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) a nd Paclitaxel (Taxol) f o r the treatment of Non Small Cell Lung Cancer.

[0008] The WEB site http://cancertrials.nci.nih.gov/types/lung/iressal2100.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 NCl'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-naive 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-naive 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 are 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)R10;

[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)2R50;

[0044] (21) —(CH2)pN(C(O)R27a)2 wherein each R27a 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;

[0057] wherein R30, R31, R32 and R33 are thesame or different;

[0058] (34)-alkenyl-CO2R9a;

[0059] (35)-alkenyl-C(O)R9a;

[0060] (36)-alkenyl-CO2R51;

[0061] (37)-alkenyl-C(O)—R27a;

[0062] (38) (CH2)p-alkenyl-CO2—R51;

[0063] (37) —(CH2)pC═NOR51; and

[0064] (39) —(CH2)p-phthalimid;

[0065] p is 0, 1, 2, 3 or 4;

[0066] each R1 and R2 is independently selected from the group consisting of:

[0067] (1) H;

[0068] (2) Halo;

[0069] (3) —CF3,

[0070] (4) —OR10;

[0071] (5) —COR10;

[0072] (6) —SR10;

[0073] (7) —S(O)tR15 wherein t is 0, 1 or 2;

[0074] (8) —N(R10)2;

[0075] (9) —NO2;

[0076] (10) —OC(O)R10;

[0077] (11) —CO2R10;

[0078] (12) —CO2R10;

[0079] (13) —CN;

[0080] (14) —NR10COOR15;

[0081] (15) —SR15C(O)OR15;

[0082] (16) —SR15N(R13)2 provided that R15 in —SR15N(R13)2 is not —CH2 and wherein each R is independently selected from the group consisting of: H and —C(O)OR15;

[0083] (17) benzotriazol-1-yloxy;

[0084] (18) tetrazol-5-ylthio;

[0085] (19) substituted tetrazol-5-ylthio;

[0086] (20) alkynyl;

[0087] (21) alkenyl; and

[0088] (22) alkyl,

[0089] said alkyl or alkenyl group optionally being substituted with halogen, —OR10 or —CO2R10;

[0090] R3 and R4 are the same or different and each independently represent H, and any of the substituents of R1 and R2;

[0091] R5, R6, R7 and R7a each independently represent: H, —CF3, —COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with —S(O)tR10, —NR10COOR15, —C(O)R10, or —CO2R10, or R5 is combined with R6 to represent ═O or ═S;

[0092] R8 is selected from the group consisting of:

[0093] R9 is selected from the group consisting of:

[0094] (1) unsubstituted heteroaryl;

[0095] (2) substituted heteroaryl;

[0096] (3) arylalkoxy;

[0097] (4) substituted arylalkoxy;

[0098] (5) heterocycloalkyl;

[0099] (6) substituted heterocycloalkyl;

[0100] (7) heterocycloalkylalkyl;

[0101] (8) substituted heterocycloalkylalkyl;

[0102] (9) unsubstituted heteroarylalkyl;

[0103] (10) substituted heteroarylalkyl;

[0104] (11) unsubstituted heteroarylalkenyl;

[0105] (12) substituted heteroarylalkenyl;

[0106] (13) unsubstituted heteroarylalkynyl; and

[0107] (14) substituted heteroarylalkynyl;

[0108] wherein said substituted R9 groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:

[0109] (1) —OH;

[0110] (2) —CO2R14;

[0111] (3) —CH2OR14,

[0112] (4) halogen (e.g. Br, Cl or F),

[0113] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0114] (6) amino;

[0115] (7) trityl;

[0116] (8) heterocycloalkyl;

[0117] (9) cycloalkyl, (e.g., cyclopropyl or cyclohexyl);

[0118] (10) arylalkyl;

[0119] (11) heteroaryl;

[0120] (12) heteroarylalkyl and

[0121] wherein R14 is independently selected from: H; alkyl; aryl, arylalkyl, heteroaryl and heteroarylalkyl;

[0122] R9a is selected from the group consisting of: alky and arylalkyl;

[0123] R10 is selected from the group consisting of: H; alkyl; aryl and arylalkyl;

[0124] R11 is selected from the group consisting of:

[0125] (1) alkyl;

[0126] (2) substituted alkyl;

[0127] (3) unsubstituted aryl;

[0128] (4) substituted aryl;

[0129] (5) unsubstituted cycloalkyl;

[0130] (6) substituted cycloalkyl;

[0131] (7) unsubstituted heteroaryl;

[0132] (8) substituted heteroaryl;

[0133] (9) heterocycloalkyl; and

[0134] (10) substituted heterocycloalkyl;

[0135] 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:

[0136] (1) —OH;

[0137] (2) fluoro; and

[0138] (3) alkyl; and

[0139] 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:

[0140] (1) —OH;

[0141] (2) halogen (e.g. Br, Cl or F); and

[0142] (3) alkyl;

[0143] R11a is selected from the group consisting of:

[0144] (1) H;

[0145] (2) OH;

[0146] (3) alkyl;

[0147] (4) substituted alkyl;

[0148] (5) aryl;

[0149] (6) substituted aryl;

[0150] (7) unsubstituted cycloalkyl;

[0151] (8) substituted cycloalkyl;

[0152] (9) unsubstituted heteroaryl;

[0153] (10) substituted heteroaryl;

[0154] (11) heterocycloalkyl; and

[0155] (12) substituted heterocycloalkyl;

[0156] 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:

[0157] (1) —OH;

[0158] (2) —CN;

[0159] (3) —CF3;

[0160] (4) fluoro;

[0161] (5) alkyl;

[0162] (6) cycloalkyl;

[0163] (7) heterocycloalkyl;

[0164] (8) arylalkyl;

[0165] (9) heteroarylalkyl;

[0166] (10) alkenyl and

[0167] (11) heteroalkenyl; and

[0168] 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:

[0169] (1) —OH;

[0170] (2) —CN;

[0171] (3) —CF3;

[0172] (4) halogen (e.g Br, Cl or F);

[0173] (5) alkyl;

[0174] (6) cycloalkyl;

[0175] (7) heterocycloalkyl;

[0176] (8) arylalkyl;

[0177] (9) heteroarylalkyl;

[0178] (10) alkenyl; and

[0179] (11) heteroalkenyl;

[0180] R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and -alkyl-(piperidine Ring V);

[0181] R15 is selected from the group consisting of: alkyl and aryl;

[0182] R21, R22 and R46 are independently selected from the group consisting of:

[0183] (1) —H;

[0184] (2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0185] (3) unsubstituted aryl, (e.g. phenyl);

[0186] (4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0187] (5) unsubstituted cycloalkyl, (e.g. cyclohexyl);

[0188] (6) substituted cycloalkyl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0189] (7) heteroaryl of the formula,

[0190] (8) heterocycloalkyl of the formula:

[0191] (i.e., piperidine Ring V) wherein R44 is selected from the group consisting of:

[0192] (a) —H,

[0193] (b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0194] (c) alkylcarbonyl (e.g., CH3C(O)—);

[0195] (d) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and —C(O)OCH3);

[0196] (e) haloalkyl (e.g., trifluoromethyl); and

[0197] (f) —C(O)NH(R51);

[0198] R26 is selected from the group consisting of:

[0199] (1) —H;

[0200] (2) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0201] (3) alkoxyl (e.g. methoxy, ethoxy, propoxy);

[0202] (4) —CH2—CN;

[0203] (5) R9;

[0204] (6) —CH2CO2H;

[0205] (7) —C(O)alkyl; and

[0206] (8) CH2CO2alkyl;

[0207] R27 is selected from the group consisting of:

[0208] (1) —H;

[0209] (2) —OH;

[0210] (3) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0211] (4) alkoxy;

[0212] R27a is selected from the group consisting of:

[0213] (1) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0214] (2) alkoxy;

[0215] R30, R31, R32 and R33 are independently selected from the group consisting of:

[0216] (1) —H;

[0217] (2) —OH;

[0218] (3) ═O;

[0219] (4) alkyl;

[0220] (5) aryl (e.g. phenyl);

[0221] (6) arylalkyl (e.g. benzyl);

[0222] (7) —OR9a;

[0223] (8) —NH2;

[0224] (9) —NHR9a; and

[0225] (10) —N(R9a)2 wherein each R9a is independently selected;

[0226] R50 is selected from the group consisting of:

[0227] (1) alkyl;

[0228] (2) unsubstituted heteroaryl;

[0229] (3) substituted heteroary; and

[0230] (4) amino;

[0231] 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;

[0232] R51 is selected from the group consisting of: H, and alkyl (e.g.; methyl, ethyl, propyl, butyl and t-butyl); and

[0233] 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

[0234] 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

[0235] 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

[0236] provided that a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and

[0237] provided that a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and

[0238] provided that the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms.

[0239] This invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula 1.0 and a pharmaceutically acceptable carrier.

[0240] 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.

[0241] 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.

[0242] 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).

[0243] 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.

[0244] 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.

[0245] 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

[0246] 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.

[0247] As used herein, the following terms have the following meanings unless otherwise described:

[0248] AUC-represents “Area Under the Curve”

[0249] BOC-represents tert-butyloxycarbonyl;

[0250] CBZ-represents —C(O)OCH2C6H5 (i.e., benzyloxycarbonyl);

[0251] CH2Cl2-represents dichloromethane;

[0252] CIMS-represents chemical ionization mass spectrum;

[0253] Cmpd-represents Compound;

[0254] DBU-represents 1,8-Diazabicyclo[5.4.0]undec-7-ene;

[0255] DEAD-represents diethylazodicarboxylate;

[0256] DEC-represents EDCI which represents 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride;

[0257] DMF-represents N,N-dimethylformamide;

[0258] Et-represents ethyl;

[0259] Et3N-represents TEA which represents triethylamine;

[0260] EtOAc-represents ethyl acetate;

[0261] EtOH-represents ethanol;

[0262] FAB-represents FABMS which represents fast atom bombardment mass spectroscopy;

[0263] HOBT-represents 1-hydroxybenzotriazole hydrate;

[0264] HRMS-represents high resolution mass spectroscopy;

[0265] IPA-represents isopropanol;

[0266] i-PrOH-represents isopropanol;

[0267] Me-represents methyl;

[0268] MeOH-represents methanol;

[0269] MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;

[0270] MS-represents mass spectroscopy;

[0271] NMM-represents N-methylmorpholine;

[0272] PPh3-represents triphenyl phosphine;

[0273] Ph-represents phenyl;

[0274] Pr-represents propyl;

[0275] SEM-represents 2,2-(Trimethylsilyl)ethoxymethyl;

[0276] 5 TBDMS-represents tert-butyldimethylsilyl;

[0277] t-BUTYL-represents —C—(CH3)3;

[0278] TFA-represents trifluoroacetic acid;

[0279] THF-represents tetrahydrofuran;

[0280] Tr-represents trityl;

[0281] Tf-represents SO2CF3;

[0282] at least one-represents one or more-(e.g. 1-6), more preferrably 1-4 with 1, 2 or 3 being most preferred;

[0283] 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;

[0284] 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;

[0285] 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;

[0286] alkylcarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (—CO—), for example, —COCH3;

[0287] alkyloxycarbonyl-represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (—CO—) through an oxygen atom, for example, —C(O)—OC2H5;

[0288] 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;

[0289] amino-represents an —NH2 moiety;

[0290] antineoplastic agent-represents a chemotherapeutic agent effective against cancer;

[0291] aryl-represents a carbocyclic group containing from 6 to 15 carbon atoms in the unsubstituted carbocyclic group and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment of said aryl group, said aryl group being unsubstituted or substituted, said substituted aryl group having one or more (e.g., 1 to 3) substituents independently selected from the group consisting of: halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, —C(O)N(R18)2, —SO2R18, —SO2N(R18)2, amino, alkylamino, dialkylamino, —COOR23 and —NO2 (preferably said substitutents are independently selected from the group consisting of: alkyl (e.g., C1-C6 alkyl), halogen (e.g., Cl and Br), —CF3 and —OH), wherein each R18 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl and cycloalkyl, and wherein R23 is selected from the group consisting of: alkyl and aryl;

[0292] arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined above;

[0293] arylheteroalkyl-represents a heteroalkyl group, as defined below, substituted with an aryl group, as defined above;

[0294] 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);

[0295] compound-with reference to the antineoplastic agents, includes the agents that are antibodies;

[0296] 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;

[0297] consecutively-means one following the other;

[0298] 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,

[0299] 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:

[0300] cycloalkylalkyl-represents an alkyl group, as defined above, substituted with a cycloalkyl group, as defined above;

[0301] 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;

[0302] 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;

[0303] halo (or halogen)-represents fluoro, chloro, bromo or iodo;

[0304] haloalkyl-represents an alkyl group, as defined above, substituted with a halo group;

[0305] heteroatom-represents a O, N or S atom;

[0306] 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;

[0307] 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;

[0308] 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;

[0309] 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:

[0310] heteroarylalkenyl-represents an alkenyl group, as defined above, substituted with a heteroaryl group, as defined below;

[0311] heteroarylalkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined above;

[0312] heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as defined below;

[0313] 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 —NR wherein R 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

[0314] heterocycloalkylalkyl-represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as above;

[0315] “in association with”-means, in reference to the combination therapies of the invention, that the agents or components are adminstered concurrently or sequentially;

[0316] patient-represents a mammal, such as a human;

[0317] 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.

[0318] The positions in the tricyclic ring system are:

[0319] A “+” or a “−” in Ring II in the compounds below indicates the “(+)-isomer” or “(−)-isomer”, respectively.

[0320] 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:

[0321] Those skilled in the art will appreciate that the compounds of formula 1.0 are also represented by compounds of formula 1.1:

[0322] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0323] (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

[0324] (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;

[0325] (C) the dotted lines (---) represent optional bonds;

[0326] (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;

[0327] (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;

[0328] (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:

[0329] (1) there are two A substituents bound to C-5 wherein each A substituent is independently selected; and

[0330] (2) there are two B substituents bound to C-6 wherein each B substituent is independently selected; and

[0331] (3) at least one of the two A substituents or one of the two B substituents are H; and

[0332] (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;

[0333] (G) A and B is independently selected from the group consisting of:

[0334] (1) —H;

[0335] (2) —R9;

[0336] (3) —R9—C(O)—R9;

[0337] (4) —R9—CO2—R9a;

[0338] (5) —(CH2)pR26;

[0339] (6) —C(O)N(R9)2, wherein each R9 is the same or different;

[0340] (7) —C(O)NHR9;

[0341] (8) —C(O)NH—CH2—C(O)—NH2;

[0342] (9) —C(O)NHR26;

[0343] (10) —(CH2)pC(R9)—O—R9a;

[0344] (11) —(CH2)p-1CH(R9)2, provided that p is not 0, and wherein each R9 is the same or different;

[0345] (12) —(CH2)pC(O)R9;

[0346] (13) —(CH2)pC(O)R27a;

[0347] (14) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[0348] (15) —(CH2)pC(O)NH(R9);

[0349] (16) —(CH2)pC(O)N(R26)2, wherein each R26 is the same or different;

[0350] (17) —(CH2)pN(R9)—R9a (e.g. —CH2—N(CH2-pyridine)-CH2-imidazole);

[0351] (18) —(CH2)pN(R26)2, wherein each R26 is the same or different (e.g., —(CH2)p—NH—CH2—CH3);

[0352] (19) —(CH2)pNHC(O)R50;

[0353] (20) —(CH2)pNHC(O)2R50;

[0354] (21) —(CH2)pN(C(O)R27a)2 wherein each R27a is the same or different;

[0355] (22) —(CH2)pNR51C(O)R27,

[0356] (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;

[0357] (24) —(CH2)pNR51C(O)NR27,

[0358] (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;

[0359] (26) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;

[0360] (27) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;

[0361] (28) —(CH2)pNHCO2R51;

[0362] (29) —(CH2)pNC(O)NHR51;

[0363] (30) —(CH2)pCO2R51;

[0364] (31) —NHR9;

[0365] (32)

[0366] wherein R30 and R31 are the same or different, and each p is independently selected;

[0367] (33)

[0368] wherein R30, R31, R32 and R33 are the same or different;

[0369] (34)-alkenyl-CO2R9a;

[0370] (35)-alkenyl-C(O)R9a;

[0371] (36)-alkenyl-CO2R51;

[0372] (37)-alkenyl-C(O)—R27a;

[0373] (38) (CH2)p-alkenyl-CO2—R51;

[0374] (39) —(CH2)pC═NOR51; and

[0375] (40) —(CH2)p-Phthalimid;

[0376] (H) p is 0, 1, 2, 3 or 4;

[0377] (I) R1 is selected from the group consisting of:

[0378] (1) H;

[0379] (2) halo;

[0380] (3) —CF3;

[0381] (4) —OR10;

[0382] (5) COR10;

[0383] (6) —SR10;

[0384] (7) —S(O)tR15;

[0385] (8) —N(R10)2;

[0386] (9) —NO2;

[0387] (10) —OC(O)R10;

[0388] (11) CO2R10;

[0389] (12) —OCO2R15;

[0390] (13) —CN;

[0391] (14) —NR10COOR15;

[0392] (15) —SR15C(O)OR15;

[0393] (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;

[0394] (17) benzotriazol-1-yloxy;

[0395] (18) tetrazol-5-ylthio;

[0396] (19) substituted tetrazol-5-ylthio;

[0397] (20) alkynyl;

[0398] (21) alkenyl;

[0399] (22) alkyl;

[0400] (23) alkyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, —OR10 and —CO2R10;

[0401] (24) alkenyl substituted with one or more (e.g., 1, 2 or 3) substitutents independently selected from the group consisting of: halogen, —OR10 and —CO2R10;

[0402] (J) Each R is independently selected from the group consisting of:

[0403] (1) halo;

[0404] (2) —CF3;

[0405] (3) —OR10;

[0406] (4) COR10;

[0407] (5) —SR10;

[0408] (6) —S(O)tR15;

[0409] (7) —N(R10)2;

[0410] (8) —NO2;

[0411] (9) —OC(O)R10;

[0412] (10) CO2R10;

[0413] (11) —OCO2R15;

[0414] (12) —CN;

[0415] (13) —NR10COOR15;

[0416] (14) —SR15C(O)OR15;

[0417] (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;

[0418] (16) benzotriazol-1-yloxy;

[0419] (17) tetrazol-5-ylthio;

[0420] (18) substituted tetrazol-5-ylthio;

[0421] (19) alkynyl;

[0422] (20) alkenyl;

[0423] (21) alkyl;

[0424] (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

[0425] (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;

[0426] (K) m is 0, 1 or 2;

[0427] (L) t is 0, 1 or 2;

[0428] (M) R5, R6, R7 and R7a are each independently selected from the group consisting of:

[0429] (1) H;

[0430] (2) —CF3;

[0431] (3) —COR10

[0432] (4) alkyl;

[0433] (5) unsubstituted aryl;

[0434] (6) alkyl substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of: —S(O)tR15, —NR10COOR15, —C(O)R10, and —CO2R10; and

[0435] (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

[0436] (N) R5 together with R6 represents ═O or ═S;

[0437] (O) R8 is selected from the group consisting of:

[0438] (P) R9 is selected from the group consisting of:

[0439] (1) unsubstituted heteroaryl;

[0440] (2) substituted heteroaryl;

[0441] (3) unsubstituted arylalkoxy;

[0442] (4) substituted arylalkoxy;

[0443] (5) heterocycloalkyl;

[0444] (6) substituted heterocycloalkyl;

[0445] (7) heterocycloalkylalkyl;

[0446] (8) substituted heterocycloalkylalkyl;

[0447] (9) unsubstituted heteroarylalkyl;

[0448] (10) substituted heteroarylalkyl;

[0449] (11) unsubstituted heteroarylalkenyl;

[0450] (12) substituted heteroarylalkenyl;

[0451] (13) unsubstituted heteroarylalkynyl and

[0452] (14) substituted heteroarylalkynyl;

[0453] 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:

[0454] (1) —OH;

[0455] (2) —CO2R14;

[0456] (3) —CH2OR14,

[0457] (4) halogen (e.g. Br, Cl or F),

[0458] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0459] (6) amino;

[0460] (7) trityl;

[0461] (8) heterocycloalkyl;

[0462] (9) cycloalkyl, (e.g. cyclopropyl or cyclohexyl);

[0463] (10) arylalkyl;

[0464] (11) heteroaryl;

[0465] (12) heteroarylalkyl and

[0466] (13)

[0467] wherein R14 is independently selected from the group consisting of: H; alkyl; aryl, arylalkyl, heteroaryl and heteroarylalkyl;

[0468] (Q) R9a is selected from the group consisting of: alky and arylalkyl;

[0469] (R) R10 is selected from the group consisting of: H; alkyl; aryl and arylalkyl;

[0470] (S) R11 is selected from:

[0471] (1) alkyl;

[0472] (2) substituted alkyl;

[0473] (3) unsubstituted aryl;

[0474] (4) substituted aryl;

[0475] (5) unsubstituted cycloalkyl;

[0476] (6) substituted cycloalkyl;

[0477] (7) unsubstituted heteroaryl;

[0478] (8) substituted heteroaryl;

[0479] (9) heterocycloalkyl; and

[0480] (10) substituted heterocycloalkyl;

[0481] 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:

[0482] (1) —OH;

[0483] (2) fluoro; and

[0484] (3) alkyl; and

[0485] 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:

[0486] (1) —OH;

[0487] (2) halogen (e.g. Br, Cl or F); and

[0488] (3) alkyl;

[0489] (T) R11a is selected from the group consisting of:

[0490] (1) H;

[0491] (2) OH;

[0492] (3) alkyl;

[0493] (4) substituted alkyl;

[0494] (5) unsubstituted aryl;

[0495] (6) substituted aryl;

[0496] (7) unsubstituted cycloalkyl;

[0497] (8) substituted cycloalkyl;

[0498] (9) unsubstituted heteroaryl;

[0499] (10) substituted heteroaryl;

[0500] (11) heterocycloalkyl; and

[0501] (12) substituted heterocycloalkyl;

[0502] 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:

[0503] (1) —OH;

[0504] (2) —CN;

[0505] (3) —CF3;

[0506] (4) fluoro;

[0507] (5) alkyl;

[0508] (6) cycloalkyl;

[0509] (7) heterocycloalkyl;

[0510] (8) arylalkyl;

[0511] (9) heteroarylalkyl;

[0512] (10) alkenyl and

[0513] (11) heteroalkenyl; and

[0514] 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:

[0515] (1) —OH;

[0516] (2) —CN;

[0517] (3) —CF3;

[0518] (4) halogen (e.g Br, Cl or F);

[0519] (5) alkyl;

[0520] (6) cycloalkyl;

[0521] (7) heterocycloalkyl;

[0522] (8) arylalkyl;

[0523] (9) heteroarylalkyl;

[0524] (10) alkenyl and

[0525] (11) heteroalkenyl;

[0526] (U) R12 is selected from the group consisting of: H, alkyl, piperidine Ring V, cycloalkyl, and -alkyl-(piperidine Ring V);

[0527] (V) R15 is selected from the group consisting of: alkyl and aryl;

[0528] (W) R21, R22 and R46 are independently selected from the group consisting of:

[0529] (1) H;

[0530] (2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0531] (3) unsubstituted aryl (e.g. phenyl);

[0532] (4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;

[0533] (5) unsubstituted cycloalkyl, (e.g. cyclohexyl);

[0534] (6) substituted cycloalkyl substituted with one or more substituents independently selected from: alkyl, halogen, CF3 or OH;

[0535] (7) heteroaryl of the formula,

[0536] (8) piperidine Ring V:

[0537] wherein R44 is selected from the group consisting of:

[0538] (a) H,

[0539] (b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);

[0540] (c) alkylcarbonyl (e.g., CH3C(O)—);

[0541] (d) alkyloxy carbonyl (e.g., —C(O)O-t-C4H9, —C(O)OC2H5, and —C(O)OCH3);

[0542] (e) haloalkyl (e.g., trifluoromethyl) and

[0543] (f) —C(O)NH(R51);

[0544] (X) R26 is selected from the group consisting of:

[0545] (1) H;

[0546] (2) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0547] (3) alkoxyl (e.g. methoxy, ethoxy, propoxy);

[0548] (4) —CH2—CN;

[0549] (5) R9;

[0550] (6) —CH2CO2H;

[0551] (7) —C(O)alkyl and

[0552] (8) CH2CO2alkyl;

[0553] (Y) R27 is selected from the group consisting of:

[0554] (1) H;

[0555] (2) —OH;

[0556] (3) alkyl (e.g. methyl, ethyl, propyl, or butyl), and

[0557] (4) alkoxy;

[0558] (Z) R27a is selected from the group consisting of:

[0559] (1) alkyl (e.g. methyl, ethyl, propyl, or butyl); and

[0560] (2) alkoxy;

[0561] (AA) R30, R31, R32 and R33 are independently selected from the group consisting of:

[0562] (1) —H;

[0563] (2) —OH;

[0564] (3) ═O;

[0565] (4) alkyl;

[0566] (5) aryl (e.g. phenyl);

[0567] (6) arylalkyl (e.g. benzyl);

[0568] (7) —OR9a;

[0569] (8) —NH2;

[0570] (9) —NHR9a; and

[0571] (10) —N(R9a)2 wherein each R9a is independently selected;

[0572] (AB) R50 is selected from the group consisting of:

[0573] (1) alkyl;

[0574] (2) unsubstituted heteroaryl;

[0575] (3) substituted heteroaryl; and

[0576] (4) amino;

[0577] 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;

[0578] (AC) R51 is selected from the group consisting of: —H and alkyl (e.g., methyl, ethyl, propyl, butyl and t-butyl); and

[0579] 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

[0580] 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

[0581] 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

[0582] provided that a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and

[0583] provided that a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and

[0584] provided that the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms.

[0585] 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

[0586] 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).

[0587] The substituted R9 groups can be substitued 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.

[0588] Thus, for example, substitued heteroarylalkyl can be substituted on the heteroaryl moiety and/or the alkyl moiety.

[0589] Piperidine Ring V includes the rings:

[0590] Examples of Ring V include, but are not limited to:

[0591] One embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0592] wherein:

[0593] (1) a, b, c, d, R3A, R5, R6, R7, R7a, R8 and X are as defined for formula 1.1;

[0594] (2) B is the group:

[0595] (3) in said B group:

[0596] (a) p of the —(CH2)p— moiety is 0;

[0597] (b) p of the

[0598] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0599] (c) when p is 1 for the moiety

[0600] 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;

[0601] (d) when p is 2 or 3 for the moiety

[0602] then: (1) for one —CR30R31— moiety, 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; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0603] (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.

[0604] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0605] wherein:

[0606] (1) R8 and X are as defined for formula 1.0;

[0607] (2) B is the group:

[0608] (3) in said B group:

[0609] (a) p of the —(CH2)p— moiety is 0;

[0610] (b) p of the

[0611] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0612] (c) when p is 1 for the moiety

[0613] 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;

[0614] (d) when p is 2 or 3 for the moiety

[0615] then: (1) for one —CR30R31— moiety, 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; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0616] (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;

[0617] (4) a is N;

[0618] (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;

[0619] (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

[0620] (7) R5, R6, R7, and R7a are H.

[0621] Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

[0622] wherein:

[0623] (1) R8 are as defined for formula 1.0;

[0624] (2) B is the group:

[0625] (3) in said B group:

[0626] (a) p of the —(CH2)p— moiety is 0;

[0627] (b) p of the

[0628] moiety is 1 to 3, preferably 1 to 2, most preferably 1;

[0629] (c) when p is 1 for the moiety

[0630] 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;

[0631] (d) when p is 2 or 3 for the moiety

[0632] then: (1) for one —CR30R31— moiety, 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; and (2) for the remaining —CR30R31— moieties R30 and R31 are hydrogen; and

[0633] (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;

[0634] (4) a is N;

[0635] (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;

[0636] (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);

[0637] (7) X is N or CH; and

[0638] (8) R5, R6, R7, and R7a are H.

[0639] In another embodiment, R8 is 2.0 in formula 1.2 wherein R11 is as defined for formula 1.0.

[0640] In another embodiment, R8 is 3.0 in formula 1.2 wherein R11 is as defined for formula 1.0.

[0641] In another embodiment, R8 is 4.0 in formula 1.2 wherein R11a and R12 are as defined for formula 1.0.

[0642] In another embodiment, R8 is 5.0 in formula 1.2 wherein R21, R22, and R46 are as defined for formula 1.0.

[0643] In another embodiment, R8 is 2.0 in formula 1.3 wherein R11 is as defined for formula 1.0.

[0644] In another embodiment, R8 is 3.0 in formula 1.3 wherein R11 is as defined for formula 1.0.

[0645] In another embodiment, R8 is 4.0 in formula 1.3 wherein R11a and R12 are as defined for formula 1.0.

[0646] In another embodiment, R8 is 5.0 in formula 1.3 wherein R21, R22, and R46 are as defined for formula 1.0.

[0647] In another embodiment, R8 is 2.0 in formula 1.4 wherein R11 is as defined for formula 1.0.

[0648] In another embodiment, R8 is 3.0 in formula 1.4 wherein R11 is as defined for formula 1.0.

[0649] In another embodiment, R8 is 4.0 in formula 1.4 wherein R11a and R12 are as defined for formula 1.0.

[0650] In another embodiment, R8 is 5.0 in formula 1.4 wherein R21, R22, and R46 are as defined for formula 1.0.

[0651] 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.

[0652] Preferably, in formulas 1.3 and 1.4, when m is 1 then R3A is preferably Cl at the C-8 position.

[0653] In formulas 1.3 and 1.4, when m is 2, then the substitution is 7,8-dihalo, or 8,10-dihalo.

[0654] 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.

[0655] Preferably, in formulas 1.2 and 1.3× is N.

[0656] Preferably, in formula 1.4× is N.

[0657] A preferred embodiment of this invention is directed to compounds of formula 1.4 having the formula:

[0658] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, and more preferably 2.0 wherein R11 is t-butyl.

[0659] A preferred embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[0660] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, and more preferably 2.0 wherein R11 is t-butyl.

[0661] Thus, one embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[0662] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, and more preferably 2.0 wherein R11 is t-butyl.

[0663] Another embodiment of the invention is directed to compounds of formula 1.5 having the formula:

[0664] wherein all substituents are as defined for formula 1.4. Preferably R8 is 2.0, most preferably 2.0 wherein R11 is alkyl, and more preferably 2.0 wherein R11 is t-butyl.

[0665] In formulas 1.2, 1.3, 1.4, 1.5, 1.6, and 1.7, R9 is preferably:

[0666] The compounds of formula 1.0 include the R isomer:

[0667] wherein:

[0668] X is N or CH;

[0669] a is N or C(N or CR1 in 1.1A); and

[0670] 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.

[0671] The compounds of formula 1.0 also include the S isomer:

[0672] wherein:

[0673] X is N or CH;

[0674] a is N or C (a is N or CR1 in 1.1B); and

[0675] 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.

[0676] 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.

[0677] 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.

[0678] 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.

[0679] In one embodiment of the invention, R8 in compounds of formula 1.0 is selected from the group consisting of:

[0680] 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.

[0681] 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:

[0682] (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;

[0683] (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

[0684] (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.

[0685] 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:

[0686] (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

[0687] (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.

[0688] 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).

[0689] 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, t-butyl, cyclohexyl or substituted cyclohexyl. In one embodiment of the invention, R11 is selected from the group consisting of: methyl, t-butyl, cyclohexyl and fluorocyclohexyl (preferably p-fluorocyclohexyl). In one embodiment of the invention, R11 is selected from the group consisting of: methyl, 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.

[0690] 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.

[0691] In one embodiment of the invention, for compounds of formula 1.0, R5, R6, R7 and R7a are H.

[0692] In one embodiment of the invention, for compounds of formula 1.0, R9 is selected from the group consisting of:

[0693] (1) unsubstituted heteroaryl;

[0694] (2) substituted heteroaryl;

[0695] (3) arylalkoxy;

[0696] (4) substituted arylalkoxy;

[0697] (5) heterocycloalkyl;

[0698] (6) substituted heterocycloalkyl;

[0699] (7) heterocycloalkylalkyl;

[0700] (8) substituted heterocycloalkylalkyl;

[0701] (9) heteroarylalkyl;

[0702] (10) substituted heteroarylalkyl;

[0703] (11) heteroarylalkenyl and

[0704] (12) substituted heteroarylalkenyl;

[0705] 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:

[0706] (1) —OH;

[0707] (2) —CO2R4, wherein R14 is selected from the group consisting of: H and alkyl (e.g., methyl and ethyl), preferably alkyl, most preferably methyl or ethyl;

[0708] (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;

[0709] (4) halo (e.g., Br, F, I, or Cl);

[0710] (5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl or butyl, preferably isopropyl, or t-butyl);

[0711] (6) amino;

[0712] (7) trityl;

[0713] (8) heterocycloalkyl;

[0714] (9) arylalkyl (e.g. benzyl);

[0715] (10) heteroaryl (e.g. pyridyl) and

[0716] (11) heteroarylalkyl;

[0717] In one embodiment of the invention, for the compounds of formula 1.0, R9 is selected from the group consisting of:

[0718] (1) heterocycloalkyl;

[0719] (2) substituted heterocycloalkyl;

[0720] (3) heterocycloalkylalkyl;

[0721] (4) substituted heterocycloalkylalkyl;

[0722] (5) unsubstituted heteroarylalkyl;

[0723] (6) substituted heteroarylalkyl;

[0724] (7) unsubstituted heteroarylalkenyl and

[0725] (8) substituted heteroarylalkenyl;

[0726] 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:

[0727] (1) —OH;

[0728] (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;

[0729] (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.

[0730] (4) halo (e.g., Br or Cl);

[0731] (5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl);

[0732] (6) amino;

[0733] (7) trityl;

[0734] (8) heterocycloalkyl;

[0735] (9) arylalkyl;

[0736] (10) heteroaryl and

[0737] (11) heteroarylalkyl;

[0738] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[0739] (1) heterocycloalkyl;

[0740] (2) substituted heterocycloalkyl;

[0741] (3) heterocycloalkylalkyl;

[0742] (4) substituted heterocycloalkylalkyl;

[0743] (5) unsubstituted heteroarylalkyl;

[0744] (6) substituted heteroarylalkyl;

[0745] (7) unsubstituted heteroarylalkenyl and

[0746] (8) substituted heteroarylalkenyl;

[0747] 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:

[0748] (1) halo (e.g., Br, or Cl);

[0749] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl);

[0750] (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).

[0751] (4) amino;

[0752] (5) trityl;

[0753] (6) arylalkyl, and

[0754] (7) heteroarylalkyl.

[0755] In one embodiment of the invention, R9 is selected from the group consisting of:

[0756] (1) heterocycloalkylalkyl;

[0757] (2) substituted heterocycloalkylalkyl;

[0758] (3) unsubstituted heteroarylalkyl and

[0759] (4) substituted heteroarylalkyl;

[0760] 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:

[0761] (1) halo (e.g., Br, or Cl);

[0762] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and t-butyl, most preferably t-butyl);

[0763] (3) amino; and

[0764] (4) trityl.

[0765] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[0766] (1) heterocycloalkylalkyl;

[0767] (2) substituted heterocycloalkylalkyl;

[0768] (3) unsubstituted heteroarylalkyl and

[0769] (4) substituted heteroarylalkyl;

[0770] 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:

[0771] (1) halo (e.g., Br, or Cl); and

[0772] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl).

[0773] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[0774] (1) piperidinyl;

[0775] (2) piperizinyl;

[0776] (3) —(CH2)p-piperidinyl;

[0777] (4) —(CH2)p-piperizinyl;

[0778] (5) —(CH2)p-morpholinyl and

[0779] (6) —(CH2)p-imidazolyl;

[0780] wherein p is 0 to 1, and wherein the ring moiety of each R9 group is optionally substituted with one, two or three substituents independently selected from the group consisting of:

[0781] (1) halo (e.g., Br, or Cl); and

[0782] (2) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl).

[0783] In one embodiment of the invention, for formula 1.0, R9 is selected from the group consisting of:

[0784] (1)-piperizinyl;

[0785] (2) —(CH2)p-piperidinyl;

[0786] (3) —(CH2)p-imidazolyl; and

[0787] (4) —(CH2)p-morpholinyl,

[0788] 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.

[0789] 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.

[0790] In one embodiment of the invention, for formula 1.0, R9 is —(CH2)-(2-methyl)-imidazolyl.

[0791] 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.

[0792] 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.

[0793] 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:

[0794] 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:

[0795] and in one embodiment of the invention Ring V is:

[0796] Thus, in one embodiment of the invention, for formula 1.0, R21, R22 and R46 are independently selected from the group consisting of:

[0797] (1) H;

[0798] (2) aryl (most preferably phenyl);

[0799] (3) heteroaryl and

[0800] (4) heterocycloalkyl (i.e., Piperidine Ring V)

[0801] wherein at least one of R21, R22, or R46 is other than H, and in one embodiment of the to 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.

[0802] In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of:

[0803] (1) —H;

[0804] (2) —R9;

[0805] (3) —R9—C(O)—R9;

[0806] (4) —R9—CO2—R9a;

[0807] (5) —C(O)NHR9;

[0808] (6) —C(O)NH—CH2—C(O)—NH2;

[0809] (7) —C(O)NHR26;

[0810] (8) —(CH2)p(R9)2 wherein each R9 is the same or different;

[0811] (9) —(CH2)pC(O)R9;

[0812] (10) —(CH2)pC(O)R27a;

[0813] (11) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[0814] (12) —(CH2)pC(O)NH(R9);

[0815] (13) —(CH2)pNHC(O)R50;

[0816] (14) —(CH2)pNHC(O)2R50;

[0817] (15) —(CH2)pN(C(O)R27a)2 wherein each R27a is the same or different;

[0818] (16) —(CH2)pNR51C(O)R27;

[0819] (17) —(CH2)pNR51C(O)R27 wherein R51 is not H, and R51 and R27, taken together with the atoms to which they are bound, form a 5 or 6 memebered heterocycloalkyl ring;

[0820] (18) —(CH2)pNR51C(O)NR27;

[0821] (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;

[0822] (20) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;

[0823] (21) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;

[0824] (22) —(CH2)pNHCO2R50;

[0825] (23) —(CH2)pCO2R51;

[0826] (24) —NHR9;

[0827] (25)

[0828] wherein R30 and R31 are the same or different and

[0829] (26)

[0830] wherein R30, R31, R32 and R33 are the same or different.

[0831] In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of:

[0832] (1) —H;

[0833] (2) —R9;

[0834] (3) —R9—C(O)—R9;

[0835] (4) —R9—CO2—R9a;

[0836] (5) —C(O)NHR9;

[0837] (6) —(CH2)p(R9)2, wherein each R9 is the same or different;

[0838] (7) —(CH2)pC(O)R9;

[0839] (8) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;

[0840] (9) —(CH2)pC(O)NH(R9);

[0841] (10) —(CH2)pNR51C(O)R27;

[0842] (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;

[0843] (12) —(CH2)pNR51C(O)NR27;

[0844] (13) —(CH2)pNR51C(O)NR27 wherein R51 is not H, and R51 and R27, taken together with the atoms to which they are bound, form a 5 or 6 membered heterocycloalkyl ring;

[0845] (14) —NHR9; and

[0846] (15)

[0847] wherein R30 and R31 are the same or different.

[0848] Examples of A and B include but are not limited to:

[0849] wherein p is 0, 1, 2, 3 or 4.

[0850] 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:

[0851] (1) heteroaryl;

[0852] (2) substituted heteroaryl;

[0853] (3) arylalkyl;

[0854] (4) substituted arylalkyl;

[0855] (5) arylalkoxy;

[0856] (6) substituted arylalkoxy;

[0857] (7) heterocycloalkyl;

[0858] (8) substituted heterocycloalkyl;

[0859] (9) heterocycloalkylalkyl;

[0860] (10) substituted heterocycloalkylalkyl;

[0861] (11) unsubstituted heteroarylalkyl;

[0862] (12) substituted heteroarylalkyl;

[0863] (13) alkenyl;

[0864] (14) substituted alkenyl;

[0865] (15) unsubstituted heteroarylalkenyl; and

[0866] (16) substituted heteroarylalkenyl,

[0867] 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:

[0868] (1) —OH;

[0869] (2) —CO2R14;

[0870] (3) —CH2OR14,

[0871] (4) halo,

[0872] (5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);

[0873] (6) amino;

[0874] (7) trityl;

[0875] (8) heterocycloalkyl;

[0876] (9) arylalkyl;

[0877] (10) heteroaryl and

[0878] (11) heteroarylalkyl,

[0879] wherein R14 is independently selected from the group consisting of: H; and alkyl, preferably methyl and ethyl.

[0880] In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9. In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R9 wherein R9 is selected from the group consisting of:

[0881] (1) arylalkyl;

[0882] (2) substituted arylalkyl;

[0883] (3) arylalkoxy;

[0884] (4) substituted arylalkoxy;

[0885] (5) heterocycloalkyl;

[0886] (6) substituted heterocycloalkyl;

[0887] (7) heterocycloalkylalkyl;

[0888] (8) substituted heterocycloalkylalkyl;

[0889] (9) unsubstituted heteroarylalkyl;

[0890] (10) substituted heteroarylalkyl;

[0891] (11) alkenyl;

[0892] (12) substituted alkenyl;

[0893] (13) unsubstituted heteroarylalkenyl; and

[0894] (14) substituted heteroarylalkenyl,

[0895] 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:

[0896] (1) —OH;

[0897] (2) halo, (preferably Br);

[0898] (3) alkyl (e.g. methyl, ethyl, propyl, butyl, or t-butyl);

[0899] (4) amino; and

[0900] (5) trityl.

[0901] 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:

[0902] (1) heterocycloalkylalkyl;

[0903] (2) substituted heterocycloalkylalkyl;

[0904] (3) unsubstituted heteroarylalkyl; and

[0905] (4) substituted heteroarylalkyl;

[0906] wherein said substituents for said substituted R9 groups are the same or different alkyl groups (e.g., C1-C4 alkyl).

[0907] 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:

[0908] (1) unsubstituted heteroaryl(C1-C3)alkyl; and

[0909] (2) substituted heteroaryl (C1-C3)alkyl;

[0910] wherein the substituents for said substituted R9 group are as defined above.

[0911] 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:

[0912] (1) unsubstituted heteroaryl(C1-C3)alkyl, with unsubstituted heteroaryl-CH2— being preferred; and

[0913] (2) substituted heteroaryl(C1-C3)alkyl, with substituted heteroaryl-CH2— being preferred;

[0914] 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).

[0915] 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:

[0916] (1) —CH2-imidazolyl;

[0917] (2) substituted imidazolyl-CH2—;

[0918] (3) —(CH2)2-imidazolyl;

[0919] (4) substituted imidazolyl-(CH2)2—;

[0920] (5) —(CH2)3-imidazolyl;

[0921] (6) substituted imidazolyl-(CH2)3—;

[0922] (7) —CH2-piperazinyl and

[0923] (8) —CH2-morpholinyl;

[0924] 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:

[0925] with the substituted imidazolyl:

[0926] being most preferred.

[0927] 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

[0928] being preferred.

[0929] 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.

[0930] 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).

[0931] In one embodiment of the invention, for compounds of formula 1.0, there is a double bond between C-5 and C-6.

[0932] Compounds of formula 1.0, having C-11 R- and S-stereochemistry include:

[0933] wherein:

[0934] X is N or C;

[0935] Q is Br or Cl; and

[0936] Y is alkyl, arylalkyl, or heteroarylalkyl.

[0937] Preferred compounds of this invention are selected from the group consisting of:

[0938] More preferred compounds of this invention are selected from the group consisting of:

100

101

102

103

[0939] Even more preferrred compounds of this invention are selected from the group consisting of:

104

105

106

107

108

109

110

111

112

[0940] Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

[0941] 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.

[0942] 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.

[0943] 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.

[0944] 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.

[0945] 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.

[0946] 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.

[0947] 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.

[0948] 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.

[0949] 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.

[0950] 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.

[0951] 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.

[0952] Examples of proliferative diseases (tumors, i.e., cancers) which may be inhibited or treated include, but are not limited to:

[0953] (A) lung cancer (e.g., lung adenocarcinoma and non small cell lung cancer);

[0954] (B) pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma);

[0955] (C) colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma);

[0956] (D) myeloid leukemias (for example, acute myelogenous leukemia (AML), CML, and CMML);

[0957] (E) thyroid follicular cancer;

[0958] (F) myelodysplastic syndrome (MDS);

[0959] (G) bladder carcinoma;

[0960] (H) epidermal carcinoma;

[0961] (I) melanoma;

[0962] (J) breast cancer;

[0963] (K) prostate cancer;

[0964] (L) head and neck cancers (e.g., squamous cell cancer of the head and neck;

[0965] (M) ovarian cancer;

[0966] (N) gliomas;

[0967] (O) cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas);

[0968] (P) sarcomas;

[0969] (O) tetracarcinomas;

[0970] (R) nuroblastomas;

[0971] (S) kidney carcinomas; and

[0972] (T) hepatomas.

[0973] For example, embodiments of this invention are directed to the methods of treating cancers described herein wherein said cancers are selected from the group consisting of: lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer, and myeloid leukemias 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 or small molecules that are inhibitors of αVβ3 integrins.

[0974] 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 of compounds of the invention and antineoplastic agent can also comprise the administration of a therapeutically effect amount of radiation.

[0975] This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

[0976] (a) an FPT inhibitor of formula 1.0;

[0977] (b) at least two different antineoplastic agents selected from:

[0978] (1) taxanes;

[0979] (2) platinum coordinator compounds;

[0980] (3) EGF inhibitors that are antibodies;

[0981] (4) EGF inhibitors that are small molecules;

[0982] (5) VEGF inhibitors that are antibodies;

[0983] (6) VEGF kinase inhibitors that are small molecules;

[0984] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[0985] (8) anti-tumor nucleoside derivatives;

[0986] (9) epothilones;

[0987] (10) topoisomerase inhibitors;

[0988] (11) vinca alkaloids;

[0989] (12) antibodies that are inhibitors of αVβ3 integrins; or

[0990] (13) small molecule inhibitors of αVβ3 integrins.

[0991] 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:

[0992] (a) an FPT inhibitor of formula 1.0;

[0993] (b) at least two different antineoplastic agents selected from:

[0994] (1) taxanes;

[0995] (2) platinum coordinator compounds;

[0996] (3) EGF inhibitors that are antibodies;

[0997] (4) EGF inhibitors that are small molecules;

[0998] (5) VEGF inhibitors that are antibodies;

[0999] (6) VEGF kinase inhibitors that are small molecules;

[1000] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[1001] (8) anti-tumor nucleoside derivatives;

[1002] (9) epothilones;

[1003] (10) topoisomerase inhibitors;

[1004] (11) vinca alkaloids;

[1005] (12) antibodies that are inhibitors of αVβ3 integrins; or

[1006] (13) small molecule inhibitors of αVβ3 integrins.

[1007] 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:

[1008] (a) an FPT inhibitor of formula 1.0;

[1009] (b) at least two different antineoplastic agents selected from:

[1010] (1) taxanes;

[1011] (2) platinum coordinator compounds;

[1012] (3) anti-tumor nucleoside derivatives;

[1013] (4) topoisomerase inhibitors; or

[1014] (5) vinca alkaloids.

[1015] 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:

[1016] (a) an FPT inhibitor of formula 1.0;

[1017] (b) carboplatin; and

[1018] (c) paclitaxel.

[1019] 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:

[1020] (a) an FPT inhibitor of formula 1.0;

[1021] (b) cisplatin; and

[1022] (c) gemcitabine.

[1023] 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:

[1024] (a) an FPT inhibitor of formula 1.0;

[1025] (b) carboplatin; and

[1026] (c) gemcitabine.

[1027] This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of:

[1028] (a) an FPT inhibitor of formula 1.0;

[1029] (b) an antineoplastic agent selected from:

[1030] (1) EGF inhibitors that are antibodies;

[1031] (2) EGF inhibitors that are small molecules;

[1032] (3) VEGF inhibitors that are antibodies; or

[1033] (4) VEGF kinase inhibitors that are small molecules.

[1034] 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:

[1035] (a) an FPT inhibitor of formula 1.0;

[1036] (b) one or more antineoplastic agents selected from:

[1037] (1) taxanes; or

[1038] (2) platinum coordinator compounds.

[1039] 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:

[1040] (a) an FPT inhibitor of formula 1.0;

[1041] (b) at least two different antineoplastic agents selected from:

[1042] (1) taxanes; or

[1043] (2) platinum coordinator compounds.

[1044] 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 during the treatment cycle.

[1045] It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes—i.e., the Ras gene itself is not activated by mutation to an oncogenic form—with said inhibition or treatment being accomplished by the administration of an effective amount (e.g. a therapeutically effective amount) of one or more (e.g., one) compounds of the invention to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

[1046] 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.

[1047] 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.

[1048] 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.

[1049] 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.

[1050] 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, lck, lyn, fyn).

[1051] For radiation therapy, γ-radiation is preferred.

[1052] 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.

[1053] Typical signal transduction inhibitors include but are not limited to:

[1054] (i) Bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec);

[1055] (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

[1056] (iii) HER-2/neu receptor inhibitors such as, for example, Herceptin® (trastuzumab).

[1057] 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.

[1058] 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).

[1059] 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.

[1060] 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.

[1061] The FPT inhibitor and antineoplastic agents are administered in a treatment protocol that usually lasts one to seven weeks. 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., Taxol or Taxotere) can be administered once a week or once every three weeks.

[1062] 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.

[1063] 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.

[1064] 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, usually 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.

[1065] 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).

[1066] The antineoplastic agents used with the FPT inhibitor are administered in their normally prescribed dosages during the treatment cycle. 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 anti-tumor nucleosides; (j) about 1 to about 100 mg/m2 for epothilones; (k) about 1 to about 350 mg/m2 for topoisomerase inhibitors; and (I) about 1 to about 50 mg/m2 for vinca alkaloids.

[1067] For example, 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 Taxol® can be administered once every three weeks in an amount of about 150 to about 225 mg/m2 with about 175 to about 225 mg/m2 being preferred.

[1068] In another example, Taxotere® can be administered once per week in an amount of about 10 to about 45 mg/m2. In another example Taxotere® can be administered once every three weeks in an amount of about 50 to about 100 mg/m2.

[1069] 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.

[1070] 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 c an be administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

[1071] Thus, in one example (e.g., treating non small cell lung cancer):

[1072] (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;

[1073] (2) 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

[1074] (3) carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

[1075] In another example (e.g., treating non small cell lung cancer):

[1076] (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;

[1077] (2) 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

[1078] (3) cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

[1079] In another example (e.g., treating non small cell lung cancer):

[1080] (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;

[1081] (2) Taxotere® is administered once per week in an amount of about 10 to about 45 mg/m2; and

[1082] (3) carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3.

[1083] In another example (e.g., treating non small cell lung cancer):

[1084] (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;

[1085] (2) Taxotere® is administered once per week in an amount of about 10 to about 45 mg/m2; and

[1086] (3) cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2.

[1087] Thus, in one example (e.g., treating non small cell lung cancer):

[1088] (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;

[1089] (2) Taxol® is administered once every three weeks in an amount of about 150 to about 225 mg/m2, with about 175 to about 225 mg/m2 being preferred; and

[1090] (3) carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

[1091] In another example (e.g., treating non small cell lung cancer):

[1092] (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;

[1093] (2) Taxol® is administered once every three weeks in an amount of about 150 to about 225 mg/m2, with about 175 to about 225 mg/m2 being preferred; and

[1094] (3) cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

[1095] In another example (e.g., treating non small cell lung cancer):

[1096] (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;

[1097] (2) Taxotere® is administered once every three weeks in an amount of about 50 to about 100 mg/m2; and

[1098] (3) carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8.

[1099] In another example (e.g., treating non small cell lung cancer):

[1100] (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;

[1101] (2) Taxotere® is administered once every three weeks in an amount of about 50 to about 100 mg/m2; and

[1102] (3) cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2.

[1103] 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.

[1104] Antineoplastic agents that can be used in combination with the FPT inhibitor are:

[1105] (1) taxanes such as paclitaxel (TAXOL®) and/or docetaxel (Taxotere®);

[1106] (2) platinum coordinator compounds, such as, for example, carboplatin, cisplatin and oxaliplatin;

[1107] (3) EGF inhibitors that are antibodies, such as: HER2 antibodies (such as, for example trastuzumab (Herceptin®), Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone Systems), EMD 72000 (Merck KGaA), anti-EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (Center of Molecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibody ICR-62 (ICR, Sutton, England); Herzyme (Elan Pharmaceutical Technologies and Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB 569 (Wyeth-Ayerst), GW 572016 (GlaxoSmithKline), CI 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);

[1108] (4) EGF inhibitors that are small molecules, such as, Tarceva (TM) (OSI-774, OSI Pharmaceuticals, Inc.), and Iressa (ZD 1839, Astra Zeneca);

[1109] (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);

[1110] (6) VEGF kinase inhibitors that are small molecules such as SU 5416 and SU 6688 (both from Sugen, Inc.);

[1111] (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.);

[1112] (8) anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine;

[1113] (9) epothilones such as BMS-247550 (Bristol-Myers Squibb), and EP0906 (Novartis Pharmaceuticals);

[1114] (10) topoisomerase inhibitors such as topotecan (Glaxo SmithKline), and Camptosar (Pharmacia);

[1115] (11) vinca alkaloids, such as, navelbine (Anvar and Fabre, France), vincristine and vinblastine; and

[1116] (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).

[1117] Preferred antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin, gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, navelbine, IMC-1C11, SU5416 or SU6688. Most preferred antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin, navelbine, gemcitabine, or Herceptin.

[1118] 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)).

[1119] 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

[1120] 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.

[1121] 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.

[1122] 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.

[1123] 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.

[1124] 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.

[1125] Preferably, non small cell lung cancer is treated in the methods described in the above embodiments.

[1126] 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.

[1127] Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the FPT inhibitor, administering a therapeutically effective amount of carboplatin once every three weeks per cycle, and administering a therapeutically effective amount of paclitaxel once every three weeks per cycle, wherein the treatment is given for one to three weeks. Preferably said FPT inhibitor is administered twice per day. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

[1128] A preferred 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 110 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.

[1129] In another 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), and administering once every three weeks per cycle about 150 to about 225 mg/m2 (preferably about 175 to about 225 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.

[1130] 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.

[1131] 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.

[1132] 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:

[1133] (1) the FPT inhibitor;

[1134] (2) a taxane; and

[1135] (3) an antineoplastic agent selected from:

[1136] (a) an EGF inhibitor that is a small molecule;

[1137] (b) a VEGF inhibitor that is an antibody; or

[1138] (c) a VEGF kinase inhibitor that is a small molecule.

[1139] 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.

[1140] 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.

[1141] 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.

[1142] 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.

[1143] 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.

[1144] 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.

[1145] 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.

[1146] 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.

[1147] Preferably, non small cell lung cancer is treated in the methods using gemcitabine in the embodiments described above.

[1148] 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.

[1149] Another embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient the FPT inhibitor and an antineoplastic agent selected from: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are antibodies, and (4) VEGF kinase inhibitors that are small molecules all as described above. The treatment is for one to seven weeks per cycle, and generally for one to four weeks per cycle. The FPT inhibitor is administered in the same manner as described above for the other embodiments of this invention. The small molecule antineoplastic agents are usually administered daily, and the antibody antineoplastic agents are usually administered once per week per cycle. The antineoplastic agents are preferably selected from: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416 or SU6688. Preferably non small cell lung cancer is treated.

[1150] 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.

[1151] 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.

[1152] 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).

[1153] 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).

[1154] 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).

[1155] In the method of treating embodiments, and in the pharmaceutical composition embodiments, the FPT inhibitor is preferably a compound of formula 1.4, most preferably a compound of formula 1.5, more preferably a compound of 1.6 or 1.7, still more preferably a compound selected from the group consisting of:

113

114

115

116

117

118

119

120

121

122

123

[1156] even more preferably a compound of the formula:

124

[1157] yet even more preferably a compound selected from the group consisting of:

125

[1158] 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.

[1159] 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.

[1160] 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.

[1161] 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.

[1162] 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.

[1163] 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.

[1164] 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.

[1165] 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.

[1166] 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

[1167] 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.

[1168] 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.

[1169] 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.

[1170] 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.

[1171] 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.

[1172] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

[1173] Other chemotherapeutics include Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabinbe, Reloxafine, and Droloxafine.

[1174] 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.

[1175] 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

[1176] 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.

[1177] 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.

[1178] Particularly preferred agents are compounds with paclitaxel-like activity. These include, but are not limited to paclitaxei 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).

[1179] 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, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247-1259).

[1180] Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41 :37-47).

[1181] 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.).

[1182] 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.

[1183] 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.

[1184] 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).

[1185] General Preparative Schemes

[1186] The following processes may be employed to produce compounds of the invention.

Pyridyl Tricyclic Compounds

[1187] 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:

126

[1188] 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, 1f and 1e respectively.

127

[1189] (wherein Rx represents R9)

[1190] 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.

128

[1191] (wherein R″ represents H or alkyl (e.g., methly and ethyl).

[1192] Synthesis of 3-carbon spaced analogs can be prepared as outlined in Scheme 3. Thus, subjecting tricyclic vinyl bromide 1 b to a Heck type reaction using ethyl acrylate and catalyzed by 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.

[1193] 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.

129

[1194] (wherein R″ represents H or alkyl (e.g., methly and ethyl).

[1195] Preparation of 6-substituted 3-carbon spaced imidazole compounds was carried out as outlined in scheme 4. A mixture of ketones 1f and 1 i were treated with N-phenytrifluoromethane sulfonimide to give a seperable mixture of 5 and 6-tricyclic triflate compounds. The 6-trilate adduct was converted to the desired 3-carbon spaced analogs using similar protocol as described for the 5-bromo tricyclic compounds outlined in scheme 3.

130

[1196] (wherein R′ represents H or alkyl (e.g., methly and ethyl).

[1197] 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 funtionalization was carried out as previously described. Suberane compounds were prepared in a similar way.

131

[1198] 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.

132

[1199] Lactams 7a can be prepared from amine 6b by reacting with bromo butanonyl acid chloride as outlined in scheme 7.

133

[1200] 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.

134

[1201] 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.

135

[1202] 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.

[1203] 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.

136

137

138

[1204] 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 12 g.

[1205] Alternatively the ester 12a can be saponified with an appropriate base such as lithium hydroxide to obtain the acid 12 h. Converting the acid 12 h 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).

139

140

[1206] 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.

141

[1207] 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.

142

[1208] 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.

143

[1209] 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.

144

[1210] 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.

145

[1211] 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.

146

[1212] 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 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.

147

[1213] 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.

148

[1214] The vinylhalide or vinyltriflate intermediates A1 and B1 (Scheme 10) are carbonylated with CO gas under a pressure of about 100 psi and a temperature of 80° C. to 100° C. using a palladium catalyst such as 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.

149

[1215] 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. Lett., (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.

150

[1216] Those skilled in the art will appreciate that Schemes 11, 12, 12a, 13, 14, 15 and 15a using reactants having the moieties

151

[1217] (related to formula 1.0), for example, are also representative of reactants having the moieties:

152

[1218] (related to compounds of formula 1.1).

153

[1219] (wherein R represents R8, and R″ represents R10)

[1220] 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.

154

[1221] (wherein R represents R8)

[1222] In Scheme 17, the synthesis of the C-linked imidazoles 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

[1223] 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:

155

156

[1224] 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.

157

158

159

160

161

[1225] 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

[1226]

162

[1227] 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

163

[1228] 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% CH30H—CH2Cl2 (saturated with ammonia) and then with 10% CH30H—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+).

164

[1229] To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1 L of CH2Cl2 at OC 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+).

165

[1230] 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 −1° 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+).

166

[1231] 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+).

167

[1232] 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 poured into ice and basified 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

[1233]

168

[1234] 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.

169

[1235] 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+).

170

[1236] 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+).

171

[1237] 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

[1238]

172

[1239] 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).

[1240] Compound 17: mp=118-119; [α]D22=+136.9° (9.00 mg/2 mL, MeOH); MS (FAB) m/z 469 (MH+).

[1241] Compound 18: mp=119-120; [α]D22=−178.2° (9.90 mg/2 mL, MeOH); MS (FAB) m/z 469 (MH+).

173

[1242] 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

[1243]

174

[1244] 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+).

175

[1245] 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.

176

[1246] 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

[1247]

177

[1248] 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+).

178

[1249] Following a similar procedure as in Preparative Example 3, Step A, the title compound (24) was prepared. MS 509 (MH+).

179

[1250] 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+).

180

[1251] 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+).

181

[1252] Following a similar procedure described in Preparative Example 3, Step C, the title compound (27) was prepared. MS 549 (MH+).

182

[1253] 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+).

183

[1254] 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

[1255]

184

[1256] Compound (20) from Preparative Example 3, Step B (0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre 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

[1257]

185

[1258] 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).

[1259] Compound 31: mp=174-175; [α]D22=+96.0° (3.6 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

[1260] Compound 32: mp=173-174; [α]D22=+21.7° (8.4 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

EXAMPLE 2

[1261]

186

[1262] 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).

[1263] Compound 33: mp=178-179; [α]D22=−30.5° (9.5 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

[1264] Compound 34: mp=172-173; [α]D22=−84° (3.5 mg/2 mL, CH2Cl2); MS (FAB) m/z 473 (MH+).

EXAMPLE 3

[1265]

187

[1266] 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% CH30H: saturated with NH3/CH2Cl2 as eluent to give 0.13 g of target compound (35) and 0.17 g of target compound (36).

[1267] Compound (35): mp=116-117; MS (FAB) m/z 487 (MH+).

[1268] Compound (36): mp=111-112; MS (FAB) m/z 487 (MH+).

EXAMPLE 4

[1269]

188

[1270] 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% CH30H (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.

[1271] Compound (37): mp=124-125; MS (FAB) m/z 498 (MH+).

[1272] Compound (38): mp=119-120; MS (FAB) m/z 498 (MH+).

EXAMPLES (5) AND (6)

[1273] By using the same procedure as above and substituting the appropriate amines, compounds of the formula:

189

[1274] 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

190

(39) AND (40).6

191

(41) AND (42).

EXAMPLE 7

[1275]

192

[1276] 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

[1277]

193

[1278] 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.

194

[1279] 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

[1280]

195

[1281] 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

[1282]

196

[1283] To SEM protected methylimidazole (30 g, 0.141 mole) prepared according to literature procedure, Whitten, 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 ½ 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).

197

[1284] 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

[1285]

198

[1286] 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).

199

[1287] 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

[1288]

200

[1289] 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

[1290]

201

[1291] 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

[1292] By substituting the appropriate isocyanates, and following the procedure described in EXAMPLE 13 above, compounds of the formula:

202

[1293] were prepared wherein R is defined in Table 2.

2TABLE 2ExR =Compound #:14

203

(58). MS 518 (MH+).15

204

(59). MS 544 (MH+).

EXAMPLE 16

[1294]

205

[1295] 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

[1296]

206

[1297] 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

[1298]

207

[1299] 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

[1300]

208

[1301] 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

[1302]

209

[1303] 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).

210

[1304] 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.

211

[1305] 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+).

212

[1306] 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, filtrated 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 white solid. MP range 120-130° C.; MS 455 (MH+).

213

[1307] 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.

214

[1308] 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

[1309]

215

[1310] 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

[1311]

216

[1312] 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

[1313]

217

[1314] 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

[1315]

218

[1316] 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

[1317]

219

[1318] 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

[1319]

220

[1320] 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

[1321] Reacting compound (75) from Example 25, in the same manner as described in Example 13, and substituting the appropriate isocyanate, compounds of the formula:

221

[1322] were prepared wherein R is defined in Table 3.

3TABLE 3ExR =Compound #:26

222

(76). mp 133-144° C.27

223

(77). mp 131-140° C.28

224

(78). mp 125-132° C.29

225

(79). mp 160-172° C.

EXAMPLE 30

[1323]

226

[1324] 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.

[1325] Step B

227

[1326] 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

[1327]

228

[1328] 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

[1329]

229

[1330] 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

[1331]

230

[1332] 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

[1333]

231

[1334] 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

[1335]

232

[1336] 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

[1337]

233

[1338] 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

[1339]

234

[1340] 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

[1341]

235

[1342] 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

[1343]

236

[1344] 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).

237

[1345] 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).

238

[1346] 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).

239

[1347] 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).

240

[1348] 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).

241

[1349] To a solution of sodium imidazole (Aldrich) in DMF was added, NaH (2 eq.). 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).

242

243

[1350] 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

[1351]

244

[1352] 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

[1353]

245

[1354] 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).

246

[1355] 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).

247

[1356] 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).

248

[1357] 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).

249

[1358] 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).

250

[1359] Compound (108A) was reacted with ethyl acrylate in a similar manner as described in Preparative Example 7, Step B affording the title compound (109).

251

[1360] 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).

252

[1361] 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).

253

[1362] 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).

254

[1363] 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).

255

[1364] 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

[1365]

256

[1366] 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

[1367] 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:

257

[1368] 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

258

(121) AND (122)40

259

(123) and (124)41

260

(125) AND (126).42

261

(127) AND (128).43

262

(129) AND (130).44

263

(131) AND (132).45

264

(133) AND (134).

EXAMPLE 46-51

[1369] 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:

265

[1370] 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

266

(135) AND (136).47

267

(137) AND (138).48

268

(139) AND (140).49

269

(141) AND (142)50

270

(143) AND (144).51

271

(145) AND (146).

EXAMPLE 52-59

[1371] 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:

272

[1372] 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

273

(147) AND (148)53

274

(149) and (150)54

275

(151) AND (152).55

276

(153) AND (154).56

277

(155) AND (156)57

278

(157) AND (158).58

279

(159) AND (160).59

280

(161) AND (162).

EXAMPLE 60-69

[1373] 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:

281

[1374] 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

282

(163) AND (164)61

283

(165) and (166)62

284

(167) AND (168)63

285

(169) AND (170)64

286

(171) (−)-isomer65

287

(172) AND (173)66

288

(174) AND (175)67

289

(176) AND (177)68

290

(178) AND (179)69

291

(180) AND (181)

[1375] PREPARATIVE EXAMPLE 11

292

[1376] Ethyl 2,2-dimethyl acrylate (50.0 g, 2.0 eq.) was stirred with imidazole (13.28 g, 200 mmol) at 900 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.

293

[1377] 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.

294

[1378] 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). CIMS: MH+=137.

295

[1379] 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 (1 N), 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

[1380]

296

[1381] 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

[1382]

297

[1383] 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

[1384]

298

[1385] 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).

299

[1386] 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.

300

[1387] 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

[1388]

301

[1389] 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

[1390]

302

[1391] 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.

[1392] Compound (192): FABMS: MH+=481; mp=109-112° C.; [α]20D=+398° (2.0 mg in 2.0 mL MeOH).

[1393] Compound (193): FABMS: MH+=481; mp=126-129° C.; [α]20D=−367° (2.0 mg in 2.0 mL MeOH).

EXAMPLE 74

[1394]

303

[1395] 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

[1396]

304

[1397] In a similar manner as described in Example 73 above, the following enantiomers were separated:

[1398] Compound (195): LCMS: MH+=483; mp=129-131° C.; [α]20D=+134° (2.0 mg in 2.0 mL MeOH).

[1399] Compound (196): LCMS: MH+=483; mp=125-126° C.; [α]20D=−105° (2.0 mg in 2.0 mL MeOH).

PREPARATIVE EXAMPLE 13

[1400]

305

[1401] 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

[1402]

306

[1403] 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

[1404]

307

[1405] 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+).

308

[1406] 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

[1407]

309

[1408] 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

[1409]

310

[1410] 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+).

311

[1411] Compound (202) was detritylated in the same manner as EXAMPLE 77 affording the title compound (203). FABMS: 495 (MH+).

EXAMPLE 78

[1412]

312

[1413] 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

[1414]

313

[1415] 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

[1416]

314

[1417] Compound (207) was detritylated in the same manner as Example 77 affording the title compound (208). FABMS: 511 (MH+).

PREPARATIVE EXAMPLE 17

[1418]

315

[1419] 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

[1420]

316

[1421] Compound (209) was detritylated in the same manner as Example 77 affording the title compound (210). FABMS: 541 (MH+).

PREPARATIVE EXAMPLE 18

[1422]

317

[1423] 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.

318

[1424] 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

[1425]

319

[1426] 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 1 N 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 Technologieso AD HPLC column obtaining the pure isomers. (214) and (215). FABMS M+1=535

EXAMPLE 82

[1427]

320

[1428] 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 3-4 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

[1429]

321

[1430] 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

[1431]

322

[1432] 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).

323

[1433] 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%).

324

[1434] 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)

325

[1435] 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

[1436]

326

[1437] To a solution of compound (221) from Preparative Example 20, Step D (51 mg; 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

[1438]

327

[1439] 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.

328

[1440] 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.

329

[1441] 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

[1442]

330

[1443] 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; 2/17/98). 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

[1444]

331

[1445] 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

[1446]

332

[1447] 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

[1448]

333

[1449] 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

[1450] 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):

334

[1451] wherein R is as defined in Table 8.

8TABLE 8Ex.RCompound #87

335

(229)(+)(148-156° C. dec.) MH+ 556.88

336

(230)(+)(155-166° C. dec.) MH+ 563.89

337

(231)(−)(145-153° C. dec.) MH+ 556.90

338

(232)(−)(159-168° C. dec.) MH+ 563.

[1452] PREPARATIVE EXAMPLE 23

339

[1453] 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.

340

[1454] 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.

341

[1455] 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.

342

[1456] 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 to 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.

343

[1457] 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.

344

[1458] 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.

345

[1459] 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.

346

[1460] 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.

[1461] Alternatively, compound (237) was converted to compound (240) by first preparing the acylimidazole followed by NaBH4 reduction using the following procedure:

[1462] 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.

347

[1463] 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

[1464]

348

[1465] 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, 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

[1466]

349

[1467] 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.

350

[1468] 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

[1469]

351

[1470] 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

[1471]

352

[1472] 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

[1473]

353

[1474] 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

[1475] 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:

354

[1476] wherein R is defined in Table 9. In Table 9, “Cmp.#” represents “Compound #”.

9TABLE 9Ex.R =Cmp. #Phys. Data94

355

249mp 133.2-144.3° C. dec. MH(+) 577.1495

356

250mp 132.1-143.8° C. dec. MH(+) 591.1696

357

251mp 134.1-144.9° C. dec. MH(+) 563.10

EXAMPLES 97-101

[1477] In essentially the same manner as in Preparative Example (20) and Example (29), compounds of the formula:

358

[1478] were prepared wherein R is as defined in Table 10. In Table 10, “Cmp.#” represents “Compound #”.

10TABLE 10EX.R =Cmp #PHYS. DATA97

359

252mp 148-159° C. dec. MH(+) 577.98

360

253mp 134-142° C. dec. MH(+) 563.99

361

254mp 90-102° C. dec. MH(+) 625.100

362

255mp 126-139° C. dec. MH(+) 577.101

363

256mp 151-164° C. dec. MH(+) 535.

EXAMPLE 102

[1479]

364

[1480] 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

[1481]

365

[1482] 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 and the isomers separated (258A) and (258B).

EXAMPLE 103

[1483]

366

[1484] 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

[1485]

367

[1486] Step A

[1487] 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.

[1488] Step B

[1489] 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.

[1490] Step C

[1491] 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

[1492]

368

[1493] Ref: Gazz. Chim. Ital. (1972) 102, 189-195; J. Org. Chem. (1991) 56, 1166-1170.

[1494] 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.

369

[1495] 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).

370

[1496] 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).

371

[1497] 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 pyridine (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.

372

[1498] 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).

373

[1499] 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

[1500]

374

[1501] 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).

[1502]

375

[1503] 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. 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)

[1504] 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%).

376

[1505] 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.

[1506] In a similar manner the (S) isomer was prepared to give compound (264) as the HCl salt.

PREPARATIVE EXAMPLE 31

[1507]

377

[1508] 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).

[1509] In a similar way the (S) isomer was prepared from 1 N-Benzyl-3(S)-hydroxy-pyrrolidines (5 g, 28.21 mmoles) to give the (S) title compound (7.15 g, 98%).

378

[1510] 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.

[1511] In a similar fashion the other isomer was prepared.

379

[1512] 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%).

[1513] 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

[1514]

380

[1515] 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.

381

[1516] 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 the 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

[1517] 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:

382

[1518] were prepared wherein R is defined in Table 11

11TABLE 11EX.R =Compound #PHYS. DATA106

383

270MH+ = 603107

384

271MH+ = 589108

385

272MH+ = 589109

386

273MH+ = 589110

387

274MH+ = 603111

388

275MH+ = 603

EXAMPLE 112

[1519]

389

[1520] 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

[1521]

390

[1522] 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

[1523]

391

[1524] 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).

392

[1525] 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)

393

[1526] 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).

394

[1527] 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).

395

[1528] 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).

396

[1529] 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 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% 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).

397

[1530] 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).

398

[1531] 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).

399

[1532] A solution of the product (285) from step H (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 hydrochloride salt of the title product (286) (0.42 g, 100% yield, MH+=371).

EXAMPLES 114 AND 115

[1533] 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

[1534] 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:

400

[1535] were prepared wherein R is defined in Table 13.

13TABLE 13EX. #PROCEDURER =CMPD #PHYS. DATA116Example 13

401

289 isomer 1MS M+ = 515117Example 13

402

290 isomer 2MS M+ = 515118Example 24

403

291a isomer 1MS M+ = 449119Example 24

404

291b isomer 2MS M+ = 449

[1536] PREPARATIVE EXAMPLE 34

405

[1537] 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).

406

[1538] 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).

[1539] 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).

407

[1540] To a stirred solution of Compound (293) from Step B above (42.9 g, 116.5 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).

408

[1541] 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)

[1542] 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).

409

[1543] 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).

410

[1544] 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).

411

[1545] 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).

412

[1546] 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).

413

[1547] 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

[1548] 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:

414

[1549] were prepared wherein R is defined in Table 14.

14TABLE 14PRO-CMPDPHYS.EX. #CEDURER =#DATA120Example 13

415

301 isomer 1MS MH+ =514121Example 13

416

302 isomer 2MS MH+ =514

[1550] PREPARATIVE EXAMPLE 35

417

[1551] 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).

418

[1552] 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).

419

[1553] 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).

[1554] 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

[1555] 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:

420

[1556] were prepared wherein R is defined in Table 15.

15TABLE 15EX. #PROCEDURER =CMPD #PHYS. DATA122Example 13

421

306 isomer 1MS MH+ = 537.1 m.p. = 118.1-119.0° C.123Example 13

422

307 isomer 2MS MH+ = 537.1 m.p. = 107.8-108.4° C.124Example 13

423

308 isomer 1MS MH+ = 528.2 m.p. = 119.6-120.2° C.125Example 13

424

309 isomer 2MS MH+ = 528.2 m.p. = 120.5-121.3° C.

[1557] PREPARATIVE EXAMPLE 36

425

[1558] 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)

426

[1559] 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).

427

[1560] 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

[1561] 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:

428

[1562] were prepared wherein R is defined in Table 16.

16TABLE 16PHYS.DATAPRO-CMPDMassEX. #CEDURER =#spec126Example 13

429

313 isomer 1M+ =577127Example 13

430

314 isomer 2M+ =577128Example 13

431

315 isomer 1M+ =558129Example 13

432

316 isomer 2M+ =558130Example 13

433

317 isomer 1M+ =570131Example 13

434

318 isomer 2M+ =570132Example 13

435

319 isomer 1M+ =511133Example 13

436

320 isomer 2M+ =511

[1563] PREPARATIVE EXAMPLE 37

437

[1564] 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).

438

[1565] 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 mg, MH+=419.1).

439

[1566] To a solution of Compound (322) from Step B above (0.566 g, 1.35 mmol) in 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%1PA/85%hexane/0.2%DEA (wave length=254 nm, Attn=64, ABS=1) to give isomer 1 (323a) (0.28 g, MH+=519.2) and isomer 2 (323b) (0.28 g, MH+=519.2)

440

[1567] 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).

[1568] 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

[1569] 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:

441

[1570] were prepared wherein R is defined in Table 17.

17TABLE 17PRO-CED-CMPDPHYS.EX. #URER =#DATA134Ex- ample 13

442

324 Isomer 1MS M+ =545.2135Ex- ample 13

443

325 Isomer 2MS M+ =545.2136Ex- ample 13

444

326 Isomer 1MS M+ =563.2137Ex- ample 13

445

327 Isomer 2MS M+ =563.2138Ex- ample 13

446

328 Isomer 1MS M+ =606.1 m.p. =62.7-63.0° C.139Ex- ample 13

447

329 Isomer 2MS M+ =606.1 m.p. =70.1-71.0° C.140Ex- ample 13

448

330 Isomer 1MS M+ =572.1 m.p. =120.1-121.4° C.141Ex- ample 13

449

331 Isomer 2MS M+ =572.1 m.p. =128.0-129.0°142Ex- ample 13

450

332 Isomer 1MS M+ =544.2143Ex- ample 13

451

333 Isomer 2MS M+ =544.2144Ex- ample 13

452

334 Isomer 1MS M+ =554.1 m.p. =111.9-112.0° C.145Ex- ample 13

453

335 Isomer 2MS M+ =554.1 m.p. =114.3-115°146Ex- ample 13

454

336 Isomer 1MS M+ =497.1 m.p. =52.4-53.3° C.147Ex- ample 13

455

337 Isomer 2MS M+ =497.1 m.p. =47.1-48.0°

PREPARATIVE EXAMPLE 38

[1571]

456

[1572] 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).

[1573] Step B

[1574] 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=72.1-73.0C) and (338b) (MS M+=491; mp=68.9-69.0° C.) and the 5-substituted compound (339a) and (339b).

457

[1575] 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.).

[1576] In a similar manner as above, starting with Compound (338b) (isomer 2), Compound (340b) (MH+=419.1) was prepared.

EXAMPLES 148-156

[1577] 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:

458

[1578] 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

459

342 isomer 1MS MH+ = 545 m.p. = 58.8-59.6° C.150Example 13

460

343 isomer 2MS MH+ = 545 m.p. = 60.8-61.2° C.151Example 13

461

344 isomer 1MS MH+ = 545 m.p. = 98.7-99.5° C.152Example 13

462

345 isomer 2MS MH+ = 545 m.p. = 111.3-112.0° C.153Example 13

463

346 isomer 1MS MH+ = 544 m.p. = 77.1-77.8° C.154Example 13

464

347 isomer 2MS MH+ = 544 m.p. = 78.9-79.0° C.155Example 13

465

348 isomer 1MS MH+ = 497 m.p. = 87.4-88.0° C.156Example 13

466

349 isomer 2MS MH+ = 497 m.p. = 88.0-89.0° C.

[1579] PREPARATIVE EXAMPLE 39

467

[1580] 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).

[1581] Compound (350b) was prepared in the same manner as above.

EXAMPLES 157-160

[1582] 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:

468

[1583] were prepared wherein R is defined in Table 19.

19TABLE 19EX. #PROCEDURER =CMPD #PHYS. DATA157PreparativeBOC351MS MH+ = 519Ex.4; Step Aisomer 1m.p. = 87.8-88.2° C.158PreparativeBOC352MS MH+ = 519Ex.4; Step Aisomer 2m.p. = 87.8-88.2 ° C.159Example 13

469

353 isomer 1MS MH+ = 563160Example 13

470

354 isomer 2MS MH+ = 563 m.p. = 130.1-131.0° C.

[1584] PREPARATIVE EXAMPLE 40

471

[1585] 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).

472

[1586] 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 1 N 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).

473

[1587] 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 1 N 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).

[1588] 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).

474

[1589] 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.

[1590] 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.

475

[1591] 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).

476

[1592] 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%1PA/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.

477

[1593] 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 (361 a) (0.292 g, 100% yield).

[1594] Compound (361 b) (isomer 2) was prepared in a similar manner as above beginning with Compound (360b) from Preparative Example 40, Step F.

EXAMPLES 161-166

[1595] Starting with the appropriate (+) or (−) isomer of Compound (361) (i.e., 361 a or 361b) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate shown in Table 20, compounds of the formula:

478

[1596] were prepared wherein R is defined in Table 20.

20TABLE 20PRO-CED-CMPDPHYS.EX. #URER =#DATA161Ex- ample 13

479

362a isomer 1MS MH+ =548162Ex- ample 13

480

362b isomer 2MS MH+ =548163Ex- ample 13

481

363a isomer 1MS MH+ =541164Ex- ample 13

482

363b isomer 2MS MH+ =541165Ex- ample 13

483

364a isomer 1MS MH+ =558166Ex- ample 13

484

364b isomer 2MS MH+ =558166.1Ex- ample 13

485

364.1Mp 201.5-208.3° C.

[1597] PREPARATIVE EXAMPLE 41

486

[1598] 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

[1599]

487

[1600] 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).

488

[1601] 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)

489

[1602] 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).

[1603] Step C.1 Alternate Preparation of Compound (368)

[1604] 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 1 N 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 h at −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.

490

[1605] 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).

491

[1606] To a solution of 2-methylimidazole (2.43 g, 29.68 mmol) in DMF (30 mL) under N2 was 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)

492

[1607] A solution of Compound (370a) (isomer 1) from Step E above (0.105 g, 0.21 mmol) in 4M HCl/Dioxane (10 mL) was stirred at room temperature for 3 hours and concentrated to dryness to afford Compound (371 a) (0.147 g, 100% yield)

[1608] 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

[1609] To a solution of compound 371 a (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

[1610] Compound 371 b (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

[1611] Compound 371 a (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

[1612] Compound 371 b (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

[1613]

493

[1614] (R is defined in Table 21).

21TABLE 21PRO-CMPDPHYS.EX. #CEDURER =#DATA167Example 13

494

372 isomer 1 S- isomerMS MH+ =550168Example 13

495

373 isomer 2 R- isomerMS MH+ =550169Example 13

496

374 isomer 1 S- isomerMS MH+ =559170Example 13

497

375 isomer 2 R- isomerMS MH+ =559170.1Example 13

498

375.1 isomer 1MS MH+ =525

[1615] PREPARATIVE EXAMPLE 43

499

[1616] 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).

500

[1617] 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).

[1618] Compound (376b) was reacted in a similiar manner as above to afford Compound (377b) (isomer 2) (MH+=420.1).

EXAMPLES 171-174

[1619] 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:

501

[1620] were made wherein R is defined in Table 22.

22TABLE 22PRO-CMPDPHYS.EX. #CEDURER =#DATA171Example 13

502

378 isomer 1MS MH+ =504172Example 13

503

379 isomer 2MS MH+ =504173Example 13

504

380 isomer 1MS MH+ =573174Example 13

505

381 isomer 2MS MH+ =573

[1621] PREPARATIVE EXAMPLE 44

506

[1622] 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

[1623]

507

[1624] 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).

508

[1625] 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).

[1626] Compound (384b) was prepared in a similar manner as above starting with Compound (383b) from Step A.

EXAMPLE 175

[1627]

509

[1628] 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).

[1629] 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

[1630]

510

[1631] 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)

511

[1632] 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).

512

[1633] 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

[1634] 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:

513

[1635] were prepard wherein R is defined in Table 23.

23TABLE 23PRO-CED-CMPDPHYS.EX. #URER =#DATA176Ex- ample 175

514

389 isomer 1MS MH+ =688177Ex- ample 175

515

390 isomer 2MS MH+ =688

EXAMPLE 178

[1636]

516

[1637] 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 (391 a) (isomer 1) (0.02 g, 42.5% yield, MH+=554.1).

[1638] Starting with Compound (388b) from Preparative Example 46, Step C, and reacting in the same manner as above, Compound (391 b) (isomer 2) was prepared (MH+=554.1).

PREPARATIVE EXAMPLE 47

[1639]

517

[1640] 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)

518

[1641] 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).

519

[1642] 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)

520

[1643] 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).

521

[1644] 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).

522

[1645] 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).

523

[1646] 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%1PA/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)

524

[1647] 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)

525

[1648] 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)

526

[1649] 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

[1650]

527

[1651] Compound (371 a) (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

[1652]

528

[1653] 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

[1654]

529

[1655] 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 24CMPDEX. #R =#PHYS. DATA180

530

407FABMS MH+ =601.1181

531

408FABMS MH+ =531.1

[1656] PREPARATIVE EXAMPLE 49

532

[1657] Compounds (51) and (52) from Example 11, Step A, were reacted with TFA in CH2Cl2 to afford compounds (51 a) and (52a).

[1658] Library Preparation

533

[1659] 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.

[1660] 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.

534

EXAMPLES 182-283

[1661]

535

[1662] (R2A is defined in Table 2)

[1663] 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

536

409Mass spec. MH+ = 552183

537

410Mass spec. MH+ = 556184

538

411Mass spec. MH+ = 571185

539

412Mass spec. MH+ = 538186

540

413Mass spec. MH+ = 568187

541

414Mass spec. MH+ = 557188

542

415Mass spec. MH+ = 544189

543

416Mass spec. MH+ = 572190

544

417Mass spec. MH+ = 606191

545

418Mass spec. MH+ = 574192

546

419Mass spec. MH+ = 574193

547

420Mass spec. MH+ = 573194

548

421Mass spec. MH+ = 519195

549

422Mass spec. MH+ = 563196

550

423Mass spec. MH+ = 539197

551

424Mass spec. MH+ = 566198

552

425Mass spec. MH+ = 505199

553

426Mass spec. MH+ = 539200

554

427Mass spec. MH+ = 544201

555

428Mass spec. MH+ = 580202

556

429Mass spec. MH+ = 556203

557

430Mass spec. MH+ = 606204

558

431Mass spec. MH+ = 518205

559

432Mass spec. MH+ = 568206

560

433Mass spec. MH+ = 574207

561

434Mass spec. MH+ = 538208

562

435Mass spec. MH+ = 580209

563

436Mass spec. MH+ = 572210

564

437Mass spec. MH+ = 553211

565

438Mass spec. MH+ = 581212

566

439Mass spec. MH+ = 538213

567

440Mass spec. MH+ = 553214

568

441Mass spec. MH+ = 497215

569

442Mass spec. MH+ = 555216

570

443Mass spec. MH+ = 538217

571

444Mass spec. MH+ = 606218

572

445Mass spec. MH+ = 556219

573

446Mass spec. MH+ = 606220

574

447Mass spec. MH+ = 519221

575

448Mass spec. MH+ = 640222

576

449Mass spec. MH+ = 630223

577

450Mass spec. MH+ = 604224

578

451Mass spec. MH+ = 610225

579

452Mass spec. MH+ = 553226

580

453Mass spec. MH+ = 568227

581

454Mass spec. M+ = 572228

582

455Mass spec. MH+ = 624229

583

456Mass spec. MH+ = 572230

584

457Mass spec. MH+ = 554231

585

458Mass spec. MH+ = 552232

586

459Mass spec. MH+ = 552233

587

460Mass spec. MH+ = 598234

588

461Mass spec. MH+ = 570235

589

462Mass spec. MH+ = 610236

590

463Mass spec. MH+ = 563237

591

464Mass spec. MH+ = 504238

592

465Mass spec. MH+ = 566239

593

466Mass spec. MH+ = 574240

594

467Mass spec. MH+ = 543241

595

468Mass spec. MH+ = 518242

596

469Mass spec. MH+ = 582243

597

470Mass spec. MH+ = 519244

598

471Mass spec. MH+ = 543245

599

472Mass spec. MH+ = 610246

600

473Mass spec. MH+ = 518247

601

474Mass spec. MH+ = 529248

602

475Mass spec. MH+ = 513249

603

476Mass spec. MH+ = 606250

604

477Mass spec. MH+ = 491251

605

478Mass spec. MH+ = 606252

606

479Mass spec. MH+ = 548253

607

480Mass spec. MH+ = 487254

608

481Mass spec. MH+ = 539255

609

482Mass spec. MH+ = 562256

610

483Mass spec. MH+ = 565257

611

484Mass spec. MH+ = 526258

612

485Mass spec. MH+ = 598259

613

486Mass spec. MH+ = 548260

614

487Mass spec. MH+ = 580261

615

488Mass spec. MH+ = 598262

616

489Mass spec. MH+ = 529263

617

490Mass spec. MH+ = 475264

618

491Mass spec. MH+ = 573265

619

492Mass spec. MH+ = 525266

620

493Mass spec. MH+ = 518267

621

494Mass spec. MH+ = 577268

622

495Mass spec. MH+ = 532269

623

496Mass spec. MH+ = 516270

624

497Mass spec. MH+ = 524271

625

498Mass spec. MH+ = 557272

626

499Mass spec. MH+ = 524273

627

500Mass spec. MH+ = 584274

628

501Mass spec. MH+ = 584275

629

502Mass spec. MH+ = 573276

630

503Mass spec. MH+ = 491277

631

504Mass spec. MH+ = 603278

632

505Mass spec. MH+ = 589279

633

506Mass spec. MH+ = 616280

634

507Mass spec. MH+ = 584281

635

508Mass spec. MH+ = 603282

636

509Mass spec. MH+ = 490283

637

510Mass spec. MH+ = 593

EXAMPLES 284-377

[1664]

638

[1665] (R2A is defined in Table 26).

26TABLE 26EX-AM-COM-PLE #R2APOUND #MH+284

639

511571285

640

512552286

641

513587287

642

514558288

643

515577289

644

516570290

645

517588291

646

518558292

647

519586293

648

520588294

649

521594295

650

522570296

651

523588297

652

524559298

653

525620299

654

526569300

655

527582301

656

528585302

657

529570303

658

530552304

659

531588305

660

532562306

661

533594307

662

534620308

663

535587309

664

536586310

665

537595311

666

538620312

667

539532313

668

540586314

669

541547315

670

542638316

671

543533317

672

544586318

673

545577319

674

546532320

675

547582321

676

548553322

677

549566323

678

550567324

679

551519325

680

552543326

681

553557327

682

554584328

683

555620329

684

556624330

685

557612331

686

558624332

687

559505333

688

560540334

689

561644335

690

562539336

691

563624337

692

564579338

693

565517339

694

566582340

695

567620341

696

568501342

697

569598343

698

570543344

699

571518345

700

572580346

701

573546347

702

574596348

703

575565349

704

576575350

705

577555351

706

578598352

707

579532353

708

580504354

709

581527355

710

582489356

711

583531357

712

584562358

713

585562359

714

586630360

715

587538361

716

588530362

717

589591363

718

590612364

719

591603365

720

592620366

721

593598367

722

594587368

723

595539369

724

596607370

725

597538371

726

598571372

727

599612373

728

600533374

729

601505375

730

602617376

731

603617377

732

604605

PREPARATIVE EXAMPLE 50

[1666]

733

[1667] 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 ⅘)CH3.

734

[1668] 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.

[1669] 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)

[1670]

735

[1671] (R2A is defined in Table 27).

27TABLE 27EX-COM-PHYSICALAM-POUNDDATAPLE #R2A#(MH+)378

736

607564379

737

608 1st Enantiomer564380

738

609 2nd Enantiomer564381

739

610575382

740

611553383

741

612564384

742

613564385

743

614520386

744

615 1st Isomer520387

745

616 2ndIsomer520388

746

617558389

747

618557390

748

619545391

749

620 1st Isomer545392

750

621 2nd Isomer545393

751

622573394

752

623555395

753

624567396H 4 TFA625420

EXAMPLES 397-401

[1672]

754

[1673] (R2A is defined in Table 28)

28TABLE 28COMPOUNDEXAMPLE #R2#PHYSICAL DATA397

755

626 2 IsomersMass spec. MH+ = 578398

756

627 2nd EnantiomerMass spec. MH+ = 578399

757

628 2nd EnantiomerMass spec. MH+ = 578400

758

629 1st EnantiomerMass spec. MH+ = 578401

759

630 2 IsomersMass spec. MH+ = 534

EXAMPLES 402-406

[1674]

760

[1675] (R2A is defined in Table 29).

29TABLE 29EXAMPLE #R2ACOMPOUND #PHYSICAL DATA402

761

631 Mixture of 4-Me and 5-MeMass spec. MH+ = 578403

762

632 2nd enantiomer of 4-MeMass spec. MH+ = 578404

763

633 2nd enantiomer of 5-Me 1st enantiomer of 4-MeMass spec. MH+ = 578405

764

634 1st enantiomer of 5-MeMass spec. MH+ = 578406

765

635 Mixture of 4-Me and 5-MeMass spec. MH+ = 534

[1676] PREPARATIVE EXAMPLE 51

766

[1677] 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:

767

[1678] (R2A is defined in Table 30).

30TABLE 30EX-AMPLECOMPOUNDPHYSICAL#R2#DATA407

768

637Mass spec. MH+ = 550408

769

638 2nd EnantiomerMass spec. MH+ = 550409

770

639 1ST EnantiomerMass spec. MH+ = 550410

771

640Mass spec. MH+ = 506

[1679] PREPARATIVE EXAMPLE 52

772

[1680] 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.

773

[1681] (R2A is defined in Table 31).

31TABLE 31EX-COM-AMPLEPOUNDPHYSICAL#R2A#DATA411

774

642Mass spec. MH+ = 520412

775

643Mass spec. MH+ = 564413

776

644 1st EnantiomerMass spec. MH+ = 564414

777

645 2nd EnantiomerMass spec. MH+ = 564

EXAMPLE 415

[1682]

778

[1683] 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

[1684]

779

[1685] 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).

[1686] Compound (242a), [α]D25=+144.8° (3.16 mg/2 mL MeOH)

[1687] Compound (242b), [α]D25=−144.8° (2.93 mg/2 mL MeOH)

PREPARATIVE EXAMPLE 54

[1688]

780

[1689] 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).

[1690] (648) (+ enantiomer, isomer A), MH+=406.1793

[1691] (649) (− enantiomer, isomer B), MH+=406.1789

PREPARATIVE EXAMPLE 55

[1692]

781

[1693] 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).

[1694] Compound (650), BOC derivative, [α]D25=+69.6° (2.5 mg/2 mL MeOH)

[1695] Compound (651), BOC derivative, [α]D25=−90.0° (3.3 mg/2 mL MeOH)

[1696] Compound (652) (+ enantiomer, isomer A), MH+=485

[1697] Compound (653) (− enantiomer, isomer B), MH+=485

PREPARATIVE EXAMPLE 56

[1698]

782

[1699] 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 (1 L). 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).

783

[1700] 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.

784

[1701] 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).

785

[1702] 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).

[1703] Compound (657), BOC derivative, [α]D25=+59.9° (3.3 mg/2 mL MeOH)

[1704] Compound (658), BOC derivative, [α]D25=−57.1° (3.3 mg/2 mL MeOH)

[1705] Compound (659), (+ enantiomer, isomer A), MH+=406

[1706] Compound (660), (− enantiomer, isomer B), MH+=406

[1707] Compound (659.1), (+ enantiomer, isomer A), MH+=406

[1708] Compound (660.1), (− enantiomer, isomer B), MH+=406

PREPARATIVE EXAMPLE 57

[1709]

786

[1710] 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.

[1711] Compound (662), BOC derivative

[1712] Compound (663), BOC derivative

[1713] Compound (664), BOC derivative

[1714] Compound (665), BOC derivative

[1715] Compound (666) (+ enantiomer, isomer A), MH+=372

[1716] Compound (667) (+ enantiomer, isomer A), MH+=372

[1717] Compound (668) (− enantiomer, isomer B), MH+=372

[1718] Compound (669) (− enantiomer, isomer B), MH+=372

PREPARATIVE EXAMPLE 58

[1719]

787

[1720] 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.

[1721] Compound (670), BOC derivative, (+ enantiomer, A)

[1722] Compound (671), BOC derivative, (+ enantiomer, A)

[1723] Compound (672), BOC derivative, (− enantiomer, B)

[1724] Compound (673), BOC derivative, (− enantiomer, B)

[1725] Compound (674), (+ enantiomer, isomer A), MH+=386

[1726] Compound (675), (+ enantiomer, isomer A), MH+=386

[1727] Compound (676), (− enantiomer, isomer B), MH+=386

[1728] Compound (677), (− enantiomer, isomer B), MH+=386

EXAMPLES 416-419

[1729]

788

[1730] (R is defined in Table 32).

[1731] 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.

32TABLE 32Example #REnantiomerComp #Phys. Data.416

789

+678Mp = 162.2-165.6° C. [α]D25 = +98.2° (3 mg/ 2 mL MeOH)417

790

−679Mp = 158.1-164.5° C. [α]D25 = −81.2° (2.6 mg/ 2 mL MeOH)418

791

+680Mp = 161.5-164.8° C. MH+ = 559.1787419

792

+681Mp = 157.7-161.7° C. MH+ = 543.2069

EXAMPLES 420 AND 421

[1732]

793

[1733] (R is defined in Table 33).

[1734] 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.

33TABLE 33Example #REnantiomerComp #Phys. Data.420

794

+682Mp = 168.8-172.3° C.421

795

−683Mp = 172.5-177.7° C.421.1

796

+683.1Mp = 157.1-160.5° C. (dec)421.2

797

+683.2Mp = 223.6-229.1° C. (dec.)

EXAMPLES 422 AND 423

[1735]

798

[1736] (R is defined in Table 34).

[1737] 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.

34TABLE 34Example #REnantiomerComp #Phys. Data.422

799

+684Mp = 155.9-165.1° C.423

800

−685Mp = 154.2-164.8° C.492

801

+806Mp = 157.1-160.5° C. MH+ = 689

EXAMPLES 424 AND 425

[1738]

802

[1739] (R is defined in Table 35).

[1740] 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.

35TABLE 35Ex-Enan-am-tio-ple #RmerComp #Phys. Data.424

803

+686Mp =166-170° C. [α]D25 =+106.8°(1.45 mg/ 2 mL MeOH)425

804

−687Mp =170-176° C. [α]D25 =−91° (2.78 mg/ 2 mL MeOH)

EXAMPLES 426 AND 427

[1741]

805

[1742] (R is defined in Table 36).

[1743] 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.

36TABLE 36Ex-am-Enan-ple #RtiomerComp #Phys. Data.426

806

+688Mp =150-153° C.427

807

−689Mp =154-158° C.

EXAMPLES 428 AND 429

[1744]

808

[1745] defined in Table 37).

[1746] 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.

37TABLE 37Ex-Enan-Phys.ample #RtiomerComp #Data.428

809

Isomer 1690MH+ =516429

810

Isomer 2691MH+ =516

EXAMPLES 430 AND 431

[1747]

811

[1748] defined in Table 38).

[1749] 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.

38TABLE 38Ex-Enan-Phys.ample #RtiomerComp #Data.430

812

Isomer 1692MH+ =530431

813

Isomer 2693MH+ =530

[1750] PREPARATIVE EXAMPLE 59

814

815

816

[1751] 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%CH2Cl2 to yield: Pure Compound (694) (0.450 g) (MH+=533) and a mixture of (694) and Compound (695) (2.55 g)(MH+=535).

[1752] Compounds (694) and (695) were further purified by chiral prep HPLC, eluting with 15%1PA/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).

817

[1753] 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%IPA/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).

818

[1754] 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

[1755] Reacting Compound (696a) (isomer 1) in essentially the same manner as in Example 13 with the appropriate chloroformate or isocyanate, the following compounds listed in Table 39 below, were prepared.

819

[1756] (R is defined in Table 39).

39TABLE 39EX-COM-AMPLEPOUNDPHYSICAL#R#DATA432

820

698MH += 519.1433

821

699MH += 577.1434

822

700MH += 570.1435

823

701MH += 585.1436

824

702—437

825

703MH += 558.1

EXAMPLES 438-442

[1757] Reacting Compound (697a) (isomer 1) in essentially the same manner as in Example 13 with the appropriate chloroformate or isocyanate, the following compounds listed in Table 40 below were prepared.

826

[1758] (R is defined in Table 40).

40TABLE 40EX-COM-AMPLEPOUNDPHYSICAL#R#DATA438

827

704MH += 521.1439

828

705MH += 579.1440

829

706MH += 572.1441

830

707MH += 587.1442

831

708MH += 560.1

[1759] PREPARATIVE EXAMPLE 60

832

[1760] 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%IPA/85%hexane/0.2%DEA to give 4 seperate compounds:

[1761] Compound (709a) isomer 1, (0.291 g, MH+=547.3), Compound (710a) isomer 1, (0.305 g, MH+=549.3) and

[1762] Compound (709b) isomer 2, (0.280 g, MH+=547.3), Compound (710b) isomer 2, (0.2 g, MH+=549.3)

833

[1763] 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).

[1764] Compounds (711b), (isomer 2); (712a) (isomer 1) and (712b) (isomer 2) were all prepared in a similar fashion to that of Compound (711 a) isomer 1 in Step B above.

[1765] (711 b) (0.085 g, 75% yield).

[1766] (712a) (0.141 g, 75% yield).

[1767] (712b) (0.106 g, 59% yield).

EXAMPLES 443-447

[1768] Reacting Compounds (71 la) and (71 lb) seperately following the procedure described in Example 13 with the appropriate chloroformates or isocyanates, the following compounds listed in Table 41 below were prepared.

834

[1769] (R is defined in Table 41).

41TABLE 41EX-COM-AMPLEPOUNDPHYSICAL#R#DATA443

835

713MH += 575.1444

836

714MH += 575.1445

837

715MH += 593.2446

838

716MH += 593.2447

839

717MH += 586.1

EXAMPLES 448-454

[1770] 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.

840

[1771] (R is defined in Table 42).

42TABLE 42EX-COM-AMPLEPOUNDPHYSICAL#R#DATA448

841

718MH += 573.1449

842

719MH += 573.1450

843

720MH += 591.1451

844

721MH += 591.1452

845

722MH += 584.1453

846

723MH += 525.1454

847

724MH += 525.1

[1772] PREPARATIVE EXAMPLE 61

848

[1773] 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).

[1774] Compound (725a) isomer 1, (0.69 g, MH+=533.1).

[1775] Compound (725b) isomer 2, (0.10 g, MH+=533.1).

[1776] Compound (726a) isomer 1, (0.35 g, MH+=535.1).

[1777] Compound (726b) isomer 2, (0.22 g, MH+=535.1).

849

[1778] In essentially the same manner as described in Preparative Example 60, Step B, the —NH derivatives were prepared:

[1779] Compounds:

[1780] (727a) isomer 1 (0.3 g, 100% yield, MH+=435.1);

[1781] (727b) isomer 2;

[1782] (728a) isomer 1; and

[1783] (728b) isomer 2.

EXAMPLES 455-459

[1784] 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.

850

[1785] (R is defined in Table 43).

43TABLE 43EX-COM-AMPLEPOUNDPHYSICAL#R#DATA455

851

729MH += 561.1456

852

730MH += 581.1457

853

731MH += 572.1458

854

732MH += 560.1459

855

733MH += 513.1

EXAMPLES 460-469

[1786] 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.

856

[1787] (R is defined in Table 44).

44TABLE 44EX-COM-AMPLEPOUNDPHYSICAL#R#DATA460

857

734MH += 559.1461

858

735MH += 559.1462

859

736MH += 579.1463

860

737MH += 579.1464

861

738MH += 570.1465

862

739MH += 570.1466

863

740MH += 558.1467

864

741MH += 558.1468

865

742MH += 511.1469

866

743MH += 511.1

EXAMPLE 470

[1788]

867

[1789] 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).

[1790] Step B

868

[1791] 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)

869

[1792] 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).

870

[1793] 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)

871

[1794] 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

[1795]

872

[1796] 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

[1797]

873

[1798] 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).

874

[1799] 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

[1800]

875

[1801] 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 and 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)

876

[1802] 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

[1803]

877

[1804] 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

[1805]

878

[1806] 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).

879

[1807] 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).

880

[1808] 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)

881

[1809] 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).

882

[1810] 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).

[1811] 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).

883

[1812] Reacting Compound (760) in essentially the same manner as Step C above, Compound (761) was prepared.

884

[1813] 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).

885

[1814] In essentially the same manner as Example 475, Step E, Compound (763) was prepared.

886

[1815] 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)

887

[1816] 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)

888

[1817] 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.

[1818] 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)

889

[1819] 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

[1820]

890

[1821] 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)

[1822] 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%).

891

[1823] 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.

[1824] In a similar manner (S) isomer was prepared.

EXAMPLE 477

[1825]

892

[1826] 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)

893

[1827] 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 (dimethyl-amino)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

[1828]

894

[1829] 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.

895

[1830] 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+)

896

[1831] 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).

897

[1832] 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

[1833]

898

[1834] 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

[1835]

899

[1836] 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

[1837] In essentially the same manner as in Examples (420) and (421), Compounds (778) and (779) were prepared.

900

[1838] (R is defined in Table 45).

45TABLE 45Compound #R =EnantiomerFABMS(M + 1)778

901

1628779

902

2628

[1839] Phys. Data

[1840] (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, brddd, 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

[1841] In essentially the same manner as in Example 70, Compounds (780) and (781) were prepared.

903

[1842] (R is defined in Table 46).

46TABLE 46Compound #R =EnantiomerFABMS(M + 1)780

904

1562781

905

2562

PREPARATIVE EXAMPLE 64

[1843]

906

[1844] 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+1504.

907

[1845] 5-Iodo-1 N-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

[1846]

908

[1847] 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+1550.

EXAMPLE (483)

[1848]

909

[1849] Compound (785) was prepared following essentially the same procedure as in Preparative Example 64 and Example 482, substituting 4-Iodo-1-trityl imidazole for 5-Iodo-1 N-methylimidazole.

EXAMPLE 484

[1850]

910

[1851] 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).

[1852] Compound (786) MH+=497; [α]D20=+15.3.

[1853] Compound (787) MH+=497; [α]D20=−13.4.

EXAMPLE 485

[1854]

911

[1855] 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.

[1856] (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

[1857]

912

[1858] 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).

913

[1859] To a solution of imidazole Grignard prepared from 5-iodo-1 N-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.

914

[1860] 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

[1861]

915

[1862] 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

[1863]

916

[1864] 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

[1865]

917

[1866] 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

[1867]

918

[1868] 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).

919

[1869] To a solution of imidazole Grignard prepared from 5-iodo-1 N-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).

920

[1870] 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.

921

[1871] 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.

[1872] Alternatively, (795.3) can be synthesized by treating (795.1) with NaN3, TFA followed by (Boc)2O, and triethyl amine.

922

[1873] Compound (795.4) can be prepared by reacting (795.3) with P(CH3)3/H2O.

PREPARATIVE EXAMPLE 66

[1874]

923

[1875] 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

[1876] 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:

924

[1877] (wherein R is defined in Table 47).

47TABLE 47Ex-ampleEnanti-CompPhys.#Romer#Data.490

925

+(804)Mp =160-165° C. [α] D25 =+84° (0.84 mg/1 mL MeOH) MH += 546491

926

—(805)Mp =158-163° C. [α] D25 =−91.6° (0.84 mg/1 mL MeOH) MH += 546

[1878] PREPARATIVE EXAMPLE 67

927

[1879] 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).

928

[1880] 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

[1881] 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:

929

[1882] (wherein R is defined in Table 48).

48TABLE 48StartingEnanti-CompPhys.Cmp. #Romer#Data.(812)

930

+816Mp =175-181° C. [α] D25 =+94.2°(1 mg/1 mL MeOH)(814)

931

−(817)Mp =182-186° C. [α] D25 =−120.3°(1 mg/1 mL MeOH)

EXAMPLE 494

[1883] 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:

932

[1884] (wherein R is defined in Table 49).

49TABLE 49StartingEnanti-CmpPhys.Cmp #Romer#Data.(813)

933

+(818)Mp =176-181° C. [α] D25 =+46.3°(0.79 mg/1 mL MeOH) MH += 584(815)

934

−(819)Mp =174-180° C. [α] D25 =−43.3°(0.94 mg/1 mL MeOH) MH += 584

[1885] PREPARATIVE EXAMPLE 68

935

[1886] 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

[1887] 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:

936

[1888] (wherein R is defined in Table 50

50TABLE 50StartingEnanti-CompPhys.Cmp #Romer#Data.(824)

937

+(828)Mp =176-182° C. [α] D25 =+84.5° (1.3 mg/1 mL MeOH) MH += 598(826)

938

−(829)Mp =175-182° C. [α] D25 =−88.8° (1.14 mg/1 mL MeOH) MH += 598

EXAMPLE 496

[1889] 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:

939

[1890] (wherein R is defined in Table 51).

51TABLE 51Starting Cmp #REnantiomerComp #Phys. Data.(825)

940

+(830)Mp = 170-174° C. [α]D25 = +39.1° (0.81 mg/1 mL MeOH) MH+ = 598(827)

941

−(831)Mp = 170-175° C. [α]D25 = −36.4° (0.96 mg/1 mL MeOH) MH+ = 598

[1891] PREPARATIVE EXAMPLE 69

942

[1892] 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

[1893] 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:

943

[1894] (wherein R is defined in Table 52).

52TABLE 52Starting Cmp #REnantiomerComp #Phys. Data.(834)

944

A(836)Mp = 172-179° C. (d) MH+ = 643(835)

945

B(837)Mp = 171.9-178.3° C. MH+ = 643

[1895] PREPARATIVE EXAMPLE 70

946

[1896] 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

[1897] 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:

947

[1898] (wherein R is defined in Table 53).

53TABLE 53Starting Cmp #REnantiomerComp #Phys. Data.(840)

948

A(842)Mp = 168-170° C. (d) [α]D25 = +64.1° (0.66 mg/1 mL MeOH)(841)

949

B(843)Mp = 166-171° C. [α]D25 = −80.9° (0.85 mg/1 mL MeOH)

[1899] PREPARATIVE EXAMPLE 71

950

[1900] 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

[1901] 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:

951

[1902] (wherein R is defined in Table 54).

54TABLE 54Starting Cmp #REnantiomerComp #Phys. Data.(846)

952

A(848)Mp = 174.2-189.3° C. (d) MH+ = 580(847)

953

B(849)Mp = 174.4-189.8° C. MH+ = 580

EXAMPLE 500

[1903]

954

[1904] Compound (850) can be prepared by following essentially the same procedure as described in Example 482.

EXAMPLE 501

[1905]

955

[1906] 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

[1907]

956

[1908] 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

[1909]

957

[1910] 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)

958

[1911] 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 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).

959

[1912] Reacting compound (854) in essentially the same manner as described in Step B above, gave the title compound (856). δH (CDCl3) 8.85 (dd, 1H), 7.85-8.0 (m, 2H), 7.8 (s, 1H), 7.25-7.31 (m, 4H)

960

[1913] 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 concentrated 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).

[1914] Step E

961

[1915] Reacting compound (856) in essentially the same manner as described in Step D above, gave the title compound (858). MH+=311

962

[1916] 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

963

[1917] Reacting compound (858) in essentially the same manner as described in Step F above, gave the title compound (860) MH+=281.

964

[1918] 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.

965

[1919] Reacting compound (861) in essentially the same manner as described in Step H above, gave the title compound (862) MH+=345.

966

[1920] 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.

967

[1921] Reacting compound (862) in essentially the same manner as described in Step J above, gave the title compound (864). MH+=347

968

[1922] 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.

969

[1923] Reacting compound (864) in essentially the same manner as described in Step L above, gave the title compound (866) MH+=515.

970

[1924] 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

971

[1925] Reacting compound (866) in essentially the same manner as described in Step N above, gave the title compound (868). MH+=501

972

[1926] 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.

973

[1927] Reacting compound (868) in essentially the same manner as described in Step P above, gave the title compound (870). MH+=487

974

[1928] Compound (869) (0.0.38 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

975

[1929] Reacting compound (870) in essentially the same manner as described in Step R above, gave the title compound (872). MH+=565

976

[1930] 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.

977

[1931] 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

[1932]

978

[1933] 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

[1934]

979

[1935] Reacting compound (874) in essentially the same manner as described in Example 503 above, gave the title compound. (878) 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

[1936]

980

[1937] 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

[1938] Diasteromeric separation of product (795.1):

981

[1939] 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).

[1940] 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.

[1941] 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

[1942]

982

[1943] Compound 795.1 b (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.

[1944] The same procedure was used to prepare 795.2a (isomer 1) from 795.1 a.

EXAMPLE 508

[1945]

983

[1946] 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.

[1947] Isomer 365a: retention time=7.65 min; MH+=492.

[1948] Isomer 365b: retention time=12.16 min; MH+=492, m.p. 95-100° C.

PREPARATIVE EXAMPLE 73

[1949]

984

[1950] Dissolve (880) (2 eq. 14.2 mmol) in THF (20 ml), add 1M 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.

985

[1951] 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).

986

[1952] 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%).

987

[1953] 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

[1954]

988

[1955] 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

[1956]

989

[1957] 365a [0.9 g, 1.83 mmol] was dissolved in dry THF (15 ml) and cooled to −75° C. (dry ice/acetone bath). (2)(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. (1) 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.

990

[1958] 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.

[1959] Step C

991

[1960] 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 1:15 ml) was added and stirred at 0° C. for 6 hours and then stored in the refrigerator for 18 hours. TLC EtoAc-H2O. Extracted with Ethyl Acetate and washed with brine, dried over MgSO4, filtered and evaporated to give 0.310 g of product, 886.

992

[1961] 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.

993

[1962] 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

[1963] 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:

994

[1964] wherein R is defined in Table 55 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

55TABLE 55Isomer 1Isomer 2ExampleRDataData511

995

m.p. 200-202° C.m.p. 197-200° C.512

996

m.p. 185-190° C.m.p. 200-205° C.513

997

m.p. 210-214° C.m.p. 185-190° C.

EXAMPLES 514-535

[1965] If one were to follow procedures similar to those of Examples 511-513 then one would obtain compounds of the formulas:

998

[1966] wherein R is defined in Table 56 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

56TABLE 56RExampleIsomer 1 and Isomer 2514

999

515

1000

516

1001

517

1002

518

1003

519

1004

520

1005

521

1006

522

1007

523

1008

524

1009

525

1010

526

1011

527

1012

528

1013

529

1014

530

1015

531

1016

532

1017

533

1018

534

1019

535

1020

EXAMPLE 536

[1967] 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:

1021

[1968] wherein R is defined in Table 57 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

57TABLE 57DataDataExampleRIsomer 1Isomer 2536

1022

m.p. 175-180° C.—

EXAMPLES 537-565

[1969] If one were to follow procedures similar to that of Example 536 then one would obtain compounds of the formulas:

1023

[1970] wherein R is defined in Table 58 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

58TABLE 58RExampleIsomer 1 and Isomer 2537

1024

538

1025

539

1026

540

1027

541

1028

542

1029

543

1030

544

1031

546

1032

547

1033

548

1034

549

1035

550

1036

551

1037

552

1038

553

1039

554

1040

555

1041

556

1042

557

1043

558

1044

559

1045

560

1046

561

1047

562

1048

563

1049

564

1050

565

1051

EXAMPLES 566-567

[1971] 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:

1052

[1972] wherein R is defined in Table 59 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

59TABLE 59DataDataExampleRIsomer 1Isomer 2566

1053

mp =215.4-217.5° C.m.p. 185-188° C.567

1054

*mp =182-186° C.*Isomer 1 for Example 567 would be obtained if one were to follow the described procedure.

EXAMPLES 568-589

[1973] If one were to follow procedured similar to those in Examples 566-567 thenone would obtain compounds of the formulas:

1055

[1974] wherein R is defined in Table 60 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

60TABLE 60RExampleIsomer 1 and Isomer 2568

1056

569

1057

570

1058

571

1059

572

1060

573

1061

574

1062

575

1063

576

1064

577

1065

578

1066

579

1067

580

1068

581

1069

582

1070

583

1071

584

1072

585

1073

586

1074

587

1075

588

1076

589

1077

EXAMPLES 590-603

[1975] 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:

1078

[1976] wherein R is defined in Table 61 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

61TABLE 61Exam-DataDatapleRIsomer 1Isomer 2590

1079

——591

1080

*179.8-182.4° C.592

1081

193.5-197.5° C.593

1082

*165.9-167.9° C.594

1083

163.8-186.6° C.mp =173-175° C.595

1084

*173.9-176.2° C.596

1085

*172-174° C.597

1086

165-170° C.185-188.5° C.598

1087

184.3-186.6° C.191.2-192.9° C.599

1088

*179.8-182.5° C.600

1089

*175-178° C.601

1090

—173-176° C.602

1091

*175-177° C.603

1092

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.

[1977] PMR data for Example 592, isomer 1, (CD3Cl) 8.44 (d, 1H), 8.23 (d, 1H), 7.54 (s, 1H), 7348 (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

[1978] If one were to follow procedured similar to those in Examples 590-603 then one would obtain compounds of the formulas:

1093

[1979] wherein R is defined in Table 62 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

62TABLE 62RExampleIsomer 1 and Isomer 2604

1094

605

1095

606

1096

607

1097

608

1098

609

1099

610

1100

611

1101

612

1102

613

1103

614

1104

[1980] PREPARATIVE EXAMPLE 74

1105

[1981] (wherein R is alkyl (e.g., ethyl) or cycloalkyl (e.g., cyclohexyl))

[1982] 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

[1983]

1106

[1984] 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.

1107

[1985] 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.

1108

[1986] 891 was separated into the respective enantiomers 891 a and 891 b, using a Chiral AD Prep HPLC Column as described in Example 507

1109

[1987] 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

[1988]

1110

[1989] Reacted 891 a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

1111

[1990] 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

[1991]

1112

[1992] Reacted 891 b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.

1113

[1993] 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

[1994]

1114

[1995] Reacted 892a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 895.

1115

[1996] 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

[1997]

1116

[1998] Reacted 892b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 896.

1117

[1999] 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

[2000]

1118

1119

[2001] 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

[2002]

1120

1121

[2003] 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

[2004]

1122

[2005] 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

[2006]

1123

[2007] 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

[2008] 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:

1124

[2009] 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.

63TABLE 63RExampleIsomer 1 and Isomer 2615

1125

616

1126

617

1127

618

1128

619

1129

620

1130

621

1131

622

1132

623

1133

624

1134

625

1135

626

1136

627

1137

628

1138

629

1139

630

1140

631

1141

632

1142

633

1143

634

1144

635

1145

636

1146

637

1147

638

1148

639

1149

EXAMPLES 640-664

[2010] If one were to disssolve 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 then one would obtain compounds of the formula:

1150

[2011] wherein R is defined in Table 64 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

64TABLE 64RExampleIsomer 1 and Isomer 2640

1151

641

1152

642

1153

643

1154

644

1155

645

1156

646

1157

647

1158

648

1159

649

1160

650

1161

651

1162

652

1163

653

1164

654

1165

655

1166

656

1167

657

1168

658

1169

659

1170

660

1171

661

1172

662

1173

663

1174

664

1175

EXAMPLES 665-689

[2012] 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:

1176

[2013] wherein R is defined in Table 65 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

65TABLE 65ExampleR665

1177

666

1178

667

1179

668

1180

669

1181

670

1182

671

1183

672

1184

673

1185

674

1186

675

1187

676

1188

677

1189

678

1190

679

1191

680

1192

681

1193

682

1194

683

1195

684

1196

685

1197

686

1198

687

1199

688

1200

689

1201

EXAMPLES 690-714

[2014] 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:

1202

[2015] wherein R is defined in Table 66 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

66TABLE 66RExampleIsomer 1 and isomer 2690

1203

691

1204

692

1205

693

1206

694

1207

695

1208

696

1209

697

1210

698

1211

699

1212

700

1213

701

1214

702

1215

703

1216

704

1217

705

1218

706

1219

707

1220

708

1221

709

1222

710

1223

711

1224

712

1225

713

1226

714

1227

EXAMPLES 715-732

[2016] 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:

1228

[2017] wherein R is defined in Table 67 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

67TABLE 67RExamplesIsomer 1 and Isomer 2715

1229

716

1230

717

1231

718

1232

719

1233

720

1234

721

1235

722

1236

723

1237

724

1238

725

1239

726

1240

727

1241

728

1242

729

1243

730

1244

731

1245

732

1246

EXAMPLES 733-750

[2018] 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:

1247

[2019] and the numbers 1 and 2 in the formulas represent

68TABLE 68RExampleIsomer 1 and Isomer 2733

1248

734

1249

735

1250

736

1251

737

1252

738

1253

739

1254

740

1255

741

1256

742

1257

743

1258

744

1259

745

1260

746

1261

747

1262

748

1263

749

1264

750

1265

EXAMPLES 751-768

[2020] 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:

1266

[2021] wherein R is defined in Table 69 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

69TABLE 69RExampleIsomer 1 and Isomer 2751

1267

752

1268

753

1269

754

1270

755

1271

756

1272

757

1273

758

1274

759

1275

760

1276

761

1277

762

1278

763

1279

764

1280

765

1281

766

1282

767

1283

768

1284

EXAMPLES 769-786

[2022] 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:

1285

[2023] where R is defined in Table 70 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

70TABLE 70RExampleIsomer 1 and Isomer 2769

1286

770

1287

771

1288

772

1289

773

1290

774

1291

775

1292

776

1293

777

1294

778

1295

779

1296

780

1297

781

1298

782

1299

783

1300

784

1301

785

1302

786

1303

EXAMPLES 787-814

[2024] 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:

1304

[2025] where R is defined in Table 71 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

71TABLE 71RExampleIsomer 1 and Isomer 2787

1305

788

1306

789

1307

790

1308

791

1309

792

1310

793

1311

794

1312

795

1313

796

1314

797

1315

798

1316

799

1317

800

1318

801

1319

802

1320

803

1321

804

1322

805

1323

806

1324

807

1325

808

1326

809

1327

810

1328

811

1329

812

1330

813

1331

814

1332

EXAMPLES 815-842

[2026] 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:

1333

[2027] wherein R is defined in Table 72 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

72TABLE 72RExampleIsomer 1 and Isomer 2815

1334

816

1335

817

1336

818

1337

819

1338

820

1339

821

1340

822

1341

823

1342

824

1343

825

1344

826

1345

827

1346

828

1347

829

1348

830

1349

831

1350

832

1351

833

1352

834

1353

835

1354

836

1355

837

1356

838

1357

839

1358

840

1359

841

1360

842

1361

EXAMPLES 843-870

[2028] 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:

1362

[2029] wherein R is defined in Table 73 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

73TABLE 73RExampleIsomer 1 and Isomer 2843

1363

844

1364

845

1365

846

1366

847

1367

848

1368

849

1369

850

1370

851

1371

852

1372

853

1373

854

1374

855

1375

856

1376

857

1377

858

1378

859

1379

860

1380

861

1381

862

1382

863

1383

864

1384

865

1385

866

1386

867

1387

868

1388

869

1389

870

1390

EXAMPLES 871-898

[2030] 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:

1391

[2031] wherein R is defined in Table 74 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

74TABLE 74RExampleIsomer 1 and Isomer 2871

1392

872

1393

873

1394

874

1395

875

1396

876

1397

877

1398

878

1399

879

1400

880

1401

881

1402

882

1403

883

1404

884

1405

885

1406

886

1407

887

1408

888

1409

889

1410

890

1411

891

1412

892

1413

893

1414

894

1415

895

1416

896

1417

897

1418

898

1419

EXAMPLE 899-922

[2032] 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:

1420

[2033] wherein R is defined in Table 75 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

75TABLE 75RExamplesIsomer 1 and Isomer 2899

1421

900

1422

901

1423

902

1424

903

1425

904

1426

905

1427

906

1428

907

1429

908

1430

909

1431

910

1432

911

1433

912

1434

913

1435

914

1436

915

1437

916

1438

917

1439

918

1440

919

1441

920

1442

921

1443

922

1444

EXAMPLES 923-946

[2034] 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:

1445

[2035] wherein R is defined in Table 76 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

76TABLE 76RExampleIsomer 1 and Isomer 2923

1446

924

1447

925

1448

926

1449

927

1450

928

1451

929

1452

930

1453

931

1454

932

1455

933

1456

934

1457

935

1458

936

1459

937

1460

938

1461

939

1462

940

1463

941

1464

942

1465

943

1466

944

1467

945

1468

946

1469

EXAMPLES 947-970

[2036] 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:

1470

[2037] wherein R is defined in Table 77 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

77TABLE 77RExampleIsomer 1 and Isomer 2947

1471

948

1472

949

1473

950

1474

951

1475

952

1476

953

1477

954

1478

955

1479

956

1480

957

1481

958

1482

959

1483

960

1484

961

1485

962

1486

963

1487

964

1488

965

1489

966

1490

967

1491

968

1492

969

1493

970

1494

EXAMPLES 971-995

[2038] 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:

1495

[2039] wherein R is defined in Table 78 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

78TABLE 78RExampleIsomer 1 and Isomer 2971

1496

972

1497

973

1498

974

1499

975

1500

976

1501

977

1502

978

1503

979

1504

980

1505

981

1506

982

1507

983

1508

984

1509

985

1510

986

1511

987

1512

989

1513

990

1514

991

1515

992

1516

993

1517

994

1518

995

1519

PREPARATIVE EXAMPLE 84

[2040]

1520

[2041] 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

[2042]

1521

[2043] 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). 30-40% yield of product 903 (7.89 g).

PREPARATIVE EXAMPLE 86

[2044]

1522

[2045] 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

[2046]

1523

[2047] 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

[2048]

1524

[2049] 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

[2050]

1525

[2051] 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

[2052]

1526

[2053] 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

[2054]

1527

[2055] 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

[2056]

1528

[2057] 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

[2058]

1529

[2059] 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

[2060]

1530

[2061] 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

[2062]

1531

[2063] 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

[2064]

1532

[2065] 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

[2066]

1533

[2067] Starting material 9121 b (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

[2068]

1534

[2069] 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 gof a brown solid, compound 916.

1535

[2070] 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

[2071]

1536

[2072] 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.

1537

[2073] 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

[2074]

1538

[2075] 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.

1539

[2076] 918 was separated by HPLC using a Chiral OD Column and eluting with 20%IPA/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

[2077]

1540

[2078] 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

[2079]

1541

[2080] 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

[2081]

1542

[2082] 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

[2083]

1543

[2084] 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

[2085] 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:

1544

[2086] wherein R is defined in Table 79 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

79TABLE 79RExampleIsomer 1 and Isomer 2996

1545

997

1546

998

1547

999

1548

1000

1549

1001

1550

1002

1551

1003

1552

1004

1553

1005

1554

1006

1555

1007

1556

1008

1557

1009

1558

1010

1559

1011

1560

1012

1561

1013

1562

1014

1563

1015

1564

1016

1565

1017

1566

1018

1567

1019

1568

1020

1569

EXAMPLES 1021-1045

[2087] 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:

1570

[2088] wherein R is defined in Table 80 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

80TABLE 80RExampleIsomer 1 and Isomer 21021

1571

1022

1572

1023

1573

1024

1574

1025

1575

1026

1576

1027

1577

1028

1578

1029

1579

1030

1580

1031

1581

1032

1582

1033

1583

1034

1584

1035

1585

1036

1586

1037

1587

1038

1588

1039

1589

1040

1590

1041

1591

1042

1592

1043

1593

1044

1594

1045

1595

EXAMPLES 1046-1073

[2089] If one were to use isomers 919a and 919b in a procedure essentially the same as that in Example 536 then one would obtain compounds of the formula:

1596

[2090] wherein R is defined in Table 81 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

81TABLE 81RExampleIsomer 1 and Isomer 21046

1597

1047

1598

1048

1599

1049

1600

1050

1601

1051

1602

1052

1603

1053

1604

1054

1605

1055

1606

1056

1607

1057

1608

1058

1609

1059

1610

1060

1611

1061

1612

1062

1613

1063

1614

1064

1615

1065

1616

1066

1617

1067

1618

1068

1619

1069

1620

1070

1621

1071

1622

1072

1623

1073

1624

EXAMPLES 1074-1102

[2091] 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:

1625

[2092] wherein R is defined in Table 82 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

82TABLE 82RExampleIsomer 1 and Isomer 21075

1626

1076

1627

1077

1628

1078

1629

1079

1630

1080

1631

1081

1632

1082

1633

1083

1634

1084

1635

1085

1636

1086

1637

1087

1638

1088

1639

1089

1640

1090

1641

1091

1642

1092

1643

1093

1644

1094

1645

1095

1646

1096

1647

1097

1648

1098

1649

1099

1650

1100

1651

1101

1652

1102

1653

EXAMPLES 1103-1121

[2093] 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:

1654

[2094] wherein R is defined in Table 83 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

83TABLE 83RExampleIsomer 1 and Isomer 21103

1655

1104

1656

1105

1657

1106

1658

1107

1659

1108

1660

1109

1661

1110

1662

1111

1663

1112

1664

1113

1665

1114

1666

1115

1667

1116

1668

1117

1669

1118

1670

1119

1671

1120

1672

1121

1673

EXAMPLES 1122-1139

[2095] If one were to use isomers 920a and 920b 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:

1674

[2096] and the numbers 1 and 2 in the formulas represent

84TABLE 84RExampleIsomer 1 and Isomere21122

1675

1123

1676

1124

1677

1125

1678

1126

1679

1127

1680

1128

1681

1129

1682

1130

1683

1131

1684

1132

1685

1133

1686

1134

1687

1135

1688

1136

1689

1137

1690

1138

1691

1139

1692

EXAMPLES 1140-1163

[2097] 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:

1693

[2098] wherein R is defined in Table 85 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

85TABLE 85RExampleIsomer 1 and Isomer 21140

1694

1141

1695

1142

1696

1143

1697

1144

1698

1145

1699

1146

1700

1147

1701

1148

1702

1149

1703

1150

1704

1151

1705

1152

1706

1153

1707

1154

1708

1155

1709

1156

1710

1157

1711

1158

1712

1159

1713

1160

1714

1161

1715

1162

1716

1163

1717

EXAMPLES 1164-1187

[2099] 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:

1718

[2100] wherein R is defined in Table 86 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

86TABLE 86RExampleIsomer 1 and Isomer 21164

1719

1165

1720

1166

1721

1167

1722

1168

1723

1169

1724

1170

1725

1171

1726

1172

1727

1173

1728

1174

1729

1175

1730

1176

1731

1177

1732

1178

1733

1179

1734

1180

1735

1181

1736

1182

1737

1183

1738

1184

1739

1185

1740

1186

1741

1187

1742

PREPARATIVE EXAMPLE 105

[2101]

1743

[2102] Compound 921 was reacted in essentially the same manner as in Preparative Example 23, Steps A-D to get compound 922.

1744

[2103] 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

[2104]

1745

[2105] 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

[2106]

1746

[2107] 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

[2108] 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:

1747

[2109] wherein R is defined in Table 87 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

87TABLE 87RExampleIsomer 1 and Isomer 21188

1748

1189

1749

1190

1750

1191

1751

1192

1752

1193

1753

1194

1754

1195

1755

1196

1756

1197

1757

1198

1758

1199

1759

1200

1760

1201

1761

1202

1762

1203

1763

1204

1764

1205

1765

1206

1766

1207

1767

1208

1768

1209

1769

1210

1770

1211

1771

1212

1772

EXAMPLES 1213-1238

[2110] 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:

1773

[2111] wherein R is defined in Table 88 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

88TABLE 88RExampleIsomer 1 and Isomer 21213

1774

1214

1775

1215

1776

1216

1777

1217

1778

1218

1779

1219

1780

1220

1781

1221

1782

1223

1783

1224

1784

1225

1785

1226

1786

1227

1787

1228

1788

1229

1789

1230

1790

1231

1791

1232

1792

1233

1793

1234

1794

1235

1795

1236

1796

1237

1797

1238

1798

EXAMPLES 1239-1266

[2112] 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:

1799

[2113] wherein R is defined in Table 89 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

89TABLE 89RExampleIsomer 1 and Isomer 21239

1800

1240

1801

1241

1802

1242

1803

1243

1804

1244

1805

1245

1806

1246

1807

1247

1808

1248

1809

1249

1810

1250

1811

1251

1812

1252

1813

1253

1814

1254

1815

1255

1816

1256

1817

1257

1818

1258

1819

1259

1820

1260

1821

1261

1822

1262

1823

1263

1824

1264

1825

1265

1826

1266

1827

EXAMPLES 1267-1294

[2114] 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:

1828

[2115] wherein R is defined in Table 90 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

90TABLE 90RExampleIsomer 1 and Isomer 21267

1829

1268

1830

1269

1831

1270

1832

1271

1833

1272

1834

1273

1835

1274

1836

1275

1837

1276

1838

1277

1839

1278

1840

1279

1841

1280

1842

1281

1843

1282

1844

1283

1845

1284

1846

1285

1847

1286

1848

1287

1849

1288

1850

1289

1851

1290

1852

1291

1853

1292

1854

1293

1855

1294

1856

EXAMPLE 1295

[2116] 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:

1857

[2117] were prepared wherein R is defined in Table 91 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

91TABLE 91ExampleRIsomer 1Isomer 21295

1858

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, 1H), 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

[2118] 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:

1859

[2119] 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.

92TABLE 92RExampleIsomer I and Isomer 21296

1860

1297

1861

1298

1862

1299

1863

1300

1864

1301

1865

1302

1866

1303

1867

1304

1868

1305

1869

1306

1870

1307

1871

1308

1872

1309

1873

1310

1874

1311

1875

1312

1876

1313

1877

EXAMPLE 1314

[2120] 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:

1878

[2121] were prepared wherein R is defined in Table 93 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.

93TABLE 93ExampleRIsomer IIsomer 21314

1879

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

[2122] 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:

1880

[2123] 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.

94TABLE 94RExampleIsomer 1 and Isomer 21315

1881

1316

1882

1317

1883

1318

1884

1319

1885

1320

1886

1321

1887

1322

1888

1323

1889

1324

1890

1325

1891

1326

1892

1327

1893

1328

1894

1329

1895

1330

1896

1331

1897

1332

1898

EXAMPLES 1333-1356

[2124] If one were to follow essentially the same procedure as Examples 566-567 using 924a and 924b compounds of the formula:

1899

[2125] 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.

95TABLE 95RExampleIsomer 1 and Isomer 21333

1900

1334

1901

1335

1902

1336

1903

1337

1904

1338

1905

1339

1906

1340

1907

1341

1908

1342

1909

1343

1910

1344

1911

1345

1912

1346

1913

1347

1914

1348

1915

1349

1916

1350

1917

1351

1918

1352

1919

1353

1920

1354

1921

1355

1922

1356

1923

EXAMPLES 1357-1380

[2126] If one were to follow essentially the same procedure as Examples 566-567 using 925a and 925b compounds of the formula:

1924

[2127] 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.

96TABLE 96RExampleIsomer 1 and Isomer 21357

1925

1358

1926

1359

1927

1360

1928

1361

1929

1362

1930

1363

1931

1364

1932

1365

1933

1366

1934

1367

1935

1368

1936

1369

1937

1370

1938

1371

1939

1372

1940

1373

1941

1374

1942

1375

1943

1376

1944

1377

1945

1378

1946

1379

1947

1380

1948

PREPARATIVE EXAMPLE 108

[2128]

1949

[2129] In essentially the same manner as in Preparative Example 23, Steps A-D, use compound 234a (from Step B) to prepare 926.

1950

[2130] In essentially the same manner as in Preparative Example 42, Step A, use 926 to prepare 927.

1951

[2131] Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 928a and 928b.

1952

[2132] 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

[2133] If one were to follow essentially the same procedure as in Examples 690-714 using 928a and 928b compounds of the formulas:

1953

[2134] 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.

97TABLE 97RExampleIsomer 1 and isomer 21381

1954

1382

1955

1383

1956

1384

1957

1385

1958

1386

1959

1387

1960

1388

1961

1389

1962

1390

1963

1391

1964

1392

1965

1393

1966

1394

1967

1395

1968

1396

1969

1397

1970

1398

1971

1399

1972

1400

1973

1401

1974

1402

1975

1403

1976

1404

1977

1405

1978

EXAMPLES 1406-1431

[2135] If one were to follow essentially the same procedure as in Examples 690-714 using 929a and 929b compounds of the formulas:

1979

[2136] 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.

98TABLE 98RExampleIsomer 1 and Isomer 21406

1980

1407

1981

1408

1982

1409

1983

1411

1984

1412

1985

1413

1986

1414

1987

1415

1988

1416

1989

1417

1990

1418

1991

1419

1992

1420

1993

1421

1994

1422

1995

1423

1996

1424

1997

1425

1998

1426

1999

1427

2000

1428

2001

1429

2002

1430

2003

1431

2004

EXAMPLES 1432-1459

[2137] If one were to follow essentially the same procedure as in Example 536 using 928a and 928b compounds of the formulas:

2005

[2138] 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.

99TABLE 99RExampleIsomer 1 and Isomer 21432

2006

1433

2007

1434

2008

1435

2009

1436

2010

1437

2011

1438

2012

1439

2013

1440

2014

1441

2015

1442

2016

1443

2017

1444

2018

1445

2019

1446

2020

1447

2021

1448

2022

1449

2023

1450

2024

1451

2025

1452

2026

1453

2027

1454

2028

1455

2029

1456

2030

1457

2031

1458

2032

1459

2033

EXAMPLES 1460-1487

[2139] If one were to follow essentially the same procedure as in Example 536 using 929a and 929b compounds of the formulas:

2034

[2140] 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.

100TABLE 100RExampleIsomer 1 and Isomer 21460

2035

1461

2036

1462

2037

1463

2038

1464

2039

1465

2040

1466

2041

1467

2042

1468

2043

1469

2044

1470

2045

1471

2046

1472

2047

1473

2048

1474

2049

1475

2050

1476

2051

1477

2052

1478

2053

1479

2054

1480

2055

1481

2056

1482

2057

1483

2058

1484

2059

1485

2060

1486

2061

1487

2062

EXAMPLES 1488-1505

[2141] 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:

2063

[2142] 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.

101TABLE 101RExampleIsomer 1 and Isomer 21488

2064

1489

2065

1490

2066

1491

2067

1492

2068

1493

2069

1494

2070

1495

2071

1496

2072

1497

2073

1498

2074

1499

2075

1500

2076

1501

2077

1502

2078

1503

2079

1504

2080

1505

2081

EXAMPLES 1506-1524

[2143] 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:

2082

[2144] 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.

102TABLE 102RExampleIsomer 1 and Isomer 21506

2083

1507

2084

1508

2085

1509

2086

1510

2087

1511

2088

1512

2089

1513

2090

1514

2091

1515

2092

1516

2093

1517

2094

1518

2095

1519

2096

1520

2097

1521

2098

1522

2099

1523

2100

1524

2101

EXAMPLES 1525-1548

[2145] If one were to follow essentially the same procedure as in Examples 566-567 using 928a and 928b compounds of the formulas:

2102

[2146] 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.

103TABLE 103RExampleIsomer 1 and Isomer 21525

2103

1526

2104

1527

2105

1528

2106

1529

2107

1530

2108

1531

2109

1532

2110

1533

2111

1534

2112

1535

2113

1536

2114

1537

2115

1538

2116

1539

2117

1540

2118

1541

2119

1542

2120

1543

2121

1544

2122

1545

2123

1546

2124

1547

2125

1548

2126

EXAMPLES 1549-1572

[2147] If one were to follow essentially the same procedure as in Examples 566-567 using 929a and 929b compounds of the formulas:

2127

[2148] 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.

104TABLE 104RExampleIsomer 1 and Isomer 21549

2128

1550

2129

1551

2130

1552

2131

1553

2132

1554

2133

1555

2134

1556

2135

1557

2136

1558

2137

1559

2138

1560

2139

1561

2140

1562

2141

1563

2142

1564

2143

1565

2144

1566

2145

1567

2146

1568

2147

1569

2148

1570

2149

1571

2150

1572

2151

EXAMPLE 1573

[2149]

2152

[2150] React 882, from Preparative Example 73 Step B, with ethylmagnesium bromide following the procedure described in Preparative Example 73 Step C.

2153

[2151] 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

[2152]

2154

[2153] 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.

2155

[2154] 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

[2155]

2156

[2156] 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

[2157] 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

[2158] 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

[2159] 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

[2160] Following essentially the same procedure as in Example 1575, compound 372 was reacted with CH31 to afford compound 938 identified in Table 105 below.

105TABLE 105

2157

ExampleR =CompoundPHYS. DATA1575

2158

934MH+ = 6411576

2159

935MH+ = 6411577

2160

936MH+ = 6411578

2161

937MH+ = 6401579

2162

938MH+ = 564

EXAMPLE 1580

[2161]

2163

2164

[2162] 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. 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.

2165

[2163] 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.

2166

[2164] 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 (0.0136 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.

2167

[2165] 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 371 a (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

[2166]

2168

[2167] 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

[2168]

2169

[2169] 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

[2170]

2170

[2171] 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 (46ul, 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

[2172]

2171

[2173] In a 50 ml flask was transferred (0.084 g, 0.084 mmol) of 944 and 2 ml of anhydrous CH2Cl2 followed 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

[2174]

2172

[2175] In a 50 ml flask was transferred (0.084 g, 0.084 mmol) of 944 and 2 ml of anhydrous CH2Cl2 followed by addition of triethylamine (58 μl, 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

[2176]

2173

[2177] 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 ul, 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 ul, 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.

2174

[2178] Compound 951 from Step A was N-protected with a Boc group using standard conditions to give 952.

2175

[2179] Compound 952 from Step B was O-protected using tetrabutyldimethylsilyl (TBDMS) to give 953.

2176

[2180] The Boc group of 953 Step C was deprotected using using HCl-Dioxane to give 954.

2177

[2181] Compound 954 from Step D was treated in a similar way to compound of Example 1580, Step D, to give 955.

2178

[2182] Compound 955 from Step E, was deprotected by treatment with tetrabutylammoniumfluoride (TBAF) to give the title compound 949.

EXAMPLE 1587

[2183]

2179

[2184] 956 and 957 were prepared in a similar manner to 949 using the appropriate substituted starting epoxide.

[2185] Assays

[2186] 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.

[2187] 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.

[2188] 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 106.

106TABLE 106Average %DoseRoute andTumorCompound 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).

[2189] Soft Agar Assay:

[2190] Anchorage-independent growth is a characteristic of tumorigenic cell lines.

[2191] Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37° C. under 5% 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.

[2192] 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.

[2193] The preferred compounds of the invention have an FPT IC50 range of between 0.05 nM-20 nM and a Soft agar IC50 range of between <0.5 nM-15 nM.

[2194] The most preferred compounds have an FPT IC50 range of between 0.05 nM-10.0 nM and Soft agar IC50 range of between <0.5 nM-10 nM.

[2195] The more preferred compounds have an FPT IC50 range of between 0.05 nM-5.0 nM and Soft agar IC50 range of between <0.5 nM-5 nM.

[2196] 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's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[2197] 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.

[2198] 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.

[2199] 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.

[2200] 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.

[2201] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[2202] The quantity of the compounds of the present invention in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, for example, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, and from about 0.01 mg to about 250 mg, according to the particular application.

[2203] The amount and frequency of administration of the compounds of the present 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 single or divided doses, preferably, in two to four divided doses.

[2204] 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 107.

107TABLE 107Examplary 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

[2205] 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.

[2206] 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.

[2207] In a 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.

[2208] 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.

[2209] 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.

[2210] 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.

[2211] 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.

[2212] 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 to 100 mg/m2 once every four weeks and the chemotherapeutic agent, Gemcitabine, which is administered at a dosage of from 65 to 175 mg/m2 once every three weeks.

[2213] 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 108.

108TABLE 108Examplary Signal Transduction Inhibitors Dosage and Dosage RegimensIressa (ZD1839) - EGF receptor 150-700 mg/day (oral)kinase inhibitor:OSI-774 - EGF receptor kinase100-1000 mg/day (oral)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/abl kinase300-1000 mg/day (oral)inhibitor:*(IV)-intravenously

[2214] 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.

[2215] 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.

[2216] 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.

[2217] The particular choice of the chemotherapeutic agent, signal transduction inhibitor and/or radiation to use with the FPT inhibitor of this invention will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.

[2218] 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).

[2219] 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.

[2220] 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.

[2221] 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.

[2222] Additional pharmaceutical and method of treating embodiments of this invention are set forth below.

[2223] 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.

[2224] 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.

[2225] 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.

[2226] 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.

[2227] 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.

[2228] 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 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.

[2229] 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.

[2230] 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.

[2231] 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.

[2232] 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.

[2233] 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.

[2234] 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.

[2235] 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.

[2236] 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:

2180

2181

2182

2183

2184

2185

2186

2187

2188

2189

2190

2191

2192

[2237] 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.

[2238] 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.

[2239] 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.

[2240] 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.

[2241] 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.

[2242] 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.

[2243] 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.

[2244] 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.

[2245] 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 conisting of: lung tumors, head and neck tumors, bladder tumors, breast tumors, prostate tumors and myeloid leukemias; and the signal transduction inhibitor is selected from the group consisting of: Gleevec, Iressa, OSI-774, Imclone C225, Abgenix ABX-EGF; and Herceptin.

[2246] 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 1.4 and at least two different antineoplastic agents selected from:

[2247] (1) taxanes;

[2248] (2) platinum coordinator compounds;

[2249] (3) EGF inhibitors that are antibodies;

[2250] (4) EGF inhibitors that are small molecules;

[2251] (5) VEGF inhibitors that are antibodies;

[2252] (6) VEGF kinase inhibitors that are small molecules;

[2253] (7) estrogen receptor antagonists or selective estrogen receptor modulators;

[2254] (8) anti-tumor nucleoside derivatives;

[2255] (9) epothilones;

[2256] (10) topoisomerase inhibitors;

[2257] (11) vinca alkaloids;

[2258] (12) antibodies that are inhibitors of αVβ3 integrins; and

[2259] (13) small molecule inhibitors of αVβ3 integrins;

[2260] 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 1.4 and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound.

[2261] 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 1.4 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.

[2262] 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 1.4 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.

[2263] 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 1.4 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.

[2264] 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 1.4 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.

[2265] 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 1.4 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.

[2266] 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 1.4 and two antineopiastic 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 300 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.

[2267] 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 1.4 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.

[2268] 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 1.4 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.

[2269] 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 1.4 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.

[2270] 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 1.4 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:

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2194

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2196

2197

2198

2199

2200

2201

2202

2203

[2271] 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 1.4 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:

2204

2205

2206

2207

2208

2209

2210

2211

2212

[2272] 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 1.4 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:

2213

[2273] 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 1.4 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:

2214

[2274] 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 1.4 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:

2215

[2275] 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 1.4 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.

[2276] 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 1.4 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.

[2277] 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 1.4 and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody.

[2278] 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 1.4 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.

[2279] 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 1.4 and two antineoplastic agents, wherein one antineoplastic agent is an antinucleoside derivative, and the other antineoplastic agent is a platinum coordinator compound.

[2280] 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 1.4 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.

[2281] 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 1.4 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.

[2282] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2283] (a) an FPT inhibitor of formula 1.4; and

[2284] (b) carboplatin; and

[2285] (c) paclitaxel.

[2286] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2287] (a) an FPT inhibitor of formula 1.4; and

[2288] (b) carboplatin; and

[2289] (c) paclitaxel,

[2290] 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.

[2291] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2292] (a) an FPT inhibitor of formula 1.4; and

[2293] (b) carboplatin; and

[2294] (c) paclitaxel,

[2295] 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 300 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.

[2296] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2297] (a) an FPT inhibitor of formula 1.4; and

[2298] (b) carboplatin; and

[2299] (c) paclitaxel,

[2300] 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 300 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

[2301] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2302] (a) an FPT inhibitor of formula 1.4; and

[2303] (b) carboplatin; and

[2304] (c) paclitaxel,

[2305] 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 300 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.

[2306] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2307] (a) an FPT inhibitor of formula 1.4; and:

[2308] (b) cisplatin; and

[2309] (c) gemcitabine.

[2310] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2311] (a) an FPT inhibitor of formula 1.4; and:

[2312] (b) cisplatin; and

[2313] (c) gemcitabine

[2314] 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.

[2315] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2316] (a) an FPT inhibitor of formula 1.4; and:

[2317] (b) cisplatin; and

[2318] (c) gemcitabine

[2319] 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.

[2320] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2321] (a) an FPT inhibitor of formula 1.4; and:

[2322] (b) cisplatin; and

[2323] (c) gemcitabine

[2324] 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.

[2325] An embodiment of this invention is directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2326] (a) an FPT inhibitor of formula 1.4; and:

[2327] (b) cisplatin; and

[2328] (c) gemcitabine

[2329] 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.

[2330] An embodiment of this invention id directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2331] (a) an FPT inhibitor of formula 1.4; and

[2332] (b) carboplatin; and

[2333] (c) gemcitabine.

[2334] An embodiment of this invention id directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2335] (a) an FPT inhibitor of formula 1.4; and

[2336] (b) carboplatin; and

[2337] (c) gemcitabine,

[2338] 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.

[2339] An embodiment of this invention id directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2340] (a) an FPT inhibitor of formula 1.4; and

[2341] (b) carboplatin; and

[2342] (c) gemcitabine,

[2343] 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.

[2344] An embodiment of this invention id directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2345] (a) an FPT inhibitor of formula 1.4; and

[2346] (b) carboplatin; and

[2347] (c) gemcitabine,

[2348] 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.

[2349] An embodiment of this invention id directed to the treatment of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

[2350] (a) an FPT inhibitor of formula 1.4; and

[2351] (b) carboplatin; and

[2352] (c) gemcitabine,

[2353] 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.

[2354] 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 1.4 and an antineoplastic agent selected from the group consisting of:

[2355] (1) EGF inhibitors that are antibodies;

[2356] (2) EGF inhibitors that are small molecules;

[2357] (3) VEGF inhibitors that are antibodies; or

[2358] (4) VEGF kinase inhibitors that are small molecules.

[2359] 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 1.4 and an antineoplastic agent selected from the group consisting of: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416, and SU6688.

[2360] 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 1.4 and an antineoplastic agent selected from the group consisting of:

[2361] (1) EGF inhibitors that are antibodies;

[2362] (2) EGF inhibitors that are small molecules;

[2363] (3) VEGF inhibitors that are antibodies; or

[2364] (4) VEGF kinase inhibitors that are small molecules,

[2365] 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.

[2366] 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 1.4 and an antineoplastic agent selected from the group consisting of:

[2367] (1) EGF inhibitors that are antibodies;

[2368] (2) EGF inhibitors that are small molecules;

[2369] (3) VEGF inhibitors that are antibodies; or

[2370] (4) VEGF kinase inhibitors that are small molecules,

[2371] 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.

[2372] 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 1.4 and an antineoplastic agent selected from the group consisting of:

[2373] (1) EGF inhibitors that are antibodies;

[2374] (2) EGF inhibitors that are small molecules;

[2375] (3) VEGF inhibitors that are antibodies; or

[2376] (4) VEGF kinase inhibitors that are small molecules,

[2377] 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.

[2378] 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 1.4 and an antineoplastic agent selected from the group consisting of:

[2379] (1) EGF inhibitors that are antibodies;

[2380] (2) EGF inhibitors that are small molecules;

[2381] (3) VEGF inhibitors that are antibodies; or

[2382] (4) VEGF kinase inhibitors that are small molecules,

[2383] 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.

[2384] 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 1.4 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 300 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.

[2385] 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 1.4 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.

[2386] For the embodiments of this invention using compounds of formula 1.4, the compounds of formula 1.4 are preferably selected from the group consisting of:

2216

2217

2218

2219

2220

2221

2222

2223

2224

2225

2226

[2387] most preferably selected from the group consisting of:

2227

2228

2229

2230

2231

2232

2233

2234

2235

[2388] more preferably

2236

[2389] and even more preferably

2237

[2390] 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	09940811	Aug 2001	US
Child	10085896	Feb 2002	US

Novel farnesyl protein transferase inhibitors as antitumor agents

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