17 Beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases

Abstract

There are disclosed compounds of the formula (I): 1

Description

BACKGROUND

[0002] 1 . Field of the Invention

[0003] The invention relates to novel inhibitors of Type3 17β-Hydroxysteroid Dehydrogenase, pharmaceutical compositions containing the compounds and the use of the compounds for the treatment or prevention of androgen dependent diseases.

[0004] 2. Description of Related Art

[0005] Androgen dependent diseases, i.e. diseases whose onset or progress is aided by androgenic activity, are well known. These diseases include but are not limited to prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperlasia and polycystic ovarian syndrome. Estrogen dependent diseases, i.e. diseases whose onset or progress is aided by estrogenic activity are also well known. These include but are not limited to breast cancer, endometriosis, leiomyoma and precocious puberty.

[0006] Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists or estrogen receptor antagonists respectively. See e.g. WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also be reduced by suppressing androgen or estrogen biosynthesis using inhibitors of enzymes that catalyze one or more steps of such biosynthesis. Type 3 17β-Hydroxysteroid Dehydrogenase (17β-HSD3) is the primary enzyme that converts androstenedione to testosterone in the testes. Androgenic and estrogenic activity may also be reduced by suppressing ovarian or testicular secretions by known methods. See e.g. WO 90/10462, WO 91/00731, WO 91/00733, and WO 86/01105. Type 5 17B-Hydroxysteroid Dehydrogenase is described in WO 97/11162. Novel inhibitors of both Type 3 and Type 5 17B-Hyroxysteroid Dehydrogenase are described in WO 99/46279.

[0007] U.S. Pat. No. 5,665,735 discloses compounds useful in the treatment of asthma, allergy and inflammation, which are of the formula: 2

[0008] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0009] AR1 (or Ar1) represents 3

[0010] AR2 (or Ar2) represents 4

[0011]  or a five-membered heterocyclic aromatic group selected from the group consisting of Formulas I to XII: 5

[0012]  wherein X represents O, S.

[0013] U.S. Pat. No. 5,432.175 discloses compounds which posess anti-allergic and anti-inflammatory activity and are of the formula: 6

[0014] wherein:

[0015] AR1 represents 7

[0016] AR2 represents 8

[0017]  or a five-membered heterocyclic aromatic group containing at least one 9

[0018]  in the ring structure,

[0019] T represents CH, C or N.

[0020] Current therapies for the treatment of androgenic and estrogenic dependent diseases include the use of glucocorticoids to block adrenal secretions, and luteinizing hormone releasing hormone (LHRH) agonists which cause medical castration. Both therapies are associated with undesirable side effects. An improved therapy would include compounds that specifically inhibit type 3 17β-Hydroxysteroid dehydrogenase, while avoiding inhibition of other 17β-Hydroxysteroid dehydrogenases. Such an improvement is provided by this invention.

SUMMARY OF THE INVENTION

[0021] The invention provides novel compounds represented by Formula (I): 10

[0022] a prodrug thereof, or a pharmaceutically acceptable salt or solvate of the compound or of said prodrug wherein,

[0023] R1 and R2 are the same or different and are independently selected from the group consisting of aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each optionally substituted with one to six groups selected from the group consisting of:

[0024] a) halogen;

[0025] b) —OCF3 or —OCHF2

[0026] c) —CF3;

[0027] d) —CN;

[0028] e) alkyl or R18-alkyl;

[0029] f) heteroalkyl or R18-heteroalkyl;

[0030] g) aryl or R18-aryl;

[0031] h) heteroaryl or R18-heteroaryl;

[0032] i) arylalkyl or R18-arylalkyl;

[0033] j) heteroarylalkyl or R18-heteroarylalkyl

[0034] k) hydroxy;

[0035] l) alkoxy;

[0036] m) aryloxy;

[0037] n) —SO2-alkyl;

[0038] o) —NR11R12;

[0039] p) —N(R11)C(O)R13,

[0040] q) methylenedioxy;

[0041] r) difluoromethylenedioxy;

[0042] s) trifluoroalkoxy;

[0043] t) —SCH3 or —SCF3; and

[0044] u) —SO2CF3 or —NHSO2CF3;

[0045] R3 is H, —OH, alkoxy or alkyl, provided that when X is N, R3 is not —OH or alkoxy;

[0046] R4, R5, R7 and R8 are the same or different and are independently selected from the group consisting of: H, —OH, —OR14, —NRR12, —N(R11)C(O)R13, alkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, 11

[0047]  provided that when Z and/or X is N, then R4, R5, R7 and R8 are each not —OH, —OR14, —NR11R12 or —N(R11)C(O)R13;

[0048] R6 is selected from the group consisting of —C(O)R15 and —SO2R15;

[0049] R9 and R10 are the same or different and are independently selected from the group consisting of: H, F, —CF3, alkyl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, —NR11R12 and —N(R11)C(O)R13; provided that when Z is N, then R9 and R10 are each not F, hydroxy, alkoxy, aryloxy, —NR11R12 or —N(R11)C(O)R13;

[0050] R11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

[0051] R12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

[0052] R13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

[0053] R14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

[0054] R15 is selected from the group consisting of: —NR16R17, —OR16, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R18;

[0055] R16 and R17 are the same or different and are independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R18, provided that when R15 is OR16, R16 is not H;

[0056] R18 is one to four substituents each independently selected from the group consisting of: lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, alkoxy carbonyl, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl and heteroaryl; and

[0057] X and Z are the same or different and are independently selected from the group consisting of C and N.

[0058] One aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) in combination or association with a pharmaceutically acceptable carrier or diluent.

[0059] Another aspect of the present invention relates to a method of inhibiting type 3 17β-hydroxysteroid dehydrogenase in a mammal, e.g. a human, which comprises administering to a patient in need thereof of an effective amount, i.e. a therapeutically effective amount, of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0060] In another aspect, the present invention provides a method of treating or preventing androgen or estrogen dependent diseases in a mammal, e.g. a human, which comprises administering to a patient in need thereof of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0061] In yet another aspect, the present invention provides a method of treating or preventing prostate cancer, and other androgen-dependent neoplasms, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, androgenic alopecia (i.e. pattern baldness in both male and female patients), hirsutism, polycystic ovary syndrome and acne in a mammal, e.g. a human, which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0062] Also, the present invention provides a method of treating or preventing androgen-dependent diseases comprising administering to a mammal in need thereof an effective amount of a compound of the invention in combination with at least one anti-androgenic agent (i.e. agents that decrease androgen synthesis or activity).

[0063] This invention also provides a method of treating or preventing benign prostatic hyperplasia comprising administering an effective amount of a compound of the invention in combination with at least one agent useful in the treatment or prevention of benign prostatic hyperplasia.

[0064] This invention further provides a method of treating or preventing hair loss, comprising administering an effective amount of a compound of the invention in combination with at least one agent useful in the treatment or prevention of alopecia, e.g., potassium channel agonists or 5α-reductase inhibitors.

[0065] The present invention also provides a method of treating or preventing proliferative diseases, especially cancers (tumors), comprising administering an effective amount (e.g., a therapeutically effective amount) of (1) a compound of the invention, described herein, to a mammal (e.g., a human) in need of such treatment in combination with (2) an effective amount of an anti-cancer agent i.e., a chemotherapeutic agent, biological agent, and/or surgery, e.g., prostatectomy and/or radiation therapy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] Unless where indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as to the “alkyl” portions of “alkoxy”, etc.

[0067] Unless otherwise known, stated or shown to be to the contrary, the point of attachment for a multiple term substituent (multiple terms that are combined to identify a single moiety) to a subject structure is through the last named term of the multiple term. For example, a cycloalkylalkyl substituent attaches to a targeted through the latter “alkyl” portion of the substituent (e.g., Structure-alkyl-cycloalkyl).

[0068] When any variable (e.g., aryl, R2) occurs more than one time in any constituent, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0069] Unless stated, shown or otherwise known to be the contrary, all atoms illustrated in chemical formulas for covalent compounds possess normal valencies. Thus, hydrogen atoms, double bonds, triple bonds and ring structures need not be expressly depicted in a general chemical formula.

[0070] Double bonds, where appropriate, may be represented by the presence of parentheses around an atom in a chemical formula. For example, a carbonyl functionality, —CO—, may also be represented in a chemical formula by —C(O)— or —C(=O)—. Similarly, a double bond between a sulfur atom and an oxygen atom may be represented in a chemical formula by —SO—, —S(O)— or —S(═O)—. One skilled in the art will be able to determine the presence or absence of double (and triple bonds) in a covalently-bonded molecule. For instance, it is readily recognized that a carboxyl functionality may be represented by —COOH, —C(O)OH, —C(═O)OH or —CO2H.

[0071] The term “substituted,” as used herein, means the replacement of one or more atoms or radicals, usually hydrogen atoms, in a given structure with an atom or radical selected from a specified group. In the situations where more than one atom or radical may be replaced with a substituent selected from the same specified group, the substituents may be, unless otherwise specified, either the same or different at every position. Radicals of specified groups, such as alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups, independently of or together with one another, may be substituents on any of the specified groups, unless otherwise indicated.

[0072] “Alkyl” represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Preferrably the number of carbon atoms is 1 to 20, more preferrably 1 to 10, most preferrably the number of carbon atoms is 1 to 6. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended. “Lower alkyl” represents a straight or branched hydrocarbon chain having 1 to 6 carbon atoms.

[0073] The term “chemically-feasible” is usually applied to a ring structure present in a compound and means that the ring structure would be expected to be stable by a skilled artisan.

[0074] The term “cycloalkyl” or “cycloalkane,” as used herein, means an unsubstituted or substituted, saturated, stable, non-aromatic, chemically-feasible carbocyclic ring, having, preferably, from three to fifteen carbon atoms, more preferably, from three to eight carbon atoms. The cycloalkyl carbon ring radical is saturated and may be fused, for example, benzofused, with one to two cycloalkyl, aromatic, heterocyclic or heteroaromatic rings. The cycloalkyl may be attached at any endocyclic carbon atom that results in a stable structure. Preferred carbocyclic rings have from five to six carbons. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0075] The term “heterocycloalkyl” refers to a cycloalkyl group which has at least one heteroatom.

[0076] The term “halogen” or “Halo” (halogen) is intended to include fluorine, chlorine, bromine or iodine.

[0077] The term “alkoxy,” as used herein, means an oxygen atom bonded to a hydrocarbon chain, such as an alkyl group (—O-alkyl). Representative alkoxy groups include methoxy, ethoxy and isopropoxy groups.

[0078] The term “aryloxy” as used herein, means an oxygen atom bonded to an aryl group (—O-aryl).

[0079] The term “fluoroalkyl” represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms, substituted with one or more fluorine atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended.

[0080] “Aryl” refers to a mono- or bicyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like. The aryl group can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, sulfhydryl, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl.

[0081] The term “arylakyl” refers to an aryl group bonded directly to a subject structure through an alkyl group.

[0082] The term “heteroatom,” as used herein, means a nitrogen, sulfur, or oxygen atom. Multiple heteroatoms in the same group may be the same or different.

[0083] The term “heteroalkyl” refers to an alkyl group which has at least one heteroatom.

[0084] The term “heterocycle” or “heterocyclic ring” is defined by all non-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.

[0085] The term “heterocyclic acidic functional group” is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

[0086] “Heteroaryl” refers to 5- or 10-membered single or benzofused aromatic rings consisting of 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S, and —N═, provided that the rings do not possess adjacent oxygen and/or sulfur atoms. The heteroaryl group can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino and dialkylamino. Representative heteroaryl groups include thiazoyl, thienyl, pyridyl, benzothienyl and quinolyl.

[0087] The term “heteroarylalkyl” refers to a heteroaryl group bonded directly to a subject structure through an alkyl group.

[0088] N-oxides can form on a tertiary nitrogen present in an R substituent, or on =N— in a heteroaryl ring substituent and are included in the compounds of formula 1.

[0089] The term “prodrug,” as used herein, represents compounds that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process (e.g., a prodrug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form). A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series (1987), and in Bioreversible Carriers in Drug Design, E. B. Roche, ed., American Pharmaceutical Assn and Pergamon Press (1987), each of which is incorporated herein by reference in its entirety.

[0090] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0091] The phrase “effective amount,” as used herein, means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

[0092] As used herein the term “disease” is intended to include any abnormal physical or mental condition, including disorders, as well as any symptoms which are subject evidence of a disease or disorder.

[0093] The term “compound having the formula I”, and the like as used herein, represents a compound having a chemical structure encompassed by formula I, and includes any and all isomers (e.g., enantiomers, stereoisomers, diastereomers, rotomers, tautomers) and prodrugs of the compound. These compounds can be neutral, acidic or alkaline, and further include their corresponding pharmaceutically-acceptable salts, solvates, esters, and the like.

[0094] All isomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds according to the invention embraces all the possible isomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Unless noted otherwise, inventive compounds designated with a 1 or 2 above the formula correspond to the first and second isomers, respectively, to elute from a chiral chromatography column during separation from a diastereomeric mixture.

[0095] The following are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); ethyl chloroformate (ClCO2Et); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC); t-butoxycarbonyl (BOC); phenyl group (Ph); trimethylsilyl isocyanate (TMSNCO); acetyl chloride (AcCl); acetonitrile (CH3CN); n-butyllithium (n-BuLi); triethylamine (TEA); methyl iodine (Mel); dimethyl sulfoxide (DMSO); diethylamine (DEA); isopropanol (IPA); N-methylmorpholine (NMM); acetic acid (AcOH); lithium aluminum hydride (LAH); di-tert-butyl dicarbonate (BOC)2O; diisubutyl aluminum hydride (DIBAL-H); methyl magnesium bromide (MeMgBr); and acetic anhydride (Ac2O).

[0096] As used herein the following terms have the following meanings unless indicated otherwise:

[0097] “At least one” means “one or more” preferrably 1 to 12, more preferrably 1 to 6, most preferrably 1, 2 or 3.

[0098] Antineoplastic agent—means a chemotherapeutic agent effective against cancer;

[0099] Concurrently—means (1) simultaneously in time; and

[0100] Sequentially—means (1) administration of one component of the method ((a) compound of the invention, or (b) antineoplastic agent and/or radiation therapy) followed by administration of the other component; after adminsitration of one component, the second component can be administered substantially immediately after the first component, or the second component can be administered after an effective time period after the administration of 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.

Chemotherapeutic Agents

[0101] Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: 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.

[0102] Alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide.

[0103] 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.

[0104] 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”), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons-α and β (especially IFN-α), Etoposide, and Teniposide.

[0105] Hormonal agents and steroids (including synthetic analogs): 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin and Zoladex.

[0106] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Ralozifine, Droloxifine and Hexamethylmelamine.

[0107] 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.

[0108] Examples of biological agents useful in the methods of this invention include, but are not limited to, interferon-α, interferon-β and gene therapy.

Microtubule Affecting Agents

[0109] As used herein, a microtubule affecting agent 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.

[0110] 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), Taxol® derivatives (e.g., derivatives (e.g., 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.

[0111] Particularly preferred microtubule affecting agents are compounds with paclitaxel-like activity. These include, but are not limited to, paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives 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).

[0112] 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).

[0113] 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).

[0114] 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.).

[0115] In a preferred embodiment, compounds with possible tubulin polymerization activity are screened in vitro. 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.

[0116] Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically, these 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.

[0117] 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” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA).

[0118] The present invention provides a method of treating or preventing androgen-dependent diseases comprising administering to a mammal in need thereof an effective amount of a compound of the invention in combination with at least one anti-androgenic agent (i.e. agents that decrease androgen synthesis or activity).

[0119] Examples of such agents include but are not limited to: inhibitors of 5α-reductase type 1 and/or type 2, e.g. finasteride, SKF105,657, LY191,704 , LY320,236, dutasteride, Flutamide, nicalutamide, bicalutamide, LHRH agonists e.g. leuprolide and zoladex, LHRH antagonists, e.g. abarelix and cetrorelix, inhibitors of 17α-hydroxylase/C17-20 lyase, e.g. YM 116, CB7630 and liarozole; inhibitors of 17β-Hydroxysteroid dehydrogenase type 5 and/or other 17β-Hyroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes, e.g. EM-1404.

[0120] Types of androgen or estrogen dependent diseases include, but are not limited to, prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, acne, seborrheas, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome, breast cancer, endometriosis and leiomyoma.

[0121] This invention also provides a method of treating or preventing benign prostatic hyperplasia comprising administering an effective amount of a compound of the invention in combination with at least one agent useful in the treatment or prevention of benign prostatic hyperplasia. Examples of such agents include, but are not limited to, alpha-1 adrenergic antagonists, e.g. tamsulosin and terazosin.

[0122] This invention also provides a method of treating or preventing hair loss, comprising administering an effective amount of a compound of the invention in combination with at least one potassium channel agonist e.g. minoxidil and KC-516, or 5α-reductase inhibitor, e.g., finasteride and dutasteride.

[0123] The present invention also provides a method of treating or preventing proliferative diseases, especially cancers (tumors), comprising administering concurrently or sequentially, (1) an effective amount (e.g., a therapeutically effective amount) of a compound of the invention, described herein, to a mammal (e.g., a human) in need of such treatment in combination with (2) an effective amount of an anti-cancer agent i.e., a chemotherapeutic agent, biological agent, and/or surgery, e.g., prostatectomy and/or radiation therapy.

[0124] Examples of cancers (i.e. tumors) which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), renal cancers, myeloid leukemias (for example, acute myelogenous leukemia (AML), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.

[0125] Preferrably for compounds of the Formula (I),

[0126] R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

[0127] a) halogen;

[0128] b) —OCF3;

[0129] c) —CF3;

[0130] d) —CN;

[0131] e) (C1-C20)alkyl or R18—(C1-C20) alkyl;

[0132] f) heteroalkyl or R18-heteroalkyl;

[0133] g) aryl or R18-aryl;

[0134] h) heteroaryl or R18-heteroaryl;

[0135] i) arylalkyl or R18-arylalkyl;

[0136] j) heteroarylalkyl or R18-heteroarylalkyl;

[0137] k) hydroxy;

[0138] l) alkoxy;

[0139] m) aryloxy;

[0140] n) —SO2-alkyl;

[0141] o) —NR11R12;

[0142] p) —N(R11)C(O)R—;

[0143] q) methylenedioxy;

[0144] r) difluoromethylenedioxy;

[0145] s) trifluoroalkoxy;

[0146] t) —SCH3; and

[0147] u) —SO2CF3;

[0148] R4, R5, R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —OR14, —NR11R1212

[0149]  provided that when Z and/or X is N then R4, R5, R7 and R8 are each not —OR14 or —NR11R12;

[0150] R11 is selected from the group consisting of H and alkyl.

[0151] More preferrably for compounds of the Formula (I),

[0152] R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

[0153] a) halogen;

[0154] b) —OCF3;

[0155] c) —CF3;

[0156] d) trifluoroalkoxy;

[0157] e) (C1-C6)alky or R18—(C1-C6)alkyl;

[0158] f) heteroalkyl or R18-heteroalkyl;

[0159] g) aryl or R18-aryl;

[0160] h) arylalkyl or R18-arylalkyl;

[0161] i) heteroarylalkyl or R18-heteroarylalkyl;

[0162] j) alkoxy;

[0163] k) —SO2-alkyl; and

[0164] l) —SO2CF3;

[0165] R4, R5, R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —OR14, —NR11R1213

[0166]  provided that when Z and/or X is N then R4, R5, R7 and R8 are each not —OR14 or —NR11R12;

[0167] R11 is selected from the group consisting of H and alkyl; and

[0168] Z is C.

[0169] Even more preferrably for compounds of the Formula (I),

[0170] R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

[0171] a) halogen;

[0172] b) —OCF3;

[0173] c) —CF3;

[0174] d) alkoxy;

[0175] e) trifluoralkoxy;

[0176] f) (C1-C6)alkyl;

[0177] g) —SO2-alkyl; and

[0178] h) —SO2CF3;

[0179] R3 is H or —OH, provided that when X is N, R3 is not —OH;

[0180] R4 and R5 are the same or different and are each independently selected from the group consisting of H, (C1-C6)alkyl, heteroalkyl and 14

[0181] R7 is selected from the group consisting of H, alkyl, —OR14 and —NR11R12, provided that when X is N, R7 is not —OR14 or —NR11R12;

[0182] R8 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

[0183] R11 is selected from the group consisting of H and alkyl; and

[0184] Z is C.

[0185] Yet even more preferrably for compounds of the Formula (I),

[0186] R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

[0187] a) halogen;

[0188] b) —OCF3,

[0189] c) alkoxy;

[0190] d) trifluoroalkoxy;

[0191] e) —CF3;

[0192] f) —SO2-alkyl; and

[0193] g) —SO2CF3;

[0194] R3 is H;

[0195] R4 and R5 are the same or different and are independently selected from the group consisting of H, (C1-C6)alkyl, heteroalkyl, and 15

[0196] R6 is selected from the group consisting of —C(O)R15 and —SO2R15;

[0197] R7 is selected from the group consisting of H, alkyl, —OR14 and —NR11R12, provided that when X is N, R7 is not —OR14 or —NR11R12;

[0198] R8 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

[0199] R11 is H or alkyl; and

[0200] Z is C.

[0201] Still even more preferrably for compounds of the Formula (I),

[0202] R1 and R2 are the same or different and are independently selected from the group consisting of phenyl and pyridyl, each optionally substituted with one to six groups selected from the group consisting of:

[0203] a) Br, F or Cl;

[0204] b) —OCF3;

[0205] c) —CF3;

[0206] d) methoxy;

[0207] e) ethoxy;

[0208] f) cyclopropylmethoxy;

[0209] g) —OCH2CF3;

[0210] h) —SO2-alkyl; and

[0211] i) —SO2CF3

[0212] R3 is H;

[0213] R4 and R5 are the same or different and are independently selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl and heteroalkyl;

[0214] R7 is selected from the group consisting of H, —OR11 and alkyl;

[0215] R8, R9, R10, R11, R12 and R14 are each independently selected from the group consisting of H and alkyl;

[0216] R13 is alkyl;

[0217] R15 is selected from the group consisting of —NR16R17, —OR16 and alkyl;

[0218] R16 and R17 are the same or different and are independently selected from the group consisting of H and alkyl, provided that when R15 is —OR16, R16 is not H; and

[0219] Z is C.

[0220] Illustrative compounds of Formula (I) are shown below in Table A, where compound numbers S1, S2, etc., are independent of the numbering used in the Example section.

16  S1
17  S2
18  S3
19  S4
20  S5
21  S6
22  S7
23  S8
24  S9
25  S10
26  S11
27  S12
28  S13
29  S14
30  S15
31  S16
32  S17
33  S18
34  S19
35  S20
36  S21
37  S22
38  S23
39  S24
40  S25
41  S26
42  S27
43  S28
44  S29
45  S30
46  S31
47  S32
48  S33
49  S34
50  S35
51  S36
52  S37
53  S38
54  S39
55  S40
56  S41
57  S42
58  S43
59  S44
60  S45
61  S46
62  S47
63  S48
64  S49
65  S50
66  S51
67  S52
68  S53
69  S54
70  S55
71  S56
72  S57
73  S58
74  S59
75  S60
76  S61
77  S62
78  S63
79  S64
80  S65
81  S66
82  S67
83  S68
84  S69
85  S70
86  S71
87  S72
88  S73
89  S74
90  S75
91  S76
92  S77
93  S78
94  S79
95  S80
96  S81
97  S82
98  S83
99  S84
100 S85
101 S86
102 S87
103 S88
104 S89
105 S90
106 S91
107 S92
108 S93
109 S94
110 S95
111 S96
112 S97
113 S98
114 S99
115 S100
116 S101
117 S102
118 S103
119 S104
120 S105
121 S106
122 S107
123 S108
124 S109
125 S110
126 S111
127 S112
128 S113
129 S114
130 S115
131 S116
132 S117
133 S118
134 S119
135 S120
136 S121
137 S122
138 S123
139 S124
140 S125
141 S126
142 S127
143 S128
144 S129
145 S130
146 S131
147 S132
148 S133
149 S134
150 S135
151 S136
152 S137
153 S138
154 S139
155 S140
156 S141
157 S142
158 S143
159 S144
160 S145
161 S146
162 S147
163 S148
164 S149
165 S150
166 S151
167 S152
168 S153
169 S154
170 S155
171 S156
172 S157
173 S158
174 S159
175 S160
176 S161
177 S162
178 S163
179 S164
180 S165
181 S166
182 S167
183 S168
184 S169
185 S170
186 S171
187 S172
188 S173
189 S174
190 S175
191 S176
192 S177
193 S178
194 S179
195 S180
196 S181
197 S182
198 S183
199 S184
200 S185
201 S186
202 S187
203 S188
204 S189
205 S190
206 S191
207 S192
208 S193
209 S194
210 S195
211 S196
212 S197
213 S198
214 S199
215 S200
216 S201
217 S202
218 S203
219 S204
220 S205
221 S206
222 S207
223 S208
224 S209
225 S210
226 S211
227 S212
228 S213
229 S214
230 S215
231 S216
232 S217
233 S218
234 S219
235 S220
236 S221
237 S222
238 S223
239 S224
240 S225
241 S226
242 S227
243 S228
244 S229
245 S230
246 S231
247 S232
248 S233
249 S234
250 S235
251 S236
252 S237
253 S238
254 S239
255 S240

[0221] Preferred are compounds represented by the following numbers from Table A above: S1-3, S5, S7-9, S11, S16, S18, S22, S26, S28, S30, S35, S37, S46, S48, S50, S52, S54-55, S57, S59, S61, S63, S65, S70, S85, S90, S92, S100-101, S105, S107-143, S145, S147-149, S156-164, S166, S168, S170, S172-175, S184, S186, and S204-240.

[0222] More preferred are compounds represented by the following numbers from Table A above: S1, S8, S11, S26, S30, S37, S44, S46, S48, S50, S52, S54-55, S57, S59, S61, S63, S65, S70, S85, S90, S92, S101, S107-108, S116-118, S122, S126-131, S139, S141, S145, S147, S157-160, S168, S170, S172-175, and S219-229.

[0223] Even more preferred, is a compound represented by the following numbers from Table A above: S1, S8, S11, S26, S30, S37, S48, S50, S54, S61, S65, S70, S85, S101, S107-108, S117, S126-128, S131, S157-160, S174-175,S219-220, and S225-228.

[0224] Yet even more preferred compounds are represented by the following numbers in Table A above: S8, S48, S50, S54, S108, S160, S174, and S220.

[0225] For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, or by separating isomers of a compound of formula I.

[0226] Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. 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 this invention.

[0227] A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids or bases. Examples of suitable bases for salt formation include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. Salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art. For purposes of the invention aluminum, gold and silver salts of the compounds are also contemplated. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms 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 sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, ammonia or sodium bicarbonate.

[0228] The method of treating proliferative diseases (cancer), according to this invention, includes a method for treating (inhibiting) the abnormal growth of cells, including transformed cells, in a patient in need of such treatment (e.g., a mammal such as a human), by administering, concurrently or sequentially, an effective amount of a compound of this invention and an effective amount of a chemotherapeutic agent, biological agent, surgery (e.g. prostatectomy) and/or radiation (preferably γ-radiation). Abnormal growth of cells means cell growth independent of normal regulatory mechanisms (e.g., contact inhibition or apoptosis), including 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.

[0229] 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 (e.g., a mammal such as a human) by administering, concurrently or sequentially, (1) an effective amount of a compound of this invention and (2) an effective amount of an antineoplastic/microtubule agent; biological agent, and/or surgery (e.g. prostatectomy) and/or radiation therapy. Examples of tumors which may be treated include, but are not limited to, epithelial cancers, e.g., prostate cancer, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), breast cancers, renal cancers, colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), ovarian cancer, and bladder carcinoma. Other cancers that can be treated include melanoma, myeloid leukemias (for example, acute myelogenous leukemia), sarcomas, thyroid follicular cancer, and myelodysplastic syndrome.

Biological Data

17β-hydroxysteroid dehydrogenase inhibition data

Methods:

[0230] To prepare human recombinant type 3 17β-hydroxysteroid dehydrogenase enzyme (17β-HSD3), HEK-293 cells stably transfected with human 17β-HSD type 3 were cultured to confluency and harvested for enzyme. The cells were suspended in isolation buffer (20 mM KH2PO4, 1 mM EDTA, 0.25 M Sucrose, 1 mM PMSF, 5 μg/ml pepstatin A, 5 μg/ml antipain and 5 μg/ml leupeptin) to a concentration between 5.0×106 and 1.0×107 cells/ml. The cells were sonicated on ice using a micro-ultrasonic cell disrupter at an output setting of No. 40 for four 10 second bursts. The broken cells were then centrifuged at 100,000×g for 60 min at 4° C., and the resulting pellet was resuspended, aliquoted into microfuge tubes, and stored at −80° C.

[0231] To measure conversion of 14C-androstenedione to 14C-testosterone, which occurs primarily through the enzymatic action of 17β-HSD3, reaction buffer (12.5 mM KH2PO4, 1 mM EDTA), NADPH cofactor (1 mM final), test compound, 17β-HSD3 enzyme (30 μg protein) and 14C-androstenedione substrate (100 nM; 2.7 nCi/tube) were added to 13×100 borosilicate glass tubes to a total volume of 0.5 mL/tube. The tubes were placed in a prewarmed 37° C. water bath for 30 minutes. The reaction was then stopped by adding 1 ml of ethyl ether. The tubes were centrifuged for 20 minutes at 3000 rpm at 4° C. in a table top centrifuge and then snap frozen in a dry ice-methanol bath. The ether layer was decanted into another glass tube, and then evaporated to dryness using compressed nitrogen gas. The samples were resuspended in chloroform (20 mL) and spotted onto silica G60 thin layer chromatography plates. 14C-Androstenedione substrate and 14C-testosterone product were separated by placing the plates in chloroform:ethyl acetate (3:1). The plates were dried, exposed overnight, scanned and quantitated on a FUJI FLA2000 phosphorimager.

[0232] The percent inhibition of 17 β-HSD3 activity is the difference between the percent of maximum specific binding (“MSB”) and 100%. The percent of MSB is defined by the following equation, wherein “dpm” represents “disintegrations per minute”: 1$\%\mathrm{MSB}=\frac{\left(\mathrm{dpm}\mathrm{of}\mathrm{unknown}\right)-\left(\mathrm{dpm}\mathrm{of}\mathrm{nonspecific}\mathrm{binding}\right)}{\left(\mathrm{dpm}\mathrm{of}\mathrm{total}\mathrm{binding}\right)-\left(\mathrm{dpm}\mathrm{of}\mathrm{nonspecific}\mathrm{binding}\right)}\times 100$

[0233] The concentration at which a compound having formula I produces 50% inhibition of binding is then used to determine an inhibition constant (“Ki”) using the Chang-Prusoff equation.

[0234] It will be recognized that the compounds having formula I can inhibit 17β-HSD3 to varying degrees. The compounds useful for practice of the invention exhibit potent affinities to bind 17β-HSD3 as measured by Ki values (in nM). The activities (potencies) for these compounds are determined by measuring their Ki values. The smaller the Ki value, the more active is a compound for inhibiting a particular NK enzyme.

[0235] Compounds of this invention have a range of 17B-Hydroxysteroid dehydrogenase Type 3 binding activity from about 0.005 nM to about >100 nM. Preferably, compounds of this invention have a binding activity in the range of about 0.005 nM to 100 nM, more preferably about 0.005 to 50 nM, and even more preferably about 0.005 nM to 10 nM. Yet even more preferred compounds have a binding activity in the range of about 0.005 nM to 0.050 nM.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] The compounds of the invention may also be deliverable transdermally. The transdermal composition 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.

[0241] Preferably, the compound is administered orally.

[0242] 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.

[0243] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.

[0244] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

[0245] The amount and frequency of administration of the compounds of formula (I) 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 disease being treated. A dosage regimen of the compound of formula (I) can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittant therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

[0246] 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. Table 1.0 below gives ranges of dosage and dosage regimens of some exemplary chemotherapeutic agents useful in the methods of the present invention. 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.

TABLE 1.0
Exemplary Chemotherapeutic Agents
Dosage and Dosage Regimens
	Cisplatin:	50-100	mg/m2 every 4 weeks (IV)*
	Carboplatin:	300-360	mg/m2 every 4 weeks (IV)
	Taxotere:	60-100	mg/m2 every 3 weeks (IV)
	Gemcitabine:	750-1350	mg/m2 every 3 weeks (IV)
	Taxol:	65-175	mg/m2 every 3 weeks (IV)
	*(IV)-intravenously

[0247] Anti-androgenic agents, anti-benign prostatic hyperplasia agents, potassium channel agonists and biological agents 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. It will be apparent to those skilled in the art that the administration of the agents can be varied depending on the disease being treated and the known effects of the agents 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 agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

[0248] Compounds of formula (I) may be produced by processes known to those skilled in the art in the following reaction schemes and in the preparations and examples below.

[0249] The compounds of this invention can be prepared as illustrated by the representative examples below. 256

[0250] As shown in Scheme 1, the piperazine-piperidine core may be added to an appropriate chloride. Deprotection and acylation gives the desired product. 257

[0251] Alternatively, for those more sterically encumbered piperazines, direct coupling is successful in giving the regiochemically desired product, as shown in Scheme 2 above. 258

[0252] The regiochemical analogs can be prepared through the sequential modification of protecting groups as shown in Scheme 3 above. 259

[0253] The synthesis of desired chlorides can be accomplished by the addition of an appropriate organometallic to an appropriate aidehyde (see Scheme 4 above). The resulting alcohol is then converted to the requisite chloride under standard conditions. 260

[0254] The substituted piperazines can be prepared through the reduction of commercially available diketopiperazines, or alternatively from the desired amino acids, as shown in Scheme 5 above. 261

[0255] The N-BOC or N-acyl piperidine acetic acid can be prepared as described previously through the reduction of 4-pyridine acetic acid (see Scheme 6 above).

[0256] The invention disclosed herein is exemplified by the following preparations and examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.

Preparative Example 1

[0257] 262

[0258] To a solution of DCC (43.2 mL, 1.0 M in CH2Cl2, 1.0 eq.) in CH2Cl2 (200 mL) at 0° C. was added N-t-BOC-L-leucine (10 g, 43.2 mmol). To the resulting slurry was added ethyl N-benzylglycinate (8.1 mL, 1.0 eq.) over 15 minutes. The resulting solution was stirred at 0° C. for 2 hours and room temperature 1 hour, filtered and the concentrated to give an oil (20.7 g, LCMS: MH+=407). The intermediate was dissolved in CH2Cl2 (150 mL) through which HCl (g) was bubbled for 4 hours. The solution was purged with N2 and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 and extracted with EtOAc (3×200 mL). The combined organics were washed with water, dried over Na2SO4, filtered and concentrated to give a solid which was used without further purification (11.3 g, 100% yield). LCMS: MH+=261.

Preparative Example 2-5.10

[0259] By essentially the same procedure set forth in Preparative Example 1, using the appropriate amino acids listed in Column 2 of Table 1 below, the compounds listed in Column 3 of Table 1 (CMPD), were prepared.

TABLE 1
Prep. Ex.	Column 2	Column 3	CMPD
2	263	264	LCMS: MH+ = 233
3	265	266	LCMS: MH+ = 261
4	267	268	LCMS: MH+ = 261
5	269	270	LCMS: MH+ = 249
5.10	271	272	LCMS: MH+ = 281

Preparative Example 6

[0260] 273

[0261] To a solution of (S)-3-isopropyl-2,5-piperazinedione (5.0 g, 32 mmol) in THF (100 mL) at 0° C. was added LAH (137 mL, 1.0 M in THF, 4.3 eq.) dropwise. After the addition was complete, the resulting solution was heated to reflux overnight. The reaction mixture was cooled to room temperature and quenched by the slow, sequential addition of water (5.23 mL), 1N NaOH (5.23 mL), and water (5.23 mL). The resulting slurry was diluted with EtOAc and filtered through a plug of Celite. The residue was washed with EtOAc (4×100 mL) and the combined organics concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 5% MeOH, 10% MeOH, 5% (10% NH4OH) in MeOH, 10% (10% NH4OH) in MeOH, and 20% (10% NH4OH) in MeOH in CH2Cl2 to give a solid (3.03 g, 74% yield). LCMS: MH+=129.

Preparative Example 7-13.1

[0262] By essentially the same procedure set forth in Preparative Example 6, using the appropriate piperazinediones listed in Column 2 of Table 2 below, the compounds listed in Column 3 of Table 2 (CMPD) were prepared.

TABLE 2
Prep. Ex.	Column 2	Column 3	CMPD
7	274	275	LCMS: MH+ = 233
8	276	277	LCMS: MH+ = 205
9	278	279	LCMS: MH+ = 233
10	280	281	LCMS: MH+ = 233
11	282	283	LCMS: MH+ = 221
12	284	285	FABMS: MH+ = 235
13	286	287	LCMS: MH+ = 143
13.1	288	289	LCMS: MH+ = 253

Preparative Example 14

[0263] 290

[0264] To a solution of the product from Preparative Example 9 (8.2 g, 31.5 mmol) in CH2Cl2 (300 mL) was added (BOC)2O (7.5 g, 1.02 eq.). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCO3 and separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% EtOAc in hexanes solution as eluent (10.6 g, 99% yield). LCMS: MH+=333.

Preparative Examples 15 and 16

[0265] By essentially the same procedure set forth in Preparative Example 14, using the appropriate compound from Preparative Example 8 and Preparative Example 12 listed in Column 2 of Table 3 below, the compounds listed in Column 3 of Table 3 were prepared:

TABLE 3
Prep. Ex.	Column 2	Column 3	CMPD
15	291	292	LCMS: MH+ = 305
16	293	294	LCMS: MH+ = 335

Preparative Example 17

Step A

[0266] 295

[0267] To a solution of piperidine-4-acetic acid (10.0 g, 70.0 mmol) in EtOH (100 mL) was added concentrated HCl (2.68 mL, 2.2 eq.). The resulting solution was heated at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and used without further purification (10 g, 84% yield).

Step B

[0268] 296

[0269] To a solution of the product from Preparative Example 17, Step A (2.0 g, 9.6 mmol) in CH2Cl2 (30 mL) at 0° C. was added TMSNCO (6.3 mL, 5.0 eq.) followed by TEA (2.0 mL, 1.5 eq.). The resulting solution was stirred at 0° C. for 3 hours and quenched by the addition water and diluted with saturated NaHCO3. The mixture was extracted with CH2Cl2 and the combined organics dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using an 8:92 (10%)NH4OH in MeOH:CH2Cl2 solution as eluent (1.2 g, 60% yield). FABMS: MH+=215.

STEP C

[0270] 297

[0271] A solution of the product from Preparative Example 17, Step B (1.23 g, 5.7 mmol) and LiOH (0.33 g, 2.4 eq.) in CH2Cl2 (29 mL), EtOH (29 mL) and water (14 mL) was heated at reflux 3 hours. The resulting solution was cooled to room temperature, neutralized by the addition of 1N HCl (16.1 mL, 2.98 eq.) and concentrated under reduced pressure. The reaction product was further dried by the azeotropic removal of water with toluene to yield a gum (1.1 g, quantitative yield). FABMS: MH+=187.

Preparative Example 18

Step A

[0272] 298

[0273] To a solution of the product from Preparative Example 17, Step A (2.5 g, 12.0 mmol) and 5-chlorodibenzosuberane (3.4 g, 1.2 eq.) in CH2Cl2 (50 mL) was added TEA (8.4 mL, 5.0 eq.) and the resulting solution stirred overnight. The reaction mixture was quenched by the addition of 1N NaOH and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 50:50 EtOAc: hexanes mix as eluent (3.45 g, 79% yield).

Step B

[0274] 299

[0275] A solution of the product from Preparative Example 18, Step A (3.45 g, 9.5 mL) was heated to reflux in MeOH (100 mL) and 1N NaOH (30 mL, 3 eq.) for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and extracted with Et2O. The aqueous layer was cooled at ˜4° C. to effect crystallization. The resulting slurry was filtered and dried in vacuo to yield colorless crystals (1.9 g, 59% yield). FABMS: MH+=336.

Preparative Example 18.10

[0276] 300

[0277] EtOAc (5.68 mmol, 1.0 eq) was added to LDA (3.97 mL, 1.4 eq, 2.0 M in THF/heptane) at −78° C. The resulting solution was stirred 20 minutes before adding N-BOCA4-pipenidone (1.13 g, 1.0 eq.) in THF (10 mL). The reaction mixture was warmed slowly to room temperature, stirred 2 hours and quenched by the addition of saturated NH4Cl. The resulting solution was diluted with H20 and extracted with EtOAC. The combined organics were washed with H2O and saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50:50 EtOAc mix as eluent (1.0 g, 61% yield). LCMS: MH+=288.

Preparative Example 18.11

[0278] 301

[0279] The compound prepared in Preparative Example 18.10 (0.24 g, 0.84 mmol) was stirred at room temperature in MeOH (3 mL) and NaOH (3 mL) overnight. The reaction mixture was concentrated under reduced pressure, diluted with H2O, and extracted with EtOAc. The aqueous layer was neutralized with 5% citric acid and extracted with EtOAc. The combined organics were washed with H2O, saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude compound was used without further purification (0.17 g, 77% yield).

Preparative Example 19

[0280] 302

[0281] To a solution of N-Boc-4-piperidine acetic acid (described in U.S. Pat. No. 5,874,442) (10.0 g, 41.1 mmol) and TEA (5.7 mL, 1.0 eq.) in toluene (50 mL) at 0° C. was added trimethylacetyl chloride (5.1 mL, 1.0 eq.). The resulting slurry was stirred at 0° C. for 1.5 hours before adding the product from Preparative Example 10 (10.0 g, 43 mmol, 1.05 eq.) in toluene (20 mL) and the resulting solution was warmed to room temperature and stirred overnight. The reaction mixture was neutralized by the addition of 1N NaOH and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 50:50 EtOAc: hexanes solution as eluent (11.1 g, 59% yield). LCMS: MH+=458.

Preparative Example 19.1

[0282] 303

[0283] By essentially the same procedure set forth in Preparative Example 19, the above compound was prepared.

Preparative Example 20

[0284] 304

[0285] By essentially the same procedure set forth in Preparative Example 19, using the product from Preparative Example 11 (0.49 g, 2.0 mmol), the above compound was prepared (0.85 g, 46% yield). LCMS: MH+=446.

Preparative Example 21

[0286] 305

[0287] To a solution of 2(S)-methyl-4-t-butoxycarbonylpiperazine (0.22 g, 1.1 and the product from Preparative Example 18, Step B (0.44 g, 1.2 eq.) in CH2Cl2 (10 mL) was added HOBt (0.19 g, 1.3 eq.), NMM (0.30 mL, 2.5 eq.) and DEC (0.27 g, 1.3 eq.) and the resulting solution stirred at room temperature overnight. The reaction mixture was quenched by the addition of saturated NaHCO3 and extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 2% MeOH in CH2Cl2 solution as eluent (0.54 g, 95% yield). FABMS: MH+=518.

Preparative Example 22

[0288] 306

[0289] By essentially the same procedure set forth in Preparative Example 21, using the product from Preparative Example 7 and N-Boc-piperidine acetic acid, the above compound was prepared. LCMS: MH+=458.

Preparative Example 23

[0290] 307

[0291] A solution of the product from Preparative Example 14 (10.4 g, 31.3 mmol) and 10% Pd/C (1.95 g) in EtOH (130 mL) was hydrogenated on a Parr apparatus at 50 psi overnight. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give the product as an oil (6.93 g, 91% yield) which was used without further purification. LCMS: MH+=243.

Preparative Examples 24-28.10

[0292] By essentially the same procedure set forth in Preparative Example 23, using the appropriate compounds from Preparative Examples 15, 16, 19, 19.1, 20, and 22 listed in Column 2 of Table 4, the compounds listed in Column 3 of Table 4 (CMPD) were prepared.

TABLE 4
Prep. Ex.	Column 2	Column 3	CMPD
24	308	309	LCMS: MH+ = 305
25	310	311	LCMS: MH+ = 245
26	312	313	LCMS: MH+ = 368
27	314	315	LCMS: MH+ = 356
28	316	317	LCMS: MH+ = 368
28.10	318	319	LCMS: MH+ =

Preparative Example 29

[0293] 320

[0294] To a solution of the product from Preparative Example 25 (0.25 g, 1.0 mmol) and 3,4-dichlorobenzaldehyde (0.23 g, 1.3 eq.) in CH2Cl2 (5 mL) was added NaHB(OAc)3 (0.32 g, 1.5 eq.) and AcOH (0.14 mL, 2.4 eq.) and the resulting solution was stirred at room temperature 96 hours. The reaction mixture was quenched by the addition of saturated NaHCO3 and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% EtOAc in CH2Cl2 solution as eluent (0.27 g, 66% yield). FABMS: MH+=403.

Preparative Example 30

[0295] 321

[0296] By essentially the same procedure set forth in Preparative Example 29, using the product from Preparative Example 26, the above compound was prepared (0.33 g, 92% yield). LCMS: MH+=526.

Preparative Example 31

[0297] 322

[0298] A solution of 2,5-dibromopyridine (10 g, 42.2 mmol), TEA (11.6 mL, 2.0 eq.), 1,1-bis(diphenylphosphino)ferrocene (1.4 g, 6 mol %), and Pd(OAc)2 (0.28 g, 3 mol %) in MeOH (40 mL) and DMF (40 mL) was stirred under CO (40 psi) at 50° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50:50 EtOAc: hexanes mix as eluent to give the desired product (5.6 g, 61% yield) and the bis-carbonylated product (1.0 g). LCMS: MH+=216.

Preparative Example 32

[0299] 323

[0300] To a solution of the product from Preparative Example 31 (1.0 g, 4.6 mmol) in CH2Cl2 (15 mL) was added DIBAL-H (10.2 mL, 1M in toluene, 2.2 eq.) at −5° C. The resulting solution was stirred 15 minutes before quenching with saturated Na2SO4. The residue was extracted with CH2Cl2 and the combined organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50:50 EtOAc: hexanes solution as eluent (0.55 g, 64% yield). LCMS: MH+=186.

Preparative Example 33

[0301] 324

[0302] To a solution of 1-chloro-4-iodobenzene (1.07 g, 1.4 eq.) in THF (10 mL) at −40° C. was added isopropylmagnesium chloride (2.3 mL, 2.0 M in THF, 1.4 eq.) dropwise. The resulting solution was stirred at −40° C. for 2 hours before adding the product from Preparative Example 32 (0.56 g, 3.2 mmol) in THF (10 mL). The reaction mixture was warmed to room temperature and stirred 3 hours. The resulting solution was quenched by the addition of saturated NH4Cl an extracted with EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20% EtOAc in hexanes solution as eluent to give an oil (0.3 g, 34% yield). LCMS: MH+=299.

Preparative Example 33.1 and 33.2

[0303] By essentially the same procedure set forth in Preparative Example 33, using the aryl halides in Column 3 and the arylaldehydes in Column 2, the products given in Column 4 of Table 4.1 below were prepared:

TABLE 4.1
Prep. Ex.	Column 2	Column 3	Column 4
33.1	325	326	327
33.2	328	329	330

Preparative Example 34-40

[0304] By essentially the same procedure set forth in Preparative Example 33, using the halides in Table 4.1, Column 2 and the arylaldehydes in Table 4.2, column 3, products in Table 4.1, Column 4 were prepared:

TABLE 4.2
Prep. Ex.	Column 2	Column 3	Column 4
34	331	332	333
35	334	335	336
36	337	338	339
37	340	341	342
38	343	344	345
39	346	347	348
40	349	350	351

Preparative Example 40.1

[0305] 352

[0306] 5-trifluoromethyl-2-furanecarboxylic acid ((500 mg, 2.78 mmol) was dissolved in anhydrous Et2O (3 mL) and LiAlH4 (1.0 M in Et2O, 2.2 mL, 2.2 mmol) was added slowly. The mixture was refluxed for 2 hr, then stirred at rt 20 hr. 5% aqueous KOH (0.15 mL) was added, the mixture was filtered, and the solvent was evaporated. 340 mg (74%) of colorless oil was obtained.

[0307] The oil (330 mg, 1.99 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL), BaMnO4 (2.05 g, 8.0 mmol) was added, and the mixture was stirred and fluxed under N2 3 hr. CH2Cl2 (20 mL) was added, the mixture was filtered through Celite, and the solvent was evaporated. Crude product (110 mg) was directly used for the preparation of Preparative Example 41.6 below.

Preparative Example 40.2

[0308] 353

[0309] 4-nitrobenzonitrile (2.96 g, 20 mmol) was mixed with (CH3)3CSNa (3.36 g, 30 mmol), anhydrous DMSO (40 mL) was added, and the mixture was stirred at rt for 20 hr. The mixture was poured into H2O (1 L) and extracted with Et2O (2×200 mL). The combined extracts were washed with H2O (3×300 mL),dried over Na2SO4, and filtered. The solvent was evaporated and the residue was purified by column chromatography on silicagel with CH2Cl2:hexane (1:1). White solid (2.38 g, 62%) was obtained.

Preparative Example 40.3

[0310] 354

[0311] 4-tert-butylthiobenzonitrile (960 mg, 5.0 mmol) was dissolved in anhydrous toluene (10 mL), the solution was cooled to 0° C., and DIBAL-H (20% in toluene, 7.1 mL, 10 mmol) was added under N2. The mixture was stirred at 0° C. for 2 hr, washed with 1 M HCl (2×100 mL), brine (100 mL), and dried over Na2SO4. After the solvent had been evaporated, 850 mg of crude aldehyde (which was used directly for the preparation of Preparative Example 41.7) was obtained.

Preparative Example 41

[0312] 355

[0313] To a solution of 4-trifluoromethoxybenzaldehyde (0.3 g, 1.6 mmol) in THF (3.0 mL) at −78° C. was added phenylmagnesium bromide (3.16 mL, 1M in THF, 2.0 eq.) dropwise. The resulting solution was stirred at −78° C. for 1 hour and stored at −4° C. overnight. The reaction was quenched by the addition of saturated NH4Cl and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% EtOAc in hexanes solution as eluent (0.39 g, 93% yield).

Preparative Examples 41.1-41.8

[0314] By essentially the same procedure set forth in Preparative Example 41, using the arylaldehydes in Column 2 of Table 4.3 and phenylmagnesium bromide, the products given in Column 3 of Table 4.3 were prepared:

Prep. Ex.	Column 2	Column 3
41.1	356	357
41.2	358	359
41.3	360	361
41.4	362	363
41.5	364	365
41.6	366	367
41.7	368	369
41.8	370	371

Preparative Examples 41.10-41.16

[0315] By essentially the same procedure set forth in Preparative Example 41 only substituting the appropriate compound in column 2 of Table 4.4, the compounds found in column 3 of Table 4.4 were prepared:

TABLE 4.4
Prep. Ex.	Column 2	Column 3
41.10	372	373
41.12	374	375
41.13	376	377
41.14	378	379
41.15	380	381
41.16	382	383

Preparative Example 42

[0316] 384

[0317] By essentially the same procedure set forth in Preparative Example 41, using the 3-bromopyridine-2-carboxaldehyde prepared in Preparative Example 32, the above compound was prepared. LCMS: MH+=264.

Preparative Example 43

[0318] 385

[0319] n-BuLi (4.25 mL, 2.5 M in hexanes, 1,2 eq.) was added dropwise to 1-bromo-3,4-dichlorobenzene (2.0 g, 8.9 mmol) in THF (20 mL) at −78° C. The resulting orange solution was stirred 40 minutes before adding pyridine-2-carboxaldehyde (1.1. mL, 1.3 eq.) dropwise. The reaction mixture was stirred 2 hours at −78° C. and quenched by the addition of water. The resulting solution was extracted with CH2Cl2, dried over Na2SO4, filtered , and concentrated. The crude product was purified by flash chromatography using a 40% EtOAc solution in hexanes as eluent. This partially purified residue was repurified using a 3% MeOH in CH2Cl2 solution as eluent to give an oil (0.37 g, 16% yield).

Preparative Example 44-54.14

[0320] By essentially the same procedure set forth in Preparative Example 43, using the halides in Table 5, Column 2 and the arylaldehydes in Table 5, Column 3, the compounds in Table 5, Column 4 were prepared:

TABLE 5
			Column 4
Prep. Ex.	Column 2	Column 3	RR′CHOH
44	386	387	388
45	389	390	391
46	392	393	394
47	395	396	397
48	398	399	400
49	401	402	403
50	404	405	406
51	407	408	409
52	410	411	412
53	413	414	415
54	416	417	418
54.1	419	420	421
54.12	422	423	424
54.13	425	426	427
54.14	428	429	430

Preparative Example 55

Step A

[0321] 431

[0322] Oxalyl chloride (0.27 mL, 1.2 eq.) was added dropwise to a solution of 2-trifluoromethyl-5-pyridinecarboxylic acid (0.50 g, 2.62 mmol) and DMF (2 drops) in CH2Cl2 (20 mL) and the resulting solution was heated to reflux. The reaction mixture was cooled and concentrated under reduced pressure. The residue was redissolved in CH2Cl2 (10 mL) and treated with diisopropylethylamine (0.7 mL, 2.3 eq.) and N, O-dimethylhydroxylamine (0.19 g, 1.2 eq.). The resulting solution was stirred at room temperature 3 days, quenched by the addition of water (25 mL) and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction was purified by flash chromatography using a 70:30 EtOAc: hexanes mix as eluent to give an oil (0.29 g, 70% yield). LCMS: MH+=235.

Step B

[0323] 432

[0324] Phenylmagnesium chloride (2.91 mL, 1.0 M in THF, 3.0 eq.) was added to the product from Preparative Example 55, Step A (0.23 g, 0.97 mmol) in THF (10 mL) at 0° C. The resulting solution was warmed slowly to room temperature and stirred 6 hours. The reaction was quenched by the addition of water and extracted with CH2Cl2. 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 (0.24 g, quantitative yield). LCMS; MH+=252.

Step C

[0325] 433

[0326] The product from Preparative Example 55, Step B (0.23 g, 0.93 mmol) in EtOH (3.0 mL) and toluene (3.0 mL) was stirred at room temperature with NaBH4 (0.053 g, 1.5 eq.) 5 hours. The resulting solution was quenched by the addition of water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 30% EtOAc in hexanes solution as eluent (0.15 g, 66% yield). LCMS: MH+=254.

Preparative Example 55.1

[0327] 434

[0328] To a solution of 4-hydroxybenzophenone (0.50 g, 2.52 mmol) and K2CO3 (0.52 g, 1.5 eq.) in DMF (6 mL) was added trifluromethansulfonic acid 2,2,2-trifluoroethyl ester and the resulting solution was heated to 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and water and extracted. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using an 80:20 hexanes: EtOAc mix as eluent (0.67 g, 94% yield). LCMS: MH+=281.

Preparative Example 55.10

[0329] 435

[0330] By essentially the same procedure set forth in Preparative Example 55, Step B only substituting 4-chlorophenylmagesium chloride, the above compound was prepared (% yield). LCMS: MH+=.

Preparative Example 55.11

[0331] 436

[0332] A solution of 4-hydroxybenzophenone (1.0 g, 5.04 mmol), dimethylaminoethyl chloride hydrochloride (1.09 g, 1.5 eq.), and K2CO3 (3.48 g, 5.0 eq.) was heated at reflux 24 hours in acetone (50 mL). The resulting solution was cooled to room temperature and stirred an additional 32 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with 1N HCl (3×25 mL) and the combined aqueous washings neutralized with 1N NaOH and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated and used without further purification (1.36 g, 100% yield): LCMS MH+=270.

Preparative Examples 55.12-55.14

[0333] By essentially the same procedure set forth in Preparative Example 55.11, only substituting the appropriate chloride in column 1 of Table 5.11, the title compounds in column 2 of Table 5.11 were prepared.

TABLE 5.11
Prep. Ex.	Column 1	Column 2
55.12	437	438
55.13	439	440
55.14	441	442

Preparative Example 55.15

[0334] 443

[0335] A solution of 4-hydroxybenzophenone (1.0 g, 5.04 mmol), sodium chlorodifluoroacetate (0.77 g, 1.0 eq.), and NaOH (0.20 g, 1.0 eq.) in DMF (10 mL) and H2O (1.4 mL) was heated to 120-125° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with 1N NaOH and extracted with EtOAc. The combined organics were washed with H2O, saturated NaCl, and dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a 15% EtOAc in hexanes solution as eluent (0.39 g, 31% yield): LCMS MH+=249.

Preparative Examples 55.16-55.17

[0336] By essentially the same procedure set forth in Preparative Example 15 only substituting the appropriate compounds in column 1 of Table 5.12, the compounds in column 2 of Table 5.12 were prepared.

TABLE 5.12
Prep. Ex.	Column 1	Column 2	CMPD
55.16	444	445	—
55.17	446	447	LCMS: MH+ = 249

Preparative Example 55.18

[0337] 448

[0338] A solution of 4-hydroxybenzophenone (2.0 g, 10.9 mmol), neopentyl bromide (3.05 g, 2 eq.), K2CO3 (2.79 g, 2.0 eq.), Kl (2.85 g, 1.7 eq.), and Cul (38 mg, 2 mol %) in DMF (10 mL) was heated to 95° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 30% EtOAc in hexanes solution as eluent (0.1 g, 4% yield).

Preparative Example 55.19

[0339] 449

[0340] Trimethylacetyl chloride (0.75 mL, 1.2 eq.) was added to a solution of 4-aminobenzophenone (1.0 g, 5.07 mmol) and TEA (1.06 mL, 1.5 eq.) in CH2Cl2 (30 mL) at 0° C. The resulting solution was stirred 1.5 hours, warmed to room temperature and quenched by the addition of saturated NaHCO3. The resulting solution was extracted with CH2Cl2, the combined organics dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 30% EtOAC in hexane solution as eluent (1.28 g, 90% yield). LCMS: MH+=282.

Preparative Example 55.191

[0341] 450

[0342] By essentially the same procedure set forth in Preparative Example 55.19, only substituting trifluorosulfonic anhydride, the above compound was prepared.

Preparative Example 55.192

[0343] 451

[0344] To a solution of the compound from Preparative Example 177 (0.25 g, 0.405 mmol) in THF (5 mL) at −78° C. was added lithium hexamethyldisilazane (0.89 mL, 2.0M in hexanes, 2.2 eq.) dropwise. The resulting solution was stirred 5 minutes and Mel (0.2 mL, 8.0 eq.) was added. The resulting solution was warmed to room temperature and stirred overnight. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 75:25 hexanes: EtOAc solution as eluent (0.030 g, 12% yield). LCMS: MH+=632.

Preparative Example 55.2

[0345] 452

[0346] By essentially the same procedure set forth in Preparative Example 55.1, only substituting 3-fluoro-4-hydroxybenzaldehyde, the above compound was prepared (0.70 g, 89% yield): LCMS MH+=223.

Preparative Example 56

[0347] 453

[0348] By essentially the same procedure set forth in Preparative Example 55, Step C, using 4-chloro-4′-hydroxybenzophenone (2.0 g, 8.6 mmol) gave the above compound (0.77 g, 34% yield).

Preparative Example 56.1

[0349] 454

[0350] By essentially the same procedure set forth in Preparative Example 55, Step C, using the product from Preparative Example 55.1, the above compound was prepared (0.63 g, 97% yield) and used without further purification.

Preparative Example 56.2

[0351] 455

[0352] 4-methylthiobenzhydrol (1.15 g, 5.0 mmol) was dissolved in acetic acid (25 mL) and H2O2 (35% in H2O, 5.0 mL) was added. The mixture was stirred at 40° C. for 3 days and poured onto NaHCO3 (100 g). Water (800 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica with CH2Cl2:EtOAc (5:1). White solid (1.21 g, 92%) was obtained.

[0353]

Preparative Example 56.3 and 56.4

[0354] 4-Trifluoromethylsulfonylbenzhydrol and 4-t-butylsulfonylbenzhydrol were prepared using a similar method to that described in Preparative Example 56.2.

Preparative Examples 56.10-56.25

[0355] By essentially the same procedure set forth in Preparative Example 56, only substituting the appropriate compounds in Column 2 of Table 5.14, the compounds in Column 2 of Table 5.14 were prepared:

TABLE 5.14
Prep. Ex.	Column 1	Column 2
56.10	456	457
56.11	458	459
56.12	460	461
56.13	462	463
56.14	464	465
56.15	466	467
56.16	468	469
56.17	470	471
56.18	472	473
56.19	474	475
56.20	476	477
56.21	478	479
56.22	480	481
56.23	482	483
56.24	484	485

Preparative Example 57

[0356] 486

[0357] To a solution of 4,4′-dichlorobenzhydrol (1.0 g, 3.95 mmol) in toluene (10 mL) at 0° C. was added SOCl2 (0.52 mL, 1.7 eq. ) dropwise. The resulting solution was stirred at 0° C. 1 hour and warmed to room temperature and stirred overnight. The crude reaction mixture was concentrated under reduced pressure to give the above compound which was used without further purification (1.02 g, 95% yield).

Preparative Examples 58-82.43

[0358] By essentially the same procedure as set forth in Preparative Example 57, the compounds in Table 6, Column 3 were prepared from the corresponding alcohols Column 2:

TABLE 6
Prep. Ex.	Column 2	Column 3
58	487	488
59	489	490
60	491	492
61	493	494
62	495	496
63	497	498
64	499	500
65	501	502
66	503	504
67	505	506
68	507	508
69	509	510
70	511	512
71	513	514
72	515	516
73	517	518
74	519	520
75	521	522
76	523	524
77	525	526
78	527	528
79	529	530
80	531	532
81	533	534
82	535	536
82.1	537	538
82.2	539	540
82.3	541	542
82.4	543	544
82.5	545	546
82.6	547	548
82.7	549	550
82.8	551	552
82.9	553	554
82.10	555	556
82.11	557	558
82.12	559	560
82.30	561	562
82.31	563	564
82.32	565	566
82.33	567	568
82.34	569	570
82.35	571	572
82.36	573	574
82.37	575	576
82.38	577	578
82.39	579	580
82.40	581	582
82.41	583	584
82.42	585	586
82.43	587	588

Preparative Example 83

[0359] 589

[0360] Ac2O (102 mg, 1.0 mmol) and TEA (303 mg, 3.0 mmol) were added under N2 to a stirred solution of bis(3-thienyl)methanol in anhydrous CH2Cl2 (5 mL). The mixture was stirred for 16 hrs, poured into saturated aqueous NaHCO3, and extracted with CH2Cl2 (3×10 mL). The extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography using. CH2Cl2 to give 70 mg (58%) of a solid.

Preparative Example 84

[0361] 590

[0362] By essentially the same procedure set forth in Preparative Example 83, using the bis(2-thienyl)methanol, the above compound was prepared.

Preparative Example 85

[0363] 591

[0364] A solution of the product from Preparative Example 26 (0.35 g, 0.95 mmol), 4-chlorobenzhydryl chloride (0.27 mL, 1.2 eq.), K2CO3 (0.33 g, 2.5 eq.), and Kl (0.063 g, 40 mol %) in CH3CN (25 mL) was heated to reflux for 22 hours. The reaction mixture was cooled, diluted with water, and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 60:40 hexanes: EtOAc mix as eluent (0.32 g, 59% yield). LCMS: MH+=568.

Preparative Examples 86-106.28L

[0365] By essentially the same procedure set forth in Preparative Example 85, using the amines listed in Column 2 and the chlorides listed in Column 3, of Table 7 below, the compounds in Table 7, Column 4 (CMPD) were prepared:

TABLE 7
Prep. Ex.	Column 2	Column 3	Column 4	CMPD
86	592	593	594	LCMS: MH+ = 312
87	595	596	597	—
88	598	599	600	—
89	601	602	603	FABMS: MH+ = 445
90	604	605	606	LCMS: MH+ = 449
91	607	608	609	FABMS: MH+ = 479
92	610	611	612	LCMS: MH+ = 569
93	613	614	615	—
94	616	617	618	LCMS: MH+ = 618
95	619	620	621	LCMS: MH+ = 602
96	622	623	624	LCMS: MH+ = 602
97	625	626	627	LCMS: MH+ = 570
98	628	629	630	LCMS: MH+ = 570
99	631	632	633	LCMS: MH+ = 590
100	634	635	636	LCMS: MH+ = 602
101	637	638	639	LCMS: MH+ = 647
102	640	641	642	LCMS: MH+ = 613
103	643	644	645	LCMS: MH+ = 697
104	646	647	648	LCMS: MH+ = 681
105	649	650	651	—
105.1	652	653	654	LCMS: MH+ = 702
105.2	655	656	657	LCMS: MH+ = 632
106	658	659	660	LCMS: MH+ = 584
106.1	661	662	663
106.2	664	665	666
106.3	667	668	669
106.4	670	671	672
106.5	673	674	675
106.6	676	677	678
106.7	679	680	681
106.8	682	683	684
106.9	685	686	687
106.10	688	689	690
106.11	691	692	693
106.12	694	695	696
106.13	697	698	699
106.14	700	701	702
106.15	703	704	705
106.16	706	707	708	LCMS: MH+ = 650
106.17	709	710	711	LCMS: MH+ = 644
106.18	712	713	714	LCMS: MH+ = 610
106.19	715	716	717	LCMS: MH+ = 622
106.20	718	719	720	LCMS: MH+ = 673
106.21	721	722	723	LCMS: MH+ = 600
106.22	724	725	726	LCMS: MH+ = 600
106.23	727	728	729	LCMS: MH+ = 621
106.24	730	731	732	LCMS: MH+ = 661
106.25	733	734	735	LCMS: MH+ = 636
106.26	736	737	738	LCMS: MH+ = 552
106.27	739	740	741	LCMS: MH+ = 620
106.28	742	743	744	LCMS: MH+ = 550
106.28A	745	746	747	LCMS: MH+ = 633
106.28B	748	749	750	LCMS: MH+ = 681
106.28C	751	752	753	LCMS: MH+ = 559
106.28D	754	755	756	LCMS: MH+ = 584
106.28E	757	758	759	LCMS: MH+ = 604
106.28F	760	761	762	LCMS: MH+ = 646
106.28G	763	764	765	LCMS: MH+ = 662
106.28H	766	767	768	LCMS: MH+ = 660
106.28I	769	770	771	LCMS: MH+ = 618
106.28J	772	773	774	LCMS: MH+ = 622
106.28K	775	776	777	LCMS: MH+ = 379
106.28L	778	779	780	LCMS: MH+ = 637

Preparative Example 106.28M

[0366] 781

[0367] By essentially the same procedure set forth in Preparative Example 21, only substituting the product from Preparative Example 106.28K, the above compound was prepared (54% yield). LCMS: MH+=604.

Preparative Examples 106.29 and 106.30

[0368] By essentially the same procedure set forth in Preparative Example 55.11, only substituting compound prepared in Preparative Example 106.28 and the iodide in Column 2 of Table 7.1, the compounds in Column 3 of Table 7.1 (CMPD) were prepared:

TABLE 7.1
Prep. Ex.	Column 2	Column 3	CMPD
106.29	Ethyl iodide	782	LCMS: MH+ = 578
106.30	Isopropyl iodide	783	LCMS: MH+ = 592

Preparative Example 107 and 108

[0369] 784

[0370] The above compounds were prepared by the separation of the diastereomers of the product from Preparative Example 92:

[0371] Preparative Example 107 (first eluting isomer-1): LCMS: MH+=569.

[0372] Preparative Example 108 (second eluting isomer-2): LCMS: MH+=569.

Preparative Example 109 and 110

[0373] 785

[0374] The above compounds were prepared by the separation of the diastereomers of the product from Preparative Example 93 by flash chromatography using a 10% hexanes in EtOAc solution as eluent:

[0375] Preparative Example 109 (first eluting isomer-1): LCMS: MH+=603.

[0376] Preparative Example 110 (second eluting isomer-2): LCMS: MH+=603.

Preparative Example 111 and 112

[0377] 786

[0378] The above compounds were prepared through the separation of diastereomers of the product from Preparative Example 101 using preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA with 0.2% DEA as eluent:

[0379] Preparative Example 111 (first eluting isomer-1): LCMS: MH+=647.

[0380] Preparative Example 112 (second eluting isomer-2): LCMS: MH+=647.

Preparative Example 113 and 114

[0381] 787

[0382] The above compounds were prepared through the separation of diastereomers of the product from Preparative Example 102 by preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA with 0.2% DEA as eluent:

[0383] Preparative Example 113 (first eluting isomer-1): LCMS: MH+=613.

[0384] Preparative Example 114 (second eluting isomer-2): LCMS: MH+=613.

Preparative Example 115 and 116

[0385] 788

[0386] The above compounds were prepared through the separation of diastereomers of the product from Preparative Example 103 by preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA with 0.2% DEA as eluent:

[0387] Preparative Example 115 (first eluting isomer-1): LCMS: MH+=697.

[0388] Preparative Example 116 (second eluting isomer-2): LCMS: MH+=697.

Preparative Example 117 and 118

[0389] 789

[0390] The above compounds were prepared through the separation of diastereomers of the product from Preparative Example 104 by preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA with 0.2% DEA as eluent:

[0391] Preparative Example 117 (first eluting isomer-1): LCMS: MH+=681.

[0392] Preparative Example 118 (second eluting isomer-2): LCMS: MH+=681.

Preparative Example 119 and 120

[0393] 790

[0394] The above compounds were prepared through the separation of diastereomers of the product from Preparative Example 105 by preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA with 0.2% DEA as eluent:

[0395] Preparative Example 119 (first eluting isomer-1): LCMS: MH+=603.

[0396] Preparative Example 120 (second eluting isomer-2): LCMS: MH+=603.

Preparative Example 124

[0397] 791

[0398] The product from Preparative Example 91 (0.28 g, 0.58 mmol) was stirred at room temperature in 4M HCl in dioxane for 1 hour. The resulting solution was concentrated under reduced pressure and used without further purification.

Preparative Examples 125-130

[0399] By essentially the same procedure set forth in Preparative Example 124, using the compounds shown in Table 9, Column 2, the compounds in Table 9, Column 3 were prepared:

TABLE 9
Prep. Ex.	Column 2	Column 3
125	792	793
126	794	795
127	796	797
128	798	799
129	800	801
130	802	803

Preparative Example 134

[0400] 804

[0401] A solution of the product from Preparative Example 57 (2.13 g, 3.52 mmol), the product from Preparative Example 6 (1.0 g, 3.52 mmol) and Nal (0.23 g, 20 mol % in CH3CN (50 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, quenched by the addition of saturated NaHCO3, and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated, The crude product was purified by flash chromatography using a 5% (10% NH4OH in CH2Cl2 solution as eluent to afford a solid (1.8 g, 64% yield). LCMS: MH30 =363.

Preparative Examples 135-144.10

[0402] By essentially the same procedure set forth in Preparative Example 134, using the chlorides as shown in Column 2 of Table 10, and the amines as shown in column 3 Table 10, the products in Column 4 of Table 10 (CMPD), were prepared:

TABLE 10
Prep. Ex.	Column 2	Column 3	Column 4	CMPD
135	805	806	807	—
136	808	809	810	LCMS: MH+ = 320
137	811	812	813	LCMS: MH+ = 331
138	814	815	816	LCMS: MH+ = 330
139	817	818	819	LCMS: MH+ = 408
140	820	821	822	LCMS: MH+ = 349
141	823	824	825	LCMS: MH+ = 349
142	826	827	828	LCMS: MH+ = 363
143	829	830	831	FABMS: MH+ = 321
144	832	833	834	LCMS: MH+ = 295
144.10	835	836		LCMS: MH+ = 377

Preparative Examples 145 and 146

[0403] 837

[0404] The products were prepared by separation of the mixture of diastereomers of the product from Preparative Example 138 by flash chromatography using a 5% (10% NH4OH in MeOH) in CH2Cl2 as eluent:

[0405] Preparative Example 145 (first eluting isomer-1): LCMS: MH+=330.

[0406] Preparative Example 146 (second eluting isomer-2): LCMS: MH+=330.

Preparative Example 149

STEP A

[0407] 838

[0408] To a solution of anhydride (1.5 g, 5.85 mmol) in THF (10 mL) at −10° C. was added MeMgBr (5.85 mL, 1.0 M in THF, 3.0 eq.). The resulting solution was stirred one hour at −10° C., warmed to room temperature and stirred one hour. The reaction mixture was quenched by the addition of saturated NH4Cl and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% MeOH in CH2Cl2 solution as eluent (0.20 g, 14% yield). LCMS: MH+=245.

STEP B

[0409] 839

[0410] The product from Preparative Example 149, Step A was stirred at room temperature in 4 M HCl in dioxane (4.0 mL) for 10 minutes and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH3CN (10 mL) and the product from Preparative Example 30 (0.24 g, 1.2 eq.), K2CO3 (0.91 g, 8 eq.), and Kl (0.054 g, 40 mol %) added. The resulting solution was heated to reflux overnight. The reaction mixture was cooled to room temperature, dilute with water and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% (10% NH4OH in MeOH) in CH2Cl2 as eluent (0.20 g, 65% yield). LCMS: MH+=379.

Preparative Example 150

[0411] 840

[0412] The product from Preparative Example 134 (0.5 g, 1.2 eq.), N-Boc-4-piperadineacetic acid (0.28 g, 1.14 mmol), DEC (0.28 g, 1.3 eq.), HOBt (0.20 g, 1.3 eq.), and NMM (90.31 mL, 2.5 eq.) were stirred at room temperature in CH2Cl2 for 3 days. The reaction mixture was poured into saturated NaHCO3 and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) in CH2Cl2 as eluent to yield a solid (0.57 g, 85% yield). LCMS: MH+=588.

Preparative Examples 151-172

[0413] By essentially the same procedure set forth in Preparative Example 150, using the compounds as shown in Column 2 of Table 11, the products in Column 3 of Table 11, were prepared:

TABLE 11
Prep. Ex.	Column 2	Column 3	CMPD
151	841	842	—
152	843	844	LCMS: MH+ = 537
153	845	846	LCMS: MH+ = 571
154	847	848	FABMS: MH+ = 602
155	849	850	FABMS: MH+ = 570
156	851	852	LCMS: MH+ = 574
157	853	854	LCMS: MH+ = 554
158	855	856	LCMS: MH+ = 545
159	857	858	LCMS: MH+ = 556
160	859	860	LCMS: MH+ = 633
161	861	862	LCMS: MH+ = 588
162	863	864	FABMS: MH+ = 493
163	865	866	FABMS: MH+ = 546
164	867	868	LCMS: MH+ = 555
165	869	870	LCMS: MH+ = 555
171	871	872	LCMS: MH+ = 604
172	873	874	LCMS: MH+ = 520

Preparative Example 172.10

[0414] 875

[0415] By essentially the same procedure set forth in Preparative Example 150, only substituting the compounds prepared in Preparative Example 144 (0.16 g, 0.55 mmol) and Preparative Example 18.11 (0.17 g, 1.2 eq.), the above compound was prepared (0.11 g, 31% yield). LCMS: MH+=536.

Preparative Examples 173 and 174

[0416] By essentially the same procedure set forth in Preparative Example 19, using the compounds shown in Table 12, Column 2, the products shown in Table 12, Column 3 (CMPD) were prepared.

TABLE 12
Prep. Ex.	Column 2	Column 3	CMPD
173	876	877	LCMS: MH+ = 574
174	878	879	LCMS: MH+ = 574

Preparative Example 175 and 176

[0417] 880

[0418] The product from Preparative Example 85 was separated into individual diastereomers by preparative HPLC with a ChiralPak AD column using a 95:5 hexanes: IPA mix with 0.2% DEA as eluent:

[0419] Preparative Example 175 (first eluting isomer-1): LCMS: MH+=568.

[0420] Preparative Example 176 (second eluting isomer-2): LCMS: MH+=568.

Preparative Example 177 and 178

[0421] 881

[0422] The product from Preparative Example 94 was separated into individual diastereomers using a ChiralPak AD column using a 95:5 hexanes: IPA mix with 0.2% DEA as eluent. Following elution of isomer 1, the eluent was adjusted to a 90:10 hexanes: IPA mix with 0.2% DEA for the elution of isomer 2.

[0423] Preparative Example 177 (first eluting isomer-1): LCMS: MH+=618.

[0424] Preparative Example 178 (second eluting isomer-2): LCMS: MH+=618.

Preparative Example 179 and 180

[0425] 882

[0426] The product from Preparative Example 95 was separated into individual diastereomers using a ChiralPak AD column using a 95:5 hexanes: IPA mix with 0.2% DEA as eluent:

[0427] Preparative Example 179 (first eluting isomer): LCMS: MH+=603, mp=69-74° C.

[0428] Preparative Example 180 (second eluting isomer):LCMS:MH+=603; mp=74-79° C.

Preparative Examples 180.1 and 180.2

[0429] 883

[0430] The product from Preparative Example 106.6 was separated into the two individual diastereomers shown here. Chromatography on a Chiralpak AD column using a 95:5 hexanes:IPA mix with 0.2% DEA as eluent afforded Preparative Example 180.1 (first eluting isomer) as a white solid and Preparative Example 180.2 (second eluting isomer) as a white solid.

Preparative Example 180.3 and 180.4

[0431] 884

[0432] The product from Preparative Example 106.1 was separated into the two individual diastereomers shown above. Chromatography on a Chiralpak AD column using a 98:2 hexanes:IPA mix with 0.2% DEA as eluent afforded Preparative Example 180.3 (first eluting isomer)=Isomer 1 and Preparative Example 180.4 (second eluting isomer)=Isomer 2.

Preparative Examples 180.5 and 180.6

[0433] 885

[0434] The product from Preparative Example 106.9 was separated into the two individual diastereomers shown above. Chromatography on a Chiralpak AD column using a 95:5 hexanes:IPA mix with 0.2% DEA as eluent afforded Preparative Example 180.5 (first eluting isomer)=Isomer 1 and Preparative Example 180.6 (second eluting isomer)=Isomer 2.

Preparative Example 180.7 and 180.8

[0435] 886

[0436] The product from Preparative Example 106.8 was separated into the two individual diastereomers shown above. Chromotography on a Chiralpak AD column using a 90:10 hexanes:IPA mix with 0.2% DEA as eluent afforded Preparative Example 180.7 (first eluting isomer)=Isomer 1 and Preparative Example 180.8 (second eluting isomer)=Isomer 2.

Preparative Examples 180.9 and 180.10

[0437] 887

[0438] The product from Preparative Example 106.12 was separated into the two individual diastereomers shown above. Chromatography on a Chiralpak AD column using a 85:15 hexanes:IPA mix with 0.2% DEA as eluent afforded Preparative Example 180.9 (first eluting isomer)=Isomer 1, and Preparative Example 180.10 (second eluting isomer)=Isomer 2.

Preparative Examples 180.10A-180.39

[0439] By essentially the same procedure set forth in Preparative Example 180, only substituting the diastereomeric mixture from the Preparative Example indicated in Column 2 of Table 12.1 and substituting the eluting solvent in Column 3 of Table 12.1, the compounds in Column 4 of Table 12.1 (CMPD) were prepared:

TABLE 12.1
Prep. Ex.	Column 2	Column 3	Column 4	CMPD
180.10A	106.16	95:5 hex: IPA with 0.2% DEA	888	LCMS: MH+ = 650
180.11	106.16		889	LCMS: MH+ = 650
180.12	106.17	97:3 hex: IPA with 0.1% DEA	890	LCMS: MH+ = 644
180.13	106.17		891	LCMS: MH+ = 644
180.14	106.18	97:3 hex: IPA with 0.1% DEA	892	LCMS: MH+ = 610
180.15	106.18		893	LCMS: MH+ = 610
180.16	106.19	97:3 hex: IPA with 0.1% DEA	894	LCMS: MH+ = 622
180.17	106.19		895	LCMS: MH+ = 622
180.18	106.20	97:3 hex: IPA with 0.2% DEA	896	LCMS: MH+ = 673
180.19	106.20		897	LCMS: MH+ = 673
180.20	106.23	93.5:6.5 hex: IPA with 0.2% DEA	898	LCMS: MH+ = 621
180.21	106.23		899	LCMS: MH+ = 621
180.22	106.24	95:5 hex: IPA with 0.1% DEA	900	LCMS: MH+ = 661
180.23	106.24		901	LCMS: MH+ = 661
180.24	106.26	97:3 hex: IPA with 0.1% DEA	902	LCMS: MH+ = 552
180.25	106.26		903	LCMS: MH+ = 552
180.26	106.27	98:2 hex: IPA with 0.1% DEA	904	LCMS: MH+ = 620
180.27	106.27		905	LCMS: MH+ = 620
180.28	106.29	95:5 hex: IPA with 0.1% DEA	906	LCMS: MH+ = 578
180.29	106.29		907	LCMS: MH+ = 578
180.30	106.28E		908
180.31	106.28E	95:5 hex: IPA with 0.1% DEA	909	LCMS: MH+ = 604
180.32	106.28F	98:2 hex: IPA with 0.1% DEA	910	LCMS: MH+ = 646
180.33	106.28F		911	LCMS: MH+ = 646
180.34	106.28G	99:1 hex: IPA with 0.1% DEA	912	LCMS: MH+ = 662
180.35	106.28G		913	LCMS: MH+ = 662
180.36	106.28L	93:7 hex: IPA with 0.2% DEA	914	LCMS: MH+ = 637
180.37	106.28L		915	LCMS: MH+ = 637
180.38	106.28M	95:5 hex: IPA with 0.2% DEA	916	LCMS: MH+ = 604
180.39	106.28M		917	LCMS: MH+ = 604

Preparative Example 181

[0440] 918

Step A

[0441] To the product from Preparative Example 10 (1.64 g, 7.06 mmol) and NaHCO3 (1.19 g, 2 eq.) in CH2Cl2 (30 mL) at 0° C. was added bromoacetyl bromide (0.68 mL, 1.1 eq.) dropwise. The resulting solution was warmed slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (2.2 g, 92% yield) was used without further purification. LCMS: MH+=353.

Step B

[0442] 919

[0443] To the product from Preparative Example 181, Step A (2.2 g, 6.23 mmol) and K2CO3 (1.72 g, 2.0 eq.) in CH3CN (50 mL) was added N-BOC-piperazine (1.35 g, 1.2 eq.). The resulting solution was heated to reflux 2 hours, cooled, and diluted with water. The resulting solution was extracted with EtOAc and the combined organics dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 50:50 EtOAc: hexanes solution as eluent (0.77 g, 27% yield). LCMS: MH+=459.

Step C

[0444] 920

[0445] The product from Preparative Example 181, Step B (0.77 g, 1.68 mmol), ammonium formate (2.12 g, 20 eq.) and 10% Pd/C (1.48 g, 50% wet) in EtOH (20 mL) was heated to reflux 4 hours. The resulting solution was cooled, filtered through a plug of Celite and concentrated. The residue was taken up in CH2Cl2 and washed with water. The crude product was purified by flash chromatography using a 7% (10% NH4OH in MeOH in CH2Cl2 solution as eluent (0.57 g, 92% yield). LCMS: MH+=369.

Step D

[0446] 921

[0447] By essentially the same procedure set forth in Preparative Example 85, using the product from Preparative Example 181, Step C, the above compound was prepared (0.14 g, 16% yield). LCMS: MH+=603.

Preparative Example 181.11

[0448] 922

[0449] By essentially the same procedure set forth in Preparative Example 181, Step A only substituting the compound prepared in Preparative Example 144.10, the above compound was prepared. LCMS: MH+=497.

Preparative Example 181.12 and 181.13

[0450] By essentially the same procedure set forth in Preparative Example 181, Step B, only substituting the compounds in Column 2 of Table 12.2, the compounds in Column 3 of Table 12.2 (CMPD) were prepared:

TABLE 12.2
Prep.
Ex.	Column 2	Column 3	CMPD
181.12	923	924	LCMS: MH+ = 531
181.13	925	926	LCMS: MH+ = 531

Preparative Example 182

Step A

[0451] 927

[0452] The product from Preparative Example 21 (0.53 g, 1.0 mmol) was stirred in 4M HCl/dioxane (8.0 mL) at room temperature 30 minutes and concentrated under reduced pressure. The crude product was diluted with CH3CN (10 mL) and by essentially the same procedure set forth in Preparative Example 134 the product was prepared (0.05 g, 25% yield). FaBMS: MH+=652.

Step B

[0453] 928

[0454] The product from Preparative Example 182, Step A (0.03 g, 0.05 mmol) in 1:1 CH2Cl2:HCO2H was stirred at room temperature 5 hours then at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradient column from 1% (10% NH4OH in MeOH) in CH2Cl2 to 20% (10% NH4OH in MeOH) in CH2Cl2 (0.01 g, 48% yield). LCMS: MH+=460.

Preparative Example 183

[0455] 929

[0456] A solution of the product from Preparative Example 150 (0.35 g, 0.59 mmol) was stirred at room temperature in 4M HCl in dioxane (4 mL) for 30 minutes. The resulting solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and neutralized by the addition of 1 N NaOH, separated, and the organics dried over Na2SO4, filtered and concentrated to give a solid (0.31 g, 94% yield) which was used without further purification. LCMS: MH+=488.

Preparative Example 239

[0457] 930

[0458] A solution of the product from Example 611 (1.00 g, 2.20 mmol) below, and HCOONH4 (2.77 g, 44.0 mmol) in anhydrous MeOH (30 mL) was added under N2 to a suspension of 10% Pd/C (1.17 g) in anhydrous MeOH (20 mL). The mixture was stirred for 16 hrs under N2, poured into 250 CH2Cl2 (250 mL), and filtered through Celite. The solvent was evaporated and the residue was purified by flash chromatography using 11% MeOH (10% NH4OH) in CH2Cl2 to give 555 mg (87%) of a solid.

Preparative Example 240

[0459] 931

[0460] Using essentially the same procedure as described in Preparative Example 239, 1.00 g (2.20 mmol) of the product from Example 612 below, was converted into 520 mg (81%) of a solid.

Preparative Example 241

[0461] 932

[0462] (−)-3(R)-Isopropyl-2,5-piperazinedione (5 g) (32 mmoles) was dissolved in dry THF (167.5 mL) and the solution was cooled to 0° C. A 1M solution of LiAlH4 in THF (115.25 mL) (115.25 mmoles) was added dropwise over 20 minutes. The mixture was heated under reflux at 65° C. for 5 h and then stirred at 25° C. for 16 h. Distilled water (37.5 mL) was added dropwise to the stirred reaction mixture, followed by 1 N NaOH (21.25 mL) and additional distilled water (37.5 mL). The mixture was extracted with ethyl acetate (1.75 L) and the latter was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (40×6.5 cm) using gradient elution with 3%, 4%, 6% and 9% (10% NH4OH in methanol)-dichloromethane as the eluant to give the product (2.4 g; 58%): [α]D25° C. +3.7° (c=5.7 mg/2 mL MeOH).

Preparative Example 242

[0463] 933

[0464] The product from Preparative Example 241 (555.2 mg) (4.33 mmoles) above, was dissolved in anhydrous DMF (16.7 mL). 4-methylmorpholine (0.476 mL) (4.33 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (830 mg) (4.33 mmoles), 1-hydroxybenzotriazole (585.2 mg) (4.33 mmoles) and N-acetylpiperidine-4-acetic acid (802.3 mg) (4.33 mmoles) was added and the mixture was stirred under argon at 25° C. for 41 h. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous NaHCO3.

[0465] The dichloromethane layer was dried (MgSO4), filtered and evaporated to dryness and the residue was chromatographed on a silica gel column (20×5 cm) using 3% (10% NH4OH in methanol)-dichloromethane as the eluant to give the product (1.25 g; 98%): [α]D25° C. +16.6° (c=5.6 mg/2 mL MeOH).

EXAMPLE 500

[0466] 934

[0467] To a solution of the product from Preparative Example 183 (0.15 g, 0.31 mmol) in CH2Cl2 (5 mL) at 0° C. was added TEA (0.21 mL, 5 eq.) and TMSNCO (0.41 mL, 10 eq.). The reaction mixture was stirred until TLC showed consumption of starting material (30 minutes). The reaction was quenched by the addition of saturated NaHCO3 and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent to yield a solid (0.10 g, 61% yield). LCMS: MH+=531; mp=115-128° C.

EXAMPLES 501-558.22

[0468] By essentially the same procedure set forth in Example 500, using the compounds shown in column 2 of Table 14, which were prepared in a similar manner to Preparative Example 183 or Example 611 from the corresponding N-BOC-protected amine, the products shown in column 3 of Table 14 (CMPD), were prepared:

TABLE 14
Ex.	Column 2	Column 3	CMPD
501	935	936	LCMS: MH+ = 469; Mp = 80-85° C.
502	937	938	LCMS: MH+ = 503; mp = 103-109° C.
503	939	940	LCMS: MH+ = 512; mp = 112-117° C.
504	941	942	LCMS: MH+ = 561; mp = 101-105° C.
505	943	944	LCMS: MH+ = 545; mp = 106-111° C.
506	945	946	LCMS: MH+ = 545; mp = 141-160° C.
507	947	948	LCMS: MH+ = 513; mp = 95-101° C.
508	949	950	LCMS: MH+ = 513; mp = 122-127° C.
509	951	952	LCMS: MH+ = 533; mp = 97-101° C.
510	953	954	LCMS: MH+ = 512; mp = 90-117° C.
511	955	956	LCMS: MH+ = 512; mp = 82-93° C.
512	957	958	LCMS: MH+ = 546; mp = 113-117° C.
513	959	960	LCMS: MH+ = 546; mp = 107-111° C.
514	961	962	LCMS: MH+ = 590; mp = 92-97° C.
515	963	964	LCMS: MH+ = 590; mp = 81-87° C.
516	965	966	LCMS: MH+ = 556; mp = 115-120° C.
518	967	968	LCMS: MH+ = 556; mp = 110-115° C.
519	969	970	LCMS: MH+ = 640; mp = 116-121° C.
520	971	972	LCMS: MH+ = 640; mp = 119-125° C.
521	973	974	LCMS: MH+ = 624; mp = 126-132° C.
522	975	976	LCMS: MH+ = 624; mp = 121-130° C.
523	977	978	LCMS: MH+ = 546; mp = 102-106° C.
524	979	980	LCMS: MH+ = 546; mp = 123-127° C.
525	981	982	LCMS: MH+ = 480; mp = 87-119° C.
526	983	984	LCMS: MH+ = 514; mp = 75-79° C.
527	985	986	LCMS: MH+ = 547; mp = 105-109° C.
528	987	988	LCMS: MH+ = 545; mp = 103-107° C.
529	989	990	LCMS: MH+ = 513; mp = 91-97° C.
530	991	992	LCMS: MH+ = 517; mp = 93-93° C.
531	993	994	LCMS: MH+ = 497; mp = 99-102° C.
532	995	996	LCMS: MH+ = 488; mp = 129-133° C.
533	997	998	LCMS: MH+ = 499; mp = 108-111° C.
534	999	1000	FABMS: MH+ = 489; mp = 126-130° C.
535	1001	1002	LCMS: MH+ = 497; mp = 75-83° C.
536	1003	1004	LCMS: MH+ = 498; mp = 85-89° C.
542	1005	1006	LCMS: MH+ = 511; mp =   ° C.
543	1007	1008	LCMS: MH+ = 511; mp = 79-83° C.
544	1009	1010	LCMS: MH+ = 561; mp =   ° C.
545	1011	1012	LCMS: MH+ = 561; mp = 51-65° C.
546	1013	1014	LCMS: MH+ = 545; mp = 107-109° C.
547	1015	1016	LCMS: MH+ = 545; mp = 84-88° C.
548	1017	1018	LCMS: MH+ = 547; mp = 110-114° C.
549	1019	1020	LCMS: MH+ = 545; mp = 91-93° C.
550	1021	1022	LCMS: MH+ = 576; mp = 89-109° C.
551	1023	1024	LCMS: MH+ = 517; mp = 105-124° C.
552	1025	1026	LCMS: MH+ = 517; mp = 100-112° C.
553	1027	1028	LCMS: MH+ = 531; mp = 99-108° C.
554	1029	1030	LCMS: MH+ = 436; mp = 106-112° C.
555	1031	1032	LCMS: MH+ = 546; mp = 119-127° C.
556	1033	1034	LCMS: MH+ = 546; mp = 98-101° C.
557	1035	1036	LCMS: MH+ = 645; mp = 85-91° C.
558	1037	1038	—
558.10	1039	1040	LCMS: MH+ = 547; mp = 100-104° C.
558.11	1041	1042	LCMS: MH+ = 547; mp = 65-68° C.
558.12	1043	1044	LCMS: MH+ = 589; mp = 92-103° C.
558.13	1045	1046	LCMS: MH+ = 589; mp = 95-190° C.
558.14	1047	1048	LCMS: MH+ = 605; mp = 59-83° C.
558.15	1049	1050	LCMS: MH+ = 605; mp = 87-99° C.
558.16	1051	1052	LCMS: MH+ = 547; mp = 65-68° C.
558.17	1053	1054	LCMS: MH+ = 561; mp = 95-101° C.
558.18	1055	1056	LCMS: MH+ = 624; mp = 97-101° C.
558.19	1057	1058	LCMS: MH+ = 580; mp = 123-127° C.
558.20	1059	1060	LCMS: MH+ = 580; mp = 121-124° C.
558.21	1061	1062	LCMS: MH+ = 547; mp = 100-103° C.
558.22	1063	1064	LCMS: MH+ = 547; mp = 109-114° C.

EXAMPLES 558.23 and 558.24

[0469] By essentially the same procedure set forth in Example 500, using the compounds shown in Column 2 of Table 14.1, the products shown in Column 3 of Table 14.1 (CMPD) were prepared.

TABLE 14.1
Ex.	Column 2	Column 3	CMPD
558.23	1065	1066	LCMS: MH+ = 574; mp = 78-103° C.
558.24	1067	1068	LCMS: MH+ = 574; mp = 58-73° C.

EXAMPLE 559

[0470] 1069

[0471] To a solution of the product from Preparative Example 183 (0.15 g, 0.31 mmol) in CH2Cl2 (5 mL) at 0° C. was added TEA (0.21 mL, 5 eq.) and AcCl (0.03 mL, 1.2 eq.). The reaction mixture was warmed to room temperature and stirred until TLC showed consumption of starting material (20 minutes). The reaction was quenched by the addition of saturated NaHCO3 and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent to yield a solid (0.12 g, 75% yield). LCMS: MH+=530; mp=75-101° C.

EXAMPLES 560-609.68

[0472] By essentially the same procedure set forth in Example 558, using the compounds shown in column 2 of Table 15, which were prepared in a similar manner to Preparative Example 183 or Example 611 from the corresponding N-BOC-protected amine, the products shown in column 3 of Table 15 (CMPD) were prepared:

TABLE 15
Ex.	Column 2	Column 3	CMPD
560	1070	1071	LCMS: MH+ = 510; mp = 81-85° C.
561	1072	1073	LCMS: MH+ = 560; mp = 68-71° C.
562	1074	1075	LCMS: MH+ = 544; mp = 86-88° C.
563	1076	1077	LCMS: MH+ = 544; mp = 125-145° C.
564	1078	1079	LCMS: MH+ = 512; mp = 69-75° C.
565	1080	1081	LCMS: MH+ = 512; mp = 79-92° C.
566	1082	1083	LCMS: MH+ = 532; mp = 70-73° C.
567	1084	1085	LCMS: MH+ = 511; mp = 68-79° C.
568	1086	1087	LCMS: MH+ = 511; mp = 74-87° C.
569	1088	1089	LCMS: MH+ = 545; mp = 93-98° C.
570	1090	1091	LCMS: MH+ = 545; mp = 95-98° C.
571	1092	1093	LCMS: MH+ = 589; mp = 81-86° C.
572	1094	1095	LCMS: MH+ = 589; mp = 69-76° C.
573	1096	1097	LCMS: MH+ = 555; mp = 68-97° C.
574	1098	1099	LCMS: MH+ = 555; mp = 63-81° C.
575	1100	1101	LCMS: MH+ = 639; mp = 80-85° C.
576	1102	1103	LCMS: MH+ = 639; mp = 119-125° C.
577	1104	1105	LCMS: MH+ = 623; mp = 126-132° C.
578	1106	1107	LCMS: MH+ = 623; mp = 102-105° C.
579	1108	1109	LCMS: MH+ = 545; mp = 86-89° C.
580	1110	1111	LCMS: MH+ = 545; mp = 71-75° C.
581	1112	1113	FABMS: MH+ = 546; mp = 81-84° C.
582	1114	1115	FABMS: MH+ = 544; mp = 75-79° C.
583	1116	1117	FABMS: MH+ = 512; mp = 59-62° C.
584	1118	1119	LCMS: MH+ = 516; mp = 60-66° C.
585	1120	1121	LCMS: MH+ = 498; mp = 68-71° C.
586	1122	1123	FABMS: MH+ = 488; mp = 76-81° C.
587	1124	1125	LCMS: MH+ = 497; mp = 75-83° C.
588	1126	1127	LCMS: MH+ = 497; mp = 74-79° C.
594	1128	1129	LCMS: MH+ = 510; mp = 69-72° C.
595	1130	1131	LCMS: MH+ = 510; mp = 56-62° C.
596	1132	1133	LCMS: MH+ = 560; mp = 62-75° C.
597	1134	1135	LCMS: MH+ = 560; mp = 59-71° C.
598	1136	1137	LCMS: MH+ = 544; mp = 83-88° C.
599	1138	1139	LCMS: MH+ = 544; mp = 77-80° C.
600	1140	1141	LCMS: MH+ = 546; mp = 89-95° C.
601	1142	1143	LCMS: MH+ = 544; mp = 69-70° C.
602	1144	1145	LCMS: MH+ = 575; mp = 73-91° C.
603	1146	1147	LCMS: MH+ = 516; mp = 69-84° C.
604	1148	1149	LCMS: MH+ = 516; mp = 62-81° C.
605	1150	1151	LCMS: MH+ = 530; mp = 75-82° C.
606	1152	1153	LCMS: MH+ = 435; mp = 76-79° C.
607	1154	1155	LCMS: MH+ = 545; mp = 97-101° C.
608	1156	1157	LCMS: MH+ = 545; mp = 65-68° C.
608.1	1158	1159	LCMS: MH+ = 645; mp = 66-72° C.
608.2	1160	1161	LCMS: MH+ = 574; mp = 87-92° C.
608.21	1162	1163	LCMS: MH+ = 564; mp = 65-69° C.
608.22	1164	1165	LCMS: MH+ = 586; mp = 73-77° C.
608.23	1166	1167	LCMS: MH+ = 542; mp = 81-84° C.
608.25	1168	1169	LCMS: MH+ = 592; mp = 85-91° C.
608.26	1170	1171	LCMS: MH+ = 592; mp = 74-80° C.
608.27	1172	1173	LCMS: MH+ = 586; mp = 82-85° C.
608.28	1174	1175	LCMS: MH+ = 586; mp = 76-80° C.
608.29	1176	1177	LCMS: MH+ = 586; mp = 48.7-49.8° C.
608.30	1178	1179	LCMS: MH+ = 586; mp = 70-73° C.
608.31	1180	1181	LCMS: MH+ = 552; mp = 48-51° C.
608.32	1182	1183	LCMS: MH+ = 552; mp = 75-79° C.
608.33	1184	1185	LCMS: MH+ = 564; mp = 76-81° C.
608.34	1186	1187	LCMS: MH+ = 564; mp = 75-78° C.
608.35	1188	1189	LCMS: MH+ = 615; mp = 97-104° C.
608.36	1190	1191	LCMS: MH+ = 615; mp = 105-110° C.
608.37	1192	1193	LCMS: MH+ = 615; mp = 100-106° C.
608.38	1194	1195	LCMS: MH+ = 563; mp = 70-73° C.
608.39	1196	1197	LCMS: MH+ = 563; mp = 64-66° C.
608.40	1198	1199	LCMS: MH+ = 563; mp = 71-73° C.
608.41	1200	1201	LCMS: MH+ = 603; mp = 58-63° C.
608.42	1202	1203	LCMS: MH+ = 603; mp = 83-86° C.
608.43	1204	1205	LCMS: MH+ = 494; mp = 64-67° C.
608.44	1206	1207	LCMS: MH+ = 494; mp = 78-81° C.
608.45	1208	1209	LCMS: MH+ = 562; mp = 57-60° C.
608.46	1210	1211	LCMS: MH+ = 562; mp = 89-91° C.
608.47	1212	1213	LCMS: MH+ = 562; mp = 78-82° C.
608.48	1214	1215	LCMS: MH+ = 520; mp = 50-52° C.
608.49	1216	1217	LCMS: MH+ = 520; mp = 42-44° C.
609.50	1218	1219	LCMS: MH+ = 575; mp = 131-135° C.
609.51	1220	1221	LCMS: MH+ = 623; mp = 73-84° C.
609.52	1222	1223	LCMS: MH+ = 501; mp = 88-90° C.
609.53	1224	1225	LCMS: MH+ = 526; mp = 110-112° C.
609.54	1226	1227	LCMS: MH+ = 546; mp = 100-104° C.
609.55	1228	1229	LCMS: MH+ = 546; mp = 85-87° C.
609.56	1230	1231	LCMS: MH+ = 574; mp = 63-70° C.
609.57	1232	1233	LCMS: MH+ = 588; mp = 67-75° C.
609.58	1234	1235	LCMS: MH+ = 588; mp = 66-88° C.
609.59	1236	1237	LCMS: MH+ = 604; mp = 53-71° C.
609.60	1238	1239	LCMS: MH+ = 604; mp = 55-72° C.
609.61	1240	1241	LCMS: MH+ = 602
609.62	1242	1243	LCMS: MH+ = 560; mp = 65-68° C.
609.63	1244	1245	LCMS: MH+ = 565; mp = 45-48° C.
609.64	1246	1247	LCMS: MH+ = 579; mp = 101-104° C.
609.65	1248	1249	LCMS: MH+ = 579; mp = 96-101° C.
609.66	1250	1251	LCMS: MH+ = 546; mp = 69-74° C.
609.67	1252	1253	LCMS: MH+ = 546; mp = 65-69° C.
609.68	1254	1255	LCMS: MH+ = 478; mp = 63-68° C.

EXAMPLES 609.69 and 609.70

[0473] By essentially the same procedure set forth in Example 559, using the compounds shown in Column 2 of Table 15.1, the products shown in Column 3 of 10 Table 15.1 (CMPD) were prepared:

TABLE 15.1
Ex.	Column 2	Column 3	CMPD
609.69	1256	1257	LCMS: MH+ = 573; mp = 50-85° C.
609.70	1258	1259	LCMS: MH+ = 573; mp = 90-97° C.

EXAMPLE 609

[0474] 1260

[0475] The product from Preparative Example 238 (0.20 g, 0.41 mmol) in CH2Cl2 (4.0 mL) was treated with Ac2O (0.038 mL, 1.0 eq) and TEA (0.057 mL, 1.0 eq.) and the resulting solution stirred at room temperature 5 hours. The reaction was quenched by the addition of saturated NaHCO3 and extracted with CH2Cl2. The combine organics were purified by flash chromatography using a 2.5% to 5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent to give the diacetate (0.12 g, 50% yield). This product was dissolved in MeOH (5.0 mL) and treated with 1N NaOH. The resulting solution was stirred at room temperature 5 hours. The reaction mixture was concentrated under reduced pressure and the crude residue purified by preparative thin layer chromatography (TLC) using a 5% (10% NH4OH in CH2Cl2 solution as eluent (0.053 g, 53% yield). LCMS: MH+=526; mp=132-137° C.

EXAMPLE 609.71 and 609.72

[0476] 1261

[0477] The above compounds were prepared through the separation of diastereomers of the compound from Example 609.60 using preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA mix with 0.1% DEA as eluent:

[0478] Example 609.61 (first eluting isomer): LCMS: MH+=602.

[0479] Example 609.62 (second eluting isomer): LCMS: MH+=602.

EXAMPLES 609.73 and 609.74

[0480] 1262

[0481] The above compounds were prepared through the separation of diastereomers of the compound from Example 609.60 using preparative HPLC with a CHIRALPAK AD column using a 95:5 hexanes: IPA mix with 0.1% DEA as eluent:

[0482] Example 609.63 (first eluting isomer): LCMS: MH+=603.

[0483] Example 609.64 (second eluting isomer): LCMS: MH+=603.

EXAMPLE 609.75

[0484] 1263

[0485] A solution of the compound from Example 608.21 (0.053 g, 0.09 mmol) was stirred in MeOH (1.0 mL) and 1N NaOH (0.1 mL) at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (1 mL) and HOBt (0.010 g), dimethylamine hydrochloride (0.015 g), DEC (0.015 g) and TEA (0.06 mL) were added and the resulting mixture stirred at room temperature overnight. The reaction mixture was quenched by the addition of saturated NaHCO3 and the resulting mixture was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, 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 (0.019 g, 54% yield): LCMS: MH+=577; mp=64-68° C.

EXAMPLE 610

[0486] The product from Example 609 (0.05 g, 0.10 mmol) in acetone (2.0 mL) was treated with Mel (0.01 mL, 1.1 eq.) and K2CO3 (0.066 g, 5 eq.) and the resulting solution stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product purified by flash chromatography using a 5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent (0.051 g, 94% yield).LCMS: MH+=541; mp=64-66° C.

EXAMPLE 611

[0487] 1264

[0488] TFA (4.0 mL) was added to a solution of the product from Preparative Example 172 (2.00 g, 3.86 mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 15 min, then 16 mL of TFA was added and the stirring was continued for another 30 min at 0° C. The mixture was poured onto solid K2CO3 (50 g), H2O (200 mL) was added, and the mixture was extracted with CH2Cl2 (4×30 mL). The extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The sticky solid was dissolved in anhydrous CH2Cl2 (30 mL), and Ac2O (0.79 g, 7.7 mmol) and TEA (1.95 g, 19.3 mmol) were added. The mixture was stirred under N2 for 24 hrs, poured into sat. NaHCO3 (50 mL), and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over Na2SO4 and filtered. The residue was purified by flash chromatography using 7% MeOH (10% NH4OH) in CH2Cl2 to give 1.63 g (92%) of a solid. LCMS: MH+=462; mp=65-71° C.

Preparative Examples 611.1-611.24

[0489] By essentially the same procedure set forth in Preparative Example 611, using the starting materials in column 2, the products given in column 2 were prepared:

Prep. Ex.	Column 2	Column 3	CMPD
611.1	1265	1266	LCMS: MH+ = 556 Mp = 78-85° C.
611.2	1267	1268	LCMS: MH+ = 624 Mp = 80-85° C.
611.3	1269	1270	LCMS: MH+ = 522 Mp = 78-85° C.
611.4	1271	1272	LCMS: MH+ = 612 Mp = 70-76° C.
611.5	1273	1274	LCMS: MH+ = 556 Mp = 76-83° C.
611.6	1275	1276	LCMS: MH+ = 554 Mp = 90-104° C.
611.7	1277	1278	LCMS: MH+ = 576 Mp = 64-70° C.
611.8	1279	1280	LCMS: MH+ = 608 Mp = 84-89° C.
611.9	1281	1282
611.10	1283	1284	LCMS: MH+ = 534 Mp = 58-61° C.
611.11	1285	1286	LCMS: MH+ =Mp = 69-75° C.
611.12	1287	1288	LCMS: MH+ = 596 Mp = 108-117° C.
611.13	1289	1290	LCMS: MH+ = 556 Mp = 69-76° C.
611.14	1291	1292	LCMS: MH+ = 542 Mp = 82-88° C.
611.15	1293	1294	LCMS: MH+ = 564 Mp = 71-77° C.
611.16	1295	1296	LCMS: MH+ = 554 Mp = 95-98° C.
611.17	1297	1298	LCMS: MH+ = 554 Mp = 93-96° C.
611.18	1299	1300	LCMS: MH+ = 556 Mp = 65-67° C.
611.18	1301	1302	LCMS: MH+ = 556 Mp = 70-72° C.
611.19	1303	1304	LCMS: MH+ = 530 Mp = 73-76° C.
611.20	1305	1306	LCMS: MH+ = 530 Mp = 74-77° C.
611.21	1307	1308	LCMS: MH+ = 608 Mp = 84-87° C.
611.22	1309	1310	LCMS: MH+ = 608 Mp = 91-94° C.
611.23	1311	1312	LCMS: MH+ = 596 Mp = 92-96° C.
611.24	1313	1314	LCMS: MH+ = 596 Mp = 107-110° C.

EXAMPLE 612

[0490] 1315

[0491] TFA (4.0 mL) was added to a solution of the product from Preparative Example 172 (2.00 g, 3.86 mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 15 min, then 16 mL of TFA was added and the stirring was continued for another 30 min at 0° C.. The mixture was poured onto solid K2CO3 (50 g), H2O (200 mL) was added and the mixture was extracted with CH2Cl2 (4×30 mL). The extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The sticky solid was dissolved in anhydrous CH2Cl2 (30 mL), and TEA (1.95 g, 19.3 mmol) and TMSNCO (4.44 g, 38.6 mmol) were added. The mixture was stirred under N2 for 3 hrs, poured into sat. NaHCO3 (200 mL), and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 11% MeOH (10% NH4OH) in CH2Cl2 to give 1.51 g (85%) of a solid. LCMS: MH+=463; mp=100-107° C.

Preparative Examples 612.1-612.8

[0492] By essentially the same procedure set forth in Preparative Example 612, using the starting materials in column 2, the products given in column 3 were prepared:

Prep. Ex.	Column 2	Column 3	CMPD
612.1	1316	1317	LCMS: MH+ = 557 Mp = 108-114° C.
612.2	1318	1319	LCMS: MH+ = 625 Mp = 114-120° C.
612.3	1320	1321	LCMS: MH+ = 523 Mp = 105-112° C.
612.4	1322	1323	LCMS: MH+ = 613 Mp = 104-109° C.
612.5	1324	1325	LCMS: MH+ = 557 Mp = 107-113° C.
612.6	1326	1327	LCMS: MH+ = 555 Mp = 132-141° C.
612.7	1328	1329	LCMS: MH+ = 577 Mp = 98-105° C.
612.8	1330	1331	LCMS: MH+ = 609 Mp = 110-115° C.

EXAMPLE 613

[0493] 1332

[0494] A mixture of the product from Preparative Example 239 (30 mg, 0.10 mmol), the product from Preparative Example 76 (30 mg, 0.11 mmol), Nal (15 mg, 0.10 mmol), and K2CO3 (60 mg, 0.45 mmol) in anhydrous CH3CN (1 mL) was stirred and refluxed under N2 for 24 hrs. The mixture was poured into 5% K2CO3 (30 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were dried over Na2SO4, the solvent was evaporated, and the residue was purified by flash chromatography using 3% MeOH (10% NH4OH) in CH2Cl2 to give 36 mg (66%) of a solid. LCMS: MH+=546; mp=113-120° C.

EXAMPLES 614-628

[0495] By essentially the same procedure set forth in Example 613, using the chlorides in Column 2 of Table 16, the products in Column 3, Table 16 (CMPD) were prepared.

TABLE 16
Ex.	Column 2	Column 3	CMPD
614	1333	1334	LCMS: MH+ = 497
615	1335	1336	LCMS: MH+ = 546; mp = 110-115° C.
616	1337	1338	LCMS: MH+ = 552; mp = 95-100° C.
617	1339	1340	LCMS: MH+ = 598; mp = 95-100° C.
618	1341	1342	LCMS: MH+ = 502.
619	1343	1344	LCMS: MH+ = 503; mp = 82-87° C.
620	1345	1346	LCMS: MH+ = 546; mp = 105-109° C.
621	1347	1348	LCMS: MH+ = 547; mp = 115-121° C.
622	1349	1350	LCMS: MH+ = 547; mp = 103-109° C.
623	1351	1352	LCMS: MH+ = 547; mp = 111-117° C.
624	1353	1354	LCMS: MH+ = 596; mp = 95-101° C.
625	1355	1356	LCMS: MH+ = 547; mp = 116-122° C.
626	1357	1358	LCMS: MH+ = 497.
627	1359	1360	LCMS: MH+ = 502; mp = 77-85° C.
628	1361	1362	LCMS: MH+ = 474; mp = 50-56° C.

EXAMPLE 629

[0496] 1363

[0497] A mixture of the product from Preparative Example 240 (30 mg, 0.10 mmol), the product from Preparative Example 76 (30 mg, 0.11 mmol), Nal (15 mg, 0.10 mmol), and K2CO3 (60 mg, 0.45 mmol) in anhydrous CH3CN (1 mL) was stirred and refluxed under N2 for 24 hrs. The mixture was poured into 5% K2CO3 (30 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were dried over Na2SO4, the solvent was evaporated, and the residue was purified by flash chromatography using 11% MeOH (10% NH4OH) in CH2Cl2 to give 27 mg (49%) of a solid. LCMS: MH+=547; mp=128-138° C.

EXAMPLES 630-635

[0498] By essentially the same procedure set forth in Example 629, using the chlorides in column 2 of Table 17, the products in column 3, Table 17 (CMPD) were prepared.

TABLE 17
Ex.	Column 2	Column 3	CMPD
630	1364	1365	LCMS: MH+ = 548; mp = 141-145° C.
631	1366	1367	LCMS: MH+ = 548; mp = 127-135° C.
632	1368	1369	LCMS: MH+ = 548; mp = 143-147° C.
633	1370	1371	LCMS: MH+ = 548; mp = 136-140° C.
634	1372	1373	LCMS: MH+ = 548; mp = 135-142° C.
635	1374	1375	LCMS: MH+ = 597; mp = 122-128° C.

EXAMPLE 636

[0499] 1376

[0500] The product from Preparative Example 242 (1 g) (3.39 mmoles) was dissolved in anhydrous acetonitrile (30 mL). To the stirred solution under argon, was added bis-(4-chlorophenyl)methyl chloride (1.04 g (3.39 mmoles), anhydrous potassium iodide (562 mg) (3.39 mmoles) and anhydrous potassium carbonate (468 mg) (3.39 mmoles) and the mixture was stirred at 25° C. for 235 h. The mixture was poured into dichloromethane (800 mL) and extracted with saturated aqueous NaHCO3. The aqueous phase was re-extracted with dichloromethane (300 mL) and the combined dichloromethane layers were dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (25×5 cm) using 1.5% increasing to 6% (10% NH4OH in methanol)-dichloromethane as the eluant to give the product (271.8 mg; 15%): HRFABMS: m/z 530.2329 (MH+), calcd for C29H38Cl2N3O2 m/z 530.2341; [α]D25° C. +33.00 (c=2.600 mg/mL MeOH); δH (CDCl3) 0.89 (3H,d, CH3), 1.07 (3H, d, CH3), 2.08 (3H, s, CH3CON—), 5.22 (1H, s, Ar2CH—) and 7.23-7.35 ppm (8H, m, ArH); δC(CDCl3) CH3: 19.2/19.5, 20.1, 21.7; CH2: 32.2/33.0, 32.2/33.0, 39.2/39.4, 39.2/39.4, 37.8, 41.9/42.2, 43.1/43.7; CH: 26.6/27.0, 33.2, 46.8, 60.0, 66.1,129.1/129.4, 129.1/129.4, 129.1/129.4, 129.1/129.4, 129.4/129.8, 129.4/129.8, 129.4/129.8,129.4/129.8; C: 133.2/133.4,133.2/133.4,139.4/140.6, 139.4/140.6,169.0, 170.3/170.6.

Preparative Example 637

[0501] 1377

[0502] Benzylimine of pivalaldehyde (5.08 g, 29 mmol) was dissolved in anhydrous THF (10 mL), Danishefsky's diene (5.00 g, 29 mmol), then ZnCl2 (0.5 M in THF, 58 mL, 29 mmol) were added under N2. The mixture was stirred at rt for 4 hrs, poured into H2O (500 mL), and extracted with EtOAc (4×50 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and the solvent was evaporated. Chromatography on silicagel with hexane: EtOAc (1:3) afforded pale yellow oil (2.68 g, 38%).

Preparative Example 638

[0503] 1378

[0504] Solution of the product from Preparative Example 637 (2.50 g, 10.3 mmol) in anhydrous THF (50 mL) was stirred under N2 at −78° C. L-Selectride (Aldrich), (1.0 M in THF, 10.3 mL, 10.3 mmol) was added slowly, the mixture was stirred at −78° C. for 1 hr, then at room temperature (rt) for 1 hr after which it was poured into H2O (500 mL) and extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and the solvent was evaporated. Chromatography on silicagel with hexane: EtOAc (4:1) afforded a pale yellow solid (1.31 g, 52%).

Preparative Example 639

[0505] 1379

[0506] Diethyl (dibromomethyl)phosphonate (1.27 g, 4.10 mol) was dissolved under N2 in anhydrous THF (10 mL) and the solution was cooled to −78° C. Lithium diisopropylamide (2.0 M in THF/heptane 1.70 mL, 3.4 mmol) was added and the solution was stirred at −78° C. for 30 min. Solution of the product from Preparative Example 638 was in dry THF (6 mL) was added and the mixture was stirred at −78° C. for 1 hr, then at rt for 6 days. The mixture was poured into H2O (250 mL) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Chromatography on silicagel with hexane: EtOAc (30:1) afforded a colorless oil (388 mg, 47%).

Preparative Example 640

[0507] 1380

[0508] Dimethoxyethane (15 mL) and H2O (3 mL) were added to a mixture of the product from Preparative Example 639 (388 mg, 0.97 mmol), phenylboronic acid (366 mg, 3.00 mmol), PdCl2(PPh3)2 (140 mg, 0.20 mmol), and Na2CO3 (1.06 g, mmol) and the mixture was stirred and refluxed under N2 for 24 hr. The mixture was poured into H2O (300 mL) plus brine (30 mL) and extracted with CH2Cl2 (5×40 mL). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Chromatography on silicagel with hexane: EtOAc (30:1) afforded a pale yellow oil (208 mg, 54%).

Preparative Example 641 and 642

[0509] 1381

[0510] A solution of the product from Preparative Example 640 (208 mg, 0.52 mmol) in anhydrous EtOH (8 mL) and a solution of ammonium formate (756 mg, 12.0 mmol) in anhydrous MeOH (8 mL) were added under N2 to 10% Pd/C (250 mg). The mixture was stirred at rt for 24 hr, then CH2Cl2 (100 mL) was added, the mixture was filtered through Celite, and the solvent was evaporated. Chromatography on silicagel with 20:1 CH2Cl2: MeOH/NH4OH (10/1) afforded 73 mg of a white solid (isomer 1=Preparative Example 641, fast eluting) and 20 mg of a colorless wax (isomer 2=Preparative Example 642, slow eluting). Both diastereomers are racemic.

Preparative Example 643

[0511] 1382

[0512] The product shown in the reaction above was prepared using the isomer 1 product of Preparative Example 641 by the procedure that is essentially identical to that described in Preparative Example 19 and afforded a colorless wax.

EXAMPLE 644

[0513] 1383

[0514] The product shown in the reaction above was prepared using the isomer 1 product from Preparative Example 643 by a procedure that is essentially identical to that described in Preparative Example 611 and afforded a colorless solid. LCMS: MH+=475; mp=61-65° C.

EXAMPLE 645

[0515] 1384

[0516] Acetylpiperidine acetic acid (85 mg, 0.50 mmol) was dissolved in anhydrous PhCH3 (1 mL) and TEA (0.06 mL). To the solution was added pivaloyl chloride (0.05 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 1 hr. A solution of the isomer 2 product from Preparative Example 642 (18 mg, 0.058 mmol) in anhydrous PhCH3 (0.5 mL) was added, followed by TEA (0.10 mL) and the mixture was stirred at rt for 4 days. The mixture was poured into saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (4×15 mL). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Chromatography on silicagel with 50:1 CH2Cl2: MeOH/NH4OH (10/1) afforded 22 mg (79%) of a colorless solid. LCMS: MH+=475; mp=49-54° C.

Preparative Example 646 and 647

[0517] 1385

[0518] BuLi (2.5 M in hexanes, 3.5 mL, 8.75 mmol) was added under N2 to a solution of diphenylmethane (1.68 g, 10.0 mmol) in anhydrous Et2O (25 mL). The solution was refluxed for 16 hr, cooled to rt, then a solution of the product from Preparative Example 638 (490 mg, 2.0 mmol) in Et2O (5 mL) was added and the mixture was stirred at rt for 6 hr. The mixture was poured into H2O plus brine and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Chromatography on silicagel afforded two colorless solids: first (isomer 1=Preparative Example 646 177 mg, 21%) eluted with 15:1 CH2Cl2:EtOAc, second (isomer 2=Preparative Example 647, 250 mg, 30%) eluted with 3:1 CH2Cl2:EtOAc.

Preparative Example 648

[0519] 1386

[0520] Anhydrous EtOH (3 mL) was added under N2 to a mixture of the isomer 1 product from Preparative Example 646 (90 mg, 0.22 mmol), 10% Pd/C (40 mg) and ammonium formate (200 mg, 3.2 mmol). The mixture was stirred and refluxed for 6 hr, then CH2Cl2 (30 mL) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography on silicagel with 20:1 CH2Cl2: MeOH/NH4OH (10/1). A white solid was obtained in an amount of 48 mg (69%).

Preparative Example 649

[0521] 1387

[0522] The product shown in the reaction above was prepared using the isomer 2 product of Preparative Example 647 by a procedure that is essentially identical to that described in Preparative Example 648 and afforded a colorless wax.

EXAMPLE 650

[0523] 1388

[0524] Acetylpiperidine acetic acid (85 mg, 0.50 mmol) was dissolved in anhydrous PhCH3 (1 mL) and TEA (0.10 mL). To the solution was added pivaloyl chloride (0.05 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 1 hr. A solution of the product from Preparative Example 648 (40 mg, 0.124 mmol) in anhydrous PhCH3 (1.0 mL) was added, followed by TEA (0.30 mL) and the mixture was stirred at rt for 3 days. The mixture was poured into saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (4×15 mL). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The residue was dissolved in MeOH (5 mL), H2O (0.5 mL) was added, then KOH (250 mg) and the mixture was stirred at rt for 4 hr. The mixture was poured into saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (4×15 mL). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Chromatography on silicagel with 30:1 CH2Cl2: MeOH/NH4OH (10/1) afforded 31 mg (51%) of white solid. LCMS: Mh+=491; mp=100-106° C.

EXAMPLE 651

[0525] 1389

[0526] The product shown in the reaction above was prepared using the isomer 2 product of Preparative Example 649 by the procedure that is essentially identical to that described in Example 650 above and afforded a white solid. LCMS: MH+=491; mp=108-115° C.

Claims

1. A compound of the formula (I):

2. The compound of claim 1 wherein: R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of: a) halogen; b) —OCF3; c) —CF3; d) —CN; e) (C1-C20)alkyl or R18—(C1-C20) alkyl; f) heteroalkyl or R18-heteroalkyl; g) aryl or R18-aryl; h) heteroaryl or R18-heteroaryl; i) arylalkyl or R18-arylalkyl; j) heteroarylalkyl or R18-heteroarylalkyl; k) hydroxy; l) alkoxy; m) aryloxy; n) —SO2-alkyl; o) —NR11R12; p) —N(R11)C(O)R13; q) methylenedioxy; r) difluoromethylenedioxy; s) trifluoroalkoxy; t) —SCH3; and u) —SO2CF3; R4, R5, R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —OR14, —NR11 R121392 provided that when Z and/or X is N then R4, R5, R7 and R8 are each not —OR14 or —NR11R12; R11 is selected from the group consisting of H and alkyl.

3. The compound of claim 1 wherein: R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of: a) halogen; b) —OCF3; c) —CF3; d). trifluoroalkoxy; e) (C1-C6)alky or R18—(C1-C6)alkyl; f) heteroalkyl or R18-heteroalkyl; g) aryl or R18-aryl; h) arylalkyl or R18-arylalkyl; i) heteroarylalkyl or R18-heteroarylalkyl; j) alkoxy; k) —SO2-alkyl; and l) —SO2CF3; R4, R5, R7 and R8are the same or different and are independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —OR14, —NR11R121393 provided that when Z and/or X is N then R4, R5, R7 and R8 are each not —OR14 or —NR11R12; R11 is selected from the group consisting of H and alkyl; and Z is C.

4. The compound of claim 1 wherein, R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of: a) halogen; b) —OCF3; c) —CF3; d) alkoxy; e) trifluoralkoxy; f) (C1-C6)alkyl; g) —SO2-alkyl; and h) —SO2CF3; R3 is H or —OH, provided that when X is N, R3 is not —OH; R4 and R5 are the same or different and are each independently selected from the group consisting of H, (C1-C6)alkyl, heteroalkyl and 1394R7 is selected from the group consisting of H, alkyl, —OR14 and —NR11R12, provided that when X is N, R7 is not —OR14 or —NR11R12; R8 is selected from the group consisting of H, alkyl, aryl and heteroaryl; R11 is selected from the group consisting of H and alkyl; and Z is C.

5. The compound of claim 1 wherein: R1 and R2 are the same or different and are independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of: a) halogen; b) —OCF3, c) alkoxy; d) trifluoroalkoxy; e) —CF3; f) —SO2-alkyl; and g) —SO2CF3; R3 is H; R4 and R5 are the same or different and are independently selected from the group consisting of H, (C1-C6)alkyl, heteroalkyl, and 1395R6 is selected from the group consisting of —C(O)R15 and —SO2R15; R7 is selected from the group consisting of H, alkyl, —OR14 and —NR11R12, provided that when X is N, R7 is not —OR14 or —NR11R12; R8 is selected from the group consisting of H, alkyl, aryl and heteroaryl; R11 is H or alkyl; and Z is C.

6. The compound of claim 1 wherein, R1 and R2 are the same or different and are independently selected from the group consisting of phenyl and pyridyl, each optionally substituted with one to six groups selected from the group consisting of: a) Br, F or Cl; b) —OCF3; c) —CF3; d) methoxy; e) ethoxy; f) cyclopropylmethoxy; g) —OCH2CF3; h) —SO2-alkyl; and i) —SO2CF3 R3 is H; R4 and R5 are the same or different and are independently selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl and heteroalkyl; R7 is selected from the group consisting of H, —OR11 and alkyl; R8, R9, R10, R11, R12 and R14 are each independently selected from the group consisting of H and alkyl; R13 is alkyl; R15 is selected from the group consisting of —NR16R17, —OR16 and alkyl; R16 and R17 are the same or different and are independently selected from the group consisting of H and alkyl, provided that when R15 is —OR16, R16 is not H; and Z is C.

7. The compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of the compound or of said prodrug selected from the group consisting of:

8. The compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug, the compound which is selected from the group consisting of:

9. The compound according to claim 8, which is:

10. The compound according to claim 8, which is:

11. The compound according to claim 8, which is:

12. The compound according to claim 8, which is:

13. The compound according to claim 8, which is:

14. The compound according to claim 8, which is:

15. The compound according to claim 8, which is:

16. The compound according to claim 8, which is:

17. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier therefor.

18. A method of treating or preventing an androgen dependent disease, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

19. The method of claim 18, wherein the androgen dependent disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenic alopecia, polycystic ovary syndrome and combinations thereof.

20. The method of claim 19, wherein the androgen dependent disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and prostatic intraepithelial neoplasia.

21. A method of inhibiting 17β-hydroxysteroid dehydrogenases, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

22. A method of treating or preventing androgen-dependent diseases comprising administering to a mammal in need thereof an effective amount of a compound of claim 1 in combination with at least one anti-androgenic agent.

23. The method of claim 22, wherein the anti-androgenic agent is selected from the group consisting of inhibitors of 5α-reductase type 1 and/or type 2, Flutamide, nicalutamide, bicalutamide, LHRH agonists, LHRH antagonists, inhibitors of 17α-hydroxylase/C17-20 lyase, inhibitors of 17β-Hydroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes, and combinations thereof.

24. A method of treating or preventing benign prostatic hyperplasia comprising administering an effective amount of a compound of claim 1 in combination with at least one agent useful in the treatment or prevention of benign prostatic hyperplasia.

25. The method of claim 24, wherein the agent useful in the treatment or prevention of benign prostatic hyperplasia is an alpha-1 adrenergic antagonist.

26. A method of treating or preventing hair loss, comprising administering an effective amount of a compound of claim 1 in combination with at least one anti-alopecia agent.

27. The method of claim 25 wherein the anti-alopecia agent is a potassium channel agonist or a 5α-reductase inhibitor.

28. A method of treating or preventing proliferative diseases comprising administering concurrently or sequentially to a mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1 in combination with an effective amount of an agent or therapy selected from the group consisting of chemotherapeutic agent, biological agent, surgery, radiation therapy and combinations thereof.

29. The method of claim 28, wherein the chemotherapeutic agent is: (a) an antineoplastic agent selected from the group consisting of Uracil mustard, Chlormethine, Cyclo-phosphamide, 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, Paclitaxel (Taxol), 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, Raloxifine, Droloxifine, and Hexamethylmelamine; or (b) a microtubule affecting agent selected from allocolchicine, Halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, thiocolchicine, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothilone A, epothilone, discodermolide estramustine, nocodazole and MAP4; and wherein the biological agent is selected from the group consisting of interferon-α, interferon-β and gene therapy; and wherein the proliferative disease is selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, renal cancer, myeloid leukemia, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, ovarian cancer, prostate cancer and combinations thereof.

30. The method of claim 28, wherein the proliferative disease treated is selected from the group consisting of prostate cancer, pancreatic cancer, breast cancer, and ovarian cancer; the chemotherapeutic agent is selected from the group consisting of Cyclophosphamide, 5-Fluorouracil, Temozolomide, Vincristine, Cisplatin, Carboplatin, Gemcitabine, Taxotere, paclitaxel and/or a paclitaxel derivative; and the biological agent is interferon-α.