, 6.43 mmol). The resulting solution was stirred at room temperature for 1 hr and concentrated to dryness. The crude product was then purified by column chromatography, eluting with 2%MeOH—NH3/98%CH2Cl2 to give Compound (753) as a white solid (0.051 g, 49.5% yield, MH+=516.1)

EXAMPLE 474

[2359]

998

[2360] To a stirred solution of 2-imidazolidone (0.22 g, 2.0 mmol) in DMF (10 mL) was added NaH (0.28 g, 2.0 mmol). The resulting solution was stirred at room temperature for 1 hr. This solution was then added into a solution of Compound (22) from Preparative Example 3, Step C (0.67 g, 1.3 mmol) in DMF (20 mL) under nitrogen inlet at room temperature. The resulting solution was heated to 90° C. for 2 hrs, concentrated to dryness, then extracted with CH2Cl2-sat.NaHCO3. The combined organic layer was then dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 3% MeOH—NH3/97% CH2Cl2 to give a light yellow solid (754) (0.17 g, 25% yield, MH+=515.1).

EXAMPLE 475

[2361]

999

[2362] To a stirred solution of Compound (12) from Preparative Example 2, Step B (15.75 g, 0.336 mmol) in DMF (200 mL) under nitrogen inlet at room temperature, was added trimethylsilylacetalene (12.14 g, 124 mmol), bis(triphenylphosphine)palladium (II)dichloride (0.47 g, 0.67 mmol), Et3N (13.1 mL, 94 mmol), CuI (0.89 g, 4.7 mmol) and NaI (1.53 g, 10 mmol). The resulting solution was stirred at room temperature overnight, concentrated to dryness, then extracted with CH2Cl2—H2O. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 20% EtOAc/80% hexane to give the product (755) (12.35 g, M=485).

1000

[2363] A solution of Compound (755) from Step A above (4.48 g, 9.24 mmol), in concentrated HCl (100 mL) was heated to reflux overnight. The solution was then cooled down to room temperature and basified with 50% NaOH solution (w/w) and then extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give an off white solid (756) (4.40 g, 100% yield, MH+=353.1).

1001

[2364] To a stirred solution of Compound (756) from step B (3.15 g, 8.93 mmol) in CH2Cl2 (100 mL) was added Et3N (2.5 mL, 17.85 mmol) and methanesulfonyl chloride (0.51 g, 4.46 mmol). The resulting solution was stirred at room temperature overnight. The solution was then washed with saturated NaHCO3 and the organic layer was dried over MgSO4, filtered and concentrated to dryness to give a crude product (4.31 g, 100% yield, MH+=431.1)

1002

[2365] The solution of Compound (757) from Step C (3.84 g, 8.91 mmol) in 4% NaClO (150 mL) and 45% NaOH solution (15 mL) was heated to reflux for 2 hrs, then cooled down to room temperature, followed by addition of saturated sodium bisulfite solution (150 mL). The solution was then adjusted to pH=6.5 and extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give a light yellow solid (3.31 g, 86% yield, MH+=433.1).

1003

[2366] To a stirred solution of Compound (758) from step D (3.31 g, 7.65 mmol) in toluene (80 mL) and MeOH (50 mL) under nitrogen at room temperature, was added (trimethylsilyl)diazomethane (2.0M in hexane)(3.4 mL, 68.8 mmol) at 0° C., until the colorless solution turned to yellow solution. The resulting solution was stirred at 0° C. for half an hour and concentrated to dryness to give a crude product (759).

[2367] To a stirred cooling solution of the crude product (759) from above, in THF (30 mL) at 0° C. was added DIBAL (15.3 mL, 15.3 mmol). The resulting solution was stirred at 0° C. for 2 hrs, followed by extraction with 10% citric acid and 1N NaOH solution. The combined organic layer was dried over MgSO4, filtered and concentrated to dryness to give a light yellow solid (760) (2.90 g, 90% yield, MH+=419.1).

1004

[2368] Reacting Compound (760) in essentially the same manner as Step C above, Compound (761) was prepared.

1005

[2369] To a stirred solution of 2-benzylaminopyridine (0.115 g, 0.624 mmol) in DMF (10 mL) at room temperature, was added NaH (9.81 g, 0.41 mmol) and stirred for 0.5 hr. To a stirred solution of mesylate compound from step F (0.2 g, 0.41 mmol) in DMF (10 mL) under nitrogen inlet, was added the solution of 2-benzylaminopyridine in DMF above. The resulting solution was heated to 90° C. for 3 hrs, concentrated to dryness followed by extraction with CH2Cl2-sat.NaHCO3, then dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 5% MeOH—NH3/CH2Cl2 to give a light yellow solid (762) (0.03 g, 13% yield, MH+=585.1).

EXAMPLE 476

[2370]

1006

[2371] In essentially the same manner as Example 475, Step E, Compound (763) was prepared.

1007

[2372] To a stirred solution of 4(5)-imidazolecarboxaldehyde (20.0 g, 0.208 mmol) in CH2Cl2 (200 mL), was added Et3N (29.0 mL, 0.208 mmol). The solution was then cooled down at 0° C., followed by addition of triphenylmethylchloride (52.8 g, 0.18 mmol) at 0° C. The resulting solution was stirred at room temperature overnight and then washed it with brine, water and concentrated to dryness to give a white solid (63.0 g, 98% yield, MH+=339.1)

1008

[2373] To a stirred solution of starting material benzyl amine (0.99 g, 8.87 mmol) in MeOH (50 mL) under nitrogen inlet at room temperature, was added sodium acetate (0.73 g, 8.87 mmol), 3°A molecular sieves (3.0 g) and aldehyde (3.0 g, 8.87 mmol). The resulting solution was stirred at room temperature overnight, followed by addition of NaBH4 (0.67 g, 17.74 mmol), then stirred for 4 hrs and concentrated to dryness, followed by extraction with CH2Cl2-1N NaOH. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 2%MeOH—NH3/98%CH2Cl2 to give light yellow oil (3.75 g, 98% yield, MH+=430.2)

1009

[2374] To a stirred solution of Compound (764) from step B (0.41 g, 1.14 mmol) in DMF (10 mL) under nitrogen at room temperature, was added NaH (0.02 g, 0.84 mmol). The resulting solution was stirred at room temperature for 1 hr.

[2375] To a stirred solution of Compound (763) from step A (0.4 g, 0.84 mmol) in acetone (30 mL) under nitrogen inlet at room temperature, was added NaI (0.12 g, 0.84 mmol). The resulting solution was heated to reflux for 1 hour and then concentrated to dryness to afford Compound (766). To crude Compound (766) was added, DMF (10 mL) and the solution of Compound (764) from above and NaH (0.02 g, 0.84 mmol). The resulting solution was heated to 90° C. for overnight, then concentrated to dryness and purified by column chromatography on silica gel, eluting with 2% MeOH—NH3/98% CH2Cl2 to give Compound (767) as a yellow solid (0.23 g, 33% yield, MH+=830.4)

1010

[2376] A solution of Compound (767) from step C (0.238 g, 0.29 mmol) in 80% acetic acid in H2O was heated to reflux for 2 hrs and then concentrated to dryness, followed by extraction with CH2Cl2-1N NaOH. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 3% MeOH—NH3/97%CH2Cl2 to give white solid (0.10 g, 62% yield, M=588.2).

PREPARATIVE EXAMPLE 62

[2377]

1011

[2378] 3(R)-(3-Methanesulfonyloxymethyl)pyrrolidine (J. Med. Chem. 1990, 33, 77-77) (0.993 g, 3.56 mmoles) was dissolved in anhydrous DMF (25 mL) and sodium imidazole (0.6 g, 10 mmoles) was added. The mixture was heated at 60° C. for 2 h and then evaporated to dryness. The product was extracted with CH2Cl2 and washed with brine. CH2Cl2 extract was evaporated to dryness to give the titled compound (1.1409 g, 100%), ESMS: FABMS (M+1)=252; δH (CDCl3) 1.45 (s, 9H), 1.5-1.7 (m, 1H), 1.9-2.1 (m, 1H), 2.5-2.7 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.6 (m, 2H), 3.9 (dd, 2H), 6.9 (s, 1H), 7.1(s, 1H), 7.45 (s, 1H)

[2379] In a similar manner, (S) isomer was prepared from 3(S)-(3-Methanesulfonyloxymethyl)pyrrolidine (0.993 g, 3.56 mmoles to give the title compound (1.1409 g, 100%).

1012

[2380] The title compound(0.48 g, 1.91 mmoles) from Step A was stirred in 4N HCl in dioxane (10 mL) for 2 h and then evaporated to dryness to give the title compound which was used to couple with the tricylic acid.

[2381] In a similar manner (S) isomer was prepared.

EXAMPLE 477

[2382]

1013

[2383] To a stirred solution of Compound (20) from preparative example 3 step B (4.86 g, 9.94 mmol) in EtOH (100 mL), was added 1N LiOH (80 mL). The resulting solution was then stirred at room temperature overnight and concentrated to dryness, followed by dissolving in CH2Cl2. The solution was then adjusted to pH=6.5-7.0 with 1N HCl. The aqueous layer was then separated and concentrated to dryness, then dissolved in THF to give the lithium salt (4.86 g, 100%yield, M+Li=467.1)

1014

[2384] To a stirred solution of Compound (769) from step A above (0.38 g, 0.84 mmol) in DMF (10 mL) under nitrogen inlet at room temperature, was added Compound (770) from Preparative Example 62 (0.163 g, 1.09 mmol), benzotriazoyl-N-oxtris (dimethylamino)phosphoniumhexafluro phosphate (0.44 g, 1.01 mmol) and Et3N (0.5 mL, 3.36 mmol). The resulting solution was stirred at room temperature overnight and concentrated to dryness, followed by extraction with CH2Cl2-10% Citric acid. The combined organic layer was then washed with saturated NaHCO3, brine, dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 3% MeOH—NH3/CH2Cl2 to give a light yellow solid (0.12 g, M=594.2).

PREPARATIVE EXAMPLE 63

[2385]

1015

[2386] To a solution of 4-hydroxy-piperidine (2 g, 19.78 mmoles) and triethylamine (4.16 mL, 29.67 mmoles) in CH2Cl2 (20 mL), di-tert-butyldicarbonate (5.18 g, 23.72 mmoles) was added and stirred at room temperature for 16 h. The solution was diluted with CH2Cl2 and washed with water, dried (MgSO4) filtered and evaporated to give the title compound (3.95 g, 99%). FABMS (M+1)=202.

1016

[2387] The title compound from Step A above (3.5 g, 17.39 mmoles) and triethylamine (4.85 mL, 34.79 mmoles) were dissolved in CH2Cl2 (30 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (1.62 mL, 20.88 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (4.68 g, 96.4%). ESMS: m/z=280 (MH+)

1017

[2388] A solution of the title compound from Step B (4.0 g, 14.32 mmoles) in DMF (120 mL) was added to a stirred solution of NaH (0.52 g, 21.66 mmoles) and imidazole (1.46 g, 21.47 mmoles) in DMF (20 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH4OH in methanol)—CH2Cl2 as eluant to give the title compound (0.94 g, 26%). FABMS (M+1)=252; □H (CDCl3) 1.4 (s, 9H), 1.6-1.8 (m, 2H), 2.0 (dd, 2H), 2.8 (dt, 2H), 4.05 (m, 1H), 4.2 m, 2H), 6.9 (s, 1H), 7.0 (s, 1H), 7.65 (s, 1H).

1018

[2389] The title compound (0.21 g, 0.836 mmoles) from Step C was stirred in 4N HCl in dioxane (5 mL) for 2 h and then evaporated to dryness to give the title compound (772)which was used to couple with the tricylic acid.

EXAMPLE 478

[2390]

1019

[2391] To a stirred solution of Compound (758) from Example 475 step D (0.2 g, 0.46 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature, was added Compound (772) from Preparative Example 63, Step D (0.19 g, 0.55 mmol), bezotriazoyl-N-oxy-tris-(dimethylamino)phosphoniumhexaflurophosphate (0.25 g, 0.55 mmol) and Et3N (0.3 mL, 1.85 mmol). The resulting solution was stirred at room temperature overnight and concentrated to dryness, followed by extraction with CH2Cl2-10% citric acid. The combined organic layer was then washed with sat. NaHCO3, brine, dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography on silica gel, eluting with 3%MeOH—NH3/CH2Cl2 to give a white solid (773) (0.013 g, 5% yield, M=566.2)

EXAMPLE 479

[2392]

1020

[2393] R=N-BOC

[2394] (774) (enantiomer 1), (M+1=584)

[2395] (775) (enantiomer 2) (M+1=584)

[2396] R=H

[2397] (776) (enantiomer 1)

[2398] (777) (enantiomer 2)

[2399] 3-bromo-8-chloroazaketone (U.S. Pat. No. 5,977,128, Preparative Example 11, step A, (1999)) was reacted in essentially the same manner as in Preparative Example 23, and Example 91 to obtain the N-BOC derivatives (774) and (775). Compounds (774) and (775) were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (776) and (777).

EXAMPLE 480

[2400] In essentially the same manner as in Examples (420) and (421), Compounds (778) and (779) were prepared.

1021

[2401] (R is defined in Table 45).

49TABLE 45Compound #R =EnantiomerFABMS (M + 1)778

1022

1628779

1023

2628

[2402] Phys. Data

[2403] (778): 1H-NMR (Varians 400 MHz, CDCl3, ppm): δ=8.564 (1H, d, J=2 Hz), 7.784 (1H:, d, J=2 Hz), 7.624 (1H, d, J=2 Hz), 7.51-7.37 (5H, m), 7.305 (1H, s), 7.267 (1H, s), 6.870 (1H, s), 6.867 (1H, s), 6.579 (1H, s), 5.282 (1H, d, J=16 Hz), 5.031 (1H, d, J=17 Hz), 4.576 (1H, s), 3.176 (4H, br ddd, J=6, 14 and 58 Hz), 2.485 (3H, s), 1.950 (4H, dd, J=6 and 9 Hz); MS (m/e) 630 (M+H), 340, 327, 293, 263, 249; HRMS (Jeol JMS-HX110A) calcd for C31H27BrClN7O 628.1227 (M+1), found 628.1229.

EXAMPLE 481

[2404] In essentially the same manner as in Example 70, Compounds (780) and (781) were prepared.

1024

[2405] (R is defined in Table 46).

50TABLE 46Compound #R =EnantiomerFABMS (M + 1)780

1025

1562781

1026

2562

PREPARATIVE EXAMPLE 64

[2406]

1027

[2407] Compound (368) from Preparative Example 42, Step C (2.34 g, 5.29 mmol) was dissolved in 25 mL CH2Cl2 at 0° C. PPh3 (1.66 g, 6.34 mmol) and NBS (1.03 g, 5.82 mmol) were added. After 90 mins, the reaction was diluted with CH2Cl2 (20 mL), washed with sat. NaHCO3, brine and dried with MgSO4. The crude product was purified on a silica gel column (4:1 hexanes/EtOAc to 2:1) to yield 1.8 g of Compound (782) as a light yellow solid. MS M+1 504.

1028

[2408] 5-Iodo-1N-methylimidazole (455 mg, 2.18 mmol) was dissolved in 10 mL THF at room temperature. EtMgBr (2.4 mL, 1.0 M in THF) was added dropwise. After 30 mins, the reaction mixture was cooled to 0° C. 10 mL THF solution of CuCN (175 mg, 1.96 mmol) and LiCl (166 mg, 3.9 mmol) was then added. 10 mins later, Compound (782) from Step A above (989 mg, 1.96 mmol, in 10 mL THF) was added. The reaction was stirred overnight. Sat. NH4Cl solution was added to quench the reaction. The resulting emulsion was filtered through a sintered funnel and the filtrate was extracted with EtOAc twice. The organic layer was washed with NaHCO3 solution and brine, dried over magnesium sulfate, filtered and evaporated in vivo. The resulting crude material was chromatographed on a silica gel column (using 1:1 hexanes/EtOAc then 10:1 CH2Cl2/MeOH) to obtain 330 mg of the title product. MS M+1=506 The enantiomers were seperated on a chiral AD column.

EXAMPLE 482

[2409]

1029

[2410] Compound (783) from Preparative Example 64, Step B above (40 mg) was dissolved in CH2Cl2 (5 mL) at room temerature followed by addition of TFA (0.5 mL). After 2 hrs, the solvent was evaporated in vivo and coevaporated with PhCH3 twice. The crude mixture was then dissolved in CH2Cl2 (4 mL) and Et3N was added dropwise till the solution became basic by PH paper. 4-Cyanophenyl isocyanate (14 mg) was added. After 5 minutes, the reaction mixture was evaporated in vivo to dryness. The crude material was then purified using prep TLC plate (10:1 CH2Cl2/MeOH) to get 23 mg of Compound (784) as a white solid. MS M+1 550.

EXAMPLE (483)

[2411]

1030

[2412] Compound (785) was prepared following essentially the same procedure as in Preparative Example 64 and Example 482, substituting 4-Iodo-1-tritylimidazole for 5-Iodo-1N-methylimidazole.

EXAMPLE 484

[2413]

1031

[2414] Compound (786) and (787) were prepared following essentially the same procedure as in Preparative Example 7, substituting ketones (15) and (16) from Preparative Example 2, Step D for ketones (9) and (10).

[2415] Compound (786) MH+=497; [α]D20=+15.3.

[2416] Compound (787) MH+=497; [α]D20=−13.4.

EXAMPLE 485

[2417]

1032

[2418] Following essentially the same procedure as in Preparative Example 33, Steps E-H, except substituting compound (365) for Compound (281) and 2-hydroxymethyl imidazole for 1-methylimidazole, compound (788) was prepared.

[2419] (788): 1H-NMR (Varians 400 MHz, CDCl3, ppm): δ=8.5 (1H, dd), 7.34 (1H, s), 7.59 (1H, d), 7.4 (2H, m), 7.25 (2H, m), 7.04 (1H, s), 6.9 (1H, s), 6.6 (1H, s), 5.37 (2H, dd), 4.8 (2H, dd), 4.6 (1H, s), 3.2 (5H, br s), 2.0 (2H, br s), 1.9 (2H, br s), 1.4 (9H, s).

PREPARATIVE EXAMPLE 65

[2420]

1033

[2421] To a solution of the alcohol (3.8 g, 8.6 mmol) in CH2Cl2 (100 mL) under nirtogen was added MnO2 (40 g). The resulting solution was stirred at room temperature for 4 days. The mixture was then filtered through a pad of Celite with ethyl acetate (500 mL) as the eluant. The filtrate was concentrated to yield a yellow liquid (4.0 g, MH+440.1). The crude material was separated into its pure isomers by HPLC, using a chiral AD column eluting with 20% IPA/80%Hexanes/0.2%DEA (isomer 1, 810 mg; isomer 2, 806 mg).

1034

[2422] To a solution of imidazole Grignard prepared from 5-iodo-1N-methylimidazole (312 mg, 1.5 mmol, preparative example 64 step B) was added a solution of aldehyde (791) (380 mg, 0.86 mmol) in CH2Cl2 (10 mL). After stirring at room temperature overnight, the mixture was heated to 40° C. for one hour. After cooling to room temperature again, saturated NH4Cl solution was added to quench the reaction. The organic layer was dried and the solvent was evaporated. The residue was then purified by silica gel column (from 2% to 10% MeOH in CH2Cl2) to give the product as a brown oil (207 mg, 46% yield, MH+=522.1). The diastereomers were then separated by HPLC, using a chiral AD column eluting with 20% IPA/80%Hexanes/0.2%DEA.

1035

[2423] To a THF solution (5 mL) of (790) (200 mg, 0.38 mmol) at room temperature was added DPPA (210 mg, 0.76 mmol) followed by addition of DBU (120 mg, 0.76 mmol). The mixture was stirred overnight and then diluted with ethyl acetate (30 mL), washed with water twice and brine once. The organic layer was dried and the solvent was evaporated. The residue was purified by prep TLC (10% MeOH in CH2Cl2 with 0.2% NH3) to give product (791) (102.8 mg, MH+547.1). Starting material (790) (58 mg) was also recovered. The diastereomers of (791) were separated on a chiral AD column.

EXAMPLE 486

[2424]

1036

[2425] To a wet THF solution (3 mL) of (791) (48 mg, 0.09 mmol) was added PPh3 (32 mg, 0.12 mmol) at room temperature. After stirring overnight, the reaction mixture was concentrated and the residue was purified with prep TLC (10% MeOH in CH2Cl2 with 0.2% NH3) to give a white solid (24.3 mg). The white solid was then redissolved in THF/H2O (5 mL/0.5 ml) and the mixture was heated to reflux overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified with prep TLC (5% MeOH in CH2Cl2 with 0.2% NH3) to yield a yellow solid (792) (8.3 mg, MH+521.1).

EXAMPLE 487

[2426]

1037

[2427] Compound (790) was converted to compound (793) following the essentially the same procedure as described in EXAMPLE 482. MS M+1 566.1.

EXAMPLE 488

[2428]

1038

[2429] Compound (790) was converted to compound (794) following essentially the same procedure as described in PREPARATIVE EXAMPLE 65, Step A. MS M+1 520.1

EXAMPLE 489

[2430]

1039

[2431] Aldehyde (789) from Preparative Example 65, Step A (150 mg, 0.34 mmol) was dissolved in THF (6 mL). To this solution was added MeMgBr (0.3 mL, 3.0M in Et2O) dropwise. After stirring at room temperature for 4 hrs, the reaction mixture was quenched with sat. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a yellow solid (150 mg). The crude product was then dissolved in CH2Cl2 (5 mL). To this solution was added Dess-Martin Periodinane (210 mg) and a drop of water. After 1 hr, aqueous Na2S2O3 solution (4 mL, 10%) was added. The mixture was stirred for 10 min. and extracted with CH2Cl2. The organic layer was washed with NaHCO3, dried and concentrated. The crude material was purified using prep TLC plates (5% methanol in CH2Cl2) to yield the methyl ketone product (795) as a yellow solid (70 mg).

1040

[2432] To a solution of imidazole Grignard prepared from 5-iodo-1N-methylimidazole (624 mg, 3 mmol, see preparative example 64 step B using ClCH2CH2Cl as solvent instead of THF) was added a ClCH2CH2Cl (6 mL) solution of methyl ketone (795) (272 mg, 0.6 mmol). The mixture was heated to 60° C. for 1.5 hours. After cooling to room temperature, saturated NH4Cl solution was added to quench the reaction. The organic layer was dried and then evaporated to dryness. The residue was then purified by silica gel column (from 2% to 10% MeOH in CH2Cl2) to give the product (795.1) as a brown solid (63 mg, 10:1 diastereomeric selectivity, MH+=536.1). Major diastereomer: (CDCl3, 300 MHz) 8.47 (d, 1H), 7.66 (d, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.34 (d, 1H), 7.25-7.22 (m, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 4.61 (s, 1H), 3.84 (s, 3H), 3.24 (br s, 4H), 2.24 (m, 2H), 2.02-2.00 (m, 2H), 1.88 (s, 3H), 1.41 (s, 9H).

1041

[2433] Compound (795.1) can be converted to acetate compound (795.2) by reacting it with 1 equivalent of acetic anhydride and 2 equivalents of pyridine.

1042

[2434] Compound (795.2) can be converted to compound (795.3) by reacting it with 1.5 equivalents of NaN3, 15-crown-5, and a catalytic amount of Pd(dba)2/PPh3.

[2435] Alternatively, (795.3) can be synthesized by treating (795.1) with NaN3, TFA followed by (Boc)2O, and triethyl amine.

1043

[2436] Compound (795.4) can be prepared by reacting (795.3) with P(CH3)3/H2O.

PREPARATIVE EXAMPLE 66

[2437]

1044

1045

1046

R = BOC
R = BOC

(796)
(+ enantiomer, A)
(797)
(+ enantiomer, A)

(798)
(+ enantiomer, B)
(799)
(+ enantiomer, B)

R = H
R = H

(800)
(+ enantiomer, A)
(801)
(+ enantiomer, A)

(802)
(+ enantiomer, B)
(803)
(+ enantiomer, B)

[2438] Compound 661 was reacted in essentially the same manner as in Preparative Example 23 and then Example 91 to obtain the N-BOC derivatives (796), (797), (798), and (799). Compounds (796), (797), (798), and (799) were then further reacted separately in essentially the same manner as in PREPARATIVE EXAMPLE 19, Step D to obtain the enantiomers (800), (801) (+ enantiomers, isomer A) and (802), (803) (− enantiomers, isomer B). The C5 and C-6 vinyl bromide intermediates were separated by silica gel chromatography using hexane:ethyl acetate (80:20) as described in PREPARATIVE EXAMPLE 23, Step B.

EXAMPLE 490-491

[2439] The appropriate (+) enantiomer (800) or (−) enantiomer (802) from Preparative Example 66 above, was taken up in CH2Cl2 treated with the corresponding isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1047

[2440] (wherein R is defined in Table 47).

52TABLE 47Exam-Enan-pletio-#RmerComp #Phys. Data.490

1048

+(804)Mp = 160-165 ° C. [α]D25 =+84°(0.84 mg/ 1 mL MeOH) MH+ = 546491

1049

−(805)Mp = 158-163 ° C. [α]D25 =−91.6°(0.84 mg/ 1 mL MeOH) MH+ = 546

PREPARATIVE EXAMPLE 67

[2441]

1050

[2442] 15.4 g (115 mmole) of CuCl2 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 1N HCl was added to the residue until the pH was neutral, then NH4OH 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 (807). Alternatively, the corresponding alcohol of 564 can be reacted as above followed by oxidation with MnO2 in CH2Cl2 to give compound (807).

53Step B

1051

1052

1053

R = BOCR = BOC(808)(enantiomer 1)(809)(enantiomer 1)(810)(enantiomer 2)(811)(enantiomer 2)R = HR = H(812)(enantiomer 1)(813)(enantiomer 1)(814)(enantiomer 2)(815)(enantiomer 2)

[2443] Compound (807) from step B above was reacted in essentially the same manner as in Preparative Example 23, and then Example 91 to obtain the N-BOC derivatives (808), (809), (810) and (811). These were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (812) and (814), as well as enantiomers (813) and (815). The C5 and C-6 vinyl bromide intermediates were separated by silica gel chromatography using hexane:ethyl acetate as described in Preparative Example 23, Step B.

EXAMPLE 493

[2444] The appropriate enantiomer (812) (enantiomer 1) or (814) (enantiomer 2) from Preparative Example 67, Step B above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1054

[2445] (wherein R is defined in Table 48).

54TABLE 48StartingEnan-Cmp.tio-#RmerComp #Phys. Data.(812)

1055

+816Mp = 175-181° C. [α]D25 =+94.2°(1 mg/1 mL MeOH)(814)

1056

−(817)Mp = 182-186° C. [α]D25 =−120.3°(1 mg/1 mL MeOH)

EXAMPLE 494

[2446] The appropriate enantiomer (813) (enantiomer 1) or (815) (enantiomer 2) from Preparative Example 67, Step B above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1057

[2447] (wherein R is defined in Table 49).

55TABLE 49StartingEnan-Cmptio-#RmerCmp #Phys. Data.(813)

1058

+(818)Mp = 176-181° C. [α]D25 =+46.3°(0.79 mg/ 1 mL MeOH) MH+ = 584(815)

1059

−(819)Mp = 174-180° C. [α]D25 =+43.3°(0.94 mg/ 1 mL MeOH) MH+ = 584

PREPARATIVE EXAMPLE 68

[2448]

1060

1061

1062

R = BOC
R = BOC

(807)
(820)
(enantiomer 1)
(821)
(enantiomer 1)

(822)
(enantiomer 2)
(823)
(enantiomer 2)

R = H
R = H

(824)
(enantiomer 1)
(825)
(enantiomer 1)

(826)
(enantiomer 2)
(827)
(enantiomer 2)

[2449] Compound (807) from Preparative Example 67, Step A above was reacted in essentially the same manner as in Preparative Example 23, and then Example 91, substituting 2-ethylimidazole for 2-methylimidazole, to obtain the N-BOC derivatives (820), (821), (822) and (823). These were then reacted seperately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (824) and (826), as well as enantiomers (825) and (827). The C5 and C-6 vinyl bromide intermediates were separated by silica gel chromatography using hexane:ethyl acetate as described in Preparative Example 23, Step B.

EXAMPLE 495

[2450] The appropriate enantiomer (824) (enantiomer 1) or (826) (enantiomer 2) from Preparative Example 68 above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1063

[2451] (wherein R is defined in Table 50

57TABLE 50StartingEnan-Cmptio-#RmerComp #Phys. Data.(824)

1064

+(828)Mp = 176-182° C. [α]D25 =+84.5°(1.3 mg/ 1 mL MeOH) MH+ = 598(826)

1065

−(829)Mp = 175-182° C. [α]D25 =−88.8°(1.14 mg/ 1 mL MeOH) MH+ = 598

EXAMPLE 496

[2452] The appropriate enantiomer (825) (enantiomer 1) or (827) (enantiomer 2) from Preparative Example 68 above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1066

[2453] (wherein R is defined in Table 51).

58TABLE 51StartingEnan-Cmptio-#RmerComp #Phys. Data.(825)

1067

+(830)Mp = 170-174° C. [α]D25 =+39.1°(0.81 mg/ 1 mL MeOH) MH+ = 598(827)

1068

−(831)Mp = 170-175° C. [α]D25 =−36.4°(0.96 mg/ 1 mL MeOH) MH+ = 598

PREPARATIVE EXAMPLE 69

[2454]

1069

[2455] 3-Bromo-8-chloroazaketone (U.S. Pat. No. 5,977,128, Preparative Example 11, Step A, (1999)) was reacted in essentially the same manner as in Preparative Example 23, and then Example 91, substituting 2-ethylimidazole for 2-methylimidazole, to obtain the N-BOC derivatives (832) and (833). These were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (834) and (835).

EXAMPLE 497

[2456] The appropriate enantiomer (834) (enantiomer 1) or (835) (enantiomer 2) from Preparative Example 69 above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1070

[2457] (wherein R is defined in Table 52).

59TABLE 52StartingEnan-Cmptio-#RmerComp #Phys. Data.(834)

1071

A(836)Mp = 172-179° C. (d) MH+ = 643(835)

1072

B(837)Mp = 171.9-178.3° C. MH+ = 643

PREPARATIVE EXAMPLE 70

[2458]

1073

[2459] Compound 661 was reacted in essentially the same manner as in Preparative Example 23, and then Example 91, substituting 2-isopropylimidazole for 2-methylimidazole, to obtain the N-BOC derivatives (838) and (839). These were then reacted separately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (840) and (841).

EXAMPLE 498

[2460] The appropriate enantiomer (840) (enantiomer 1) or (841) (enantiomer 2) from Preparative Example 70 above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1074

[2461] (wherein R is defined in Table 53).

60TABLE 53StartingEnan-Cmptio-#RmerComp #Phys. Data.(840)

1075

A(842)Mp = 168-170° C. (d) [α]D25 =+64.1°(0.66 mg/ 1 mL MeOH)(841)

1076

B(843)Mp = 166-171° C. [α]D25 =−80.9°(0.85 mg/ 1 mL MeOH)

PREPARATIVE EXAMPLE 71

[2462]

1077

[2463] 3-Methoxy-8-chloroazaketone (U.S. Pat. No. 5,977,128 (1999), Example 2, step D) was reacted in the same manner as in Preparative Example 23, and Example 91 to obtain the N-BOC derivatives (844) and (845). These compoounds were then reacted seperately in essentially the same manner as in Preparative Example 19, Step D to obtain the enantiomers (846) (A) and (847) (B).

EXAMPLE 499

[2464] The appropriate enantiomer (846) (enantiomer A) or (847) (enantiomer B) from Preparative Example 71 above, was taken up in CH2Cl2, treated with 4-cyanophenyl isocyanate and stirred at room temperature over night. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel column chromatography to afford compounds of the formula:

1078

[2465] (wherein R is defined in Table 54).

61TABLE 54StartingEnan-Cmptio-#RmerComp #Phys. Data.(846)

1079

A(848)Mp = 174.2-189.3° C. (d) MH+ = 580(847)

1080

B(849)Mp = 174.4-189.8° C. MH+ = 580

EXAMPLE 500

[2466]

1081

[2467] Compound (850) can be prepared by following essentially the same procedure as described in Example 482.

EXAMPLE 501

[2468]

1082

[2469] Starting with compound (240) from Preparative Example 23, Step H, compound (851) can be prepared following essentially the same procedure as described in Preparative Example 65, Steps A and B.

EXAMPLE 502

[2470]

1083

[2471] Starting with compound (240) from Preparative Example 23, Step H, compound (852) can be prepared following essentially the same procedures as described in Preparative Example 65, Step A and Example 489, Steps A-E.

PREPARATIVE EXAMPLE 72

[2472]

1084

[2473] The starting tricyclic keto compound (disclosed in U.S. Pat. No. 5,151,423) (56.5 g; 270 mmol) was combined with NBS (105 g; 590 mmol) and benzoyl peroxide (0.92 g) in CCl4. The reaction was heated at 80° C. for 5 hr. The mixture was cooled and the resulting precipitate was filtered and treated with DBU (25.59 ml) in THF (300 mL). The resulting solution was stirred at room temperature for 24 hrs, then evaporated, followed by extraction with CH2Cl2—H2O. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give a mixture of two compounds which were separated on a flash silica gel column eluting with Hexane-50% EtOAc to give the title compound (853) δH (CDCl3) 8.8 (dd, 1H), 8.45 (dd, 1H), 7.99 (m, 1H), 7.92 (s, 1H), 7.59-7.64 (m, 3H), 7.23 (dd, 1H) and (854) δH (CDCl3) 8.19 (dd, 1H), 7.99 (dd, 1H), 7.82 (dd, 1H), 7.25-7.65(m, 4H), 7.22 (s, 1H)

1085

[2474] Compound (853) (25 g), triphenyl phosphine (13.75 g), and palladium chloride (1.5 g) were combine in MeOH (30 ml) and toluene (200 ml). To the mixture was added DBU (18 ml) and the mixture was sealed in a parr bomb. The mixture was stirred and subjected to 100 psi of CO at 80° C. for 5 hr. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and

[2475] purified by flash chromatography eluting with CH2Cl2-10% EtOAc to give the title compound (855). δH (CDCl3) 8.8 (dd, 1H), 8.40 (dd, 1H), 8.2 (s 1H), 8.04 (dd, 1H), 7.59-7.64 (m, 4H), 3.95 (s, 3H).

1086

[2476] Reacting compound (854) in essentially the same manner as described in Step B above, gave the title compound (856). 8H (CDCl3) 8.85 (dd, 1H), 7.85-8.0 (m, 2H), 7.8 (s, 1H), 7.28-7.37 (m, 4).

1087

[2477] Compound (855) (19.5 g, 73.5 m mol) was dissolved in CH2Cl2 (100 mL) and cooled to 0° C. Tetrabutyl ammonium nitrate (31.36 g, 103 n mol) and trifluoro acetic anhydride (18.52 g, 88 m mol) were added and the mixture stirred at room temperature for 5 hrs. The reaction mixture was concentrated to dryness, followed by extraction with CH2Cl2—NaHCO3. The combine organic layer was dried over MgSO4 and concentration to dryness and the residue was chromatographed on silica gel using CH2Cl2 -EtOAc (25%) to give the title compound (857) (12.4 g), δH (CDCl3) 9.45 (dd, 1H), 9.05 (dd, 1H), 8.28 (s, 1H), 8.0 (dd, 1H), 7.65 (m, 3H), 3.98 (s, 3H).

1088

[2478] Reacting compound (856) in essentially the same manner as described in Step D above, gave the title compound (858). MH+=311

1089

[2479] Compound (857) (6 g) was balloon hydrogenated in MeOH (100 mL) over Raney-Ni)4.2 g) at room temperature overnight. The catalyst was filtered off and the filtrate was evaporated to dryness to give the title compound (859) (4.66 g) MH+=281

1090

[2480] Reacting compound (858) in essentially the same manner as described in Step F above, gave the title compound (860) MH+=281.

1091

[2481] To a suspension of compound (859) (2.1 g) in 48% HBr, was added sodium nitrite (1.55 g) followed by bromine (2.11 mL) at 0° C. The mixture was stirred at room temperature overnight. Concentrated NH4OH was then added dropwise until basic pH (to litmus paper). The reaction was extracted with CH2Cl2, washed with brine, dried over MgSO4, filtered and the solvent evaporated to give the title compound (861) (1.75 g) MH+=345.

1092

[2482] Reacting compound (861) in essentially the same manner as described in Step H above, gave the title compound (862) MH+=345.

1093

[2483] To a stirred solution of compound (861) (1.6 g, 4.64 mmole) in MeOH (30 mL) under nitrogen at 0° C. was added NaBH4 (0.3 g, 7.9 mmole). The resulting solution was stirred at room temperature for 24 hrs, then evaporated, followed by extraction with CH2Cl2—H2O. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give the title compound (863) (1.58 g) MH+=347.

1094

[2484] Reacting compound (862) in essentially the same manner as described in Step J above, gave the title compound (864). MH+=347

1095

[2485] Compound 863 (1.57 g,) was stirred in thionyl chloride (10 mL) at room temperature for 4 hrs then evaporated to dryness. The resulting crude oil as taken up in acetonitrile (50 mL) and refluxed with N-Boc-piparazine (1.41 g) and triethyl amine (3.91 g) overnight. The mixture was evaporated to dryness, followed by extraction with CH2Cl2—NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give a brown gum which was purified by column chromatography on silica gel, eluting with Hexane −20% EtOAc to give the title compound (865) (0.69 g). MH+=515.

1096

[2486] Reacting compound (864) in essentially the same manner as described in Step L above, gave the title compound (866) MH+=515.

1097

[2487] Compound (865) (0.65 g, 1.26 mmole) was refluxed with LiOH (0.45 g, 18.79 mmole) in MeOH (15 mL) and water (1 mL) for 2 hrs. 10% aq. Citric acid was added until pH=3.5, followed by extraction with CH2Cl2-brine. The organic layer was dried over MgSO4 filtered and evaporated to dryness to give a white solid (867) (0.60 g) MH+=501

1098

[2488] Reacting compound (866) in essentially the same manner as described in Step N above, gave the title compound (868). MH+=501

1099

[2489] Compound (867) (0.60 g, 1.21 mmole) was stirred with carbonyl diimidazole (0.59 g, 3.63 mmole) in THF (15 mL) at at 40° C. overnight. The reaction mixture was cooled in an ice-bath then added NaBH4 (0.28 g, 7.31 mmole) and stirred at room temperature overnight. The mixture was evaporated to dryness, followed by extraction with CH2Cl2-water. The organic layer was dried over MgSO4, filtered and evaporated to give a brown gum which was purified by column chromatography on silica gel, eluting with Hexane −50% EtOAc to give the title compound (869)(0.493 g) MH+=487.

1100

[2490] Reacting compound (868) in essentially the same manner as described in Step P above, gave the title compound (870). MH+=487

1101

[2491] Compound (869) (0.38 g, 0.78 mmole) was stirred with methanesulfonyl-chloride (0.33 g, 1.296 mmole) and triethylamine (0.68 g, 6.72 mmole) in THF (10 mL) at room temperature overnight. The mixture was evaporated to dryness, followed by extraction with CH2Cl2—water. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give the title compound (871)(0.369 g). MH+=565

1102

[2492] Reacting compound (870) in essentially the same manner as described in Step R above, gave the title compound (872). MH+=565

1103

[2493] Compound (871) (0.0.369 g, 0.653 mmole) was stirred with 2-methylimidazole (0.188 g, 2.28 mmole) in DMF (5 mL) at room temperature overnight. The mixture was evaporated to dryness, followed by extraction with CH2Cl2—water. The organic layer was dried over MgSO4, filtered, evaporated to dryness and then purified on silica-gel prep-plate chromatography, eluting with CH2Cl2-5% (MeOH-10% NH4OH) to give the product as a mixture of isomers (1.126 g) MH+=551. Separation of the product mixture by HPLC using a prep AD column, eluting with 20% IPA/80%hexane/0.2%DEA (isocratic 60 ml/min.) afforded pure isomer 1 (873) (0.06 g, MH+=551 and isomer 2 (874) (0.0061 g) MH+=551.

1104

[2494] Reacting compound (872) in essentially the same manner as described in Step T above, gave the title compounds (875). MH+=551, and (876) MH+=551.

EXAMPLE 503

[2495]

1105

[2496] Compound (873) (0.043 g, 0.078 mmole) was stirred with TFA (5 mL) in CH2Cl2 (5 mL) for 4 hrs. at room temperature. The mixture was then evaporated to dryness. To the residue was added p-cyanophenylisocyanate (0.0123 g, 0.086 mmole) and triethylamine (0.5 mL) in CH2Cl2 (5 mL) and the mixture stirred at room temperature for 2 hrs. The mixture was evaporated to dryness, followed by extraction with CH2Cl2-brine. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give a brown gum which was purified by prep-plate chromatography on silica gel, eluting with CH2Cl2-5% (MeOH-10% NH4OH) to give the title compound (877) (0.0394 g). MH+=595, δH (CDCl3) 8.6 (1H); 8.05 (1H); 7.22-7.5 (8H); 6.99 (1H); 6.95 (1H); 6.93 (1H); 4.99-5.25 (2H); 4.6 (1H); 3.1-3.25 (4H); 2.25 (3H), 1.8-2.05 (4H).

EXAMPLE 504

[2497]

1106

[2498] Reacting compound (874) in essentially the same manner as described in Example 503 above, gave the title compound. (873) MH+=595, δH (CDCl3) 8.6 (1H); 8.05 (1H); 7.22-7.5 (8H); 6.99 (1H); 6.95 (1H); 6.93 (1H); 4.99-5.25 (2H); 4.6 (1H); 3.1-3.25 (4H); 2.25 (3H), 1.8-2.05 (4H).

EXAMPLE 505

[2499]

1107

[2500] Reacting compound (875) in essentially the same manner as described in Example 503 above, gave the title compound (879). MH+=595, δH (CDCl3) 8.55 (1H); 7.78 (1H); 7.65 (1H);7.4-7.51 (6H); 6.98 (1H); 6.9 (1H); 6.85 (1H); 5.05-5.3 (2H); 4.6 (1H); 3.1-3.25 (4H); 2.5 (3H), 1.8-2.00 (4H).

EXAMPLE 506

[2501] Diasteromeric separation of product (795.1):

1108

[2502] from Example 489, Step B, 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., 795.1b).

[2503] Isomer-1—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, 1H), 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.

[2504] Isomer-2—MH+=536.1 (CDCL3, 400 MHz) 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

[2505]

1109

[2506] Compound 795.1b (isomer 2, 0.093 g, 0.173 mmoles) was converted to 795.2b by reacting it with CH2Cl2(5.0 ml)/TFA(1.0 ml) at room temperature under N2.

[2507] The same procedure was used to prepare 795.2a (isomer 1) from 795.1 a.

EXAMPLE 508

[2508]

1110

[2509] 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.

[2510] Isomer 365a: retention time=7.65 min; MH+=492.

[2511] Isomer 365b: retention time=12.16 min; MH+=492, m.p. 95-100° C.

PREPARATIVE EXAMPLE 73

[2512]

1111

[2513] Dissolve (880) (2 eq. 14.2 mmol) in THF (20 ml), add 1 M LiOH(16 ml) and stir at room temperature for 1 hour or until reaction is complete. evaporate to dryness, then evaporate 3×with toluene, to obtain crude (881) as a solid.

1112

[2514] Take crude (881) from Step A, and dissolve in DMF (60 ml), and add NH(OMe)Me(3.14 g), DEC(6.14 g), HOBT(2.16 g), NMM(11 ml), 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 NaCl, and extract with (4×).CH2Cl2. Dry with MgSO4, filter and evaporate to obtain product (882) (3.23 g).

1113

[2515] Took crude (882) (14.2 mmol), and dissolve in THF (100 ml). Cool in an iced bath and add MeMgBr (3 Molar in diethyl ether); (22.2 ml), 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 3×with CH2Cl2. Dry with MgSO4, filter and evaporate. Store under vacuum to obtain crystals—(883)(1.78 g, 74%).

1114

[2516] Dissolve 365 (0.24 g, 0.49 mmol) in THF (2.5 ml). Cool under N2 to −78° C., add (1) (BuLi, 2.5M, 0.2 ml) and stir the resulting dark brown solution for 15 minutes. Dissolved 883 (0.116 g) 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(2×). Dry with MgSO4, filter and evaporate to obtain a yellow solid. Purified crude (0.29 g) by Prep Plate Chromatography to afford 0.0.15 g, 42% yield of the desired product (795.1).

EXAMPLE 509

[2517]

1115

[2518] 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

[2519]

1116

[2520] 365a [0.9 g, 1.83 mmol] was dissolved in dry THF (15 ml) and cooled to −75° C. (dry ice/acetone bath). (N-BuLi)[(2.5N in Hexanes); 0.24 g, 1.5 ml, 3.74 mmol], was added dropwise at −75° C. and stirred for ˜20 minutes. 5-Formyl-1-Methyl Imidazole (0.3 g, 2.75 mmol in 2 ml THF was added quickly and stirred at −75° C. for 3 hours. TLC with (H2O-Ethyl Acetate). Reaction completed. Worked up by adding 10 ml of H2O and extracted with Ethyl Acetate and washed with brine, dried over MgSO4, filtered and evaporated to give crude product. Crude was purified by Flash Chromatography (silica gel column) using CH2Cl2/5% CH3OH (15% NH4OH) to give 0.54 g of compound 884, 56% yield.

1117

[2521] Starting material 884 (0.54G) was dissolved in CH2Cl2, and MnO2 (5 g) was added and stirred at room temperature overnight. TLC in 75% CH2Cl2/25% EtoAc/5% MeOH (15% NH4OH). Filtered off the inorganics and evaporated to dryness to give 0.49 g of 885, 90% yield.

1118

[2522] 0.35 g, 1.71 mmol of (CH3)3 S+I− was dissolved in dry DMSO (5 ml) and THF (5 ml). Sodium hydride (0.068 g, 1.71 mmol) was added, stirred for 10 minutes. The mixture was cooled to 0° C. Starting material 885 (0.3 g, 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 H2O. Extracted with Ethyl Acetate and washed with brine, dried over MgSO4, filtered and evaporated to give 0.310 g of product, 886.

1119

[2523] Dissolved 886 (0.28 g, 0.48 mmol) in THF(5 ml), added Li (Et)3BH (0.8 ml, 0.8 mmol). After stirring for 1 hour, added to reaction ˜10 ml of 1N HCL and stirred for 5 min. Added saturated sodium bicarbonate slowly until basic, and extracted with Ethyl Acetate (3×). Organic was dried over MgSO4, filtered and evaporated to give crude product. Column chromatography on 12 g of silica and eluting with 2% to 4% MeOH.NH4OH/CH2Cl2 to gave 170 mg, 66% yield of pure product, 887.

1120

[2524] 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

[2525] Each isomer, 795.2a and 795.2b from Example 507 was dissolved in CH2Cl2, 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:

1121

[2526] wherein R is defined in Table 55 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

62TABLE 55Isomer 1Isomer 2ExampleRDataData511

1122

m.p. 200-202° C.m.p. 197-200° C.512

1123

m.p. 185-190° C.m.p. 200-205° C.513

1124

m.p. 210-214° C.m.p. 185-190° C.

EXAMPLES 514-535

[2527] If one were to follow procedures similar to those of Examples 511-513 then one would obtain compounds of the formulas:

1125

[2528] wherein R is defined in Table 56 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

63TABLE 56RExampleIsomer 1 and Isomer 2514

1126

515

1127

516

1128

517

1129

518

1130

519

1131

520

1132

521

1133

522

1134

523

1135

524

1136

525

1137

526

1138

527

1139

528

1140

529

1141

530

1142

531

1143

532

1144

533

1145

534

1146

535

1147

EXAMPLE 536

[2529] 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:

1148

[2530] wherein R is defined in Table 57 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

64TABLE 57DataDataExampleRIsomer 1Isomer 2536

1149

m.p. 175-180° C.—

EXAMPLES 537-565

[2531] If one were to follow procedures similar to that of Example 536 then one would obtain compounds of the formulas:

1150

[2532] wherein R is defined in Table 58 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

65TABLE 58RExampleIsomer 1 and Isomer 2537

1151

538

1152

539

1153

540

1154

541

1155

542

1156

543

1157

544

1158

546

1159

547

1160

548

1161

549

1162

550

1163

551

1164

552

1165

553

1166

554

1167

555

1168

556

1169

557

1170

558

1171

559

1172

560

1173

561

1174

562

1175

563

1176

564

1177

565

1178

EXAMPLES 566-567

[2533] Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous CH2Cl2 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 CH2Cl2. Organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography eluting with methanol-CH2Cl2 afforded compounds of the formula:

1179

[2534] wherein R is defined in Table 59 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

66TABLE 59DataDataExampleRIsomer 1Isomer 2566

1180

mp = 215.4-217.5° C.m.p. 185-188° C.567

1181

*mp = 182-186° C.* Isomer 1 for Example 567 would be obtained if one were to follow the described procedure.

EXAMPLES 568-589

[2535] If one were to follow procedured similar to those in Examples 566-567 thenone would obtain compounds of the formulas:

1182

[2536] wherein R is defined in Table 60 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

67TABLE 60RExampleIsomer 1 and Isomer 2568

1183

570

1184

571

1185

572

1186

573

1187

575

1188

576

1189

577

1190

578

1191

579

1192

580

1193

581

1194

582

1195

583

1196

584

1197

585

1198

586

1199

587

1200

588

1201

589

1202

EXAMPLES 590-603

[2537] 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 MgSO4, filtered and concentrated to yield crude products. Purification by Prep TLC using methylene chloride/acetone (95%/5%) afforded the compounds:

1203

[2538] wherein R is defined in Table 61 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

68TABLE 61DataDataExampleRIsomer 1Isomer 2590

1204

——591

1205

*179.8-182.4° C.592

1206

195-200° C.193.5-197.5° C.593

1207

*165.9-167.9° C.594

1208

163.8-186.6° C.mp = 173-175° C.595

1209

*173.9-176.2° C.596

1210

180-182° C.172-174° C.597

1211

165-170° C. 185-188.5° C.598

1212

184.3-186.6° C.191.2-192.9° C.599

1213

*179.8-182.5° C.600

1214

175-180° C.175-178° C.601

1215

175-177° C.173-176° C.602

1216

177-180° C.175-177° C.603

1217

169.4-173.2° C.164.4-167.2° C.* Isomer 1 for these examples would be obtained if one were to follow the described procedure.

[2539] PMR data for Example 592, isomer 1, (CD3Cl) 8.44 (d, 1H), 8.23 (d, 1H), 7.54 (s, 1H), 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, 1H), 4.58 (s, 1H), 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).

EXAMPLES 604-614

[2540] If one were to follow procedured similar to those in Examples 590-603 then one would obtain compounds of the formulas:

1218

[2541] wherein R is defined in Table 62 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

69TABLE 62RExampleIsomer 1 and Isomer 2604

1219

605

1220

606

1221

607

1222

608

1223

609

1224

610

1225

611

1226

612

1227

613

1228

614

1229

PREPARATIVE EXAMPLE 74

[2542]

1230

[2543] (wherein R is alkyl (e.g., ethyl) or cycloalkyl (e.g., cyclohexyl))

[2544] Dissolve Phosgene (3 mL, 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

[2545]

1231

[2546] 15.4 g (115 mmole) of CuCl2 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 1N HCl was added to the residue until the pH was neutral, then NH4OH 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. Alternatively, the corresponding alcohol of 889 can be reacted as above followed by oxidation with MnO2 in CH2Cl2 to give compound 890.

1232

[2547] Compound 890 from Step A above was reacted in essentially the same manner as in Preparative Example 23, Steps A-D, to get Compounds 891 and 892.

1233

[2548] 891 was separated into the respective enantiomers 891a and 891b, using a Chiral AD Prep HPLC Column as described in Example 508.

1234

[2549] 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

[2550]

1235

[2551] Reacted 891a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

1236

[2552] 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

[2553]

1237

[2554] Reacted 891 b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

1238

[2555] 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

[2556]

1239

[2557] Reacted 892a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 895.

1240

[2558] 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

[2559]

1241

[2560] Reacted 892b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 896.

1242

[2561] 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

[2562]

1243

[2563] Compound 893a, and 893b, are converted to 897a, and 897b, by reacting them with CH2Cl2/TFA at room temperature under N2, for 2 hours. Concentrated under vacuum. Dissolve residue in CH2Cl2, and wash with 1.0 NaOH. Dry over MgSO4, filter and concentrate to give 897a (i.e., isomer 1) and 897b (i.e., isomer 2).

PREPARATIVE EXAMPLE 81

[2564]

1244

[2565] 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

[2566]

1245

[2567] 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

[2568]

1246

[2569] 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).

EXAMPLES 615-639

[2570] If one were to dissolve each isomer, 897A and 897B, in CH2Cl2, treat with the corresponding isocyanates, stir at room temperature overnight, and purify the crude product directly by silica gel preparative thin layer chromatography or silica gel chromatography, then compounds of the formula:

1247

[2571] would be obtained wherein R is defined in Table 63, and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

70TABLE 63RExampleIsomer 1 and Isomer 2615

1248

616

1249

617

1250

618

1251

619

1252

620

1253

621

1254

622

1255

623

1256

624

1257

625

1258

626

1259

627

1260

628

1261

629

1262

630

1263

631

1264

632

1265

633

1266

634

1267

635

1268

636

1269

637

1270

638

1271

639

1272

EXAMPLES 640-664

[2572] If one were to dissolve each isomer, 898a and 898b, in CH2Cl2, treat with the corresponding isocyanates, stir at room temperature overnight, and purify the crude product directly by silica gel preparative thin layer chromatography or silica gel chromatography obtain compounds of the formula:

1273

[2573] wherein R is defined in Table 64 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

71TABLE 64RExampleIsomer 1 and Isomer 2640

1274

641

1275

642

1276

643

1277

644

1278

645

1279

646

1280

647

1281

648

1282

649

1283

650

1284

651

1285

652

1286

653

1287

654

1288

655

1289

656

1290

657

1291

658

1292

659

1293

660

1294

661

1295

662

1296

663

1297

664

1298

EXAMPLES 665-689

[2574] If one were to dissolve each isomer, 899a and 899b, in CH2Cl2, treat with the corresponding isocyanates, stir at room temperature overnight and purify the crude product directly by silica gel preparative thin layer chromatography or silica gel chromatography one would obtain compounds of the formula:

1299

[2575] wherein R is defined in Table 65 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

72TABLE 65ExampleR665

1300

666

1301

667

1302

668

1303

669

1304

670

1305

671

1306

672

1307

673

1308

674

1309

675

1310

676

1311

677

1312

678

1313

679

1314

680

1315

681

1316

682

1317

683

1318

684

1319

685

1320

686

1321

687

1322

688

1323

689

1324

EXAMPLES 690-714

[2576] If one were to dissolve each isomer, 900a and 900b, in CH2Cl2, treat with the corresponding isocyanates, stir at room temperature overnight, and purify the crude product directly by silica gel preparative thin layer chromatography or silica gel chromatography one would obtain compounds of the formula:

1325

[2577] wherein R is defined in Table 66 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

73TABLE 66RExampleIsomer 1 and isomer 2690

1326

691

1327

692

1328

693

1329

694

1330

695

1331

696

1332

697

1333

698

1334

699

1335

700

1336

701

1337

702

1338

703

1339

704

1340

705

1341

706

1342

707

1343

708

1344

709

1345

710

1346

711

1347

712

1348

713

1349

714

1350

EXAMPLES 715-732

[2578] If one were to react each isomer, 897a and 897b following essentially the same procedure as in Examples 590-603 (see Preparative Example 74 for preparation of chloroformates), then one would obtain compounds of the formula:

1351

[2579] wherein R is defined in Table 67 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

74TABLE 67RExamplesIsomer 1 and Isomer 2715

1352

716

1353

717

1354

718

1355

719

1356

720

1357

721

1358

722

1359

723

1360

724

1361

725

1362

726

1363

727

1364

728

1365

729

1366

730

1367

731

1368

732

1369

EXAMPLES 733-750

[2580] If one were to react each isomer, 898a and 898b following essentially the same procedure as in Examples 590-603 (see Preparative Example 74 for preparation of chloroformates), then one would obtain compounds of the formula:

1370

[2581] wherein R is defined in Table 68 and the numbers 1 and 2 in the formulas represent isomer 1 and isomer 2, rsepectively.

75TABLE 68RExampleIsomer 1 and Isomer 2733

1371

734

1372

735

1373

736

1374

737

1375

738

1376

739

1377

740

1378

741

1379

742

1380

743

1381

744

1382

745

1383

746

1384

747

1385

748

1386

749

1387

750

1388

EXAMPLES 751-768

[2582] If one were to react each isomer, 899a and 899b following essentially the same procedure as in Examples 590-603 (see Preparative Example 74 for preparation of chloroformates), then one would obtain compounds of the formula:

1389

[2583] wherein R is defined in Table 69 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

76TABLE 69RExampleIsomer 1 and Isomer 2751

1390

752

1391

753

1392

754

1393

755

1394

756

1395

757

1396

758

1397

759

1398

760

1399

761

1400

762

1401

763

1402

764

1403

765

1404

766

1405

767

1406

768

1407

EXAMPLES 769-786

[2584] If one were to react each isomer, 900a and 900b following essentially the same procedure as in Examples 590-603 (see Preparative Example 74 for preparation of chloroformates), then one would obtain compounds of the formula:

1408

[2585] wherein R is defined in Table 70 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

77TABLE 70RExampleIsomer 1 and Isomer 2769

1409

770

1410

771

1411

772

1412

773

1413

774

1414

775

1415

776

1416

777

1417

778

1418

779

1419

780

1420

781

1421

782

1422

783

1423

784

1424

785

1425

786

1426

EXAMPLES 787-814

[2586] If one were to use 897a and 897b and follow essentially the same procedure as in Example 536 then one would obtain compounds of the formula:

1427

[2587] wherein R is defined in Table 71 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

78TABLE 71RExampleIsomer 1 and Isomer 2787

1428

788

1429

789

1430

790

1431

791

1432

792

1433

793

1434

794

1435

795

1436

796

1437

797

1438

798

1439

799

1440

800

1441

801

1442

802

1443

803

1444

804

1445

805

1446

806

1447

807

1448

808

1449

809

1450

810

1451

811

1452

812

1453

813

1454

814

1455

EXAMPLES 815-842

[2588] If one were to use 898a and 898b and follow essentially the same procedure as in Example 536 then one would obtain compounds of the formula:

1456

[2589] wherein R is defined in Table 72 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

79TABLE 72RExampleIsomer 1 and Isomer 2815

1457

816

1458

817

1459

818

1460

819

1461

820

1462

821

1463

822

1464

823

1465

824

1466

825

1467

826

1468

827

1469

828

1470

829

1471

830

1472

831

1473

832

1474

833

1475

834

1476

835

1477

836

1478

837

1479

838

1480

839

1481

840

1482

841

1483

842

1484

EXAMPLES 843-870

[2590] If one were to use 899a and 899b and follow essentially the same procedure as in Example 536 then one would obtain compounds of the formula:

1485

[2591] wherein R is defined in Table 73 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

80TABLE 73RExampleIsomer 1 and Isomer 2843

1486

844

1487

845

1488

846

1489

847

1490

848

1491

849

1492

850

1493

851

1494

852

1495

853

1496

854

1497

855

1498

856

1499

857

1500

858

1501

859

1502

860

1503

861

1504

862

1505

863

1506

864

1507

865

1508

866

1509

867

1510

868

1511

869

1512

870

1513

EXAMPLES 871-898

[2592] If one were to use 900a and 900b and follow essentially the same procedure as in Example 536 then one would obtain compounds of the formula:

1514

[2593] wherein R is defined in Table 74 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

81TABLE 74RExampleIsomer 1 and Isomer 2871

1515

872

1516

873

1517

874

1518

875

1519

876

1520

877

1521

878

1522

879

1523

880

1524

881

1525

882

1526

883

1527

884

1528

885

1529

886

1530

887

1531

888

1532

889

1533

890

1534

891

1535

892

1536

893

1537

894

1538

895

1539

896

1540

897

1541

898

1542

EXAMPLE 899-922

[2594] If one were to use 897a and 897b and follow essentially the same procedure as in Examples 566-567 then one would obtain compounds of the formula:

1543

[2595] wherein R is defined in Table 75 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

82TABLE 75RExamplesIsomer 1 and Isomer 2899

1544

900

1545

902

1546

903

1547

904

1548

905

1549

907

1550

908

1551

909

1552

910

1553

911

1554

912

1555

913

1556

915

1557

916

1558

917

1559

918

1560

919

1561

920

1562

921

1563

922

1564

EXAMPLES 923-946

[2596] If one were to use 898a and 898b and follow essentially the same procedure as in Examples 566-567 then one would obtain compounds of the formula:

1565

[2597] wherein R is defined in Table 76 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

83TABLE 76RExampleIsomer 1 and Isomer 2923

1566

924

1567

926

1568

927

1569

928

1570

929

1571

931

1572

932

1573

933

1574

934

1575

935

1576

936

1577

937

1578

939

1579

940

1580

941

1581

942

1582

943

1583

944

1584

945

1585

946

1586

EXAMPLES 947-970

[2598] If one were to use 899a and 899b and follow essentially the same procedure as in Examples 566-567 then one would obtain compounds of the formula:

1587

[2599] wherein R is defined in Table 77 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

84TABLE 77RExampleIsomer 1 and Isomer 2947

1588

948

1589

950

1590

951

1591

952

1592

953

1593

955

1594

956

1595

957

1596

958

1597

959

1598

960

1599

961

1600

963

1601

964

1602

965

1603

966

1604

967

1605

968

1606

969

1607

970

1608

EXAMPLES 971-995

[2600] If one were to use 900a and 900b and follow essentially the same procedure as in Examples 566-567 then one would obtain compounds of the formula:

1609

[2601] wherein R is defined in Table 78 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

85TABLE 78RExampleIsomer 1 and Isomer 2971

1610

973

1611

974

1612

975

1613

976

1614

977

1615

979

1616

980

1617

981

1618

982

1619

983

1620

984

1621

985

1622

987

1623

989

1624

990

1625

991

1626

992

1627

993

1628

994

1629

995

1630

PREPARATIVE EXAMPLE 84

[2602]

1631

[2603] Starting material 901 (25 g, 78 mmol) was combined with DBU (15.7 ML, 105.3 mmol, 1.35 eq.); Ph3P (9.44 g 0.39 mmol, 0.5 eq.); PdCl2(1.38 g, 7.8 mmol, 0.1 eq.); MeOH (50 ML)/Toluene (200 ML) 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 MgSO4 and evaporated to get a black syrup. (71 g) Column chromatography (silica gel) and eluting with Hexanes, then 20%Ethyl Acetate/Hexanes to 40% E/H to give producct 902, (39 g).

PREPARATIVE EXAMPLE 85

[2604]

1632

[2605] Dissolve (Bu)4NNO3 (21.15 g) in CH2Cl2 (220 ML) and cool in an ice bath under N2 and dripped in TFAA(9.8 ML) and stir for 15 minutes. The resulting yellow solution is added slowly to a solution of starting material 902, (18.97 g) in CH2Cl2 (200 ML) 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 NaHCO3 and extracted with CH2Cl2. Isolated the organic layer and dried over MgSO4, evaporated to dryness t give product as a syrup. Crude was chromatograph (twice) on SiO2 using Hexanes, then eluting with 20% & 40% Ehyl Acetate/Hexanes). 3040% yield of product 903 (7.89 g).

PREPARATIVE EXAMPLE 86

[2606]

1633

[2607] Ra-Ni ((50%in H2O), 50 g), is washed with ETOH (5×, then decanted), the washed with MeOH (3×), then added to starting material 903 (7.89 g) in MeOH (80 ML), the resulting mixture is stirred under H2 (balloom) overnight. Reaction is monitored by TLC. Added more RaNi (25 g, washed 5×with ETOH, then 3×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 (3.88 g of product).

PREPARATIVE EXAMPLE 87

[2608]

1634

[2609] Suspend starting material 904 (0.5 g) in CH3CN (20 ML), add CuBr (0.42 g) and cool in an ice bath under N2. Add t-BuONO (0.28 g) 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 1N HCL and stir. Then add Conc. NH4OH until blue (basic). Extract with CH2Cl2, isolate the organic layer, dried over MgSO4, filter and concentrated to give product 905.

PREPARATIVE EXAMPLE 88

[2610]

1635

[2611] Starting material 905 (3 g, 7.92 mmol) is stirred in MeOH(100 ML) 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 (20 ML) of 1.0 N HCL, stir for 10 minutes, basified with saturated NaHCO3, added to brine, extract with Ethyl Acetate, dried over MgSO4, filtered and evaporated to dryness to give 3.6 g of compound 906.

PREPARATIVE EXAMPLE 89

[2612]

1636

[2613] SOCl2 (2.1 ML) was added to the solution of 906 (3.5 g) in CH2Cl2 (50 ML), stirred at room temperature for 5 hours. Additional (1.0 ML) of SOCl2 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 3.6 g of crude product 907.

PREPARATIVE EXAMPLE 90

[2614]

1637

[2615] Boc-Piperazine (2.2 g, 2.5 eq.) was added to a mixture of starting material 907 (1.78 g, 4.68 mmol) and TEA (1.9 ML, 3 eq) was stirred in CH3CN (100 ML), under N2, heat to 80° C. for 5 hours. TLC then stirred at 80° C. over the weekend. Reaction is treated with 1.0N HCl and extracted with ethyl acetate, wash with brine followed by 1.0N NaOH, dried over MgSO4. Filter and evaporated reaction to dryness to give crude 908 (62% yield).

PREPARATIVE EXAMPLE 91

[2616]

1638

[2617] 12 ML of a 10% LiOH solution (˜4M) was added to a solution of starting material 908 (1.6 g) in MeOH (50 ML) 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% K2HPO4, and extracted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated to dryness to give 1.5 g of compound 909.

PREPARATIVE EXAMPLE 92

[2618]

1639

[2619] Combined starting materials 909 (1.5 g, ˜7.8 mmol); NHCH3OCH3.HCl; NMM; HOBT; & DMAP in CH2Cl2 (20 ML) and stirred for 10 minutes, then EDC (0.64 g, 1.2 eq.) was added and stirred overnight at room temperature. Reaction was treated with 1N HCl, extracted with ethyl acetate, washed with brine followed by 1N NaOH. dried over MgSO4, filtered and evaporated the filtrate to dryness to give 1.45 g) crude compound 910.

PREPARATIVE EXAMPLE 93

[2620]

1640

[2621] A 3M solution of CH3MgBr/Ether (3.8 ML, 4.5 eq) was added dropwise to a solution of 910 (1.45 g, 2.5 mmol) in THF (50 ML), a dark brown solution resulted. Reaction was stirred under N2 at room temperature for 2 hours. Reaction was then treated with a saturated NH4Cl solution and extracted with ethyl acetate. Washed with brine and dried over MgSO4, filtered and evaporated to dryness to get a yellow solid compound, which after column chromatography gave 1.33 g of compound 911 as a racemic mixture.

PREPARATIVE EXAMPLE 94

[2622]

1641

[2623] Starting material 911 (0.90 g) was dissolved in CH2Cl2 (35 ML) and TFA (35 ML) and stirred at room temperature overnight. Washed with 1.0 N NaOH, dried over MgSO4, filtered and evaporated to dryness to give compound 912.

PREPARATIVE EXAMPLE 95

[2624]

1642

[2625] 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

[2626]

1643

[2627] Starting material 912a (0.284 g 0.656 mmol) was dissolved in CH2Cl2 (5 ML), TEA (1.83 ML, 2.0 eq.) and (BOC)2O (0.215 g, 1.5 eq), and stirred at room temperature overnight. Reaction was evaporated and crude was purified by column chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0.3 g of compound 913a.

PREPARATIVE EXAMPLE 97

[2628]

1644

[2629] Starting material 9121b (0.254 g 0.587 mmol) was dissolved in CH2Cl2 (5 ML), TEA (1.64 ML, 2.0 eq.) and (BOC)2O (0.192 g, 1.5 eq), and stirred at room temperature overnight. Reaction was evaporated and crude was purified by column chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0.255 g of compound 913b.

PREPARATIVE EXAMPLE 98

[2630]

1645

[2631] Suspended commercially available (from Acros) 915 (30 g, 68.8 mmol) in dry THF (600 ml) under dry N2. Stirred at room temperature under N2 until it formed a clear solution. Added CH31 (50 ml, 114 g, 803.2 mmol) 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/CH2Cl2). Filtered the suspension, washed solid with dry THF. Dried the solid under house Vacuum at 40° C. to give 31.11 g of a brown solid, compound 916.

1646

[2632] Suspended 916 (31.1 g, 53.79 mmol) in 200 ML of 50%HOAC/H2O and heat under reflux overnight. Follow by TLC. When completed, allowed to cool to room temperature, filtered the resulting suspension. Washed with 50%HOAC/H2O. Evaporated to dryness. Suspended the solid in CH2Cl2. Basified to pH 10-11 with 1N NaOH. Separated CH2Cl2 layer and extracted the aqueous phase 3×with CH2CL2. Combined organic layers and washed with Saturated NaCl solution. Dried over MgSO4, evaporated to dryness to give 914 (8.68 g of an off-white solid).

PREPARATIVE EXAMPLE 99

[2633]

1647

[2634] EtMgBr (3Molar in Et2O) solution (2.89 mmol, 963 uL, 5.5 eq.) was dripped into a solution of 914 (0.656 g, 3.15 mmol, 6 eq.) in ClCH2CH2Cl (6 ML) for 30 minutes. To the white suspended mixture, 913a (0.280 g, 0.525 mmol) was then added and stirred at 60° C. for 3 hours. Reaction was treated with saturated NH4Cl at 0° C. by pouring the reaction into the cold NH4Cl. Extracted with Ethyl Acetate, dried over MgSO4 and evaporated to dryness. Column Chromatography (SiO2) eluted with 1%, 2% & 3% MeOH/CH2Cl2 gave 0.054 g of compound 917.

1648

[2635] 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

[2636]

1649

[2637] EtMgBr (3Molar in Et2O) solution (791 uL), was dripped into a solution of 914 (0.518 g, 3.15 mmol, 6 eq.) in ClCH2CH2Cl (6 ML), for 30 minutes. To the white suspended mixture, 913b (0.280 g, 0.525 mmol) was then added and stirred at 60° C. for 3 hours. Reaction was treated with saturated NH4Cl at 0° C. by pouring the reaction into the cold NH4Cl. Extracted with Ethyl Acetate, dried over MgSO4 and evaporated to dryness. Column Chromatography (SiO2), eluted with 1%, 2% & 3% MeOH/CH2Cl2 gave 0.054 g of compound 918.

1650

[2638] 918 was separated by HPLC using a Chiral OD Column and eluting with 20%1PA/Hexanes to give Isomers 918a 1H NMR (400 MHz, CDCl3, TMS) δ 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, 1H), 3.540 (s, 1H), 3.738 (s, 1H), 3.760 (s, 1H), 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=2.4 Hz, 1H), 8.221 (s, 1H), 8.486 (d, J=2.8 Hz, 1H). (21) Mp=188-190° C., and 918b.

PREPARATIVE EXAMPLE 101

[2639]

1651

[2640] Compound 917a was converted to 919a by reacting with CH2Cl2/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 MgSO4, filtered and concentrated to give compound 919a.

PREPARATIVE EXAMPLE 102

[2641]

1652

[2642] Compound Carmen 917b was converted to 919b by reacting with CH2Cl2/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 MgSO4, filtered and concentrated to give compound 919b.

PREPARATIVE EXAMPLE 103

[2643]

1653

[2644] Compound 918a, was converted to 920a, by reacting with CH2Cl2/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 MgSO4, filtered and concentrated to give compounds 920a.

PREPARATIVE EXAMPLE 104

[2645]

1654

[2646] Compound 918b was converted to 920b by reacting with CH2Cl2/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 MgSO4, filtered and concentrated to give compound 920b.

EXAMPLES 996-1020

[2647] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Examples 690-714 then one would obtain compounds of the formula:

1655

[2648] wherein R is defined in Table 79 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

86TABLE 79RExampleIsomer 1 and Isomer 2996

1656

997

1657

998

1658

999

1659

1000

1660

1001

1661

1002

1662

1003

1663

1004

1664

1005

1665

1006

1666

1007

1667

1008

1668

1009

1669

1010

1670

1011

1671

1012

1672

1013

1673

1014

1674

1015

1675

1016

1676

1017

1677

1018

1678

1019

1679

1020

1680

EXAMPLES 1021-1045

[2649] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Examples 690-714 then one would obtain compounds of the formula:

1681

[2650] wherein R is defined in Table 80 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

87TABLE 80RExampleIsomer 1 and Isomer 21021

1682

1022

1683

1023

1684

1024

1685

1025

1686

1026

1687

1027

1688

1028

1689

1029

1690

1030

1691

1031

1692

1032

1693

1033

1694

1034

1695

1035

1696

1036

1697

1037

1698

1038

1699

1039

1700

1040

1701

1041

1702

1042

1703

1043

1704

1044

1705

1045

1706

EXAMPLES 1046-1073

[2651] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Example 536 the one would obtain compounds of the formula:

1707

[2652] wherein R is defined in Table 81 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

88TABLE 81RExampleIsomer 1 and Isomer 21046

1708

1047

1709

1048

1710

1049

1711

1050

1712

1051

1713

1052

1714

1053

1715

1054

1716

1055

1717

1056

1718

1057

1719

1058

1720

1059

1721

1060

1722

1061

1723

1062

1724

1063

1725

1064

1726

1065

1727

1066

1728

1067

1729

1068

1730

1069

1731

1070

1732

1071

1733

1072

1734

1073

1735

EXAMPLES 1074-1102

[2653] If one were to use isomers 920a and 920b in a procedure essentially the same as that in Example 536 then one would obtain compounds of the formula:

1736

[2654] wherein R is defined in Table 82 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

89TABLE 82RExampleIsomer 1 and Isomer 21075

1737

1076

1738

1077

1739

1078

1740

1079

1741

1080

1742

1081

1743

1082

1744

1083

1745

1084

1746

1085

1747

1086

1748

1087

1749

1088

1750

1089

1751

1090

1752

1091

1753

1092

1754

1093

1755

1094

1756

1095

1757

1096

1758

1097

1759

1098

1760

1099

1761

1100

1762

1101

1763

1102

1764

EXAMPLES 1103-1121

[2655] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Examples 590-603 (wherein the chloroformates would be prepared according to Preparative Example 74) then one would obtain compounds of the formula:

1765

[2656] wherein R is defined in Table 83 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

90TABLE 83RExampleIsomer 1 and Isomer 21103

1766

1104

1767

1105

1768

1106

1769

1107

1770

1108

1771

1109

1772

1110

1773

1111

1774

1112

1775

1113

1776

1114

1777

1115

1778

1116

1779

1117

1780

1118

1781

1120

1782

1121

1783

EXAMPLES 1122-1139

[2657] If one were to use isomer 920a and 920b in a procedure essentially the same as that in Example 590-603 (wherein the chloroformates would be prepared according to Preparative Example 74) then one would obtain compounds of the formula:

1784

[2658] wherein R is defined in Table 84 and and the numbers 1 and 2 in the formulas represent isomer 1 and isomer 2, respectively.

91TABLE 84RExampleIsomer 1 and Isomer 21122

1785

1123

1786

1124

1787

1125

1788

1126

1789

1127

1790

1128

1791

1129

1792

1130

1793

1131

1794

1132

1795

1133

1796

1134

1797

1135

1798

1136

1799

1137

1800

1138

1801

1139

1802

EXAMPLES 1140-1163

[2659] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Examples 566-567 then one would obtain compounds of the formula:

1803

[2660] wherein R is defined in Table 85 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

92TABLE 85RExampleIsomer 1 and Isomer 21140

1804

1141

1805

1143

1806

1144

1807

1145

1808

1146

1809

1148

1810

1149

1811

1150

1812

1151

1813

1152

1814

1153

1815

1154

1816

1156

1817

1157

1818

1158

1819

1159

1820

1160

1821

1161

1822

1162

1823

1163

1824

EXAMPLES 1164-1187

[2661] If one were to use isomers 920a and 920b in a procedure essentially the same as that in Examples 566-567 then one would obtain compounds of the formula:

1825

[2662] wherein R is defined in Table 86 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

93TABLE 86RExampleIsomer 1 and Isomer 21164

1826

1165

1827

1167

1828

1168

1829

1169

1830

1170

1831

1172

1832

1173

1833

1174

1834

1175

1835

1176

1836

1177

1837

1178

1838

1180

1839

1181

1840

1182

1841

1183

1842

1184

1843

1185

1844

1186

1845

1187

1846

PREPARATIVE EXAMPLE 105

[2663]

1847

[2664] Compound 922 was reacted in essentially the same manner as in Preparative Example 23, Steps A-D to get compound 922.

1848

[2665] In essentially the same manner as in Preparative Example 42, Step A, using 922 as the starting material, compound 923 is prepared.

PREPARATIVE EXAMPLE 106

[2666]

1849

[2667] 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

[2668]

1850

[2669] 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).

EXAMPLES 1188-1212

[2670] If one were to follow essential the same procedure as in Examples 690-714 using 924a and 924b then one would obtain compounds of the formula:

1851

[2671] wherein R is defined in Table 87 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

94TABLE 87RExampleIsomer 1 and Isomer 21188

1852

1189

1853

1190

1854

1191

1855

1192

1856

1193

1857

1194

1858

1195

1859

1196

1860

1197

1861

1198

1862

1199

1863

1200

1864

1201

1865

1202

1866

1203

1867

1204

1868

1205

1869

1206

1870

1207

1871

1208

1872

1209

1873

1210

1874

1211

1875

1212

1876

EXAMPLES 1213-1238

[2672] If one were to follow essential the same procedure as in Examples 690-714 using 925a and 925b then one would obtain compounds of the formula:

1877

[2673] wherein R is defined in Table 88 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

95TABLE 88RExampleIsomer 1 and Isomer 21213

1878

1214

1879

1215

1880

1216

1881

1217

1882

1218

1883

1219

1884

1220

1885

1221

1886

1223

1887

1224

1888

1225

1889

1226

1890

1227

1891

1228

1892

1229

1893

1230

1894

1231

1895

1232

1896

1233

1897

1234

1898

1235

1899

1236

1900

1237

1901

1238

1902

EXAMPLES 1239-1266

[2674] If one were to follow essentially the same procedure as in Example 536 using 924a and 924b then one would obtain compounds of the formula:

1903

[2675] wherein R is defined in Table 89 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

96TABLE 89RExampleIsomer 1 and Isomer 21239

1904

1240

1905

1241

1906

1242

1907

1243

1908

1244

1909

1245

1910

1246

1911

1247

1912

1248

1913

1249

1914

1250

1915

1251

1916

1252

1917

1253

1918

1254

1919

1255

1920

1256

1921

1257

1922

1258

1923

1259

1924

1260

1925

1261

1926

1262

1927

1263

1928

1264

1929

1265

1930

1266

1931

EXAMPLES 1267-1294

[2676] If one were to follow essentially the same procedure as in Example 536 using 925a and 925b then one would obtain compounds of the formula:

1932

[2677] wherein R is defined in Table 90 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

97TABLE 90RExampleIsomer 1 and Isomer 21267

1933

1268

1934

1269

1935

1270

1936

1271

1937

1272

1938

1273

1939

1274

1940

1275

1941

1276

1942

1277

1943

1278

1944

1279

1945

1280

1946

1281

1947

1282

1948

1283

1949

1284

1950

1285

1951

1286

1952

1287

1953

1288

1954

1289

1955

1290

1956

1291

1957

1292

1958

1293

1959

1294

1960

EXAMPLE 1295

[2678] 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:

1961

[2679] were prepared wherein R is defined in Table 91 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

98TABLE 91ExampleRIsomer 1Isomer 21295

1962

1H NMR (400 MHz, CDCl33, TMS)δ 1.417 (s, 9H), 1.454 (d, J=1.6 Hz, 1H), 1.857 (s, 3H), 2.20-2.05 (m, 4H), 3.205 (broad, 1 H), 3.432 (s, 1H), 3.612 (s, 1H), 3.731 (d, J=6.4 Hz, 1H), 3.853 (s, 3H), 4.575 (s, 1H), 6.538 (s, 1H), 7.086 (s, 1H), 7.114 (s, 1H), 7.262 (d, 2H), 7.540 (s, 1H), 8.530 (d, J=2.0 Hz, 1H), 8.876 (d, J=2.0 Hz, 1H).mp = 184-185° C.

EXAMPLES 1296-1313

[2680] If one were to Follow essentially the same procedure as Examples 590-603 (wherein the chloroformates would be prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula:

1963

[2681] would be obtained wherein R is defined in Table 92 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

99TABLE 92RExampleIsomer 1 and Isomer 21296

1964

1297

1965

1298

1966

1299

1967

1300

1968

1301

1969

1302

1970

1303

1971

1304

1972

1305

1973

1306

1974

1307

1975

1308

1976

1309

1977

1310

1978

1311

1979

1312

1980

1313

1981

EXAMPLE 1314

[2682] 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:

1982

[2683] were prepared wherein R is defined in Table 93 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

100TABLE 93ExampleRIsomer 1Isomer 21314

1983

1H NMR (400 MHz, CDCl3, TMS) δ 1.418 (s, 9H), 1.456 (s, 1H), 1.859 (s, 3H), 2.20-2.05 (m, 4H), 3.205 (broad, 1H), 3.612 (s, 1H), 3.692 (s, 1H), 3.740 (s, 1H), 3.854 (s, 3H), 4.576 (s, 1H), 6.541 (s, 1H), 7.090 (s, 1H), 7.116 (s, 1H), 7.262 (d, 2H), 7.548 (s, 1H), 8.530 (d, J=2.0 Hz, 1H), 8.864 (d, J=2.0 Hz, 1H)mp = 183-184° C.

EXAMPLES 1315-1332

[2684] If one were to follow essentially the same procedure as Examples 590-603 (wherein the chloroformates would be prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula:

1984

[2685] would be obtained wherein R is defined in Table 94 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

101TABLE 94RExampleIsomer 1 and Isomer 21315

1985

1316

1986

1317

1987

1318

1988

1319

1989

1320

1990

1321

1991

1322

1992

1323

1993

1324

1994

1325

1995

1326

1996

1327

1997

1328

1998

1329

1999

1330

2000

1331

2001

1332

2002

EXAMPLES 1333-1356

[2686] If one were to follow essentially the same procedure as Examples 566-567 using the 924a and 924b compounds of the formula:

2003

[2687] would be obtained wherein R is defined in Table 95 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

102TABLE 95RExampleIsomer 1 and Isomer 21333

2004

1334

2005

1336

2006

1337

2007

1338

2008

1339

2009

1341

2010

1342

2011

1343

2012

1344

2013

1345

2014

1346

2015

1347

2016

1349

2017

1350

2018

1351

2019

1352

2020

1353

2021

1354

2022

1355

2023

1356

2024

EXAMPLES 1357-1380

[2688] If one were to follow essentially the same procedure as Examples 566-567 using 925a and 925b compounds of the formula:

2025

[2689] would be obtained wherein R is defined in Table 96 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

103TABLE 96RExampleIsomer 1 and Isomer 21357

2026

1358

2027

1360

2028

1361

2029

1362

2030

1363

2031

1365

2032

1366

2033

1367

2034

1368

2035

1369

2036

1370

2037

1371

2038

1373

2039

1374

2040

1375

2041

1376

2042

1377

2043

1378

2044

1379

2045

1380

2046

PREPARATIVE EXAMPLE 108

[2690]

2047

[2691] In essentially the same manner as in Preparative Example 23, Steps A-D, use compound 234a (from Step B) to prepare 926.

2048

[2692] In essentially the same manner as in Preparative Example 42, Step A, use 926 to prepare 927.

2049

[2693] Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 928a and 928b.

2050

[2694] Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 929a and 929b.

EXAMPLES 1381-1405

[2695] If one were to follow essentially the same procedure as in Examples 690-714 using 928a and 928b compounds of the formulas:

2051

[2696] would be obtained wherein R is defined in Table 97 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

104TABLE 97RExampleIsomer 1 and isomer 21381

2052

1382

2053

1383

2054

1384

2055

1385

2056

1386

2057

1387

2058

1388

2059

1389

2060

1390

2061

1391

2062

1392

2063

1393

2064

1394

2065

1395

2066

1396

2067

1397

2068

1398

2069

1399

2070

1400

2071

1401

2072

1402

2073

1403

2074

1404

2075

1405

2076

EXAMPLES 1406-1431

[2697] If one were to follow essentially the same procedure as in Examples 690-714 using 929a and 929b compounds of the formulas:

2077

[2698] would be obtained wherein R is defined in Table 98 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

105TABLE 98RExampleIsomer 1 and Isomer 21406

2078

1407

2079

1408

2080

1409

2081

1411

2082

1412

2083

1413

2084

1414

2085

1415

2086

1416

2087

1417

2088

1418

2089

1419

2090

1420

2091

1421

2092

1422

2093

1423

2094

1424

2095

1425

2096

1426

2097

1427

2098

1428

2099

1429

2100

1430

2101

1431

2102

EXAMPLES 1432-1459

[2699] If one were to follow essentially the same procedure as in Example 536 using 928a and 928b compounds of the formulas:

2103

[2700] would be obtained wherein R is defined in Table 99 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

106TABLE 99RExampleIsomer 1 and Isomer 21432

2104

1433

2105

1434

2106

1435

2107

1436

2108

1437

2109

1438

2110

1439

2111

1440

2112

1441

2113

1442

2114

1443

2115

1444

2116

1445

2117

1446

2118

1447

2119

1448

2120

1449

2121

1450

2122

1451

2123

1452

2124

1453

2125

1454

2126

1455

2127

1456

2128

1457

2129

1458

2130

1459

2131

EXAMPLES 1460-1487

[2701] If one were to follow essentially the same procedure as in Example 536 using 929a and 929b compounds of the formulas:

2132

[2702] would be obtained wherein R is defined in Table 100 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

107TABLE 100RExampleIsomer 1 and Isomer 21460

2133

1461

2134

1462

2135

1463

2136

1464

2137

1465

2138

1466

2139

1467

2140

1468

2141

1469

2142

1470

2143

1471

2144

1472

2145

1473

2146

1474

2147

1475

2148

1476

2149

1477

2150

1478

2151

1479

2152

1480

2153

1481

2154

1482

2155

1483

2156

1484

2157

1485

2158

1486

2159

1487

2160

EXAMPLES 1488-1505

[2703] If one were to follow essentially the same procedure as in Examples 590-603 using 928a and 928b (wherein the chloroformates could be prepared following essentially the same procedure as in Preparative Example 74) compounds of the formulas:

2161

[2704] would be obtained wherein R is defined in Table 101 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

108TABLE 101RExampleIsomer 1 and Isomer 21488

2162

1489

2163

1490

2164

1491

2165

1492

2166

1493

2167

1494

2168

1495

2169

1496

2170

1497

2171

1498

2172

1499

2173

1500

2174

1501

2175

1502

2176

1503

2177

1504

2178

1505

2179

EXAMPLES 1506-1524

[2705] If one were to follow essentially the same procedure as in Examples 590-603 using 929a and 929b (wherein the chloroformates could be prepared following essentially the same procedure as in Preparative Example 74) compounds of the formulas:

2180

[2706] would be obtained wherein R is defined in Table 102 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

109TABLE 102RExampleIsomer 1 and Isomer 21506

2181

1507

2182

1508

2183

1509

2184

1510

2185

1511

2186

1512

2187

1513

2188

1514

2189

1515

2190

1516

2191

1517

2192

1518

2193

1519

2194

1520

2195

1521

2196

1522

2197

1523

2198

1524

2199

EXAMPLES 1525-1548

[2707] If one were to follow essentially the same procedure as in Examples 566-567 using 928a and 928b compounds of the formulas:

2200

[2708] would be obtained wherein R is defined in Table 103 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

110TABLE 103RExampleIsomer 1 and Isomer 21525

2201

1526

2202

1527

2203

1528

2204

1529

2205

1530

2206

1531

2207

1533

2208

1534

2209

1535

2210

1536

2211

1537

2212

1538

2213

1539

2214

1541

2215

1542

2216

1543

2217

1544

2218

1545

2219

1546

2220

1547

2221

1548

2222

EXAMPLES 1549-1572

[2709] If one were to follow essentially the same procedure as in Examples 566-567 using 929a and 929b compounds of the formulas:

2223

[2710] would be obtained wherein R is defined in Table 104 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

111TABLE 104RExampleIsomer 1 and Isomer 21549

2224

1550

2225

1552

2226

1553

2227

1554

2228

1555

2229

1557

2230

1558

2231

1559

2232

1560

2233

1561

2234

1562

2235

1563

2236

1565

2237

1566

2238

1567

2239

1568

2240

1569

2241

1570

2242

1571

2243

1572

2244

EXAMPLE 1573

[2711]

2245

[2712] React 882, from Preparative Example 73 Step B, with ethylmagnesium bromide following the procedure described in Preparative Example 73 Step C.

2246

[2713] 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

[2714]

2247

[2715] Dissolve 880 (1.4 g, 10 mol), CF3TMS (1.46 g, 10.25 mol), and CsF (15.2 mg, 0.1 mmol) 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.

2248

[2716] 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

[2717]

2249

[2718] React 372 (Example 167) (0.06 g, 0.097 mmol) with 5 equivalents (0.019 g, 0.48 mmol) of NaH (60% in oil) in 2 ml of dry THF at 0° C. for 5 min. Add 0.027 g (0.11 mmol) 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% CH3OH in CH2Cl2 containing NH4OH. Partition between ethyl acetate and brine. Dry organic layer over Na2SO4, concentrate and chromatograph on silica gel, eluting with 1%-4% CH3OH in CH2Cl2 containing NH4OH, to give 934 as a light yellow solid.

EXAMPLE 1576

[2719] 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

[2720] 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

[2721] 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

[2722] Following essentially the same procedure as in Example 1575, compound 372 was reacted with CH31 to afford compound 938 identified in Table 105 below.

112TABLE 105

2250

ExampleR ═CompoundPHYS. DATA1575

2251

934MH += 6411576

2252

935MH += 6411577

2253

936MH += 6411578

2254

937MH += 6401579

2255

938MH += 564

EXAMPLE 1580

[2723]

2256

[2724] To a 125 ml flask, was added 4-hydroxymethyl piperidine (940) (1 g, 8.68 mmol) and 20 ml of MeOH, cool to 0° C., then added Boc-anhydride (2.84 g, 13.02 mmol, 1.5 eq.), and adjust to pH 8.5-9.5 over 1 hour with 13 ml, 13.0 mmol, 1.5 eq. of 1.0 N NaOH. 1o Reaction was allowed to warm to room temperature and stirred for 1 hour. TLC with 20% EtoAc/CH2Cl2. Removed most MeOH via evaporation. Added CH2Cl2 and washed with H2O, brine and filtered through Na2SO4. The solvent was evaporated to give 1.82 g of a clear oil. Oily product crystallized upon standing to give a white solid product 941.

2257

[2725] 941 (0.3 g, 1.395 mmol) was transferred into a flask and dissolved in anhydrous CH2Cl2. Cool to 0° C. Added 129 ul, 1.67 mmol, 1.2 eq., of methanesulfonyl chloride and triethylamine (129 ul, 2.09 mmol, 1.5 eq.). Allowed to warm to room temperature while stirring for 1 hour. TLC with 20% EtoAc/CH2Cl2. Added saturated NaHCO3, and stir 3-4 minutes, separated the CH2Cl2 layer, washed with H2O, brine and filtered through Na2SO4. Solvent was evaporated to give 0.423 g of a clear oil, compound 942.

2258

[2726] 942 (0.1 g, 3.413 mmol) was transferred into a reaction flask and added anhydrous CH2Cl2 (1 ml), followed by addition of (1) 4-aminobenzonitrile (0.040 g, 3.4 mmol) and triethylamine (61 ul, 4.4 mmol, 1.3 eq.) and stir at room temperature for 10 minutes. TLC with 10% EtoAc/CH2Cl2, reaction still did not complete. Stir for 1½ hour, TLC again, reaction stopped. Removed solvent to dryness. Added to residue, (1 ml) of anhydrous THF at room temperature, then added 0.0136 g, 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 (0.136 g, 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 CH2Cl2 and washed with H2O, then brine. Filtered through Na2SO4, removed solvent to dryness to give 0.125 g of crude product. Crude was purified by flash chromatography using (silica gel) and eluting with CH2Cl2 then with 1-5% EtoAc/CH2Cl2. Isolated 0.035 g of product, 943.

2259

[2727] 943 (0.034 g, 0.11 mmol) was transferred into a reaction flask and dissolved in CH2Cl2 (3 ml) and cooled to 0° C. TEA (60 ul, 0.43 mmol, 4 eq.) was added, followed by (213 ul, 0.0427 g, 0.43 mmol, 4 eq.) of a 20% phosgene/toluene solution. Reaction was allowed to stir at 0° C. for 1½ hours. After 1½ hours, N2 was bubbled into the reaction for 10 minutes, then added 0.056 g, 0.12 mmol, 1.1 eq., of starting material (2)-compound 371a (Preparative Example 42, Step F) followed by triethylamine (33 ul, 0.24 mmol, 2.2 eq.) in 1 ml of CH2Cl2. Allowed to stir at 0° C. for 1½ hours. Reaction mixture was washed with NaHCO3, then H2O, then brine and organic layer was filtered through Na2SO4. Removed solvent to dryness to give 0.083 g of crude product. Purified on flash silica gel column eluting with 2, 4, 6, 8%(10%NH4OH/CH3OH)/CH2Cl2). Isolated product gave 0.039 g of 939, MH+=747.

EXAMPLE 1581

[2728]

2260

[2729] 939 was reacted in the same manner as Compound 360a (Preparative Example 40, STEP G), using (0.118 g, 0.25 mmol) of 939 and (5 ml) of 4N HCL in dioxane to give 0.252 g of 944, MH+=647.

EXAMPLE 1582

[2730]

2261

[2731] In a 100 ml flask was added 944 (0.073 g, 0.067024 mmol) and 5 ml of anhydrous CH2Cl2 and stirred followed by addition of TEA (37 ul, 4 eq.) and trimethylsilyl isocyanate (90 ul, 0.07 mmol, 10 eq.). Reaction was allowed to stir at room temperature for 1 hour. TLC with 7% (10% NH4OH/CH3OH)/CH2Cl2. Stir 1½ hours, then added saturated NaHCO3 and stirred for 10 minutes, separated CH2Cl2 layer, and washed with H2O, brine and dried over Na2SO4, filtered and concentrated filtrate to dryness to give 0.056 g of crude product. Purified on Flash silica gel column eluting with CH2Cl2, then with 1-7%(10% NH4OH/CH3OH)/CH2Cl2. Isolated 0.038 g of the desired product, 945, MH+=690.

EXAMPLE 1583

[2732]

2262

[2733] In a 50 ml reaction flask was added (0.0092 g, 0.0882 mmol, 1.05 eq.) of 2-hydroxy isobutyric acid [CAS 594-61-6] in 1 ml of anhydrous DMF and 1 ml of anhydrous CH2Cl2 followed by addition of NMM (46 ul, 0.42 mmol, 5 eq.); HOBT (0.0178 g, 0.11 mmol, 1.3 eq.), DEC (0.024 g, 0.13 mmol, 1.5 eq.). Reaction mixture was allowed to stir at room temperature for ˜10 minutes, then added 944 (0.084 g, 0.08 mmol, 1 eq.) in 1 ml of DMF and 1 ml of CH2Cl2. Reaction was allowed to stir at room temperature overnight. Removed solvent in rotary evaporator, added EtoAc and washed with saturated NaHCO3, then 3(X) with H2O, then with Brine. Organic layer was filtered through Na2SO4, evaporated filtrate to dryness to give 0.087 g of crude product. Purified crude on a Flash silica gel column eluting with CH2Cl2— 1-5% (10%NH4OH/CH3OH)/CH2Cl2, to give 0.048 g of a white solid Compound 946, MH+=733.

EXAMPLE 1584

[2734]

2263

[2735] In a 50 ml flask was transferred (0.084 g, 0.084 mmol) of 944 and 2 ml of anhydrous CH2Cl2followed by addition of triethylamine (50 ul, 4.2 mmol, 5 eq.) and methanesulfonylchloride (7.8 ul, 0.10 mmol. 1.2 eq.). Reaction was allowed to stir at room temperature overnight. Tic with 5% (10%NH4OH/CH3OH)/CH2Cl2. Added saturated NaHCO3 and stirred vigorously 5-10 minutes. Separated CH2Cl2 layer and washed with H2O, Brine and filtered through Na2SO4. Filtrate was evaporated to dryness to give 0.080 g of crude product. Purified crude on a Flash silica gel column eluting with CH2Cl2-1-4% (10%NH4OH/CH3OH)/CH2Cl2, to give 0.041 g—compound 947, MH+=725.

EXAMPLE 1585

[2736]

2264

[2737] In a 50 ml flask was transferred (0.084 g, 0.084 mmol) of 944 and 2 ml of anhydrous CH2Cl2followed by addition of triethylamine (58 ul, 4.2 mmol, 5 eq.) and triflic anhydride (16.9 ul, 0.1008 mmol, 1.2 eq.). Reaction was allowed to stir at room temperature overnight. TLC with 5% (10%NH4OH/CH3OH)/CH2Cl2. Added saturated NaHCO3 and stirred vigorously 5-10 minutes. Separated CH2Cl2 layer and washed with H2O, brine and filtered through Na2SO4. Filtrate was evaporated to dryness to give 0.065 g of crude product. Purified crude on a Flash silica gel column eluting with CH2Cl2-1-4% (10%NH4OH/CH3OH)/CH2Cl2, to give 0.028 g—compound 948, MH+=779.

EXAMPLE 1586

[2738]

2265

[2739] 4-aminobenzonitrile (0.1 g, 0.85 mmol) was dissolved in (5 ml)of CH2Cl2. To this solution was added isobutylene oxide (61 mg, 0.85 mmol) and 1 g of silica gel. Reaction mixture was stirred at room temperature for 16 hours. Isobutylene oxide (0.75 μl, 8 mmol) was added and reaction was heated to 60° C. for 16 hours. 4-aminobenzonitrile (200 mg, 1.6 mmol) and isobutylene oxide(0.75 μl, 8 mmol) 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/CH2Cl2, to give 295 mg of the desired product-951.

2266

[2740] Compound 951 from Step A was N-protected with a Boc group using standard conditions to give 952.

2267

[2741] Compound 952 from Step B was O-protected using tetrabutyldimethylsilyl(TBDMS) to give 953.

2268

[2742] The Boc group of 953 Step C was deprotected using using HCl-Dioxane to give 954.

2269

[2743] Compound 954 from Step D was treated in a similar way to compound of Example 1580, Step D, to give 955.

2270

[2744] Compound 955 from Step E, was deprotected by treatment with tetrabutylammoniumfluoride(TBAF) to give the title compound 949.

EXAMPLE 1587

[2745]

2271

[2746] 956 and 957 were prepared in a similar manner to 949 using the appropriate substituted starting epoxide.

PREPARATIVE EXAMPLE 109

[2747]

2272

[2748] To a stirred solution of 1,2-dimethylimidazole, compound 958 (1.92 g, 1 eq. 20 mmol) in 50 ml of Et2O, 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 ml of DMF, stirred for 2-5 hours or until reaction was complete. Quench reaction with NH4Cl solution and extract with CH2Cl2, wash organic 3×with brine. Isolate organic and evaporate to dryness to obtain product as a crude. Purification from Prep Plate Chromatography 10:1 CH2Cl2: MeOH:2N NH3 afforded 0.52 g of compound 959, ˜21%.

2273

[2749] Following essentially the same procedures as in Example 510 (Step A), but using compound 959 (0.25 g, 2 mmol) as the intermediate, compound 960 was prepared. Yellow solid (0.54 g), 50% yield.

2274

[2750] Following essentially the same procedures as in Example 510 (Step B) but using Compound 960 (0.45 g, 0.84 mmol) as the starting material, compound 961 was prepared. Light yellow solid (0.372).

2275

[2751] Following essentially the same procedures as in Example 510 (Step C) but using Compound 961 (0.267 g, 0.5 mmol) as the starting material, compound 962 was prepared.

2276

[2752] Following essentially the same procedures as in Example 510 (Step D) but using Compound 962 (0.5 mmol) as the starting material, compound 963 was prepared. (0.18 g).

2277

[2753] 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 IPA (10%) hexanes (80%)+0.2% DEA

[2754] Isomer 1, compound 963a: retention time=7.61 min

[2755] Isomer 2, compound 963b: retention time=10.56 min

PREPARATIVE EXAMPLE 110

[2756]

2278

[2757] To a stirred solution of 964 (Ethyl 4-methyl-5-imidazole carboxylate, 7.7 g, 50 mmol) in 100 ml of acetone at room temperature, was added K2CO3 (6.9 g, 50 mmol) portionwise. Stirred at room temperature for 25 minutes, added in MeI (5 ml, 80 mmol) stirred for 2½ h, (monitored reaction by TLC). Additional K2CO3 (3.09 g, 22 mmol) and MeI (3 ml) were added. Stirred reaction for 16 h, then filtered reaction mixture and rinsed with acetone (80 ml). A clear filtrate obtained. Filtrate was evaporated and the residue was chromatographed (eluent methylene chloride/methanol (60:1) to afford 1.8 g of solid. This solid was purified by Prep Plate chromatography ((20:1) CH2Cl2: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.

2279

[2758] To a stirred solution of compound 965 (680 mg) in 10 ml THF at −78° C. was added dropwise 1.0M LAH in THF (5.0 ml). Reaction was stirred and allowed to warm to room temperature overnight. Cooled reaction mixture to 0° C. then added 5 ml of H2O dropwise. Allowed reaction to warm to room temperature while stirring for 1 hr. Filtered through celite and rinsed with 20 ml THF/40 ml H2O. A clear filtrate obtained. Filtrate afforded compound 966.

2280

[2759] To a stirred solution of compound 966 (˜4 mmol) at room temperature was added (3.0 g) of MnO2, a suspension resulted. Heated reaction mixture to a gentle reflux for 18 hr. Additional MnO2/THF was added (6.0 g/20 ml). Stirred at reflux for 24 hr. Cooled to room temperature, filtered through celite and rinsed with 50 ml MeOH Solvent was evaporated and azeotroped residue with toluene to afford crude product. Crude was purified by column chromatography (20:1 CH2Cl2/MeOH), then (8:1 CH2Cl2:MeOH) to elute out desired product as a white solid, compound 967.

2281

[2760] 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 could be prepared.

2282

[2761] If one were to follow essentially the same procedures as in Example 510 (Step B), but using compound 968 as the starting materithen al, then one could prepare compound 969.

2283

[2762] 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.

2284

[2763] 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.

2285

[2764] 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 971a and 971b.

PREPARATIVE EXAMPLE 111

[2765]

2286

[2766] To a stirred solution of 972 (ethyl 4-methyl-5-imidazole carboxylate, 3.08 g, 20 mmol) in 30 ml of THF, at room temperature, was added NaH (0.8 g, 20 mmol) portionwise. Stirred at room temperature for 10 minutes, then cooled to 0° C. Added in MeI (1.5 ml, 24 mmol) stirred for 2 h, quenched with saturated NH4Cl, extracted with ethyl acetate (2×), and washed with brine. Purified crude by column chromatography using a 20:1 CH2Cl2:MeOH, to afford product, compound 973.

[2767] Step B

2287

[2768] To a stirred solution of compound 973 (0.9 g) in 15 ml THF, was added 3 ml of a 10% LiOH solution and stirred reaction for 2 days. Evaporated solvent, azeotroped once with toluene, evaporated solvent to afford product, compound 974.

2288

[2769] To a stirred solution of compound 974 (˜5.4 mmol) in 40 ml of anhydrous DMF at room temperature under N2, was added, 1.05 g, 10.8 mmol of (1); 2.07 g, 10.8 mmol of (2); 0.729 g, 5.4 mmol of (3); and 5.5 ml, 50 mmol of (4). Reaction mixture was stirred at room temperature for 5 hours. Reaction progress was monitored by TLC. Added 1N HCl until pH<5, extracted with diethyl ether (2×), cooled to 0° C. then basified with saturated NaHCO3, extracted with CH2Cl2, dry with MgSO4, evaporated the solvent to afford 0.6 g of compound 975, brown oil.

2289

[2770] To compound 975 (0.590 g, 3.2 mmol) in 5 ml of toluene at −70° C., was added (3.6 ml, 3.6 mmol 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 4 ml brine, and stirred at room temperature for 20 minutes. Reaction was eluted through a cake of celite with ethyl acetate/CH2Cl2. Dried filtrate, evaporated solvent to afford 0.162 g of product (yellow oil), compound 976.

2290

[2771] Following essentially the same procedures as in Example 510 (Step A), reacting compound 365a (0.612 g, 1.25 mmol) but using compound 976 (0.152 g) as the intermediate, compound 977 was prepared.(Yellow solid, 0.408 g).

2291

[2772] 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.

2292

[2773] 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.

2293

[2774] 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.

2294

[2775] 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

[2776]

2295

[2777] To a stirred solution of 4-iodo-1-trityl-1H-imidazole (4.36 g, 10 mmol) in THF (100 ml) was added EtMgBr (4 ml, 12 mmol) and let stir for 30 minutes. DMF (0.93 ml, 12 mmol) 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 MgSO4, filtered, and concentrated under vacuo to yield 3.5 g of light yellow solid.

2296

[2778] Following essentially the same procedures as in Example 510 (Step A), but using compound 981 (0.72 g) as the intermediate and MgBr.Et2O (2.58 g in 50 ml THF, 7.5 ml), crude compound 982 was obtained. The crude material was purified via preparative plate chromatography (1-3% MeOH with NH3/CH2Cl2) to obtain pure product, compound 982 (0.29, 39%).

2297

[2779] Following essentially the same procedures as in Example 510 (Step B), but using compound 982 (0.29 g) as the starting material, compound 983 was prepared (0.29 g). The crude material was purified via preparative plate chromatography (2% MeOH with NH3/CH2Cl2) to yield 0.237 g of pure product, compound 983.

2298

[2780] Following essentially the same procedures as in Example 510 (Step C), but using compound 983 (230 mg) as the starting material, compound 984 was prepared (222 mg).

2299

[2781] Following essentially the same procedures as in Example 510 (Step D), but using compound 984 (0.2 g) 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/CH2Cl2) to obtain 0.16 g of pure 985a and 0.06 g of pure 985b.

PREPARATIVE EXAMPLE 113

[2782]

2300

[2783] To compound 982 (390 mg) dissolved in THF (3 ml) was added NaH (60% in mineral oil, 28 mg). 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

[2784]

2301

[2785] To a stirred solution of 987 (2-methyl-1H-imidazole-4-carboxaldehyde, 1 g, 9.09 mmol) in 10 ml of DMF at 0° C. was added NaH (60% in mineral oil (0.36 g)) portionwise. Stirred mixture for ½ hr, then added SEM-CI (2.02 ml, 9.9 mmol). Stirred reaction until completed. Added reaction mixture to brine and extracted with CH2Cl2 (3×). Evaporated solvent to get an oil. Column chromatography (CH2Cl2 (100%-2% MeOH.NH3/CH2Cl2) afforded 1.68 g of product, compound 988 (77%).

2302

[2786] Following essentially the same procedures as in Example 510 (Step A), reacting compound 365a (0.12 g, 0.25 mmol) but using compound 988 (0.1 g) as the intermediate, compound 989 was prepared (96 mg, 56%).

2303

[2787] Following essentially the same procedures as in Example 510 (Step B), but using Compound 989 (0.52 g, 0.79 mmol) as the starting material, compound 990 was prepared.

2304

[2788] Following essentially the same procedures as in Example 510 (Step C), but using compound 990 (0.51 g, 0.79 mmol) as the starting material, compound 991 was prepared.

2305

[2789] Following essentially the same procedures as in Example 510 (Step D), but using Compound 991 (0.79 mmol) as the starting material, compound 992 was prepared.

2306

[2790] To compound 992 (0.1 g) dissolved in THF (5 ml) at room temperature under N2, was added 0.2 ml of tetrabutylammonium fluoride 1 M solution in THF (TBAF). Stirred reaction for 2 hr. Additional TBAF was added (0.2 ml), monitored reaction by TLC. No reaction after 4 hours. Reaction was treated with 0.5 ml of TBAF and heated to 85° C. After 2 hr, reaction completed. Cooled reaction and added to brine and extracted with CH2Cl2 (3×), dried organic over MgSO4, filter and evaporated solvent to give crude product. Purification by Prep Plate Chromatography using 95% CH2Cl2/MeOH.NH3 (5%) afforded 0.12 g of product, compound 993.

2307

[2791] 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

[2792]

2308

[2793] To a stirred solution of 994 (3.08 g, 20 mmol) in 15 ml of DMF at 0° C. was added NaH (60% in mineral oil, 0.80 g) portionwise. After stirring for several minutes, SEM-CI (3.54 ml, 20 mmol) 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 (CH2Cl2/MeOH, 50:1 to 20:1) to afford 4.54 g of yellow oil, compound 995.

2309

[2794] To a stirred solution of compound 995 (3.5 g) in THF (50 ml) was added a LiOH solution (1 M, 24 ml) and stirred for 2 days. The reaction was not complete; therefore, 25 ml of MeOH and another 10 ml 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.

2310

[2795] Following a similar procedure to that described in Preparative Example 111 Step C, but using compound 996, compound 997 was prepared (5.37 g crude).

2311

[2796] Following a similar procedure to that described in Preparative Example 111 Step D, but using compound 997 (4.2 g), compound 998 was prepared.

PREPARATIVE EXAMPLE 116

[2797]

2312

[2798] 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.

2313

[2799] 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.

2314

[2800] 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.

2315

[2801] 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.

2316

[2802] 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.

2317

[2803] 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

[2804] 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.

2318

EXAMPLE 1589

[2805] Compound 971a (Isomer 1) and compound 971b (Isomer 2) were converted to compound 1005a and compound 1005b by following a similar procedure as described in Example 507.

2319

EXAMPLE 1590

[2806] 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.

2320

EXAMPLE 1591

[2807] Isomers 985a and 985b were converted to compound 1007a and compound 1007b by following a similar procedure as described in Example 507.

2321

EXAMPLE 1592

[2808] To the product from Preparative Example 113 dissolved in CH2Cl2 (5 ml) 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.

2322

EXAMPLE 1593

[2809] 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.

2323

EXAMPLE 1594

[2810] 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.

2324

EXAMPLE 1595-1619

[2811] If one were to react each isomer, 1004a and 1004b, from Example 1588 in essentially the same manner as in Example 511-513, then one would obtain compounds of the formulas:

2325

[2812] wherein R is defined in Table 106 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

113TABLE 106RExampleIsomer 1 and Isomer 21595

2326

1596

2327

1597

2328

1598

2329

1599

2330

1600

2331

1601

2332

1602

2333

1603

2334

1604

2335

1605

2336

1606

2337

1607

2338

1608

2339

1609

2340

1610

2341

1611

2342

1612

2343

1613

2344

1614

2345

1615

2346

1616

2347

1617

2348

1618

2349

1619

2350

EXAMPLE 1620-1647

[2813] If one were to react each isomer, 1004a 1004b, from Example 1588 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2351

[2814] wherein R is defined in Table 107 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

114TABLE 107RExampleIsomer 1 and Isomer 21620

2352

1621

2353

1622

2354

1623

2355

1624

2356

1625

2357

1626

2358

1627

2359

1628

2360

1629

2361

1630

2362

1631

2363

1632

2364

1633

2365

1634

2366

1635

2367

1636

2368

1637

2369

1638

2370

1639

2371

1640

2372

1641

2373

1642

2374

1643

2375

1644

2376

1645

2377

1646

2378

1647

2379

EXAMPLE 1648-1671

[2815] If one were to react each isomer, 1004a and 1004b, from Example 1588 in essentially the same manner as in Examples 566 then one would obtain compounds of the formulas:

2380

[2816] wherein R is defined in Table 108 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

115TABLE 108RExampleIsomer 1 and Isomer 21648

2381

1650

2382

1651

2383

1652

2384

1653

2385

1654

2386

1656

2387

1657

2388

1658

2389

1659

2390

1660

2391

1662

2392

1663

2393

1664

2394

1665

2395

1666

2396

1667

2397

1668

2398

1669

2399

1670

2400

1671

2401

EXAMPLE 1672-1690

[2817] If one were to react each isomer, 1004a and 1004b, from Example 1588 in essentially the same manner as in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74), then one would obtain compounds of the formulas:

2402

[2818] wherein R is defined in Table 109 and the numbers 1 and 2 in the formulas represent isomer 1 and isomer 2, respectively.

116TABLE 109RExampleIsomer 1 and Isomer 21672

2403

1673

2404

1674

2405

1675

2406

1676

2407

1677

2408

1678

2409

1679

2410

1680

2411

1681

2412

1682

2413

1683

2414

1684

2415

1685

2416

1686

2417

1688

2418

1689

2419

1690

2420

EXAMPLES 1691-1715

[2819] If one were to react each isomer, 1005a and 1005b, from Example 1589 in essentially the same manner as in Examples 511-513 then one would obtain compounds of the formulas:

2421

[2820] wherein R is defined in Table 110 and the numbers 1 and 2 in the formulas represent isomer 1 and isomer 2, respectively.

117TABLE 110RExampleIsomer 1 and Isomer 21691

2422

1692

2423

1693

2424

1694

2425

1695

2426

1696

2427

1697

2428

1698

2429

1699

2430

1700

2431

1701

2432

1702

2433

1703

2434

1704

2435

1705

2436

1706

2437

1707

2438

1708

2439

1709

2440

1710

2441

1711

2442

1712

2443

1713

2444

1714

2445

1715

2446

EXAMPLES 1716-1743

[2821] If one were to react each isomer, 1005a and 1005b, from Example 1589 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2447

[2822] wherein R is defined in Table 111 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

118TABLE 111RExampleIsomer 1 and Isomer 21716

2448

1717

2449

1718

2450

1719

2451

1720

2452

1721

2453

1722

2454

1723

2455

1724

2456

1725

2457

1726

2458

1727

2459

1728

2460

1729

2461

1730

2462

1731

2463

1732

2464

1733

2465

1734

2466

1735

2467

1736

2468

1737

2469

1738

2470

1739

2471

1740

2472

1741

2473

1742

2474

1743

2475

EXAMPLES 1744-1767

[2823] If one were to react each isomer, 1005a and 1005b, from Example 1589 in essentially the same manner as in Examples 566-567, then one would obtain compounds of the formulas:

2476

[2824] wherein R is defined in Table 112 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

119TABLE 112RExampleIsomer 1 and Isomer 21744

2477

1745

2478

1747

2479

1748

2480

1749

2481

1750

2482

1752

2483

1753

2484

1754

2485

1755

2486

1756

2487

1757

2488

1758

2489

1760

2490

1761

2491

1762

2492

1763

2493

1764

2494

1765

2495

1766

2496

1767

2497

EXAMPLES 1768-1786

[2825] If one were to react each isomer, 1005a and 1005a, from Example 1589 in essentially the same manner as in Examples 590-603 (wherein the chloroformates would be prepared according to Preparative Example 74) then one would obtain compounds of the formulas:

2498

[2826] wherein R is defined in Table 113 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

120TABLE 113RExampleIsomer 1 and Isomer 21768

2499

1769

2500

1770

2501

1771

2502

1772

2503

1773

2504

1774

2505

1775

2506

1776

2507

1777

2508

1778

2509

1779

2510

1780

2511

1781

2512

1782

2513

1783

2514

1784

2515

1785

2516

1786

2517

EXAMPLES 1787-1811

[2827] If one were to react each isomer, 1006a and 1006b, from Example 1590 in essentially the same manner as in Examples 511-513 then one would obtain compounds of the formulas:

2518

[2828] wherein R is defined in Table 114 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

121TABLE 114RExampleIsomer 1 and Isomer 21787

2519

1788

2520

1789

2521

1790

2522

1791

2523

1792

2524

1793

2525

1794

2526

1795

2527

1796

2528

1797

2529

1798

2530

1799

2531

1800

2532

1801

2533

1802

2534

1803

2535

1804

2536

1805

2537

1806

2538

1807

2539

1808

2540

1809

2541

1810

2542

1811

2543

EXAMPLES 1812-1839

[2829] If one were to react each isomer, 1006a and 1006b, from Example 1590 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2544

[2830] wherein R is defined in Table 115 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

122TABLE 115ExampleIsomer 1 and Isomer 21812

2545

1813

2546

1814

2547

1815

2548

1816

2549

1817

2550

1818

2551

1819

2552

1820

2553

1821

2554

1822

2555

1823

2556

1824

2557

1825

2558

1826

2559

1827

2560

1828

2561

1829

2562

1830

2563

1831

2564

1832

2565

1833

2566

1834

2567

1835

2568

1836

2569

1837

2570

1838

2571

1839

2572

EXAMPLES 1840-1861

[2831] If one were to react each isomer, 1006a and 1006b, from Example 1590 in essentially the same manner as in Examples 566-567, then one would obtain compounds of the formulas:

2573

[2832] wherein R is defined in Table 116 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

123TABLE 116RExampleIsomer 1 and Isomer 21840

2574

1841

2575

1842

2576

1843

2577

1844

2578

1845

2579

1847

2580

1848

2581

1849

2582

1850

2583

1851

2584

1852

2585

1853

2586

1854

2587

1855

2588

1856

2589

1857

2590

1858

2591

1859

2592

1860

2593

1861

2594

EXAMPLES 1862-1880

[2833] If one were to react each isomer, 1006a and 1006b, from Example 1590 in essentially the same manner as in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74), then one would obtain compounds of the formulas:

2595

[2834] wherein R is defined in Table 117 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

124TABLE 117RExampleIsomer 1 and Isomer 21862

2596

1863

2597

1864

2598

1865

2599

1866

2600

1867

2601

1868

2602

1869

2603

1870

2604

1871

2605

1872

2606

1873

2607

1874

2608

1875

2609

1876

2610

1877

2611

1878

2612

1879

2613

1880

2614

EXAMPLES 1881-1905

[2835] If one were to react each isomer, 1007a and 1007b, from Example 1591 in essentially the same manner as in Examples 511-513 then one would obtain compounds of the formulas:

2615

[2836] wherein R is defined in Table 118 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

125TABLE 118RExampleIsomer 1 and Isomer 21881

2616

1882

2617

1883

2618

1884

2619

1885

2620

1886

2621

1887

2622

1888

2623

1889

2624

1890

2625

1891

2626

1892

2627

1893

2628

1894

2629

1895

2630

1896

2631

1897

2632

1898

2633

1899

2634

1900

2635

1901

2636

1902

2637

1903

2638

1904

2639

1905

2640

EXAMPLES 1906-1933

[2837] If one were to react each isomer, 1007a and 1007b, from Example 1591 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2641

[2838] wherein R is defined in Table 119 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

126TABLE 119RExampleIsomer 1 and Isomer 21906

2642

1907

2643

1908

2644

1909

2645

1910

2646

1911

2647

1912

2648

1913

2649

1914

2650

1915

2651

1916

2652

1917

2653

1918

2654

1919

2655

1920

2656

1921

2657

1922

2658

1923

2659

1924

2660

1925

2661

1926

2662

1927

2663

1928

2664

1929

2665

1930

2666

1931

2667

1932

2668

1933

2669

EXAMPLES 1934-1956

[2839] If one were to react each isomer, 1007a and 1007b, from Example 1591 in essentially the same manner as in Examples 566-567, then one would obtain compounds of the formulas:

2670

[2840] wherein R is defined in Table 120 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

127TABLE 120RExampleIsomer 1 and Isomer 21935

2671

1936

2672

1937

2673

1938

2674

1939

2675

1940

2676

1942

2677

1943

2678

1944

2679

1945

2680

1946

2681

1947

2682

1948

2683

1949

2684

1950

2685

1951

2686

1952

2687

1953

2688

1954

2689

1955

2690

1956

2691

EXAMPLES 1957-1975

[2841] If one were to react each isomer, 1007a and 1007b, from Example 1591 in essentially the same manner as in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74), then one would obtain compounds of the formulas:

2692

[2842] wherein R is defined in Table 121 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

128TABLE 121RExampleIsomer 1 and Isomer 21957

2693

1958

2694

1959

2695

1960

2696

1961

2697

1962

2698

1963

2699

1964

2700

1965

2701

1966

2702

1967

2703

1968

2704

1969

2705

1970

2706

1971

2707

1972

2708

1973

2709

1974

2710

1975

2711

EXAMPLES 1976-2000

[2843] If one were to react each isomer, 1009a and 1009b, from Example 1593 in essentially the same manner as in Examples 511-513 then one would obtain compounds of the formulas:

2712

[2844] wherein R is defined in Table 122 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

129TABLE 122RExampleIsomer 1 and Isomer 21976

2713

1977

2714

1978

2715

1979

2716

1980

2717

1981

2718

1982

2719

1983

2720

1984

2721

1985

2722

1986

2723

1987

2724

1988

2725

1989

2726

1990

2727

1991

2728

1992

2729

1993

2730

1994

2731

1995

2732

1996

2733

1997

2734

1998

2735

1999

2736

2000

2737

EXAMPLES 2001-2028

[2845] If one were to react each isomer, 1009a and 1009b, from Example 1593 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2738

[2846] wherein R is defined in Table 123 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

130TABLE 123RExampleIsomer 1 and Isomer 22001

2739

2002

2740

2003

2741

2004

2742

2005

2743

2006

2744

2007

2745

2008

2746

2009

2747

2010

2748

2011

2749

2012

2750

2013

2751

2014

2752

2015

2753

2016

2754

2017

2755

2018

2756

2019

2757

2020

2758

2021

2759

2022

2760

2023

2761

2024

2762

2025

2763

2026

2764

2027

2765

2028

2766

EXAMPLES 2028-2049

[2847] If one were to react each isomer, 1009a and 1009b, from Example 1593 in essentially the same manner as in Examples 566-567, then one would obtain compounds of the formulas:

2767

[2848] wherein R is defined in Table 124 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

131TABLE 124RExampleIsomer 1 and Isomer 22028

2768

2029

2769

2030

2770

2031

2771

2032

2772

2033

2773

2035

2774

2036

2775

2037

2776

2038

2777

2039

2778

2040

2779

2041

2780

2042

2781

2043

2782

2044

2783

2045

2784

2046

2785

2047

2786

2048

2787

2049

2788

EXAMPLES 2050-2068

[2849] If one were to react each isomer, 1009a and 1009b, from Example 1593 in essentially the same manner as in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74), then one would obtain compounds of the formulas:

2789

[2850] wherein R is defined in Table 125 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

132TABLE 125RExampleIsomer 1 and Isomer 22050

2790

2051

2791

2052

2792

2053

2793

2054

2794

2055

2795

2056

2796

2057

2797

2058

2798

2059

2799

2060

2800

2061

2801

2062

2802

2063

2803

2064

2804

2065

2805

2066

2806

2067

2807

2068

2808

EXAMPLES 2069-2093

[2851] If one were to react isomer, 1010a and 1010b, from Example 1594 in essentially the same manner as in Examples 511-513 then one would obtain compounds of the formulas:

2809

[2852] wherein R is defined in table 126 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

133TABLE 126RExampleIsomer 1 and Isomer 22069

2810

2070

2811

2070

2812

2071

2813

2072

2814

2073

2815

2074

2816

2075

2817

2076

2818

2077

2819

2078

2820

2079

2821

2080

2822

2081

2823

2082

2824

2083

2825

2084

2826

2085

2827

2086

2828

2087

2829

2088

2830

2089

2831

2090

2832

2091

2833

2092

2834

2093

2835

EXAMPLES 2094-3021

[2853] If one were to react each isomer, 1010a and 1010b, from Example 1594 in essentially the same manner as in Example 536, then one would obtain compounds of the formulas:

2836

[2854] wherein R is defined in Table 127 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

134TABLE 127RExampleIsomer 1 and Isomer 22094

2837

2095

2838

2096

2839

2097

2840

2098

2841

2099

2842

3000

2843

3001

2844

3002

2845

3003

2846

3004

2847

3005

2848

3006

2849

3007

2850

3008

2851

3009

2852

3010

2853

3011

2854

3012

2855

3013

2856

3014

2857

3015

2858

3016

2859

3017

2860

3018

2861

3019

2862

3020

2863

3021

2864

EXAMPLES 3022-3043

[2855] If one were to react each isomer, 1010a and 1010b, from Example 1594 in essentially the same manner as in Examples 566-567, then one would obtain compounds of the formulas:

2865

[2856] wherein R is defined in Table 128 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

135TABLE 128RExampleIsomer 1 and Isomer 23022

2866

3023

2867

3024

2868

3025

2869

3026

2870

3027

2871

3029

2872

3030

2873

3031

2874

3032

2875

3033

2876

3034

2877

3035

2878

3036

2879

3037

2880

3038

2881

3039

2882

3040

2883

3041

2884

3042

2885

3043

2886

EXAMPLES 3044-3062

[2857] If one were to react each isomer, 1010a and 1010b, from Example 1594 in essentially the same manner as in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74), then one would obtain compounds of the formulas:

2887

[2858] wherein R is defined in Table 129 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

136TABLE 129RExampleIsomer 1 and Isomer 23044

2888

3045

2889

3046

2890

3047

2891

3048

2892

3049

2893

3050

2894

3051

2895

3052

2896

3053

2897

3054

2898

3055

2899

3056

2900

3057

2901

3058

2902

3059

2903

3060

2904

3061

2905

3062

2906

EXAMPLES 3063-3087

[2859] If one were to follow procedures similar to those in Examples 511-513, but using compound 1008 from Example 1592, then one would obtain compounds of the formula:

2907

[2860] wherein R is defined in Table 130.

137TABLE 130ExampleR3063

2908

3064

2909

3065

2910

3066

2911

3067

2912

3068

2913

3069

2914

3070

2915

3071

2916

3072

2917

3073

2918

3074

2919

3075

2920

3076

2921

3077

2922

3078

2923

3079

2924

3080

2925

3081

2926

3082

2927

3083

2928

3084

2929

3985

2930

3086

2931

3087

2932

EXAMPLES 3088-3115

[2861] If one were to follow a procedure similar to that in Example 536, but using compound 1008 from Example 1592, then one would obtain compounds of the formula:

2933

[2862] wherein R is defined in Table 131.

138TABLE 131ExampleR3088

2934

3089

2935

3090

2936

3091

2937

3092

2938

3093

2939

3094

2940

3095

2941

3096

2942

3097

2943

3098

2944

3099

2945

3100

2946

3101

2947

3102

2948

3103

2949

3104

2950

3105

2951

3106

2952

3107

2953

3108

2954

3109

2955

3110

2956

3111

2957

3112

2958

3113

2959

3114

2960

3115

2961

EXAMPLES 3116-3137

[2863] If one were to follow procedures similar to those in Examples 566-567, but using compound 1008 from Example 1592, then one would obtain compounds of the formula:

2962

[2864] wherein R is defined in Table 132.

139TABLE 132ExampleR3116

2963

3117

2964

3118

2965

3119

2966

3120

2967

3121

2968

3123

2969

3124

2970

3125

2971

3126

2972

3127

2973

3128

2974

3129

2975

3130

2976

3131

2977

3132

2978

3133

2979

3134

2980

3135

2981

3136

2982

3137

2983

EXAMPLES 3138-3156

[2865] If one were to follow procedures similar to those in Examples 590-603 (wherein the chloroformates would be prepared according to Preparative Example 74), but using compound 1008 from Example 1592), then one would obtain compounds of the formula:

2984

[2866] wherein R is defined in Table 133

140TABLE 133ExampleR3138

2985

3139

2986

3140

2987

3141

2988

3142

2989

3143

2990

3144

2991

3145

2992

3146

2993

3147

2994

3148

2995

3149

2996

3150

2997

3151

2998

3152

2999

3153

3000

3154

3001

3155

3002

3156

3003

PREPARATIVE EXAMPLE 117

[2867]

3004

[2868] Following the same procedure as described in Example 510 Step C, but using compound 795 (3 g) from Example 489, the desired crude product was obtained (3.3 g).

3005

[2869] The crude material above (1011) was separated by flash column chromatography (40% EtOAc/Hex) to yield pure isomer A (1011 a) (1.23 g) and an impure isomer B (1011b) (1.64 g). Impure isomer B was triterated in CH2Cl2/MeOH and filtered to give pure isomer 1011b (0.7 g).

3006

[2870] 2-Methylimidazole (1.1 g) was dissolved in dry DMF (15 ml) followed by the addition of NaH (60% in mineral oil, 300 mg). After stirring for 20 minutes, compound 1011b (1.2 g) was added and the solution was heated to 90° C. for 4 hours. The reaction was concentrated under vacuo, dissolved in CH2Cl2 and washed with brine. The organic layer was dried, concentrated under vacuo and purified via flash column chromatography (6% MeOH/CH2Cl2+NH4OH) to give the desired product (1.47 g).

3007

[2871] Compound 1012 (1.4 g) was converted to compound 1013 (1.09 g) by following the procedure set forth in Example 507.

PREPARATIVE EXAMPLE 118

[2872]

3008

[2873] Following the same procedure as described in Preparative Example 117 Step C, but using compound 1011a (696 mg), the desired compound was obtained (903 mg).

3009

[2874] Compound 1014 (0.9 g) was converted to compound 1015 (0.58 g) by following the procedure set forth in Example 507.

EXAMPLES 3157-3162

[2875]

3010

[2876] 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.

141TABLE 134ExampleCompound3157

3011

3158

3012

3159

3013

3160

3014

3161

3015

3162

3016

EXAMPLES 3163-3168

[2877]

3017

[2878] 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.

142TABLE 135ExampleCompound3163

3018

3164

3019

3165

3020

3166

3021

3167

3022

3168

3023

EXAMPLES 3169-3187

[2879] If one were to follow procedures similar to those in Examples 511-513, but using compounds 1013 (Preparative Example 117) and 1015 (Preparative Example 118), then one would obtain compounds of the formulas:

3024

[2880] respectively, wherein R is defined in Table 136.

143TABLE 136ExampleR Isomer 1 and Isomer 23169

3025

3170

3026

3171

3027

3172

3028

3173

3029

3174

3030

3175

3031

3176

3032

3177

3033

3178

3034

3179

3035

3180

3036

3181

3037

3182

3038

3183

3039

3184

3040

3185

3041

3187

3042

EXAMPLES 3188-3215

[2881] If one were to follow a procedure similar to that in Example 536, but using compounds 1013 (Preparative Example 117) and 1015 (Preparative Example 118), then one would obtain compounds of the formulas:

3043

[2882] respectively, wherein R is defined in Table 137.

144TABLE 137ExampleR Isomer 1 and Isomer 23188

3044

3189

3045

3190

3046

3191

3047

3192

3048

3193

3049

3194

3050

3195

3051

3196

3052

3197

3053

3198

3054

3199

3055

3200

3056

3201

3057

3202

3058

3203

3059

3204

3060

3205

3061

3206

3062

3207

3063

3208

3064

3209

3065

3210

3066

3211

3067

3212

3068

3213

3069

3214

3070

3215

3071

EXAMPLES 3216-3237

[2883] If one were to follow procedures similar to those in Examples 566-567 but using compounds 1013 (Preparative Example 117) and 1015 (Preparative Example 118), then one would obtain compounds of the formulas:

3072

[2884] respectively, wherein R is defined in Table 138.

145TABLE 138ExampleR Isomer 1 and Isomer 23216

3073

3217

3074

3218

3075

3219

3076

3220

3077

3221

3078

3223

3079

3224

3080

3225

3081

3226

3082

3227

3083

3228

3084

3229

3085

3230

3086

3231

3087

3232

3088

3233

3089

3234

3090

3235

3091

3236

3092

3237

3093

EXAMPLES 3237-3255

[2885] If one were to follow procedures similar to those in Examples 590-603 (wherein the chloroformates could be prepared according to Preparative Example 74, but using compounds 1013 (Preparative Example 117) and 1015 (Preparative Example 118), then one would obtain compounds of the formulas:

3094

[2886] respectively, wherein R is defined in Table 139.

146TABLE 139ExampleR3237

3095

3238

3096

3239

3097

3240

3098

3241

3099

3242

3100

3243

3101

3244

3102

3245

3103

3246

3104

3247

3105

3248

3106

3249

3107

3250

3108

3251

3109

3252

3110

3253

3111

3254

3112

3255

3113

EXAMPLE 3256

[2887]

3114

[2888] 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.

[2889] 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 MeI (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 CH2Cl2 (5 mL) and TFA (1 mL) was added. One hour later, the mixture was evaporated to dryness. The crude was retaken up in CH2Cl2 and made to PH>8 by addition of triethyl amine (ca. 0.6 mL). (Boc)2O (320 mg, 1.5 mmol) was then added. After stirring for 30 mins, the solvents 1o 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)/CH2Cl2 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, MH+=536) 1s and 1019b (53.6 mg, isomer 2, MH+=536).

EXAMPLE 3257

[2890]

3115

3116

[2891] Compound 1019b (isomer 2) was converted to 1020b by reacting it with 20% 4M HCl(dioxane)/CH2Cl2 at room temperature under N2 overnight.

[2892] The same procedure was used to prepare 1020a (isomer 1) from 1019a.

EXAMPLES 3258-3260

[2893] Each isomer, 1020a and 1020b from Example 3257 was dissolved in CH2Cl2, 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:

3117

[2894] wherein R is defined in Table 140 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

147TABLE 140Isomer 1Isomer 2EXAMPLERDataData3258

3118

MH+ 535MH+ 5353259

3119

MH+ 561MH+ 5613260

3120

MH+ 580MH+ 580

EXAMPLES 3261-3263

[2895] Isomer 1020a from Example 3257 was dissolved in CH2Cl2 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 1N HCl till pH=2. After stirring for 5 min, it was then basicified with sat. NaHCO3 followed by extraction of CH2Cl2. The organic solvent was concentrated in vacuo and the residue was then purified by silica gel column to give compounds of the formula:

3121

[2896] wherein R is defined in Table 141 and the number 1 in the formula represents isomer 1.

148TABLE 141EXAMPLERIsomer 1 Data3261

3122

MH+ 5223262

3123

MH+ 5843263

3124

MH+ 584

EXAMPLE 3264

[2897] Isomer 1020b from Example 3257 was dissolved in CH2Cl2 at 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 CH2Cl2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give a compound of the formula:

3125

[2898] wherein R is defined in Table 142 and the number 2 in the formula represents isomer 2.

149TABLE 142EXAMPLERIsomer 2 Data3264

3126

MH+ 514

EXAMPLES 3265-3267

[2899] Isomer 1020b from Example 3257 was dissolved in CH2Cl2 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 CH2Cl2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formula:

3127

[2900] wherein R is defined in Table 142 and the number 2 in the formula represents isomer 2.

150TABLE 142EXAMPLERIsomer 2 Data3265

3128

MH+ 5223266

3129

MH+ 5623267

3130

MH+ 564

EXAMPLE 3268

[2901]

3131

PREPARATIVE EXAMPLE 65

[2902] 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

[2903]

3132

3133

[2904] Compound 791b (isomer 2) was converted to 1021 b by reacting it with 20% 4M HCl(dioxane)/CH2Cl2 at room temperature under N2 overnight.

[2905] The same procedure was used to prepare 1021 a (isomer 1) from 791 a.

EXAMPLE 3270

[2906] Each isomer, 1021a and 1021b from Example 3269 was dissolved in CH2Cl2, 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

3134

[2907] wherein R is defined in Table 144 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

151TABLE 144Isomer 1Isomer 2EXAMPLERDataData3270

3135

MH+ 591MH+ 591

EXAMPLE 3271

[2908] Each isomer, 1021a and 1021b from Example 3269 was dissolved in CH2Cl2at 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 1N HCl till pH=2. After stirring for 5 min, it was then basicified with sat. NaHCO3 followed by extraction of CH2Cl2. The organic solvent was concentrated in vacuo and the residue was then purified by silica gel column to give compounds of the formulas:

3136

[2909] wherein R is defined in Table 145 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

152TABLE 145Isomer 1Isomer 2EXAMPLERDataData3271

3137

MH+ 533MH+ 533

EXAMPLE 3272

[2910] Each isomer, 1021a and 1021b from Example 3269 was dissolved in CH2Cl2 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 CH2Cl2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formulas:

3138

[2911] wherein R is defined in Table 146 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

153TABLE 146Isomer 1Isomer 2EXAMPLERDataData3272

3139

MH+ 525MH+ 525

EXAMPLE 3273

[2912] Each isomer, 1021 a and 1021 b from Example 3269 was dissolved in CH2Cl2 at 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 CH2Cl2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formulas:

3140

[2913] wherein R is defined in Table 147 and the number 1 and 2 in the formulas represent isomers 1 and 2, respectively.

154TABLE 147Isomer 1Isomer 2EXAMPLERDataData3273

3141

MH+ 533MH+ 533

EXAMPLES 3274-3278

[2914]

3142

3143

[2915] Each isomer from Examples 3268 and 3270-3273 was dissolved in MeOH at room temperature under nitrogen, followed by addition of excess SnCl2. Reactions were stirred at room temperature overnight and then concentrated in vacuo. The residue was stirred in a mixture of 1N 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:

3144

[2916] wherein R is defined in Table 148 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

155TABLE 148Isomer 1Isomer 2EXAMPLERDataData3274

3145

MH+ 521MH+ 5213275

3146

MH+ 565MH+ 5653276

3147

MH+ 499MH+ 4993277

3148

—*MH+ 507*Isomer 1 of Example 3277 was not made.

EXAMPLES 3278-3279

[2917] Following a procedure similar to that of Example 3270 the azide compound

3149

[2918] is prepared wherein R is

3150

[2919] and the number 2 in the formula represents isomer 2.

[2920] Then, following a procedure similar to that of Examples 3274 to 3278 the amino compound of formula:

3151

[2921] is prepared from the azide compound wherein R is defined in Table 149 and the number 2 in the formula represenst isomer 2.

156TABLE 149Isomer 2EXAMPLERData3278

3152

MH+ 5473279

3153

MH+ 521

EXAMPLE 3280

[2922]

3154

3155

[2923] Isomer 2 of Compound 791 (70 mg, 0.13 mmol) was dissolved in CH2Cl2 (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 CH2Cl2 (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 CH2Cl2 twice. The organic layer was dried and concentrated. The crude was purified with prep TLC plates using 10% methanol (2M NH3)/CH2Cl2 to give Compound 1032 as a light yellow solid (50 mg). MS M+1 533.

[2924] Compound 1032 (160 mg, 0.3 mmol) was dissolved in MeOH (5 mL) at room temperature and SnCl2 (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 1N 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)/CH2Cl2 to give compound 1033 as a light yellow solid (90.0 mg). M.P. 132-135° C. MS M+1 507.

EXAMPLE 3281

[2925]

3156

3157

[2926] To a solution of compound 792 (Example 486) (0.052 gm, 0.1 mmole) in 5 ml of dry dichloromethane was added 0.02 gm of triethylamine and 0.01 g 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 offinal product. MH+ 579 (Isomer 1) and MH+ 579 (Isomer 2).

EXAMPLES 3282-3287f

[2927] 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:

3158

[2928] were prepared wherein R9b is defined in Table 150 and the numbers 1 and 2 in the formulas represent Isomers 1 and 2, respectively.

157TABLE 150Isomer 1Isomer 2ExampleR9bDataData3282

3159

MH+ 563MH+ 5633283

3160

MH+ 564MH+ 5643284

3161

MH+ 592MH+ 5923285

3162

MH+ 599MH+ 5993286

3163

MH+ 607MH+ 6073287

3164

MH+ 620MH+ 6203287a

3165

—MH+ 593.13287b

3166

MH+ 606.13287c

3167

MH+ 589.13287d

3168

MH+ 591.33287e

3169

MH+ 605.13287f

3170

MH+ 593.3

EXAMPLE 3288

[2929]

3171

3172

3173

[2930] To a solution of the compound of Example 3282 (Isomer 2) (150 mg) was added 10 ml of dichloromethane and 2 ml 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

[2931] Following a procedure similar to that in Example 3288 compounds of the formula:

3174

[2932] 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.

158TABLE 151Isomer 2ExampleRData3289

3175

MH+ 5493290

3176

MH+ 5623291

3177

MH+ 591

EXAMPLES 3291-3297

[2933] Using the compound of Example 3287 (Isomer 2) and following a procedure similar to that in Example 3288 compounds of the formula:

3178

[2934] 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.

159TABLE 152Isomer 2ExampleRData3292

3179

MH+ 6643293

3180

MH+ 5983294

3181

MH+ 6483295

3182

MH+ 6193296

3183

MH+ 6453297

3184

MH+ 606

EXAMPLES 3298-3302

[2935] Using the compound of Example 3285 (Isomer 2) and following a procedure similar to that in Example 3288 compounds of the formula:

3185

[2936] 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.

160TABLE 153Isomer 2ExampleRData3298

3186

MH+ 5983299

3187

MH+ 5423300

3188

MH+ 5853301

3189

MH+ 6273302

3190

MH+ 577

EXAMPLES 3303-4618

[2937] 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:

3191

3192

3193

3194

3195

3196

3197

[2938] 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.

161TABLE 154Ex.Compd.Ex.Compd.Ex.CompdR3303 3304 3305 3306 3307 33081022a 1022b 1023a 1023b 1024a 1024b3309 3310 3311 3312 3313 3314 33151025a 1025b 1026a 1026b 1027a 1027b 1028a3316 3317 3318 3319 3320 # 33211028b 1029a 1030a 1030b 1031a 1031b

3198

3322 3323 3324 3325 3326 33271022a 1022b 1023a 1023b 1024a 1024b3328 3329 3330 3331 3332 3333 33341025a 1025b 1026a 1026b 1027a 1027b 1028a3335 3336 3337 3338 3339 # 3340 33411028b 1029a 1029b 1030a 1030b 1031a 1031b

3199

3342 3343 3344 3345 3346 33471022a 1022b 1023a 1023b 1024a 1024b3348 3349 3350 3351 3352 3353 33541025a 1025b 1026a 1026b 1027a 1027b 1028a3355 3356 3357 3358 3359 # 3360 33611028b 1029a 1029b 1030a 1030b 1031a 1031b

3200

3362 3363 3364 3365 3366 33671022a 1022b 1023a 1023b 1024a 1024b3368 3369 3370 3371 3372 3373 33741025a 1025b 1026a 1026b 1027a 1027b 1028a3375 3376 3377 3378 3379 # 3380 33811028b 1029a 1029b 1030a 1030b 1031a 1031b

3201

3382 3383 3384 33951023a 1023b 1025a 1025b3386 3387 3388 3389 33901026a 1027a 1027b 1028a 1028b3391 3392 3393 3394 33951028b 1029a 1030a 1030b 1031a

3202

3396 3397 3398 3399 3400 34011022a 1022b 1023a 1023b 1024a 1024b3402 3403 3404 3405 3406 3407 34081025a 1025b 1026a 1026b 1027a 1027b 1028a3409 3410 3411 3412 3413 # 3414 34151028b 1029a 1029b 1030a 1030b 1031a 1031b

3203

3416 3417 3418 3419 3420 34211022a 1022b 1023a 1023b 1024a 1024b3422 3423 3424 3425 3426 3427 34281025a 1025b 1026a 1026b 1027a 1027b 1028a3409 3430 3431 3432 3433 # 3434 34351028b 1029a 1029b 1030a 1030b 1031a 1031b

3204

3436 3437 3438 3439 3440 34411022a 1022b 1023a 1023b 1024a 1024b3442 3443 3444 3445 3446 3447 34481025a 1025b 1026a 1026b 1027a 1027b 1028a3449 3450 3451 3452 3453 # 3454 34551028b 1029a 1029b 1030a 1030b 1031a 1031b

3205

3456 3457 3458 3459 3460 34611022a 1022b 1023a 1023b 1024a 1024b3462 3463 3464 3465 3466 3467 34681025a 1025b 1026a 1026b 1027a 1027b 1028a3469 3470 3471 3472 3473 # 3474 34751028b 1029a 1029b 1030a 1030b 1031a 1031b

3206

3476 3477 3478 3479 3480 34811022a 1022b 1023a 1023b 1024a 1024b3482 3483 3484 3485 3486 3487 34881025a 1025b 1026a 1026b 1027a 1027b 1028a3489 3490 3491 3492 3493 # 34941028b 1029a 1029b 1030a 1030b 1031a

3207

3495 3496 3497 3498 3499 35001022a 1022b 1023a 1023b 1024a 1024b3501 3502 3503 3504 3505 3506 35071025a 1025b 1026a 1026b 1027a 1027b 1028a3508 3509 3510 3511 3512 # 3513 35141028b 1029a 1029b 1030a 1030b 1031a 1031b

3208

3515 3516 3517 3518 3519 35201022a 1022b 1023a 1023b 1024a 1024b3521 3522 3523 3524 3525 35261025a 1025b 1026a 1027a 1027b 1028a3527 3528 3529 3530 3531 # 35321028b 1029a 1029b 1030a 1030b 1031a

3209

3533 3534 3535 3536 3537 35381022a 1022b 1023a 1023b 1024a 1024b3539 3540 3541 3542 3543 3544 35451025a 1025b 1026a 1026b 1027a 1027b 1028a3546 3547 3547 3548 3549 # 3550 35511028b 1029a 1029b 1030a 1030b 1031a 1031b

3210

3552 3553 3554 3555 3556 35571022a 1022b 1023a 1023b 1024a 1024b3558 3559 3560 3561 3562 3563 36641025a 1025b 1026a 1026b 1027a 1027b 1028a3565 3566 3567 3568 3569 # 3570 35711028b 1029a 1029b 1030a 1030b 1031a 1031b

3211

3572 3573 3574 3575 3576 35771022a 1022b 1023a 1023b 1024a 1024b3578 3579 3580 3581 3582 3583 35841025a 1025b 1026a 1026b 1027a 1027b 1028a3585 3586 3587 3588 3589 # 3580 35911028b 1029a 1029b 1030a 1030b 1031a 1031b

3212

3592 3593 3594 3595 3596 35971022a 1022b 1023a 1023b 1024a 1024b3598 3599 3600 3601 3602 3603 36041025a 1025b 1026a 1026b 1027a 1027b 1028a3605 3606 3607 3608 3609 # 3610 36111028b 1029a 1029b 1030a 1030b 1031a 1031b

3213

3612 3613 3614 3615 3616 36171022a 1022b 1023a 1023b 1024a 1024b3618 3619 3620 3621 3622 3623 36241025a 1025b 1026a 1026b 1027a 1027b 1028a3625 3626 3627 3628 3629 # 3630 36311028b 1029a 1029b 1030a 1030b 1031a 1031b

3214

3632 3633 3634 3635 3636 36371022a 1022b 1023a 1023b 1024a 1024b3638 3639 3640 3641 3642 3643 36441025a 1025b 1026a 1026b 1027a 1027b 1028a3645 3646 3647 3648 3649 # 3650 36511028b 1029a 1029b 1030a 1030b 1031a 1031b

3215

3652 3653 3654 3655 3656 36571022a 1022b 1023a 1023b 1024a 1024b3658 3659 3660 3661 3662 3663 36641025a 1025b 1026a 1026b 1027a 1027b 1028a3665 3666 3667 3668 3669 # 3670 36711028b 1029a 1029b 1030a 1030b 1031a 1031b

3216

3672 3673 3674 3675 3676 36771022a 1022b 1023a 1023b 1024a 1024b3678 3679 3680 3681 3682 3683 36841025a 1025b 1026a 1026b 1027a 1027b 1028a3685 3686 3687 3688 3689 # 3690 36911028b 1029a 1029b 1030a 1030b 1031a 1031b

3217

3692 3693 3694 3695 3696 36971022a 1022b 1023a 1023b 1024a 1024b3698 3699 3700 3701 3702 3703 37041025a 1025b 1026a 1026b 1027a 1027b 1028a3705 3706 3707 3708 3709 # 3710 37111028b 1029a 1029b 1030a 1030b 1031a 1031b

3218

3712 3713 3714 3715 3716 37171022a 1022b 1023a 1023b 1024a 1024b3718 3719 3720 3721 3722 3723 37241025a 1025b 1026a 1026b 1027a 1027b 1028a3725 3726 3727 3728 3729 # 3730 37311028b 1029a 1029b 1030a 1030b 1031a 1031b

3219

3732 3733 3734 3735 3736 37371022a 1022b 1023a 1023b 1024a 1024b3738 3739 3740 3741 3742 3743 37441025a 1025b 1026a 1026b 1027a 1027b 1028a3745 3746 3747 3748 3749 # 3750 37511028b 1029a 1029b 1030a 1030b 1031a 1031b

3220

3752 3753 3754 3755 3756 37571022a 1022b 1023a 1023b 1024a 1024b3758 3759 3760 3761 3762 3763 37641025a 1025b 1026a 1026b 1027a 1027b 1028a3765 3766 3767 3768 3769 # 3770 37711028b 1029a 1029b 1030a 1030b 1031a 1031b

3221

3772 3773 3774 3775 3776 37771022a 1022b 1023a 1023b 1024a 1024b3778 3779 3780 3781 3782 3783 37841025a 1025b 1026a 1026b 1027a 1027b 1028a3785 3786 3787 3788 3789 # 3790 37911028b 1029a 1029b 1030a 1030b 1031a 1031b

3222

3792 3793 3794 3795 3796 37971022a 1022b 1023a 1023b 1024a 1024b3798 3799 3800 3801 3802 3803 38041025a 1025b 1026a 1026b 1027a 1027b 1028a3805 3806 3807 3808 3809 # 3810 38111028b 1029a 1029b 1030a 1030b 1031a 1031b

3223

3812 3813 3814 3815 3816 38171022a 1022b 1023a 1023b 1024a 1024b3818 3819 3820 3821 3822 3823 38241025a 1025b 1026a 1026b 1027a 1027b 1028a3825 3826 3827 3828 3829 # 3830 38311028b 1029a 1029b 1030a 1030b 1031a 1031b

3224

3832 3833 3834 3835 3836 38371022a 1022b 1023a 1023b 1024a 1024b3838 3839 3840 3841 3842 3843 38441025a 1025b 1026a 1026b 1027a 1027b 1028a3845 3846 3847 3848 3849 # 3850 38511028b 1029a 1029b 1030a 1030b 1031a 1031b

3225

3852 3853 3854 3855 3856 38571022a 1022b 1023a 1023b 1024a 1024b3858 3859 3860 3861 3862 3863 38641025a 1025b 1026a 1026b 1027a 1027b 1028a3865 3866 3867 3868 3869 # 3870 38711028b 1029a 1029b 1030a 1030b 1031a 1031b

3226

3872 3873 3874 3875 3876 38771022a 1022b 1023a 1023b 1024a 1024b3878 3879 3880 3881 3882 3883 38841025a 1025b 1026a 1026b 1027a 1027b 1028a3885 3886 3887 3888 3889 # 3890 38911028b 1029a 1029b 1030a 1030b 1031a 1031b

3227

3892 3893 3894 3895 38961022b 1023a 1023b 1024a 1024b3897 3898 3899 3900 3901 3902 39031025a 1025b 1026a 1026b 1027a 1027b 1028a3904 3905 3906 3907 3908 3909 3910#1028b 1029a 1029b 1030a 1030b 1031a 1031b

3228

3911 3912 3913 3914 39151022b 1023a 1023b 1024a 1024b3916 3917 3918 3919 3920 3921 39221025a 1025b 1026a 1026b 1027a 1027b 1028a3923 3924 3925 3926 3927 3928 3929#1028b 1029a 1029b 1030a 1030b 1031a 1031b

3229

3930 3931 3932 3933 39341022b 1024a 1025a 1025b 1026a3935 3936 3937 3938 39401026b 1027a 1027b 1028a 1028b3941 3942 3943 3944 39451029a 1029b 1030a 1030b 1031a 1031b#

3230

3946 3947 3948 3949 3950 39511022a 1022b 1023a 1023b 1024a 1024b3952 3953 3954 3955 3956 3957 39581025a 1025b 1026a 1026b 1027a 1027b 1028a3959 3960 3961 3962 3963 # 3964 39651028b 1029a 1029b 1030a 1030b 1031a 1031b

3231

3966 3967 3968 3969 3970 39711022a 1022b 1023a 1023b 1024a 1024b3972 3973 3974 3975 3976 3977 39781025a 1025b 1026a 1026b 1027a 1027b 1028a3979 3980 3981 3982 3983 # 3984 39851028b 1029a 1029b 1030a 1030b 1031a 1031b

3232

3986 3987 3988 3989 3990 39911022a 1022b 1023a 1023b 1024a 1024b3992 3993 3994 3995 3996 3997 39981025a 1025b 1026a 1026b 1027a 1027b 1028a3999 3400 3401 3402 3403 # 3404 34051028b 1029a 1029b 1030a 1030b 1031a 1031b

3233

3406 3407 3408 3409 3410 34111022a 1022b 1023a 1023b 1024a 1024b3412 3413 3414 3415 3416 3417 34181025a 1025b 1026a 1026b 1027a 1027b 1028a3419 3420 3421 3422 3423 # 3424 34251028b 1029a 1029b 1030a 1030b 1031a 1031b

3234

3426 3427 3428 3429 3430 34311022a 1022b 1023a 1023b 1024a 1024b3432 3433 3434 3435 3436 3437 34381025a 1025b 1026a 1026b 1027a 1027b 1028a3439 3440 3441 3442 3443 # 3444 34451028b 1029a 1029b 1030a 1030b 1031a 1031b

3235

3446 3447 3448 3449 3450 34511022a 1022b 1023a 1023b 1024a 1024b3452 3453 3454 3455 3456 3457 34581025a 1025b 1026a 1026b 1027a 1027b 1028a3459 3460 3461 3462 3463 # 3464 34651028b 1029a 1029b 1030a 1030b 1031a 1031b

3236

3466 3467 3468 3469 3470 34711022a 1022b 1023a 1023b 1024a 1024b3472 3473 3474 3475 3476 3477 34781025a 1025b 1026a 1026b 1027a 1027b 1028a3479 3480 3481 3482 3483 # 3484 34851028b 1029a 1029b 1030a 1030b 1031a 1031b

3237

3486 3487 3488 3489 3490 34911022a 1022b 1023a 1023b 1024a 1024b3492 3493 3494 3495 3496 3497 34981025a 1025b 1026a 1026b 1027a 1027b 1028a3499 3500 3501 3502 3503 # 3504 35051028b 1029a 1029b 1030a 1030b 1031a 1031b

3238

3506 3507 3508 3509 3510 35111022a 1022b 1023a 1023b 1024a 1024b3512 3513 3514 3515 3516 3517 35181025a 1025b 1026a 1026b 1027a 1027b 1028a3519 3520 3521 3522 3523 # 3524 35251028b 1029a 1029b 1030a 1030b 1031a 1031b

3239

3526 3527 3528 3529 3530 35311022a 1022b 1023a 1023b 1024a 1024b3532 3533 3534 3535 3536 3537 35381025a 1025b 1026a 1026b 1027a 1027b 1028a3539 3540 3541 3542 3543 # 3544 35451028b 1029a 1029b 1030a 1030b 1031a 1031b

3240

3546 3547 3548 3549 3550 35511022a 1022b 1023a 1023b 1024a 1024b3552 3553 3554 3555 3556 3557 35581025a 1025b 1026a 1026b 1027a 1027b 1028a3559 3560 3561 3562 3563 # 3564 35651028b 1029a 1029b 1030a 1030b 1031a 1031b

3241

3566 3567 3568 3569 3570 35711022a 1022b 1023a 1023b 1024a 1024b3572 3573 3574 3575 3576 3577 35781025a 1025b 1026a 1026b 1027a 1027b 1028a3579 3580 3581 3582 3583 # 3584 35851028b 1029a 1029b 1030a 1030b 1031a 1031b

3242

3586 3587 3588 3589 3590 35911022a 1022b 1023a 1023b 1024a 1024b3592 3593 3594 3595 3596 3597 35981025a 1025b 1026a 1026b 1027a 1027b 1028a3599 3600 3601 3602 3603 # 3604 36051028b 1029a 1029b 1030a 1030b 1031a 1031b

3243

3606 3607 3608 3609 3610 36111022a 1022b 1023a 1023b 1024a 1024b3612 3613 3614 3615 3616 3617 36181025a 1025b 1026a 1026b 1027a 1027b 1028a3619 3620 3621 3622 3623 # 3624 36251028b 1029a 1029b 1030a 1030b 1031a 1031b

3244

3626 3627 3628 3629 3630 36311022a 1022b 1023a 1023b 1024a 1024b3632 3633 3634 3635 3636 3637 36381025a 1025b 1026a 1026b 1027a 1027b 1028a3639 3640 3641 3642 3643 # 3644 36451028b 1029a 1029b 1030a 1030b 1031a 1031b

3245

3646 3647 3648 3649 3650 36511022a 1022b 1023a 1023b 1024a 1024b3652 3653 3654 3655 3656 3657 36581025a 1025b 1026a 1026b 1027a 1027b 1028a3659 3660 3661 3662 3663 # 3664 36651028b 1029a 1029b 1030a 1030b 1031a 1031b

3246

3666 3667 3668 3669 3670 36711022a 1022b 1023a 1023b 1024a 1024b3672 3673 3674 3675 3676 3677 36781025a 1025b 1026a 1026b 1027a 1027b 1028a3679 3680 3681 3682 3683 # 3684 36851028b 1029a 1029b 1030a 1030b 1031a 1031b

3247

3686 3687 3688 3689 3690 36911022a 1022b 1023a 1023b 1024a 1024b3692 3693 3694 3695 3696 3697 36981025a 1025b 1026a 1026b 1027a 1027b 1028a3699 3700 3701 3702 3703 # 3704 37051028b 1029a 1029b 1030a 1030b 1031a 1031b

3248

3706 3707 3708 3709 3710 37111022a 1022b 1023a 1023b 1024a 1024b3712 3713 3714 3715 3716 3717 37181025a 1025b 1026a 1026b 1027a 1027b 1028a3719 3720 3721 3722 3723 # 3724 37251028b 1029a 1029b 1030a 1030b 1031a 1031b

3249

3726 3727 3728 3729 3730 37311022a 1022b 1023a 1023b 1024a 1024b3732 3733 3734 3735 3736 3737 37381025a 1025b 1026a 1026b 1027a 1027b 1028a3739 3740 3741 3742 3743 # 3744 37451028b 1029a 1029b 1030a 1030b 1031a 1031b

3250

3746 3747 3748 3749 3750 37511022a 1022b 1023a 1023b 1024a 1024b3752 3753 3754 3755 3756 3757 37581025a 1025b 1026a 1026b 1027a 1027b 1028a3759 3760 3761 3762 3763 # 3764 37651028b 1029a 1029b 1030a 1030b 1031a 1031b

3251

3766 3767 3768 3769 3770 37711022a 1022b 1023a 1023b 1024a 1024b3772 3773 3774 3775 3776 3777 37781025a 1025b 1026a 1026b 1027a 1027b 1028a3779 3780 3781 3782 3783 # 3784 37851028b 1029a 1029b 1030a 1030b 1031a 1031b

3252

3786 3787 3788 3789 3790 37911022a 1022b 1023a 1023b 1024a 1024b3792 3793 3794 3795 3796 3797 37981025a 1025b 1026a 1026b 1027a 1027b 1028a3799 3800 3801 3802 3803 # 3804 38051028b 1029a 1029b 1030a 1030b 1031a 1031b

3253

3806 3807 3808 3809 3810 38111022a 1022b 1023a 1023b 1024a 1024b3812 3813 3814 3815 3816 38171025a 1025b 1026a 1026b 1027a 1027b3818 3819 3820 3821 3822 3823#1028a 1028b 1029a 1030a 1030b 1031a

3254

3824 3825 3826 3827 3828 38291022a 1022b 1023a 1023b 1024a 1024b3830 3831 3832 3833 3834 3835 38361025a 1025b 1026a 1026b 1027a 1027b 1028a3837 3838 3839 3840 3841 # 3842 38431028b 1029a 1029b 1030a 1030b 1031a 1031b

3255

3844 3845 3846 3847 3848 38491022a 1022b 1023a 1023b 1024a 1024b3850 3851 3852 3853 3854 3855 38561025a 1025b 1026a 1026b 1027a 1027b 1028a3857 3858 3859 3860 3861 # 3862 38631028b 1029a 1029b 1030a 1030b 1031a 1031b

3256

3864 3865 3866 3867 3868 38691022a 1022b 1023a 1023b 1024a 1024b3870 3871 3872 3873 3874 3875 38761025a 1025b 1026a 1026b 1027a 1027b 1028a3877 3878 3879 3880 3881 # 3882 38831028b 1029a 1029b 1030a 1030b 1031a 1031b

3257

3884 3885 3886 3887 3888 38891022a 1022b 1023a 1023b 1024a 1024b3890 3891 3892 3893 3894 3895 38961025a 1025b 1026a 1026b 1027a 1027b 1028a3897 3898 3899 3900 3901 # 3902 39031028b 1029a 1029b 1030a 1030b 1031a 1031b

3258

3904 3905 3906 3907 3908 39091022a 1022b 1023a 1023b 1024a 1024b3910 3911 3912 3913 3914 3915 39161025a 1025b 1026a 1026b 1027a 1027b 1028a3917 3918 3919 3920 3921 # 3922 39231028b 1029a 1029b 1030a 1030b 1031a 1031b

3259

3944 3945 3946 3947 3948 39491022a 1022b 1023a 1023b 1024a 1024b3950 3951 3952 3953 3954 3955 39561025a 1025b 1026a 1026b 1027a 1027b 1028a3957 3958 3959 3960 3961 # 3962 39631028b 1029a 1029b 1030a 1030b 1031a 1031b

3260

3964 3965 3966 3967 3968 39691022a 1022b 1023a 1023b 1024a 1024b3970 3971 3972 3973 3974 3975 39761025a 1025b 1026a 1026b 1027a 1027b 1028a3977 3978 3979 3980 3981 # 3982 39831028b 1029a 1029b 1030a 1030b 1031a 1031b

3261

3984 3985 3986 3987 3988 39891022a 1022b 1023a 1023b 1024a 1024b3990 3991 3992 3993 3994 3995 39961025a 1025b 1026a 1026b 1027a 1027b 1028a3997 3998 3999 4000 4001 # 4002 40031028b 1029a 1029b 1030a 1030b 1031a 1031b

3262

4004 4005 4006 4007 4008 40091022a 1022b 1023a 1023b 1024a 1024b4010 4011 4012 4013 4014 4015 40161025a 1025b 1026a 1026b 1027a 1027b 1028a4017 4018 4019 4020 4021 # 4022 40231028b 1029a 1029b 1030a 1030b 1031a 1031b

3263

4024 4025 4026 4027 4028 40291022a 1022b 1023a 1023b 1024a 1024b4030 4031 4032 4033 4034 4035 40361025a 1025b 1026a 1026b 1027a 1027b 1028a4037 4038 4039 4040 4041 # 4042 40431028b 1029a 1029b 1030a 1030b 1031a 1031b

3264

4044 4045 4046 4047 4048 40491022a 1022b 1023a 1023b 1024a 1024b4050 4051 4052 4053 4054 4055 40561025a 1025b 1026a 1026b 1027a 1027b 1028a4057 4058 4059 4060 4061 # 4062 40631028b 1029a 1029b 1030a 1030b 1031a 1031b

3265

4064 4065 4066 4067 4068 40691022a 1022b 1023a 1023b 1024a 1024b4070 4071 4072 4073 4074 4075 40761025a 1025b 1026a 1026b 1027a 1027b 1028a4077 4078 4079 4080 4081 # 4082 40831028b 1029a 1029b 1030a 1030b 1031a 1031b

3266

4084 4085 4086 4087 4088 40891022a 1022b 1023a 1023b 1024a 1024b4090 4091 4092 4093 4094 4095 40961025a 1025b 1026a 1026b 1027a 1027b 1028a4097 4098 4099 4100 4101 # 4012 40131028b 1029a 1029b 1030a 1030b 1031a 1031b

3267

4104 4105 4106 4107 4108 41091022a 1022b 1023a 1023b 1024a 1024b4110 4111 4112 4113 4114 4115 41161025a 1025b 1026a 1026b 1027a 1027b 1028a4117 4118 4119 4120 4121 # 4122 41231028b 1029a 1029b 1030a 1030b 1031a 1031b

3268

4124 4125 4126 4127 4128 41291022a 1022b 1023a 1023b 1024a 1024b4130 4131 4132 4133 4134 4135 41361025a 1025b 1026a 1026b 1027a 1027b 1028a4137 4138 4139 4140 4141 # 4142 41431028b 1029a 1029b 1030a 1030b 1031a 1031b

3269

4144 4145 4146 4147 4148 41491022a 1022b 1023a 1023b 1024a 1024b4150 4151 4152 4153 4154 4155 41561025a 1025b 1026a 1026b 1027a 1027b 1028a4157 4158 4159 4160 4161 # 4162 41631028b 1029a 1029b 1030a 1030b 1031a 1031b

3270

4164 4165 4166 4167 4168 41691022a 1022b 1023a 1023b 1024a 1024b4170 4171 4172 4173 4174 4175 41761025a 1025b 1026a 1026b 1027a 1027b 1028a4177 4178 4179 4180 4181 # 4182 41831028b 1029a 1029b 1030a 1030b 1031a 1031b

3271

4184 4185 4186 4187 4188 41891022a 1022b 1023a 1023b 1024a 1024b4190 4191 4192 4193 4194 4195 41961025a 1025b 1026a 1026b 1027a 1027b 1028a4197 4198 4199 4200 4201 # 4202 42031028b 1029a 1029b 1030a 1030b 1031a 1031b

3272

4204 4205 4206 4207 4208 42091022a 1022b 1023a 1023b 1024a 1024b4210 4211 4212 4213 4214 4215 42161025a 1025b 1026a 1026b 1027a 1027b 1028a4217 4218 4219 4220 4221 # 4222 42231028b 1029a 1029b 1030a 1030b 1031a 1031b

3273

4224 4225 4226 4227 4228 42291022a 1022b 1023a 1023b 1024a 1024b4230 4231 4232 4233 4234 4235 42361025a 1025b 1026a 1026b 1027a 1027b 1028a4237 4238 4239 4240 4241 # 4242 42431028b 1029a 1029b 1030a 1030b 1031a 1031b

3274

4244 4245 4246 4247 4248 42491022a 1022b 1023a 1023b 1024a 1024b4250 4251 4252 4253 4254 4255 42561025a 1025b 1026a 1026b 1027a 1027b 1028a4257 4258 4259 4260 4261 # 4262 42631028b 1029a 1029b 1030a 1030b 1031a 1031b

3275

4264 4265 4266 4267 4268 42691022a 1022b 1023a 1023b 1024a 1024b4270 4271 4272 4273 4274 4275 42761025a 1025b 1026a 1026b 1027a 1027b 1028a4277 4278 4279 4280 4281 # 4282 42831028b 1029a 1029b 1030a 1030b 1031a 1031b

3276

4284 4285 4286 4287 4288 42891022a 1022b 1023a 1023b 1024a 1024b4290 4291 4292 4293 4294 4295 42961025a 1025b 1026a 1026b 1027a 1027b 1028a4297 4298 4299 4300 4301 # 4302 43031028b 1029a 1029b 1030a 1030b 1031a 1031b

3277

4304 4305 4306 4307 4308 43091022a 1022b 1023a 1023b 1024a 1024b4310 4311 4312 4313 4314 43151025a 1025b 1026a 1027a 1027b 1028a4316 4317 4317 4320#1028b 1029a 1030a 1031a

3278

4321 4322 4323 4324 4325 43261022a 1022b 1023a 1023b 1024a 1024b4327 4328 4329 4330 4331 4332 43331025a 1025b 1026a 1026b 1027a 1027b 1028a4334 4335 4336 4337 4338 # 4339 43401028b 1029a 1029b 1030a 1030b 1031a 1031b

3279

4341 4342 4343 4344 4345 43461022a 1022b 1023a 1023b 1024a 1024b4347 4348 4349 4350 4351 4352 43531025a 1025b 1026a 1026b 1027a 1027b 1028a4354 4355 4356 4357 4358 # 4359 43601028b 1029a 1029b 1030a 1030b 1031a 1031b

3280

4361 4362 4363 4364 4365 43661022a 1022b 1023a 1023b 1024a 1024b4367 4368 4369 4370 4371 4372 43731025a 1025b 1026a 1026b 1027a 1027b 1028a4374 4375 4376 4377 4378 # 4379 43801028b 1029a 1029b 1030a 1030b 1031a 1031b

3281

4381 4382 4383 4384 4385 43861022a 1022b 1023a 1023b 1024a 1024b4387 4388 4389 4390 4391 4392 43931025a 1025b 1026a 1026b 1027a 1027b 1028a4394 4395 4396 4397 4398 # 4399 44001028b 1029a 1029b 1030a 1030b 1031a 1031b

3282

4401 4402 4403 4404 4405 44061022a 1022b 1023a 1023b 1024a 1024b4407 4408 4409 4410 4411 4412 44131025a 1025b 1026a 1026b 1027a 1027b 1028a4414 4415 4416 4417 4418 # 4419 44201028b 1029a 1029b 1030a 1030b 1031a 1031b

3283

4421 4422 4423 4424 4425 44261022a 1022b 1023a 1023b 1024a 1024b4427 4428 4429 4430 4431 4432 44331025a 1025b 1026a 1026b 1027a 1027b 1028a4434 4435 4436 4437 4438 # 4439 44401028b 1029a 1029b 1030a 1030b 1031a 1031b

3284

4441 4442 4443 4444 4445 44461022a 1022b 1023a 1023b 1024a 1024b4447 4448 4449 4450 4451 4452 44531025a 1025b 1026a 1026b 1027a 1027b 1028a4454 4455 4456 4457 4458 # 4459 44601028b 1029a 1029b 1030a 1030b 1031a 1031b

3285

4461 4462 4463 4464 4465 43661022a 1022b 1023a 1023b 1024a 1024b4467 4468 4469 4470 4471 4472 44731025a 1025b 1026a 1026b 1027a 1027b 1028a4474 4475 4476 4477 4478 # 4479 44801028b 1029a 1029b 1030a 1030b 1031a 1031b

3286

4481 4482 4483 4484 4485 44861022a 1022b 1023a 1023b 1024a 1024b4487 4488 4489 4490 4491 4492 44931025a 1025b 1026a 1026b 1027a 1027b 1028a4494 4495 4496 4497 4498 # 4499 45001028b 1029a 1029b 1030a 1030b 1031a 1031b

3287

4501 4502 4503 4504 4505 45061022a 1022b 1023a 1023b 1024a 1024b4507 4508 4509 4510 4511 4512 45131025a 1025b 1026a 1026b 1027a 1027b 1028a4514 4515 4516 4517 4518 # 4519 45201028b 1029a 1029b 1030a 1030b 1031a 1031b

3288

4521 4522 4523 4524 4525 45261022a 1022b 1023a 1023b 1024a 1024b4527 4528 4529 4530 4531 4532 45331025a 1025b 1026a 1026b 1027a 1027b 1028a4534 4535 4536 4537 4538 # 4539 45401028b 1029a 1029b 1030a 1030b 1031a 1031b

3289

4541 4542 4543 4544 4545 45461022a 1022b 1023a 1023b 1024a 1024b4547 4548 4549 4550 4551 4552 45531025a 1025b 1026a 1026b 1027a 1027b 1028a4554 4555 4556 4557 4558 # 4559 45601028b 1029a 1029b 1030a 1030b 1031a 1031b

3290

4561 4562 4563 4564 4565 45661022a 1022b 1023a 1023b 1024a 1024b4567 4568 4569 4570 4571 4572 45731025a 1025b 1026a 1026b 1027a 1027b 1028a4574 4575 4576 4577 4578 # 4579 45801028b 1029a 1029b 1030a 1030b 1031a 1031b

3291

4581 4582 4583 4584 4585 45861022a 1022b 1023a 1023b 1024a 1024b4587 4588 4589 4590 4591 4592 45931025a 1025b 1026a 1026b 1027a 1027b 1028a4594 4595 4596 4597 4598 # 4599 46001028b 1029a 1029b 1030a 1030b 1031a 1031b

3292

4601 4602 4603 4604 4605 46061022a 1022b 1023a 1023b 1024a 1024b4607 4608 4609 4600 4611 46121025a 1025b 1026a 1027a 1027b 1028a4613 4614 4615 4616 4617 # 46181028b 1029a 1030a 1030b 1031a 1031b

3293

EXAMPLE 4619

[2939]

3294

[2940] To a CH2Cl2 (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 NaHCO3 solution and extracted with CH2Cl2 several times. The combined organic solution was dried (MgSO4) and evaporated to dryness. The residue was purified by prep TLC plates using 10% methanol (2M NH3)/CH2Cl2 to give compound 5001 as an off white solid (15.0 mg). M.P. 152-155° C. (dec). MS M+1 593.

[2941] Assays

[2942] 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 pH 7.7, 5 MM MgCl2, 5 μM Zn++, 5 mM DTT, 0.1% Triton-X, 0.05 μM peptide, 0.03 nM purified human farnesyl protein transferase, 0.180 μM [3H] farnesyl pyrophosphate, plus the indicated concentration of tricyclic compound or vehicle control in a total volume of 100 μl. The reaction was incubated in a Vortemp shaking incubator at 37° C., 45 RPM for 60 minutes and stopped with 150 μl 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.

[2943] COS Cell IC50 (Cell-Based Assay) were determined following the assay procedures described in WO 95/10516, published Apr. 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.

[2944] Various tumor cells (5×105 to 8×106) 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 (×1), 2 (×2) or 3 (×3) weeks. The percent inhibition of tumor growth relative to vehicle controls were determined by tumor measurements. The results are reported in Table 155.

162TABLE 155AverageDoseRoute and% TumorCompound No.Tumor(MPK)ScheduleInhibition(372)H-Ras fibroblasts40po, BID, x292″H-Ras fibroblasts10po, BID, x270″H-Ras fibroblasts80po, QD, x291″H-Ras fibroblasts20po, QD, x255″H-Ras fibroblasts60po, BID, x298″H-Ras fibroblasts20po, BID, x259″H-Ras fibroblasts6.6po, BID, x219″HTB-17760po, BID, x387″HTB-17720po, BID, x343″HTB-177120po, QD, x354″HTB-17740po, QD, x311″HTB-17780po, BID, x396″HTB-17740po, BID, x379″HTB-17720po, BID, x347″LOX15po, BID, x120.9″LOX30po, BID, x154.8″LOX60po, BID, x190.3(The schedule ″po, BID, x3”, for example, means orally, twice a day for 7 days (14 times per week) for 3 weeks).

[2945] Soft Agar Assay:

[2946] 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 370C under 5% CO2 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 IC50's can be determined.

[2947] There are compounds of this invention have an FPT IC50 in the range of 0.05 nM to 100 nM and a Soft Agar IC50 in the range of <0.5 nM to 50 nM.

[2948] The compound of Example 4916 had an FPT IC50 of 1.2 nM, and a Soft Agar IC50 of <0.5 nM.

[2949] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically 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 pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.

[2950] 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.

[2951] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[2952] 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.

[2953] 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.

[2954] Preferably the compound is administered orally.

[2955] 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.

[2956] 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.

[2957] 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.

[2958] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically 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.

[2959] 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.

163TABLE 156Examplary Chemotherapeutic Agents Dosage and Dosage RegimensCisplatin: 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

[2960] 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.

[2961] In an example of combination therapy in the treatment of pancreatic cancer, the 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.

[2962] In an example of combination therapy in the treatment of lung cancer, the 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.

[2963] In an example of combination therapy in the treatment of gliomas, the 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.

[2964] In another example of combination therapy in the treatment of cancer, the 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.

[2965] In another example of combination therapy in the treatment of cancer, the 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.

[2966] In another example of combination therapy in the treatment of cancer, the 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.

[2967] In another example of combination therapy in the treatment of cancer, the 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 tol 00 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.

[2968] 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.

164TABLE 157Examplary Signal Transduction InhibitorsDosage and Dosage RegimensIressa (ZD1839) - EGF receptor 150-700 mg/day (oral)kinase inhibitor:OSI-774 - EGF receptor100-1000 mg/day (oral)kinase inhibitor: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 0.2-2 mg/kg every 2 weeks (IV)antibody:Gleevec (STI-571) - bcr/abl300-1000 mg/day (oral)kinase inhibitor:*(IV)-intravenously

[2969] 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.

[2970] In another example of combination therapy in the treatment of cancer, the 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.

[2971] The FPT inhibitor 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 compound of formula (1.0) 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.

[2972] 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 judgernent of the condition of the patient and the appropriate treatment protocol.

[2973] The FPT inhibitor 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 compound of formula (1.0).

[2974] If the FPT inhibitor compound of formula (1.0), chemotherapeutic agent, signal transduction inhibitor and/or radiation are not administered simultaneously then the FPT inhibitor compound of formula (1.0) 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 compound of formula (1.0). 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.

[2975] 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 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.

[2976] 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.

[2977] Additional pharmaceutical and method of treating embodiments of this invention are set forth below.

[2978] An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of compound of formula 1.0 in combination with a pharmaceutically acceptable carrier.

[2979] 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 pharmaceutically acceptable carrier.

[2980] 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 formula 1.0.

[2981] 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 formula 1.0.

[2982] 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 formula 1.0.

[2983] 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 formula 1.0

[2984] 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 formula 1.0.

[2985] 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 formula 1.0.

[2986] 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.

[2987] 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 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.

[2988] 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 said tumors are selected from the group consisting of lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias.

[2989] 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 said chemotherapeutic agent is an antineoplastic agent selected from: Uracil mustard, Chlormethine, 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 17α-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.

[2990] 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 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.

[2991] 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 said chemotherapeutic agent is selected from Gemcitabine, Cisplatin, Carboplatin, paclitaxel, paclitaxel derivatives, and Taxotere.

[2992] 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:

3295

3296

3297

3298

3299

3300

3301

3302

3303

3304

3305

3306

3307

3308

3309

3310

3311

3312

3313

3314

3315

3316

3317

3318

3319

[2993] 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:

3320

3321

3322

3323

3324

3325

3326

3327

3328

3329

3330

3331

3332

3333

3334

[2994] 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:

3335

3336

3337

3338

[2995] 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 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.

[2996] 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 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.

[2997] 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 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.

[2998] 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 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.

[2999] 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 signal transduction inhibitor.

[3000] 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 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.

[3001] 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 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.

[3002] 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 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.

[3003] 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 signal transduction inhibitor, wherein the tumors treated are selected from the group consisting 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.

[3004] 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:

[3005] (1) taxanes;

[3006] (2) platinum coordinator compounds;

[3007] (3) EGF inhibitors that are antibodies;

[3008] (4) EGF inhibitors that are small molecules;

[3009] (5) VEGF inhibitors that are antibodies;

[3010] (6) VEGF kinase inhibitors that are small molecules;

[3011] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[3012] (8) anti-tumor nucleoside derivatives;

[3013] (9) epothilones;

[3014] (10) topoisomerase inhibitors;

[3015] (11) vinca alkaloids;

[3016] (12) antibodies that are inhibitors of αVβ3 integrins; or

[3017] (13) small molecule inhibitors of αVβ3 integrins

[3018] (14) folate antagonists;

[3019] (15) ribonucleotide reductase inhibitors;

[3020] (16) anthracyclines;

[3021] (17) biologics;

[3022] (18) Thalidomide (or related Imid); and

[3023] (19) Gleevec.

[3024] 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:

[3025] (1) taxanes;

[3026] (2) platinum coordinator compounds;

[3027] (3) EGF inhibitors that are antibodies;

[3028] (4) EGF inhibitors that are small molecules;

[3029] (5) VEGF inhibitors that are antibodies;

[3030] (6) VEGF kinase inhibitors that are small molecules;

[3031] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[3032] (8) anti-tumor nucleoside derivatives;

[3033] (9) epothilones;

[3034] (10) topoisomerase inhibitors;

[3035] (11) vinca alkaloids;

[3036] (12) antibodies that are inhibitors of αVβ3 integrins; or

[3037] (13) small molecule inhibitors of αVβ3 integrins

[3038] (14) folate antagonists;

[3039] (15) ribonucleotide reductase inhibitors;

[3040] (16) anthracyclines;

[3041] (17) biologics; and

[3042] (18) Thalidomide (or related Imid).

[3043] 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:

[3044] (1) taxanes;

[3045] (2) platinum coordinator compounds;

[3046] (3) EGF inhibitors that are antibodies;

[3047] (4) EGF inhibitors that are small molecules;

[3048] (5) VEGF inhibitors that are antibodies;

[3049] (6) VEGF kinase inhibitors that are small molecules;

[3050] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[3051] (8) anti-tumor nucleoside derivatives;

[3052] (9) epothilones;

[3053] (10) topoisomerase inhibitors;

[3054] (11) vinca alkaloids;

[3055] (12) antibodies that are inhibitors of αVβ3 integrins; or

[3056] (13) small molecule inhibitors of αVβ3 integrins

[3057] (14) folate antagonists;

[3058] (15) ribonucleotide reductase inhibitors;

[3059] (16) anthracyclines; and

[3060] (17) biologics.

[3061] 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:

[3062] (1) taxanes;

[3063] (2) platinum coordinator compounds;

[3064] (3) EGF inhibitors that are antibodies;

[3065] (4) EGF inhibitors that are small molecules;

[3066] (5) VEGF inhibitors that are antibodies;

[3067] (6) VEGF kinase inhibitors that are small molecules;

[3068] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[3069] (8) anti-tumor nucleoside derivatives;

[3070] (9) epothilones;

[3071] (10) topoisomerase inhibitors;

[3072] (11) vinca alkaloids;

[3073] (12) antibodies that are inhibitors of αVβ3 integrins; and

[3074] (13) small molecule inhibitors of αVβ3 integrins.

[3075] 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.

[3076] 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.

[3077] 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.

[3078] 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.

[3079] 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.

[3080] 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.

[3081] 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.

[3082] 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.

[3083] 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.

[3084] 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.

[3085] 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 antineop!astic agent is a platinum coordinator compound, wherein said FPT inhibitor is selected from the group consisting of:

3339

3340

3341

3342

3343

3344

3345

3346

3347

3348

3349

3350

3351

3352

3353

3354

3355

3356

3357

3358

3359

3360

3361

3362

3363

[3086] 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:

3364

3365

3366

3367

3368

3369

3370

3371

3372

3373

3374

3375

3376

3377

3378

[3087] 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:

3379

3380

3381

3382

[3088] 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:

3383

[3089] 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:

3384

[3090] 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:

3385

[3091] 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.

[3092] 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.

[3093] 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.

[3094] 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.

[3095] 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.

[3096] 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.

[3097] 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.

[3098] 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:

[3099] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3100] (b) carboplatin; and

[3101] (c) paclitaxel.

[3102] 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:

[3103] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3104] (b) carboplatin; and

[3105] (c) paclitaxel,

[3106] 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.

[3107] 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:

[3108] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3109] (b) carboplatin; and

[3110] (c) paclitaxel,

[3111] 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.

[3112] 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:

[3113] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3114] (b) carboplatin; and

[3115] (c) paclitaxel,

[3116] 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/m2, said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle

[3117] 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:

[3118] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3119] (b) carboplatin; and

[3120] (c) paclitaxel,

[3121] 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.

[3122] 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:

[3123] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3124] (b) carboplatin; and

[3125] (c) paclitaxel,

[3126] 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.

[3127] 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:

[3128] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3129] (b) carboplatin; and

[3130] (c) paclitaxel,

[3131] 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.

[3132] 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:

[3133] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:

[3134] (b) cisplatin; and

[3135] (c) gemcitabine.

[3136] 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:

[3137] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:

[3138] (b) cisplatin; and

[3139] (c) gemcitabine

[3140] 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.

[3141] 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:

[3142] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:

[3143] (b) cisplatin; and

[3144] (c) gemcitabine

[3145] 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.

[3146] 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:

[3147] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:

[3148] (b) cisplatin; and

[3149] (c) gemcitabine

[3150] 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.

[3151] 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:

[3152] (a) an-FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:

[3153] (b) cisplatin; and

[3154] (c) gemcitabine

[3155] 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.

[3156] 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:

[3157] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3158] (b) carboplatin; and

[3159] (c) gemcitabine.

[3160] 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:

[3161] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3162] (b) carboplatin; and

[3163] (c) gemcitabine,

[3164] 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.

[3165] 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:

[3166] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3167] (b) carboplatin; and

[3168] (c) gemcitabine,

[3169] 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.

[3170] 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:

[3171] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3172] (b) carboplatin; and

[3173] (c) gemcitabine,

[3174] 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 mg!m2, and said treatment being given for one to seven weeks per cycle.

[3175] 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:

[3176] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3177] (b) carboplatin; and

[3178] (c) gemcitabine,

[3179] 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.

[3180] 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:

[3181] (1) EGF inhibitors that are antibodies;

[3182] (2) EGF inhibitors that are small molecules;

[3183] (3) VEGF inhibitors that are antibodies; or

[3184] (4) VEGF kinase inhibitors that are small molecules.

[3185] 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.

[3186] 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:

[3187] (1) EGF inhibitors that are antibodies;

[3188] (2) EGF inhibitors that are small molecules;

[3189] (3) VEGF inhibitors that are antibodies; or

[3190] (4) VEGF kinase inhibitors that are small molecules,

[3191] 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.

[3192] 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:

[3193] (1) EGF inhibitors that are antibodies;

[3194] (2) EGF inhibitors that are small molecules;

[3195] (3) VEGF inhibitors that are antibodies; or

[3196] (4) VEGF kinase inhibitors that are small molecules,

[3197] wherein said FPT inhibitor is administered in an amount of about 50 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.

[3198] 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:

[3199] (1) EGF inhibitors that are antibodies;

[3200] (2) EGF inhibitors that are small molecules;

[3201] (3) VEGF inhibitors that are antibodies; or

[3202] (4) VEGF kinase inhibitors that are small molecules,

[3203] 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.

[3204] 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:

[3205] (1) EGF inhibitors that are antibodies;

[3206] (2) EGF inhibitors that are small molecules;

[3207] (3) VEGF inhibitors that are antibodies; or

[3208] (4) VEGF kinase inhibitors that are small molecules,

[3209] 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.

[3210] 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.

[3211] 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.

[3212] 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:

[3213] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3214] (b) carboplatin; and

[3215] (c) docetaxel.

[3216] 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:

[3217] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and

[3218] (b) one or more antineoplastic agents selected from the group consisting of:

[3219] (1) taxanes; and

[3220] (2) platinum coordinator compounds.

[3221] 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:

[3222] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3223] (b) at least two different antineoplastic agents selected from the group consisting of

[3224] (1) taxanes;

[3225] (2) platinum coordinator compounds; and

[3226] (3) anti-tumor nucleoside derivatives (e.g., 5-Fluorouracil).

[3227] 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:

[3228] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3229] (b) Gleevec; and

[3230] (c) interferon (e.g., Intron-A).

[3231] 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:

[3232] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3233] (b) Gleevec; and

[3234] (c) pegylated interferon (e.g., Peg-Intron, and Pegasys).

[3235] 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:

[3236] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3237] (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)).

[3238] 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:

[3239] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3240] (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)); and

[3241] (c) an anthracycline.

[3242] An embodiment of this invention is directed to a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[3243] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3244] (b) Rituximab (Rituxan).

[3245] An embodiment of this invention is directed to a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[3246] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3247] (b) Rituximab (Rituxan); and

[3248] (c) an anti-tumor nucleoside derivative (e.g., Fludarabine (i.e., F-ara-A).

[3249] An embodiment of this invention is directed to a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[3250] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3251] (b) Genasense (antisense to BCL-2).

[3252] 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:

[3253] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3254] (b) a proteosome inhibitor (e.g., PS-341 (Millenium)).

[3255] 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:

[3256] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3257] (b) Thalidomide or related imid.

[3258] 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:

[3259] (a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);

[3260] (b) Thalidomide.

[3261] 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.

[3262] 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:

3386

3387

3388

3389

3390

3391

3392

3393

3394

3395

3396

3397

3398

3399

3400

3401

3402

3403

3404

3405

3406

3407

3408

3409

[3263] more preferably selected from the group consisting of:

3410

3411

3412

3413

3414

3415

3416

3417

[3264] most preferably selected from the group consisting of:

3418

3419

[3265] even more preferably

3420

[3266] and still more preferably

3421

[3267] 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.

	Number	Date	Country
Parent	10085896	Feb 2002	US
Child	10325896	Dec 2002	US
Parent	09940811	Aug 2001	US
Child	10325896	Dec 2002	US

Novel farnesyl protein transferase inhibitors as antitumor agents

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Abstract

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REFERENCE TO RELATED APPLICATIONS

Continuation in Parts (2)