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WO2006015263A2 - Analogues de lonidamine - Google Patents

Analogues de lonidamine Download PDF

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Publication number
WO2006015263A2
WO2006015263A2 PCT/US2005/027092 US2005027092W WO2006015263A2 WO 2006015263 A2 WO2006015263 A2 WO 2006015263A2 US 2005027092 W US2005027092 W US 2005027092W WO 2006015263 A2 WO2006015263 A2 WO 2006015263A2
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WIPO (PCT)
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group
alkyl
compound
aryl
cor
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PCT/US2005/027092
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English (en)
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WO2006015263A3 (fr
Inventor
Mark Matteucci
Photon Rao
Jian-Xin Duan
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Threshold Pharmaceuticals, Inc.
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Priority to US11/346,632 priority Critical patent/US20070043057A1/en
Priority to US11/351,347 priority patent/US20070015771A1/en
Publication of WO2006015263A2 publication Critical patent/WO2006015263A2/fr
Publication of WO2006015263A3 publication Critical patent/WO2006015263A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Lonidamine also known as l-(2,4-dichlorobenzyl)-IH-indazole-3-carboxylic acid
  • LND is an anti-cancer drug approved for the treatment of lung, breast, prostate, and brain cancer.
  • the mechanism of action of lonidamine may involve interference with the energy metabolism of neoplastic cells by disruption of the mitochondrial membrane and by inhibition of hexokinase.
  • Lonidamine also has anti-spermatogenic activity and has been shown to inhibit germ cell respiration. Lonidamine has perhaps been most extensively been studied for use in the treatment of advanced breast cancer. For example, the reference Mansi et al, Sep. 1991, Br. J.
  • Cancer 64(3): 593-7 reports a phase II study in which lonidamine was administered in a daily divided oral dose of 600 mg. Of the 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months); three (11%) a minor response; two had stable disease (greater than 3 months); and 20 progressed. The investigators reported no clear relationship between lonidamine levels and clinical response or toxicity and concluded that lonidamine appeared to be active against advanced breast cancer; and that lonidamine's low toxicity would allow combination studies.
  • Treat 49(3): 209-17 multicenter prospective randomized trial — reports modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer
  • Dogliotti et al, 1998, Cancer Chemother Pharmacol 41(4): 333-8 pilot study of cisplatin, epirubicin, and lonidamine combination regimen as first-line chemotherapy for metastatic breast cancer
  • Treat 56(3): 233-7 (study of weekly dosed epirubicin plus lonidamine in advanced breast carcinoma); and Pacini et al, May 2000, Eur J Cancer 36(8): 966-75 (multicentric randomised study of FEC (5- fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment).
  • FEC fluorouracil, epidoxorubicin and cyclophosphamide
  • EM epidoxorubicin and mitomycin-C
  • Lonidamine has also been studied in lung cancer, particularly non-small cell lung cancer ⁇ see Joss et al, Sep. 1984, Cancer Treat Rev 11(3): 205-36) in combination with radiation or other anti-cancer agents.
  • lung cancer particularly non-small cell lung cancer ⁇ see Joss et al, Sep. 1984, Cancer Treat Rev 11(3): 205-36
  • radiation or other anti-cancer agents see Privitera et al, Dec. 1987, Radiother Oncol 10(4): 285-90 (phase II double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung); Gallo-Curcio et al, Dec. 1988, Semin Oncol 15(6 Suppl 7): 26-31 (chemotherapy or radiation therapy plus and minus lonidamine); Giaccone et al, 28 Feb.
  • Lonidamine has been studied as a treatment for other cancers (see Robustelli et al , Apr. 1991, Semin. Oncol. 18(2 Suppl 4):18-22; and Pacilio et al, 1984, Oncology 41 Suppl 1:108-12), including: favorable B-cell neoplasms (see Robins et al, Apr. 1990, bit JRadiat Oncol Biol Phys . 18(4):909-20, which describes two pilot clinical trials and laboratory investigations of adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation); advanced colorectal cancer (see the references Passalacqua et al, Jun.
  • metastatic cancers see the references Weinerman, 1990, Cancer Invest. 8(5):505-8, which describes a phase I study of lonidamine and human lymphoblastoid alpha interferon; DeAngelis et al, Sep. 1989, J Neurooncol 7(3):241-7, and U.S. Patent No. 5,260,327, which describe the combined use of radiation therapy and lonidamine in the treatment of brain metastases; and Weinerman et al, Jun. 1986, Cancer Treat Rep 70(6):751-4, which reports a phase II study of lonidamine in patients with metastatic renal cell carcinoma); advanced ovarian cancer (see the references Bottalico et al, Nov.-Dec.
  • BPH Benign Prostatic Hypertrophy or Benign Prostatic Hyperplasia
  • the present invention provides lonidamine analogs and pharmaceutical formulations of those compounds suitable for use as drugs in the methods of the invention for treating cancer and/or BPH.
  • the drugs can have high aqueous solubility and extended pharmacokinetics in vivo.
  • the present invention provides compounds which are analogs of lonidamine.
  • the compounds of the present invention have the formula (I): the formula (I):
  • A-B is a 7,5, 6,5 or a 5,5 cyclic ring system, optionally substituted with from one to five V 6 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Ci-C8)alkyl, (C 1 -C 6 ) alkoxy, nitro, acetamido, L ⁇ -CO 2 H, L'-dialkylamino, (Ci-Cs)heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl 5 (C r C 8 )heterocyclyl, aryl, heteroaryl; U !
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - Cs)alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C 6 ) alkoxy, cyano, nitro, amino, -NO, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to the same
  • R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, -NO, R 3 , U ! -R 3 , U ⁇ COR 3 , U 1 -CUNR 3 R 7 , U !
  • each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, (C,-C 6 )alkenyl, (C 2 -
  • Y is CR 8 2 , CR 8 , NR 8 , S or O;
  • U is O, S, NR 3 , NCOR 3 , or NCONR 3 R 7 ;
  • U 1 is O or S; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • the present invention provides lonidamine analogs that have improved aqueous solubility and extended pharmacokinetics in vivo.
  • the present invention provides methods for treating cancer in a subject, comprising administering to the subject an effective amount of a compound of the invention.
  • the present invention provides methods for treating BPH in a subject, comprising administering to the subject an effective amount of a compound of the invention.
  • the present invention provides methods for synthesizing the compounds of the invention and compounds useful as intermediates in such synthetic methods. [0014] In a sixth aspect, the present invention provides pharmaceutical formulations of the compounds of the invention.
  • Figure 1 shows the morphology of prostate in a normal mouse.
  • Figure 2 shows the morphology of prostate in a mouse treated with 5 mg/kg Compound 1.
  • Figure 3 shows the morphology of prostate in a mouse treated with 20 mg/kg Compound 1.
  • Figure 4 illustrates a dose dependent reduction in relative right testis weight upon administration of Compound 1.
  • Figure 5 illustrates a dose dependent reduction in relative left testis weight upon administration of Compound 1.
  • Figure 6 illustrates a dose dependent reduction in relative whole prostate weight upon administration of Compound 1.
  • Figure 7 illustrates a dose dependent reduction in relative dorsal prostate weight upon administration of Compound 1.
  • Figure 8 illustrates a dose dependent reduction in relative ventral prostate weight upon administration of Compound 1.
  • Figure 9 illustrates a dose dependent reduction in absolute ventral prostate weight upon administration of Compound 1.
  • Figure 10 illustrates a dose dependent reduction in absolute dorsal prostate weight upon administration of Compound 1.
  • Figure 11 illustrates a dose dependent reduction in absolute whole prostate weight upon administration of Compound 1
  • Figure 12 illustrates a dose dependent reduction in absolute right testis weight upon administration of Compound 1.
  • Figure 13 illustrates a dose dependent reduction in absolute left testis weight upon administration of Compound 1.
  • Figure 14 illustrates a reduction in absolute ventral prostate weight upon administration of Compound 3.
  • Figure 15 illustrates a reduction in absolute dorsal prostate weight upon administration of Compound 3.
  • Figure 16 illustrates a reduction in absolute anterior prostate weight upon administration of Compound 3.
  • Figure 17 illustrates a reduction in absolute right testis weight upon administration of Compound 3.
  • Figure 18 illustrates a reduction in absolute left testis weight upon administration of Compound 3.
  • Alkyl refers to a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix.
  • (C j -C 8 )alkyl is meant to include methyl, ethyl, n- propyl, 2-propyl, n- butyl, 2-butyl, tert-butyl, pentyl, and the like.
  • (C 1 -C 8 ) Alkyl may be further substituted with substituents, including for example, hydroxyl, amino, mono or di(C]-C 6 )alkyl amino, halo, (C 2 -C 6 ) alkenyl ether, cyano, nitro, ethenyl, ethynyl, (C 1 -C 6 ) alkoxy, (Ci-C 6 ) alkylthio, acyl, - COOH, -CONH 2 , mono- or di-(C r C 6 )alkyl-carboxamido, -SO 2 NH 2 , -OSO 2 -(C] -C 6 )alkyl, mono or di(Ci-C 6 ) alkylsulfonamido, cyclohexyl, heterocyclyl, aryl and heteroaryl.
  • substituents including for example, hydroxyl, amino, mono or di(C]-C 6 )
  • acyl or "alkanoyl” means the group -C(O)R', where R' is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and variations of these groups in which one or more carbon atoms have been replaced with heteroatoms.
  • Alkylene refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix.
  • (C 1 -C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • alkenyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but no more than three double bonds.
  • (C 2 -C 6 )alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix.
  • alkynyl is also meant to include those alkyl groups having one triple bond and one double bond. For example, (C2-
  • C6)alkynyl is meant to include ethynyl, propynyl, and the like.
  • Alkoxy As used herein, the terms "Alkoxy”, “aryloxy” or “araalkyloxy” refer to a radical - OR wherein R is an alkyl, aryl or arylalkyl, respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, and the like.
  • Aryl or “arylene” or “arene” refer to a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylaniino, haloalkyl, haloalkoxy, heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), -(CR'R") n -COOR (where n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloal
  • R x and R y together is heterocyclyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted forms thereof.
  • Alkyl or “Aryl(Ci-C x )alkyl” refer to the radical -
  • R X RY where R x is an alkylene group (having eight or fewer main chain carbon atoms) and
  • RY is an aryl group as defined above.
  • arabinarykyl refers to groups such as, for example, benzyl, phenylethyl, 3-(4-nitrophenyl)-2-methylbutyl, and the like.
  • Araalkenyl means a radical -R X RY where R x is an alkenylene group (an alkylene group having one or two double bonds) and RY is an aryl group as defined above, e.g., styryl, 3-phenyl-2- propenyl, and the like.
  • cyclic ring system means a single heterocyclyl, cycloalkyl, aryl, or heteroaryl ring or combination of heterocyclyl, cycloalkyl, aryl, or heteroaryl rings as defined herein.
  • Cycloalkyl refers to a monovalent cyclic hydrocarbon radical of three to seven ring carbons.
  • the cycloalkyl group may have double bonds which may but not necessarily be referred to as “cycloalkene” or “cycloalkenyl”.
  • the cycloalkyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, -COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), -(CR 3 R") -
  • R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R") n -CONR X R y x y
  • n is an integer from 0 to 5
  • R' and R" are independently hydrogen or alkyl
  • R and R are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl.
  • cycloalkyl includes, for example, cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2- carboxamidocyclohexenyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
  • Cycloalkyl-alkyl means a radical -R X RY wherein R x is an alkylene group and Ry is a cycloalkyl group as defined herein, e.g., cyclopropylmethyl, cyclohexenylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
  • the prefix indicating the number of carbon atoms ⁇ e.g., C4-C10) refers to the total number of carbon atoms from both the cycloalkyl portion and the alkyl portion.
  • halo and the term “halogen” when used to describe a substituent, refer to -F, -Cl, -Br and -I.
  • Heteroalkyl means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, -OR , -NR R , and - S(O) R (where p is an integer from 0 to 2 ), with the understanding that the point of
  • W attachment of the heteroalkyl radical is through a carbon atom of the heteroalkyl radical.
  • R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl.
  • R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl.
  • R y is hydrogen, alkyl, cycloalkyl, cycloalkyl- alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di- alkylcarbamoyl or alkylsulfonyl.
  • R is hydrogen (provided that p is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl.
  • Representative examples include, for example, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2- methoxyethyl, benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl-ethyl.
  • R 5 R , R , and R can be further substituted by amino, fluorine, alkylamino, di- alkylamino, OH or alkoxy. Additionally, the prefix indicating the number of carbon atoms (e.g., C 1 -C 10 ) refers to the total number of carbon atoms in the portion of the heteroalkyl
  • heteroalkyl by itself or in combination with another term, also refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini ⁇ e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 5 C(O) 2 .
  • heteroaryl or “heteroaryl ring” means a monovalent monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl, -(CR'R") n -C00R (where n is an integer from O to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), or -(CR'R")n-CONR X R y (where n is an integer from O to 5, R' and R" are independently
  • R x and R y together is heterocyclyl. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, indazolyl, pyrrolopyrymidinyl, indolizinyl, pyrazolopy
  • heterocycle means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one to four ring atoms are heteroatoms selected from O, NR (where R is independently hydrogen or alkyl) or S(O) (where p is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di- alkylamino, haloalkyl, haloalkoxy, -COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), -(CR'R") n -C00R (n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R") n -CONR R
  • R' and R" are independently hydrogen or alkyl, R and R are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More specifically the term heterocyclyl includes, but is not limited to, pyridyl, tetrahydropyranyl, N- methylpi ⁇ eridin-3-yl, N-methylpyrrolidin-3-yl, 2-pyrrolidon-l-yl, furyl, quinolyl, thienyl, benzothienyl, pyrrolidinyl, piperidinyl, morpholmyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, l,l-dioxo-hexahydro-l ⁇ 6 -thiopyran-4-yl, tetrahydroimidazo [4,5-c] pyridin
  • the prefix indicating the number of carbon atoms refers to the total number of carbon atoms in the portion of the cycloheteroalkyl or heterocyclyl group exclusive of the number of heteroatoms.
  • R x and R y together is heterocyclyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2- naphthyl, and the substituted forms thereof.
  • Heterocyclylalkyl or “Cycloheteroalkyl-alkyl” means a radical -R X R V where R x is an alkylene group and R v is a heterocyclyl group as defined herein, e.g., tetrahydropyran-2-ylmethyl, 4-(4-substituted-phenyl)piperazin-l-ylmethyl, 3- piperidinylethyl, and the like.
  • halo and “halogen” are used interchangeably; the terms “hydroxy” and “hydroxyl” are used interchangeably; and the terms “COOR 3 " and "CO 2 R 3 " are used interchangeably.
  • heterocyclyl group optionally mono- or di- substituted with an alkyl group means that the alkyl may, but need not be, present, and the description includes situations where the heterocyclyl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with an alkyl group.
  • Optionally substituted means a ring which is optionally substituted independently with substituents.
  • alkyl in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. For brevity, the terms (e.g., “alkyl,” “aryl” and “heteroaryl”) will refer to substituted or unsubstituted versions as provided below.
  • Substituents for the radicals can be a variety of groups and are generally selected from: -halogen, -OR', -NR'R", -SR', -SiR'R "R'", -OC(O)R', -C(O)R', -CO 2 R', -CONR'R",
  • C 2 _g alkynyl unsubstituted aryl and heteroaryl, (unsubstituted aryl)-Ci-4 alkyl, and unsubstituted aryloxy-Ci-4 alkyl, aryl substituted with 1-3 halogens, unsubstituted Cj-g alkyl, Cj-g alkoxy or C ⁇ -g thioalkoxy groups, or unsubstituted aryl-Ci-4 alkyl groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, A-, 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U 3 -, wherein T and
  • U 3 are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O) 2NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH2) s -X-(CH2)t-, where s and t are independently integers of from 0 to 3, and X is -O-, - NR'-, -S-, -S(O)-, -S(O)2-, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted Ci -g alkyl.
  • di-alkylamino refers to an amino moiety bearing two alkyl groups that can be the same, or different.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 4 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • compounds of Formula I would exclude compounds which contain a N-CO 2 H, NSO 2 H or NSO 3 H moiety.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art ⁇ see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992).
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulf
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Greene and P.G. Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al, COMPENDIUM OF SYNTHETIC ORGANIC METHODS, VOIS. 1-8 (John Wiley and Sons. 1971-1996).
  • Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2- trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.
  • hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • the term "pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • treating refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer or BPH, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, and other beneficial results described below.
  • administering or “administration of a drug to a subject (and grammatical equivalents of this phrase) includes both direct administration, including self- administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self- administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • a "therapeutically effective amount" of a drug is an amount of a drug that, when administered to a subject with cancer or BPH, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer or BPH in the subject.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • a prophylactically effective amount of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of disease or symptoms, or reducing the likelihood of the onset (or reoccurrence) of disease or symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • A-B is a 7,5, 6,5 or a 5,5 cyclic ring system, optionally substituted with from one to five V 6 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Ci-C 8 )alkyl, (Ci-C 6 ) alkoxy, nitro, acetamido, l ⁇ C0 2 H, i ⁇ dialkylamino, (Ci-C 8 )heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C !
  • L 1 is selected from the group consisting of (d-C 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (CrC 4 )alkyl, (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (C 1 -C 6 ) alkoxy, cyano, nitro, amino, -NO, (Ci-C 4 )alkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1 attached to the
  • each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -
  • Y is CR 8 2 , CR 8 , NR 8 , S or O;
  • U is O 5 S, NR 3 , NCOR 3 , or NCONR 3 R 7 ;
  • U 1 is O or S; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • the present invention further includes all salts thereof, and particularly, pharmaceutically acceptable salts thereof.
  • the invention includes compounds that are single isomers of the above formula (e.g., single enantiomers of compounds having a single chiral center), as well as solvate, hydrate and tautomeric forms thereof.
  • isomers include single geometric isomers such as cis, trans, E and Z forms of compounds with geometric isomers, or single tautomers of compounds having two or more tautomers.
  • an amino or alkylamino functionality present in a compound of formula (I) can be further substituted with one or more acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl groups.
  • an acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or arylsulfonyl group is part of a cyclic structure.
  • groups e.g., certain sets of compounds of the invention are referred to as "groups," e.g.,.
  • the five analogs above can be called Group A analogs, and the set of compounds defined by formula (I) and not including the aforementioned Group A analogs can be refered to as GROUP 1 compounds.
  • the present invention provides compounds of formula (III)
  • R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents that are independently selected from the group consisting of halo and a straight or branched chain (C 1 -C 8 )alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or (Ci-C 8 )heterocyclyl, or aryl or heteroaryl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (Ci-C 8 )alkyl or (Ci-Csjheteroalkyl, (C 3 -C 8 )cyclo alkyl or (Ci-C 8 )heterocyclyl, or aryl or heteroaryl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • Ar is a substituted or unsubstituted aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , C-R 8 , CU, O, NR 7 and S; each W 6 , W 7 ; W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 4 ) alkyl or (C 1 - C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (C]-C 4 ) alkylamino and (C 1 -C 4 ) dialkylamino; Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, a straight or branched chain (Ci-Cs)alkyl or (Ci-Cs)heteroalkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; with the proviso that when W 1 , W 4 , and W 5 are C; W 2 and W 3 are N; W 6 and W 7 are CH, Y is
  • R 6 is Cl; and R 1 is not COOR 3 or COR 4 .
  • the compounds of the present invention have the formula (I) with the proviso that the compound is not one of the following compounds (a)-(i) as defined below.
  • GROUP 2 compounds (i) as defined below can be referred to as GROUP 2 compounds.
  • R 2a is a group having the formula:
  • R 3a is hydrogen
  • R la is CO 2 H
  • R 2a is selected from the group consisting of 4-chlorophenyl, 3-chlorophenyl, 2- chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-trifluoromethylphenyl, 4- cyanophenyl, 4-phenylsulfonyl-phenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,6- dichlorophenyl, 2,4-dibromophenyl, 2,4,5-trichlorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 3-benzoylphenyl, 4-methylsulfonylphenyl, 4-chloronaphthylmethyl, 2,4-dimethylphenyl and 2-methyl-4-chlorophenyl; and
  • R 3a is hydrogen; iii) R la is CO 2 H
  • R 2a is 4-chlorophenyl
  • R 3a is chloro, OH, methyl, or OMe; iv) R la is selected from the group consisting Of CO 2 Me, CO 2 Et, -CO-glyceryl, COCH 3 , CONH 2 , CH 2 CO 2 H, CH 2 CH 2 CO 2 H and
  • R 2a is 4-chlorophenyl, and R 3a isH;
  • R 2a is 2, 4-dichlorophenyl
  • R 3a is selected from the group consisting of-(OCH3) n io wherein nl o is 1 or 2, chloro, bromo, fluoro, CO 2 H, and CH 2 CO 2 H. [Cheng];
  • R la is -0-PO 3 H, -0-SO 3 H, -0-CH 2 CO 2 H, 0-CH(CO 2 H) 2 , NHCH(CO 2 H) 2 , CH 2 CH(NH 2 )CO 2 H, CONHCH(CO 2 H) 2 , and CONH(CH 2 ) n ii-cyclopropyl wherein nil is O or 1,
  • R 2a is 2, 4-dichlorophenyl, R 3a is H;
  • R Ia is selected from the group consisting of -COCH 3 , -SH, -tetrahydrofurfuryl, - CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -H, -CH 3 , -CH 2 OH, -NH 2 , -CN, -tetrazin-2-yl, , O-(CH 2 )i- 2 CO 2 H, 0-CH 2 CO 2 Ci -C 4 alkyl, -0-PO 3 H, -0-SO 3 H, 0-CH(CO 2 H) 2 , NHCH(CO 2 H) 2 and CH 2 CHNH 2 CO 2 H;
  • R 2a is selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methyl ⁇ henyl, trifluoromethylphenyl, 3- benzoyl, 4-halophenyl, 4-methylsulfonylphenyl, 4-methylphenyl, 4-cyano ⁇ henyl, A- phenylsulfonylphenyl, 4-methoxyphenyl, 4-chloronapth-l-yl, 2,3-dimethylphenyl, 2,4- dihalophenyl, 2,4-dimethylphenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 3,4- dichlorophenyl, bis-trifluoromethylphenyl, 4-chloro-2-methylphenyl, 5-chloro-2- methoxyphenyl, 2,4,5-trichlorophenyl,
  • R 3a is selected from the group consisting of H, 2-dimethylaminoethyl, 5-amino, chloro, bromo, 5-hydroxy, 5-methyl, methoxy, dimethoxy, fluoro, CO 2 H, CH 2 CO 2 H, 5-nitro, 5-acetamido and 7-chloro;
  • R !a is COOH, CONH 2 , COO CH 2 CH 2 OH, COOCH 2 CHOHCH 2 OH, or
  • R 22a is H or halo
  • R 20a is halo, Me, methoxy, trifluoromethyl, C0NH2, or methanesulfonyl, and
  • R 21a is H, Me, halo, or a group forming with the benzene ring to which it is attached a naphthyl ring.
  • R lb is CO 2 H
  • R 2b is phenyl
  • R 3b is H
  • R lc is CH 2 CONH 2 ;
  • R 2c is phenyl, 2-phenyl-phenyl, 2-benzyl-phenyl, 3-chlorophenyl, 3-trifluorophenyl, 4-phenyl-phenyl, naphthyl, 3,5-di-t-butylphenyl, benzyl, 2-thienyl, 3-(thien-2-yl)thienyl, cyclohexyhnethyl, 3-methoxyphenyl, 3-nitrophenyl, cyclop entylmethyl, cycloheptylmethyl, pentyl, 4-heptyl, 1-adamantyl, trans-4-pentyl-cyclohexyl, 2-phenylethenyl, 2 -phenyl ethyl,
  • R 3c is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH 2 CH 2 CH 2 ) 1-4 CO 2 H, -OCH 2 -tetraazo-2-yl and -SCH 3 ;
  • R lc when R lc is COCONH 2 ;
  • R 5c and R 2c are defined as set forth in Table 2A below;
  • R 3c is benzyl, then compounds i-xxv, xxvii, xxix, xxxvii, and xxxix are excluded;
  • R 3c is Me, then compound xxvi is excluded;
  • R 3c is H, then compounds i-xxix, xxxviii, and xxxix are excluded;
  • R 3c is -CH 2 -CO 2 Me, then compounds i, ii, iv, vi, viii-xxiii, xxiv, xxx-xxxviii, and xxxix are excluded;
  • R 3 ° is -CH 2 -CO 2 Et, then compounds iii, v, and vii are excluded; and R 3c is -CH 2 -CO 2 H, then compounds i-xxix, xxx-xxxvii, and xxxix are excluded.
  • R 20c is 3-chloro
  • R 23c is CH 2 -tetrazolyl, CH 2 -2-pyridyl, CH 2 -4-pyridyl, CH 2 -2-quinolinyl, -(CH2) 3 - CO 2 Et, -(CH 2 ) 3 -CO 2 H, -(CH 2 ) 2 -CO 2 H,
  • R 5c is ethyl
  • R 20c is 2-phenyl
  • R 23c is OCH 2 CO 2 H, R 5c is ethyl and R 20c is H; (d) R 23o is Me or H, and
  • R 5c is ethyl when R 20c is hydrogen
  • R 5c is cylopropyl when R 20c is 2-phenyl
  • R 5c is ethyl when R 2Oc is 2-phenyl
  • R 23c is -(CH 2 ) 3 -CO 2 Et or -(CH 2 ) 3 -CO 2 H
  • R 5c is ethyl when R 20 ° is hydrogen
  • R 5c is cylopropyl when R 20c is 2-phenyl
  • R 5c is ethyl when R 20c is 2-phenyl
  • R 23c is -(CH 2 ) 2 -CO 2 Et, -(CH 2 ) 2 -CO 2 H, -CH 2 -CO 2 Et or -CH 2 -CO 2 H, R 5c is ethyl and R 20c is 2-phenyl;
  • R ld is CH 2 CONH 2 ;
  • R 2d is selected from the group consisting of phenyl, 2-phenyl-phenyl, 2-benzyl- phenyl, 3-chlorophenyl, 3-trifluorophenyl, 4-phenyl-phenyl, naphthyl, 3,5-di-t-butylphenyl, benzyl, 2-thienyl, 3-(thien-2-yl)thienyl, cyclohexylmethyl, 3-methoxyphenyl, 3-nitrophenyl, cyclopentylmethyl, cycloheptylmethyl, pentyl, 4-heptyl, 1-adamantyl, trans-4-pentyl- cyclohexyl, 2-phenylethenyl and 2-phenylethyl;
  • R 3d is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH 2 CH 2 CH 2 ) 1-4 CO 2 H, -OCH 2 -tetraazo-2-yl and -SCH 3 ; [0084] Within this embodiment referring to formula (e):
  • R le is CH 2 CONH 2 ,
  • R 2e is selected from the group consisting of phenyl, 2-phenyl-phenyl, 2-benzyl- phenyl, 3-chlorophenyl, 3-trifluorophenyl, 4-phenyl-phenyl, naphthyl, 3,5-di-t-butyl ⁇ henyl, benzyl, 2-thienyl, 3-(thien-2-yl)thienyl, cyclohexylmethyl, 3-methoxyphenyl, 3-nitrophenyl, cyclopentylmethyl, cycloheptylmethyl, pentyl, 4-heptyl, 1-adamantyl, trans-4-pentyl- cyclohexyl, 2-phenylethenyl and 2- ⁇ henylethyl;
  • R 3e is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - 0(CH 2 CH 2 CH 2 ) I-4 CO 2 H, -OCH 2 -tetraazo-2-yl and -SCH 3 ; [0085] Within this embodiment, referring to formula (f):
  • R lf is CO 2 H
  • R 2f is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2, 5-dichlorophenyl, 2, 6-dichlorophenyl, 3, 4- dichlorophenyl and 3, 5-dichlorophenyl;
  • R 3f is H; [0086] Within this embodiment, referring to formula (g): R lg is CO 2 Et;
  • R 2g is phenyl
  • R 3g is H
  • R 2h is phenyl
  • R 3h is H, 5-methyl or 7-methyl
  • R H is CONHCH 2 CH 2 Cl or CONHCH 2 CH 2 -piperazin-4-yl
  • R 2 ' is benzyl
  • R 3i is H.
  • the present invention excludes compounds specifically disclosed in the following references: Corsi et al, 1976, J Med Chem 19:778-83; Cheng et al, 2001, BiolReprod. 65:449-61; Silvestrini, 1981, Chemotherapy 27:9-20; Andreani et al., Arch. Pharm., Weinheim, 1984, 317: 847-51, Besner et al, Drug. Metab. Rev., 1997, 29(1 and 2): 219-34, Palacios et al, Tetrahedron 1995, 52(12):3683-90, Kakehi et al., Bull. Chem. Soc.
  • the compounds of the present invention have the formula (I) with the proviso that the compound does not have the formula:
  • R 1 is -COOH; -CONR 3 R 4 , -CONHNR 6 R 7 ; -COOR 5 or -COO- Z+; Z+ is a pharmaceutically acceptable cation;
  • R represents a aryl or heteroaryl group, optionally substituted by one, two, or three substituents independently selected from the group consisting of halo, alkyl and CF 3 ;
  • R 3 and R 4 may be independently alkyl or hydrogen;
  • R 6 and R are usually -H or -CH 3 ;
  • X represents a straight chain or branched chain, saturated or unsaturated hydrocarbon linkage group; Y is-CHR 7 -; and n is 0 or 1.
  • Y is NR 8 .
  • hi other embodiments Y is NH.
  • Y is O.
  • Y is S.
  • hi other embodiments Y is CR 8 .
  • Y is CR 8 2 .
  • hi other embodiments Y is CH 2 .
  • the present invention provides R 8 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Cr Cg)alkyl, (C 1 -C 6 ) alkoxy, nitro, acetamido, L ⁇ CO 2 H, L ⁇ dialkylamino, (CrC 8 )heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl; U 1 - R 3 , U 1 -COR 3 , U 1 -CUNR 3 R 7 , U 1 -CU 2 R 3 , R 4 , NR 3 OR 3 , NR 3 -CUR 3 , N-(CUR 3 ) 2 , NR 3 - CUNR 3 R 7 , N-(CU) 2 , NR 3
  • the present invention provides R substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (C 1 -C 8 )alkyl, (C ! -C 8 )heteroalkyl, (C 2 -Cg)alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl; U 1 -R 3 , R 4 , NR 3 - CUR 3 , N-(CUR 3 ) 2 , NR 3 -CUNR 3 R 7 , N-(CUNR 3 R 7 ) 2 , NR 3 -CU 2 R 3 , N-(CU 2 R 3 ) 2 , NR 3 -SO 2 R 3 , N-(SO 2 R 3 ) 2 , NR 3 -PU 2 R 3 , N-(PU 2 R 3 , N
  • the present invention provides R 8 selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl or (Q-C ⁇ heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino, and (Ci-C 4 ) dialkylamino.
  • the present invention provides R selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • the present invention provides compounds of Formula I, wherein A-B is a 7,5-fused (C 1 -C 8 )CyCHc ring system. In one embodiment the present invention provides compounds of Formula I, wherein A-B is a 6,5-fused (Ci-C 8 )cyclic ring system, m other embodiments the present invention provides compounds of Formula I, wherein A-B is a 5,5-fused (C 1 -C 8 )CyCHc ring system.
  • GROUP 4 the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula IIA:
  • each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 W 9 or W 12 is independently N, NV 6 , CO, CS, SO, SO 2 or CV 6 ; represents a single or double bond;
  • R 1 , Y, R 2 and V 6 are as defined above in formula (I); and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • the substitution pattern of the 5-membered ring is such that none of W 1 , W 3 , W 4 , and W 5 is CH or CV 6 .
  • all of W 6 - W 9 and W 12 are independently CV 6 .
  • three of W 6 -W 9 and W 12 are independently CV 6 and the other is CH or N.
  • two of W 6 -W 9 and W 12 are independently CV 6 and the rest are CH or N.
  • one of W 6 -W 9 and W 12 is CV 6 and the rest are CH or N.
  • the present invention provides V 6 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Cr C 8 )alkyl, (Ci-C 8 )heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci- C 8 )heterocyclyl, aryl, heteroaryl; U 1 -R 3 , R 4 , NR 3 -CUR 3 , N-(CUR 3 ) 2 , NR 3 -CUNR 3 R 7 , N- (CUNR 3 R 7 ) 2 , NR 3 -CU 2 R 3 , N-(CU 2 R 3 ) 2 , NR 3 -SO 2 R 3 , N-(SO 2 R 3 ) 2 , NR 3 -PU 2 R 3 , N-(PU 2
  • the present invention provides V 6 selected from the group consisting of hydrogen, (Ci-C 4 ) alkyl or (Ci-C 4 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (CpC 4 ) alkylamino, and (Ci-C 4 ) dialkylamino.
  • the present invention provides V 6 selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 or W 9 is independently N, NV 6 , CO, CS, SO, SO 2 or CV 6 ; represents a single or double bond;
  • R 1 , Y, R 2 and V 6 are as defined above in formula (I); and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • the substitution pattern of the 5-membered ring is such that none of W 1 , W 3 , W 4 , and W 5 is CH or CV 6 .
  • all of W 6 - W 9 are independently CV 6 .
  • three of W 6 - W 9 are independently CV 0 and the other is CH or N.
  • W 6 -W 9 are independently CV 6 and the rest are CH or N.
  • one of W 6 - W 9 is CV 6 and the rest are CH or N.
  • V is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fiuoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 4 ) alkyl or (d-C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 4 ) (Ci-C 6 ) alkoxy, cyano, nitro, amino, (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino or V 1 and V 3 together form a (C 3 -C 8 )cycloalkyl, a (C 1 -C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, (Ci-C 4 ) alkylamino or (C 1 -C 4 ) dialkylamino, then the other is hydrogen or
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents that are independently selected from the group consisting of halo and (Ci- C 8 )alkyl;
  • R 3 is H, (Ci-Cs)alkyl, (Ci-C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, (C r C 8 )heterocyclyl, aryl or heteroaryl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (d-C 8 )alkyl, (d-C ⁇ heteroalkyl, (C 3 -C 8 )cycloalkyl, (C r C 8 )heterocyclyl, aryl or heteroaryl;
  • R and R together are (Q-C ⁇ heteroalkyl or heteroaryl;
  • Ar is aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, oxo, U ⁇ R 3 , U 1 -COR 3 , (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • GROUP 7 the present invention provides compounds of formula IIIA wherein the A-B ring moiety has the following structure
  • W 6 -W 9 is defined as follows in Table IB:
  • the present invention provides compounds of formulae IIIA and for each ring B 1-21, W 6 - W 9 is defined as follows in Table 1C:
  • V 6 and U are as defined above.
  • W 1 -W 5 of formula (IV) are as defined in Table IA above; and for each W 1 -W 5 as defined above, W 6 - W 8 are defined as follows in Table ID:
  • A-B in formula IVA is selected from the group consisting of:
  • V 1 , V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 4 ) alkyl or halogen, hydroxy, (C 1 -C 4 ) (C 1 -C 6 ) alkoxy, cyano, nitro, amino, (CrC 4 ) alkylamino and (Ci-C 4 ) dialkylamino or V 1 and V 3 together form a (C 3 -C 8 )cycloalkyl, a (Ci-C 8 )heterocycloalkyl, a (C 3 -Cg)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, (Ci -C 4 ) alkylamin
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R ⁇ substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl;
  • R 3 is H, (C 1 -C 8 )alkyl or (C 1 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or (Ci-C 8 )heterocyclyl, or aryl or heteroaryl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or (Ci-Cg)heterocyclyl, or aryl or heteroaryl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • Ar is a substituted or unsubstituted aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W is a member selected from the group consisting of N, CR , CO, O, NR and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (Ci- C 8 )heteroalkyl, halogen, hydroxy, (C 1 -Ce) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, a straight or branched chain (CrC 8 )alkyl or (CrC 8 )heteroalkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • each V 1 , V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (d-C 8 )heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, cyano, nitro, amino, (C 1 -C 4 ) alkylamino and (C 1 -C 4 ) dialkylamino or V 1 and V 3 together form a (C 3 -C 8 )cycloalkyl, a (Ci- C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, (Ci-C 4 ) alkylamino or (Ci-C 4 ) dialkyla
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (d-C 8 )alkyl;
  • R 3 is H, (C 1 -C 8 )alkyl or (C r C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (C 1 -C 8 )alkyl or (Ci-C 8 )heteroalkyl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • Ar is a substituted or unsubstituted aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (Ci- C 8 )heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino and (C 1 -C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, a straight or branched chain (Ci-Cs)alkyl or (Ci-C 8 )heteroalkyl group; represents a single, double or normalized bond.
  • the compounds of the present invention have the formula (HID), (HD) or (HE):
  • each V 1 , V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (Ci-Cs)heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, cyano, nitro, amino, (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino or V 1 and V 3 together form a (C 3 -Cs)cycloalkyl, a (Ci- C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, (Ci-C 4 ) alkylamino or (C 1 -C 4 ) dialkylamino
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (d-C 8 )alkyl or (Ci-C 8 )heteroalkyl;
  • R 3 and R 7 together are (CrC 8 )heteroalkyl or heteroaryl;
  • Ar is a substituted or unsubstituted aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C]-C 4 ) alkyl or (Ci- C 8 )heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, a straight or branched chain (Ci-C 8 )alkyl or (Ci -C 8 )hetero alkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and in formula (HE) or (IIE):
  • V 1 , V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj-C 4 alkyl or (Ci-C 8 )heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, cyano, nitro, amino, Cj-C 4 alkylamino, and CpC 4 dialkylamino or V 1 and V 3 together form a (C 3 -Cs)cyclo alkyl, a (Ci-C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, Cj-C 4 alkylamino, or Ci-C 4 dialkylamino, then the other is hydrogen or alky
  • R 3 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 7 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • R 5 is H, OH or halogen
  • R 6 is halo or a straight or branched chain (C 1 -C 8 )alkyl
  • Ar is a substituted or unsubstituted aryl or heteroaryl
  • Y is CH 2 , CHR 8 , CR 8 , NR 8 , S or O;
  • R is H or a straight or branched chain (Ci-C 8 )alkyl group
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl.
  • the compounds of the present invention have the formula (HID), (HIE), (IID) or (HE):
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting of NR 3 R 7 ,NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • R 7 is H, (Ci-Cs)alkyl or (Ci-C 8 )heteroalkyl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • Ar is a substituted or unsubstituted aryl or heteroaryl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, NR 7 and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1 -C 4 ) alkyl or (Ci- C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 4 ) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R is H, a straight or branched chain (Ci-C 8 )alkyl or (C]-C 8 )heteroalkyl group; represents a single, double or normalized bond; and in formula (V):
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl;
  • R 3 is H, (C r C 8 )alkyl or (C,-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting Of NR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen
  • R 7 is H or (Ci-C 8 )alkyl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N, C or CH;
  • Y is CHR 8 , NH, or O
  • R 8 is H or a straight or branched chain (Ci-C 8 )alkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and in formula (HID) or (HIE):
  • V 1 , V 2 , V 3 , and V 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 4 alkyl or (C)-C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 4 ) alkoxy, cyano, nitro, amino, Ci-C 4 alkylamino, and Ci-C 4 dialkylamino or V 1 and V 3 together form a (C 3 -C 8 )cycloalkyl, a (Ci-C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V and V is hydroxyl, amino, Ci-C 4 alkylamino, or Ci-C 4 dialkylamino, then the other is hydrogen or alkyl; and
  • R 3 is H, (C 1 -C 8 )alkyl or (C 1 -C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 7 is H, (Ci-C 8 )alkyl or (d-C 8 )heteroalkyl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl;
  • R 5 is H, OH or halogen
  • R 6 is halo or a straight or branched chain (C 1 -C 8 )alkyl
  • Ar is a substituted or unsubstituted aryl or heteroaryl
  • Y is CH 2 , CHR 8 , CR 8 , NR 8 , S or O;
  • R is H or a straight or branched chain (C 1 -Cs)alkyl group
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (C 1 -C 8 ) ⁇ yI.
  • R 1 is L 1 -V 5 wherein L 1 selected from the group consisting of -C ⁇ £-,
  • V ⁇ l 5 V is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (Ci-Cg)heteroalkyl, halogen, hydroxy, (Ci-C 4 ) alkoxy, cyano, nitro, amino, (Ci-C 4 ) alkylamino, and (Ci-C 4 ) dialkylamino or V 1 and V 3 together form a (C 3 -Cs)cycloalkyl, a (Ci-Cs)heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V 1 and V 2 is hydroxyl, amino, (Ci-C 4 ) alkylamino, or (Ci-C 4 ) dialkylamino, then the other is hydrogen or alkyl; and if one of V 3 and
  • R 2 is an aryl or. heteroaryl group, optionally substituted with from one to three R 6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
  • R 3 is H, (Ci-Cs)alkyl or (Ci-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 and NR 3 CN;
  • R 5 is H, OH or halogen
  • Ar is a substituted or unsubstituted aryl or heteroaryl
  • R 7 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl;
  • R 3 and R 7 together are (Ci-C 8 )heteroalkyl or heteroaryl; each W 1 , W 3 , W 4 , or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, NR 7 , CR 5 , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N or CV 6 wherein V 6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or (Ci- C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 4 ) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino, and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 , S, or O;
  • R 8 is H or a straight or branched chain (Ci-C 8 )alkyl group; and represents a single, double or normalized bond.
  • R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cg)alkyl;
  • R 3 is H 5 (Ci-Cs)alkyl or (C r C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen
  • R 7 is H or (Ci-C 8 )alkyl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W is a member selected from the group consisting of N, CR , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N, C or CH;
  • Y is CHR 8 , NH, or O
  • R 8 is H or a straight or branched chain (d-C 8 )alkyl group; represents a single, double or normalized bond.
  • the compounds of the present invention have the formula (HIE), (HF) or (IIG):
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl;
  • R 3 is H, (d-C 8 )alkyl or (Ci-C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen
  • R 7 is H or (CrC 8 )alkyl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N, C or CH;
  • Y is CHR 8 , NH, or O
  • R 8 is H or a straight or branched chain (d-C 8 )alkyl group; represents a single, double or normalized bond; with the proviso that when
  • W 1 , W 4 , and W 5 are C; W 2 and W 3 are N; W 6 and W 7 are CH, Y is CH 2 ; R 6 is Cl; R 1 is not COOR 3 or COR 4 ; and the compound does not have the formula selected from the group consisting of:
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl; and
  • Y is CH 2 , O, NH, or S.
  • the compounds of the present invention have the formula (HE), (VI) or (VII):
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (C r C 8 )heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen
  • R 7 is H or (Ci-C 8 )alkyl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N 5 C or CH;
  • Y is CHR 8 , NH, or O
  • R 8 is H or a straight or branched chain (d-C 8 )alkyl group; represents a single, double or normalized bond; with the proviso that when
  • W 1 , W 4 , and W 5 are C; W 2 and W 3 are N; W 6 and W 7 are CH, Y is CH 2 ; R 6 is Cl; R 1 is not COOR 3 or COR 4 ; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and in formula (IIF) and (IIG):
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl; and
  • Y is CH 2 , O, NH, or S.
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (C 1 -C 8 )alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (d-C 8 )heteroalkyl; each R 4 is NHCN;
  • R 5 is H, OH or halogen
  • R 7 is H or (C r C 8 )alkyl; each W 1 , W 3 , W 4 or W 5 is independently N or C;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N, C or CH;
  • Y is CHR 8 , NH, or O
  • R is H or a straight or branched chain (CrC 8 )alkyl group; represents a single, double or normalized bond; with the proviso that when
  • W 1 , W 4 , and W 5 are C; W 2 and W 3 are N; W 6 and W 7 are CH, Y is CH 2 ; R 6 is Cl; R 1 is not COOR 3 or COR 4 ; pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C 8 )alkyl;
  • R 3 is H, (Ci-C 8 )alkyl or (Ci-Cg)heteroalkyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 and NHNR 3 R 7 ;
  • R 5 is H, OH or halogen
  • R 7 is H or (Ci-C 8 )alkyl; each W 1 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 or W 9 is independently N, C or CH;
  • W 2 is a member selected from the group consisting of N, CR 5 , CO, O, and S;
  • Y is CHR 8 , NH, or O
  • R is H or a straight or branched chain (Ci-Cg)alkyl group; represents a single, double or normalized bond; with the proviso that when
  • W 1 , W 4 , and W 5 are C; W 2 and W 3 are N; W 6 and W 7 are CH, Y is CH 2 ; R 6 is Cl; R 1 is not
  • W -W are independently CV 6 .
  • three of W 6 - W 9 are independently CV 6 and the other is CH or N.
  • two of W 6 -W 9 are independently CV 6 and the rest are CH or N.
  • one of W 6 - W 9 is CV 6 and the rest are CH or N.
  • V is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • R 1 is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • R 1 is a COOR 3 or L ⁇ CO 2 R 3 , wherein L 1 is defined as above in formula (I) and R 3 is H or (CH 2 ) q NR 9 R 10 and each R 9 and R 10 is a straight or branched chain (Ci-C 8 )alkyl, or optionally, if both are present on the same substituent, joined together to form a three- to eight-membered heterocyclyl ring system; and the subscript q is an integer of from 1 to 4.
  • the (Q-C ⁇ heterocycloalkyl, (C 3 -Cs)cycloalkenyl, aryl, or heteroaryl ring is a five-membered ring.
  • the heteroaryl ring contains one or more nitrogen atoms.
  • R 1 is preferably a COOR 3 moiety
  • R 3 is preferably H or (CH 2 ) n NR 9 R 10 wherein each R 9 and R 10 is a straight or branched chain (Cr Cg)alkyl, or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • any R 1 and V 6 or any two V 6 attached to the same, adjacent or within two atoms may be taken together with the atoms with which they are attached to form a (C 3 -Cg)cycloalkyl, a (Ci-C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring.
  • the (C 3 -Cg)cycloalkyl moiety is selected from the group consisting of cyclopentane, cyclobutane, cyclohexane, and cycloheptane.
  • (C 3 -C 8 )cycloalkenyl moiety is selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
  • the aryl moiety is selected from benzene or naphthalene.
  • the heteraryl moiety selected from the group consisting of pyridine, furane, thiophene, thiazole, isothiazole, triazole, imidazole, isoxazole, pyrrole, pyrazole, pyridazine, pyrimidine, benzofurane, tetrahydrobenzofurane, isobenzofurane, benzothiazole, benzoisothiazole, benzotriazole, indole, isoindole, benzoxazole, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, benzisoxazole benzothiophene, indazole, pyrrolopyrymidine, indolizine, pyrazolopyridine, triazolopyridine, pyrazolopyrimidine, triazolopyrimidine, pyrrolotriazme, pyrazolotriazine,
  • the (C]-C 8 )heterocyclyl moiety is selected from the group consisting of piperidine, tetrahydropyran, N-methylpiperidine, N-methylpyrrolidine, pyrrolidone, tetrahydrofurane, morpholine, pyrrolidine, tetrahydrothiophene, 1,1-dioxo-hexahydro-l ⁇ 6 - thiopyran, tetrahydroimidazo [4,5-c] pyridine, imidazoline, and piperazine.
  • two V 6 groups together forms a (Ci-Cs)heterocycle moiety selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the present invention provides a compound wherein the R 1 group is attached to the A-B ring system such that it is rotationally restricted.
  • W 1 or a sunstituent thereon
  • W 2 or W 6 or a sunstituent thereon
  • W 1 taken together with W 2 or W 6 (or a sunstituent thereon) form a (C 3 -Cs)cycloalkyl, a (C 1 -C 8 ) heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring, such as for example
  • W 1 taken together with W 2 or W 6 form a (Ci-C 8 )heterocycle moiety selected from the group consisting of
  • straight line indicates the point of attachment to W 1 and the wavy line and indicates the points of attachment within two atoms of W 1 on the rest of the molecule. In one embodiment the straight line indicates the point of attachment to W 2 . In another embodiment the straight line indicates the point of attachment to W 6 .
  • ring A, W 1 , W 3 , Y, and R 2 are defined as in formula (II), and each W 13 , W 14 and W 15 is independently selected from the group consisting of N, NV 6 , CO, CS, SO, SO 2 and CV 6 wherein V 6 is as defined above in formula (I).
  • compounds of the present invention have the formulae:
  • W ⁇ W 6 and W 13 -W 15 is as defined above.
  • W ⁇ W 6 and W 13 -W 15 is as defined above and the remaining variables are as defined herein.
  • the present invention provides R 6 substituents, each independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, -NO, R 3 , U !
  • the present invention provides R 6 each independently selected from the group consisting of hydrogen, (Ci-C 4 ) alkyl or (Ci-C 4 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino, and (Ci-C 4 ) dialkylamino.
  • the present invention provides R 6 each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • R 6 the present invention provides each independently selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ CH and -C ⁇ C-CH 3 .
  • R 2 has 1 or 2 substituents. In another embodiment, R 2 has two R 6 substituents. R 6 substituents are independently selected from the group consisting of halo and a straight or branched chain (Q-C ⁇ alkyl.
  • R 2 is selected from the group consisting of pyrroyl, pyrazoyl, imidazoyl, pyridinyl, dihydropyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and phenyl, optionally substituted with from one to two substituents selected from the group consisting of halo or (d-C 8 )alkyl.
  • R 2 is selected from the group consisting of
  • each W 10 or W 11 is preferably, independently selected from the group consisting of N, C and CH.
  • R 6 is preferably halo or a straight or branched chain (C]- C 8 )alkyl; and the wavy line indicates the point of attachment to the rest of the molecule.
  • R 2 is more preferably phenyl and R 6 is preferably independently selected from the group consisting of Cl, Br, or CH 3 , and more preferably is Cl.
  • R 2 is selected from the group consisting of:
  • R 3 , R 7 , and R 8 are independently selected from the group consisting of: H, -CH 3 , -CH 2 CH 3 ,
  • Y is preferably NH, O, CR 8 or CHR 8 . In another embodiment, Y is preferably NH, O, or CHR 8 . R 8 is preferably H.
  • (GROUP 31) compounds preferably have the formula:
  • R 1 , R 6 and Y are defined as in formula (IIID).
  • compounds preferably have the formula:
  • R 3 is H, (C r C 8 )alkyl or (C,-C 8 )heteroalkyl;
  • each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen;
  • R 7 is H or (C 1 -C 8 )alkyl; and
  • R 6 is halo or a straight or branched chain (C 1 -C 8 )alkyl.
  • R 6 is preferably independently selected from the group consisting of Cl, Br, or CH 3 , and more preferably is Cl.
  • R 1 , R 6 and Y are defined as in formulae (I) and (II).
  • compounds preferably have the formula:
  • R 3 is H, (Ci-Cg)alkyl or (C,-C 8 )heteroalkyl;
  • each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NHOR 3 , NHNR 3 R 7 and NHCN;
  • R 5 is H, OH or halogen;
  • R 7 is H or (d-C 8 )alkyl; and
  • R 6 is halo or a straight or branched chain (C]-C 8 )alkyl.
  • R is preferably independently selected from the group consisting of Cl, Br, or CH 3 , and more preferably is Cl.
  • (GROUP 32) compounds have the formula: ein R 1 , W 2 , Y, and R 6 are defined as in formula (HID).
  • R 1 is COOR 3 or - CV ⁇ CV ⁇ R 3 .
  • R 3 is H or (CH 2 ) n NR 10 R n , wherein each R 10 and R 1 ' is a straight or branched chain (Ci-C 8 )alkyl, or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered (Ci-C 8 )heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • R 1 is preferably COOR 3 .
  • R 3 is preferably H or (CH ⁇ n NR 10 R 11 , wherein each R 10 and R 11 is a straight or branched chain (C 1 -C 8 )alkyl, or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • R 6 is preferably independently selected from the group consisting of Cl, Br, or CH 3 , and more preferably is Cl. [0140]
  • (GROUP 40) the compounds have the formula:
  • L 1 is selected from the group consisting of (Ci-Cs)alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, -NO, (C)-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to the same or adjacent atoms may be taken together with the atom
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 9 substituents independently selected from the group consisting of halo and a straight or branched chain (C 1 -Cg)alkyl; each R 3 is a member independently selected from the group consisting of H, (C]- C 8 )alkyl, (Ci-Cs)heteroalkyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl and heteroaryl; each R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 and
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, (C 3 - Cg)cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a (C ! -C 8 )heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H, (Ci-C 8 )alkyl or (Ci-C 8 )heteroalkyl.
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl; (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, -NO, (C]-C 4 )alkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1 attached to
  • R 7 is selected from the group consisting of H, (CpC 8 )alkyl, (CpC 8 )heteroalkyl, (C 3 - C 8 )cycloalkyl, (CpCg)heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a (CpCs)heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 , S or O;
  • R 8 is H 3 (Ci-C 8 )alkyl or (CpC 8 )heteroalkyl.
  • (GROUP 34) compounds have the formula:
  • each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ €-CH 3 ;
  • the compounds have the formula:
  • each R 6 independently is R 6 is hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ CH and -C ⁇ €-CH 3 ;
  • the compound has the formula:
  • each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ €-CH 3 ;
  • each R 6 independently is R 6 is hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ €-CH 3 ;
  • the compounds has the formula: wherein R is
  • V 6 is hydrogen, amino, or alkylamino.
  • V 6 is hydrogen, amino, or alkylamino.
  • R 3 is phenyl, pyridyl or SO 2 R 7 ; and V 6 is H or NHR 3 .
  • the present invention provides the compounds having the formula selected from the group consisting of:
  • R 3 is phenyl, pyridyl or SO 2 R 7 ; and V 6 is H or NHR 3 .
  • R 1 is L 1 -V 5 or CO 2 R 3 .
  • R 1 is C 2 alkenyl-CO 2 R 3 .
  • R 3 is H or (CH 2 ) q NR 13 2 ; each R 13 is independently (Ci-Cs)alkyl, or, if both present on the same substituent may be joined together to form a three- to eight-membered heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • each R 3 is a member independently selected from the group consisting of H, (Ci Cg)alkyl, aryl, (Ci-Cg)heteroalkyl and (Ci-Cg)heterocyclyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 and NR 7 NR 3 R 7 ; each R 6 is a member independently selected from the group consisting of H, halo, (Ci
  • R 7 is selected from the group consisting of H, (Ci C 8 )alkyl, (Ci-C 8 )heteroalkyl, aryl and (Q-
  • each V is independently a member selected from the group consisting of hydrogen, halo, oxo; cyano, (d-C 8 )alkyl, (C r C 8 )heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -
  • any two V 6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C 3 -C 8 )cycloalkyl, a (Ci-C 8 )heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring; the subscript plO is an integer of from 0 to 4;
  • Y is CH 2 , NH, S or O
  • W 1 and W 2 is each C or N.
  • V 6 is H.
  • Wl and W2 are CR 5 .
  • W 1 is CR 5 and W 2 is N.
  • W 1 is N and W 2 is CR 5 .
  • Y is O. hi another embodiment, Y is S. hi another embodiment, Y is
  • Y is CH 2 .
  • the compound has the formula:
  • R 1 is selected from the group consisting of: CO 2 R 3 , COR 4 , CONHSO 2 CR 3 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci C 8 )alkyl, aryl, (Ci-C 8 )heterocyclyl; each R 4 is a member independently selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 ,
  • R 6 is independently selected from the group consisting of H, halo, (Ci-Csjheteroalkyl
  • R 7 is H, (Ci C 8 )alkyl, (Ci-C 8 )heteroalkyl, aryl, (Ci-C 8 )heterocyclyl;
  • L 1 is selected from the group consisting of (d-C 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (d-C 4 )alkoxy, cyano, nitro, amino, -NO, (C 1 -C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to the same
  • R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 1 -Cg)heteroalkyl, (C 3 - Cs)cycloalkyl, (Ci-Cs)heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a (Ci-Cs ⁇ eterocyclyl or heteroaryl ring;
  • Y is CHR 8 , C(R 8 ) 2 , NR 8 , S or O;
  • (GROUP 48) compounds have the formula:
  • each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ CH and -C ⁇ £-CH 3 ; pio is 1-4; each V 6 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-propynyl, 0-Me, O-Et, O-cyclopro ⁇ yl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAc, NH-CONH 2 , NMe-CONMe 2 , NH-CSNH 2 ,
  • each R 5 independently is R 6 is hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ CH and -C ⁇ €-CH 3 ; plO is 1-4, each V 6 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3- furanyl, ethynyl, 1-propynyl, 3-propynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAc, NH-CONH 2 , NMe-CONMe 2 , NH- CSNH 2 , NH-C(
  • (GROUP 49) compounds preferably have the formula:
  • L 1 is selected from the group consisting of (CrC 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (Q- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (d-C 4 )alkoxy, cyano, nitro, amino, -NO, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to the same or adjacent
  • R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (Ci-C 8 )heteroalkyl, (C 3 - C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a (d-C 8 )heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , C(R 8 ) 2 , NR 8 , S or O;
  • Y is CH 2 ; each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ £-CH 3 ; p I0 is 1-4;
  • Y is CH ; each R independently is R is hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ €-CH 3 ; plO is 1-4, each V 6 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1-propynyl, 3-propynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAc, NH-CONH 2 , NMe-CONMe 2 , NH-CSNH 2
  • (GROUP 50) compounds have the formula:
  • L 1 is selected from the group consisting of (CrC 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (C 1 - C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, -NO, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to the
  • Y is CHR 8 , C(R 8 ) 2 , NR 8 , S or O;
  • Y is CH 2 ; each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ C-CH 3 ; ⁇ 1Q is 1-4; each V 6 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-propynyl, 0-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAc, NH-CONH 2 , NMe-CONMe 2
  • L 1 is selected from the group consisting of (C 1 -Cg)alkylene, (C 2 -C 8 )alkenyl, (C 2 - Cg)alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 wherein each V 1 is independently selected from the group consisting of (Ci-C 4 )alkyl, (Ci- C 8 )heteroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C r C 8 )heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (C 1 -C 4 )alkoxy, cyano, nitro, amino, -NO, (Q-C ⁇ alkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1 attached to the same or
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, (C 3 - C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a (Ci-C 8 )heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , C(R 8 ) 2 , NR 8 , S or O;
  • Y is CH 2 ; each R 6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ CH and -C -C-CH 3 ; p 10 is 1-4; each V 5 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-propynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAC, NH-CONH 2 , NMe-CONMe
  • Y is CH 2 ; each R 6 independently is R 6 is hydrogen, F, Cl, Br, CN, CF 3 , CH 3 , CHMe 2 , -C ⁇ €H and -C ⁇ C-CH 3 ; plO is 1-4, each V 6 independently is hydrogen, halo, oxo; cyano, CH 3 , CH 2 CH 3 , CH(Me) 2 , methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1-propynyl, 3-pro ⁇ ynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH 2 , NHMe, NMe 2 , NHAc, NHOH, NHNH 2 , NHNHAc, NH-CONH 2 , NMe-CONMe 2 , NH-
  • R 1 is i ⁇ v 5 or CO 2 R 3 .
  • R 1 is C 2 alkenyl-CO 2 R 3 .
  • R 3 is H or (CH 2 ) q NR 13 2 ; each R 13 is independently (CrCs)alkyl, or, if both present on the same substituent may be joined together to form a three-to eight-membered heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • R 6 is independently selected from the group consisting of Cl, Br, or CH 3 .
  • each R 6 is CL
  • R 6 is independently selected from the group consisting of Cl, Br, or CH 3 . In another embodiment, each R 6 is Cl.
  • Examples of compounds of Formula 1 include:
  • R is selected from the group consisting of H, F, Br, CN, CF 3 , CH 3 CHMe 2 and -
  • the compounds of the present invention include all of the compounds of the examples.
  • R 1 is a bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof selected from a cyclic 4, 5, or 6 membered heterocycle, arene or heteroerene.
  • a squaric acid or a derivative thereof is a cyclic 4 membered arene based bioisostere Of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof.
  • the squaric acid derivative can have a formula:
  • the bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof contains a hydroxyl substituted 5 or 6 membered arene or a heteroerene.
  • the bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof contains in the substituted 5 or 6 membered (C 1 -C 8 )heterocycle , arene or a heteroerene a moiety or formula
  • the bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof contains a moiety of formula
  • the bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof have a formula selected from the group consisting of:
  • the present invention provides carboxylic acid bioisosteres: COR 3 , COCOR 3 , COCHR 3 COR 3 , COC(R 3 ) 2 COR 3 , COCHR 3 CO 2 R 3 , COC(R 3 ) 2 CO 2 R 3 , COCHR 3 COR 4 , COC(R 3 ) 2 COR 4 , COCHR 3 COCOR 3 , COC(R 3 ) 2 COCOR 3 , COCHR 3 COCO 2 R 3 , COC(R 3 ) 2 COCO 2 R 3 , COCHR 3 COCOR 4 , COC(R 3 ) 2 COCOR 4 , and CF 3 .
  • the present invention provides carboxylic acid bioisosteres: COCF 3 ,
  • Bioisosteres of carboxylic acid and derivatives, and indazole useful for the compounds of the present invention can be adapted for example from the references Lipinski et al., Annual Reports in Medicinal Chemistry-21, 1986, pages 283-91; Marfat, US Pat. No. 6,391,872; Straub et al, Bioorg. Med. Chem. Lett., 2001, 11:781-4, Fenton , et al., US Pat. No. 6,762,199; Gaster , et al., US Pat. No. 5,705,498 ; Nicolaou, I. et al., J. Med. Chem., 2004; 41(10); 2706-9; and Hazeldine et al., J. Med. Chem., 2002; 45: 3130-7.
  • the present invention provides a multimeric-compound containing two or more lonidamine analog moieties.
  • the lonidamine analogs in the multimeric compound are both joined covalently by R 9 substituents.
  • the lonidamine analogs in the multimeric compound are both joined covalently by R 1 substituents.
  • the lonidamine analogs in the multimeric compound are both joined covalently by V 1 substituents.
  • one of the lonidamine analogs in the multimeric compound is joined by one of R 9 , R 1 , or V 1 substituent and the other lonidamine analogs in the multimeric compound is joined by one of R 9 , R 1 , or V 1 substituent.
  • the multimeric-compound as provided according to the present invention can have a higher affinity to a target organ, and or target cells and show fewer side-effects upon administration.
  • the present invention provides prodrugs of lonidamine analogs of formula (I).
  • a prodrug is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property.
  • a pharmaceutically active lonidamine analog or a suitable precursor thereof is modified chemically such that the modified form is less active or inactive, at least with respect to one biological property, relative to the pharmaceutically active compound, but the chemical modification is effectively reversible under certain biological conditions such that a pharmaceutically active form of the compound is generated by metabolic or other biological processes.
  • a lonidamine analog prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor, for example (see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). Prodrugs can also be prepared using compounds that are not drugs.
  • the present invention provides prodrugs of lonidamine analogs of formula (I) wherein when R 1 represents COOR , and R represents a group of the formula (CR 15 R 16 ) m NR 17 R 18 wherein each R 15 and R 16 is independently H, a straight or branched chain (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, (Ci-C 8 )cycloalkyl, or (Ci-C 8 )heterocyclyl or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered (C 1 -C 8 )cycloalkyl or (Q-C ⁇ heterocyclyl ring system.
  • R 1 represents COOR
  • R represents a group of the formula (CR 15 R 16 ) m NR 17 R 18 wherein each R 15 and R 16 is independently H, a straight or branched chain (Ci-C 8 )alkyl, (
  • Each R 17 and R 18 is a straight or branched chain (Ci-C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 1 - C 8 )heterocyclyl or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered cycloalkyl or (CrC 8 )heterocyclyl ring system.
  • R 1 is preferably a COOR 3 moiety.
  • R 3 can be a straight or branched chain (C 1 -C 8 ) alkyl or (Ci-C 6 ) alkoxy, or a three- to eight-membered cycloalkyl or heterocyclyl ring system.
  • R 3 can be (CrC 6 ) alkoxymethyl, such as methoxymethyl; (Ci-C 6 ) alkanoyloxymethyl esters such as pivaloyloxymethyl; phthalidyl esters; (C 3 -C 8 )cycloalkoxycarbonyloxy(Ci-C 6 )alkyl such as 1- cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, such as 5-methyl-l,3- dioxolen-2-on-ylmethyl; and (C 1 -C 6 )alkoxycarbonyloxyethyl such as 1- methoxycarbonyloxyethyl.
  • each R 15 and R 16 is preferably independently selected from the group, H, CH 3 , and a member in which R 15 and R 16 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,1-dioxo-hexahydro-l ⁇ 6 - thiopyran-4-yl or tetrahydropyran-4-yl group.
  • the prodrugs of the invention provide for the release of a drug lonidamine and its analogs.
  • the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7.5. Any amines having a pKa within 1 unit of 7.5 are suitable alternatives amines for this purpose.
  • the amine may be provided by the amine of a morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine.
  • the basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood.
  • the prodrug moiety is cleaved by esterases which are naturally present in the serum to release lonidamine or the lonidamine analog. More strongly basic amines, such as a trialkyl derivatives with no heteroatom substitutions, will be nearly completely protonated under physiological conditions and will not be as efficiently adsorbed as shown.
  • the serum half live of the prodrug of the lonidamine and lonidamine analogs of the present invention is increased in vivo (compared to the parental form) by the presence of R 15 and R 16 groups.
  • the R 15 and R 16 groups in the prodrug can independently be selected to modulate the rate of cleavage of the prodrug moiety from lonidamine. Increasing the amount of steric hindrance proximal to the ester carbonyl of lonidamine decreases the rate of cleavage of the prodrug moiety. Slowing the rate of cleavage of the prodrug moiety has the effect of increasing serum half life.
  • Hydrogen groups facilitate cleavage of the prodrug moiety and alkyl groups hinder it.
  • the larger and more branched the alkyl group the more cleavage is hindered and the more serum half life is increased.
  • the closer the non-hydrogen substitution is to the lonidamine carbonyl the more cleavage of the prodrug moiety is hindered and the more serum half life of the prodrug form is increased.
  • linkage of the tertiary amine to the lonidamine is stable enough so that the serum half life of the prodrug is from about 8 to about 24 hours.
  • R 4 and R 5 may be joined together to form a cyclic group further comprising heteroatoms. This aspect of the invention further improves upon the aqueous solubility of the compounds of the invention.
  • the present invention provides a prodrug D-Z-M of lonidamine or a lonidamine analog, said prodrug comprising, lonidamine or an analog, D; joined by a cleavable linker Z; to a moiety M.
  • Prodrugs with this structure may be referred to as "linker prodrugs.”
  • the prodrug has a higher V max for a transporter expressed in plasma membranes of cells than D alone, hi some embodiments, the cells are epithelial cells lining a human colon, or small intestine, a prostate, or the like.
  • the transporter is expressed in the plasma membranes of epithelial cell lining in the human gut.
  • the transporter is expressed in the plasma membranes of epithelial cell lining in the prostate.
  • the transporter is expressed in human kidney, brain, lung, liver and/or heart, hi one embodiment, the moiety M is selected from the group consisting of an amino acid, a dipeptide, a tripeptide, a bile acid, and their derivatives.
  • the transporter is selected from the group consisting of ATBO, CAT-I, FATP4, MCTl, MCT4, NADCl, NADC2, OCTN2, PEPTl, PGT, RFC, SAT-I, SAT-6, SMVT, SUT2 and SVCTl (for a description of these transporters see, e.g., Gallop et al., WO02100347).
  • the transporter is PEPT2, which is expressed in human kidney, brain, lung, liver, and heart.
  • the transport system is carrier mediated.
  • the transport system is receptor mediated.
  • the prodrug compound exhibits selective uptake by a subject's prostate as compared to another organ, such as the testis, heart, kidney, brain, lung, and/or liver.
  • the prodrug is selectively taken up by subject's prostate compared to other organs.
  • the prodrug compound exhibits selective uptake by prostate epithelial cells as compared to other epithelial cells of, for example, the testis, heart, kidney, brain, lung, and/or liver.
  • the prodrug is selectively taken up by prostate epithelial cell as compared to other epithelial cells.
  • the M moiety is an androgen, an androgen analog, or a functional androgen analog exhibits selective uptake by a subject's prostate as compared to another organ such as, for example, the testis, heart, kidney, brain, lung, and/or liver, hi a related embodiment, the prodrug D is selectively taken up by subject's prostate.
  • the M moiety is an androgen, an androgen analog, or a functional androgen analog that exhibits selective uptake by prostate epithelial cells as compared to epithelial cells such as, for example, the testis, heart, kidney, brain, lung, and/or liver, hi a related embodiment, the prodrug is selectively taken up by prostate epithelial cells as compared to other epithelial cells.
  • the present invention provides a prodrug of lonidamine or a lonidamine analog comprising a lonidamine- or a lonidamine analog-peptide conjugate, the peptide comprising an amino acid sequence having a cleavage site specific for an enzyme having a proteolytic activity of prostate specific antigen and wherein the peptide is linked to lonidamine or the lonidamine analog to inhibit the therapeutic activity of lonidamine or the lonidamine analog, and wherein lonidamine or the lonidamine analog is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of prostate specific antigen (PSA).
  • PSA prostate specific antigen
  • the present invention provides a prodrug of lonidamine or a lonidamine analog comprising a lonidamine- or a lonidamine analog-peptide conjugate, the peptide comprising an amino acid sequence having a cleavage site specific for an enzyme having a proteolytic activity of prostate specific antigen, wherein the peptide is 20 or fewer amino acids in length, wherein the sequence comprises the amino acids
  • G 5 -G 4 -G 3 -G 2 -G 1 wherein G 5 is from 0 to 16 amino acids; G 4 is serine, isoleucine, or lysine; G 3 is serine or lysine; G 2 is leucine or lysine; and Gi is glutamine, asparagine or tyrosine, and wherein the peptide is linked to lonidamine or the lonidamine analog to inhibit the therapeutic activity of the lonidamine or the lonidamine analog, and wherein lonidamine or the lonidamine analog is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of prostate specific antigen (PSA).
  • PSA prostate specific antigen
  • the present invention provides a prodrug of lonidamine or an analog comprising a cephalosporin moiety, a dihydronicotinamide moiety, a triglyceride, a long chain fatty acid, or a long chain fatty alcohol.
  • the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is a vitamin or a vitamin precursor
  • the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is vitamin-D, a vitamin-D analog, or a vitamin-D precursor.
  • the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is vitamin-E, a vitamin-E analog, or a vitamin-E precursor.
  • the moiety M is ⁇ -tocopherol.
  • the moiety M is an ⁇ -tocopherol-PEG conjugate. In another related embodiment, the moiety M is an ⁇ -tocopherol- ⁇ , ⁇ -dicarboxylic acid-PEG conjugate. In another related embodiment, the moiety M is an ⁇ -tocopherol-succinic acid-PEG conjugate.
  • Various ⁇ -tocopherol based conjugates employed in the present invention can be adapted from those described in the U.S. Patent Application No. US2005/0142189, to Lambert et al. [0198J
  • the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is a hormone or a hormone precursor.
  • the present invention provides a prodrug of lonidamine or a lonidamine analog wherein the prodrug is enzymatically modified to yield lonidamine or the lonidamine analog, wherein the enzyme is carboxypeptidase, aminohydrolase, or glycosidase.
  • the prodrug contains an Aryl-O-CO-N ⁇ moiety which is cleaved by a carboxypeptidase to yield lonidamine or a lonidamine analog from the prodrug.
  • Moiety M and linker Z that can be employed in a D-Z-M prodrug of the present invention is provided for example, in the reference Silverman, January 15, 1992, Organic Chemistry of Drug Design and Drug Action, Academic Press; 1st edition.
  • M moieties including but not limited to a bile acid, an amino acid, and a peptide, and linker Z moieties that can be used in the compounds of the invention are described in the following US Patent Application Nos. 2004/0161424, 2003/0158254, 2003/0158089, and 2003/0017964; and PCT Publication Nos.
  • the moiety can be a targeting peptide, to target lonidamine or a lonidamine analog to a specific cell type. See, e.g., U.S. patent publication No. 2002/0147138.
  • the present invention provides a prodrug D-Z-M of lonidamine or a lonidamine analog, said prodrug comprising lonidamine or an analog, D, joined by a cleavable peptide linker Z, to a stabilizing moiety M.
  • the peptide linker can be any cleavable peptide linker.
  • the linker is cleavable by an endogenous enzyme, hi some embodiments, the linker is a tripeptide, P1-P2-P3, comprising natural or synthetic amino acids.
  • Pl is Leucine, Sarcosine, Tyrosine, Phenylalanine, p-Cl- Phenylalanine, p-Nitrophenylalanine, Valine, Norleucine, Norvaline, Phenylglycine, Tryptophan, tetrahydroisoquinoline-3-carboxylic acid, 3-Pyridylalanine, Alanine, Glycine, or 2-Thienylalanine.
  • P2 can be Alanine, Leucine, Tyrosine, Glycine, Serine, 3-Pyridylalanine, or 2-Thienylalanine.
  • P3 can be Leucine, Phenylalanine, Isoleucine, Alanine, Glycine, Tyrosine, 2-Naphthylalanine, or Serine.
  • the peptide linker can be one of the following: Leu- Ala- Leu, Tyr- Ala-Leu, Met- Ala-Leu, Tyr-Ala-Ile, Phe-Gly-Leu, Met-Gly-Leu, Met-Gly-Ile, Phe-Gly- He, Met-Gly-Phe, Leu-Ala-Gly, NIe- Ala-Leu, Phe-Gly-Phe, and Leu-Tyr-Leu. See also U.S. Patent Publication No. 2003/0181359.
  • moiety M is a stabilizing moiety that protects the prodrug from cleavage in circulating blood when it is administered to the patient and allows the prodrug to reach the vicinity of the target cell relatively intact.
  • the stabilizing group typically protects the prodrug from cleavage in blood and blood serum.
  • the stabilizing group is useful in the prodrug when it serves to protect the prodrug from degradation, i.e., inactivation, when tested by storage of the prodrug compound in human blood at 37 0 C. for 2 hours and results in less than 20%, particularly less than 2%, inactivation of the prodrug by the enzymes present in the human blood under the given assay conditions.
  • the stabilizing group can be, for example, an amino acid or an amino acid that is either (i) a non-genetically-encoded amino acid having four or more carbons or (ii) aspartic acid or glutamic acid attached to the N-terminus of the oligopeptide at the beta-carboxyl group of aspartic acid or the gamma-carboxyl group of glutamic acid.
  • dicarboxylic (or a higher order carboxylic) acid or a pharmaceutically acceptable salt thereof may be used as a stabilizing group.
  • the stabilizing group is not an amino acid.
  • linker prodrugs of the following formulae are provided:
  • D is a lonidamine analog of formula (I);
  • Q 1 is O or CH 2 ;
  • Zj and Z 2 are cleavable linkers;
  • R' is alpha-OH or hydrogen;
  • R" is alpha-OH, beta-OH or hydrogen;
  • W is - CH(CH 3 )Wi, wherein Wi is a substituted alkyl group containing a moiety which is negatively charged at physiological pH, said moiety is selected from the group consisting of CO 2 H, SO 3 H, SO 2 H, -P(O)(OR)(OH), -OP(O)(OR)(OH), and OSO 3 H wherein R is Ci-C 6 alkyl, (C,- Cg)heteroalkyl, (C 3 -C 8 )cycloalkyl, (Ci-C 8 )heterocyclyl, aryl, or heteroaryl; and an individual isomer, a racemic or non-racemic mixture of isomers, a bio
  • R 3H c is alkyl (e.g., C 1 -C 6 alkyl); and D is lonidamine or a lonidamine analog, and an individual isomer, a racemic or non-racemic mixture of isomers, a bioisostere, a pharmacophore, a pharmaceutically acceptable salt, a solvate or a hydrate thereof.
  • R ⁇ is lower alkyl.
  • D when D is covalently attached to a heteroatom in the formula above, then D is a lonidamine analog of formula (I), as defined above.
  • the term "cleavable linker”, such as, e.g., Z, refers to a linker which has a short half life in vivo.
  • the breakdown of the linker Z in a compound D-Z- M (supra) releases or generates lonidamine or a lonidamine analog.
  • the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes.
  • the cleavable linker is hydrolyzed by an esterase enzyme.
  • the linker is a self-immolating linker, such as that disclosed in U.S. patent publication 2002/0147138, to Firestone; PCT Appl. No. US05/08161 and PCT Pub. No. 2004/087075.
  • the linker is a substrate for enzymes. See generally Rooseboom et al., 2004, Pharmacol. Rev. 56:53-102.
  • Lonidamine analogs of the invention can be prepared using by known synthetic methods in combination with the teaching herein. Synthesis of lonidamine is described in U.S. Patent No. 3,895,026. Synthesis of certain lonidamine analogs, including tolnidamine (TND), has also been described (see, e.g., Corsi et al, 1976, "l-Halobenzyl-lH-Indazole-3- Carboxylic Acids. A New Class of Antispermatogenic Agents", Journal of Medicinal Chemistry 19:778-83; Cheng et al, 2001, "Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis" Biol Reprod.
  • PCT/US05/ (filed July 8, 2005) entitled “Tertiary amine prodrugs of lonidamine and analogs," and U.S. provisional application nos. 60/586,934 (filed July 8, 2004) and 60/624,505 (filed Nov 1, 2004).
  • Other exemplary lonidamine analogs are described in copending PCT application No. PCT/US05/ (filed July 29, 2005), U.S. provisional application No. 60/592,677 (filed July 29, 2004); No. 60,599,664, (filed Aug 05, 2004); and No. 60/651671 (filed Feb. 9, 2005) all entitled “Multicyclic Lonidamine Analogs.”
  • Each of the aforementioned applications is incorporated herein by reference.
  • acrylic acid analogs of the present invention are synthesized from suitable formyl precursors as shown below:
  • a cyclopropano compound of formula (I) is synthesized by reacting an acrylate ester analog of formula (I) with substituted or unsubstituted carbene as shown below in Scheme XX.
  • Diazomethane (CH 2 N 2 ) or alkylsubstituted diazomethane (R aIk CHN 2 wherein R ⁇ is a substituted or unsubstituted Cj-C 4 alkyl group) is inserted into aN acrylate ester or an acrylate ester analog double bond to yield a cyclopropano analog following rhodium or copper catalyzed insertion reactions.
  • Simmons Smith reaction is used to insert a methylene group into an acrylate ester or an acrylate ester analog.
  • propionic acid analogs of formula (I) are synthesized by reduction of final products obtained in Schemes I-XX. The reduction is performed employing Pd-charcoal, Pt ⁇ 2 -charcoal, Ra-Ni, Wilkinson's catalyst, Li-liquid ammonia depending on the nature of substituents present in the starting compounds.
  • compounds of formula I wherein one of W 6 - W 9 is a carbon atom substituted with a substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted (Ci-C 4 ) heteroalkyl, halogen, hydroxy, (C]-C 4 ) alkoxy, amino, cyano, nitro, Ci-C 4 alkylamino, and Ci-C 4 dialkylamino group are synthesized by employing methods described above and further employing starting materials which is suitably substituted. In another embodiment, employing as starting material:
  • a compound of the present invention wherein W 1 -W 9 define a pyrazolopyridine ring can be prepared by adapting synthetic procedures described by the references Lavecchia et al., Tetrahedron Lett., 2004, 45:2389-92; Straub et al, Bioorg. Med. Chem., 2001, 10:1711-7; and Straub et al., Bioorg. Med. Chem. Lett., 2001, 11 :781 — 4.
  • a compound of the present invention wherein W -W define a pyrrolo[2,3-d]-pyrimidine or a -pyrazolo[3,4-d]-pyrimidine ring can be prepared by adapting synthetic procedure described by the reference Kelley et al., J. Med. Chem. 1996, 38:3884-8.
  • a compound of the present invention wherein W ! -W 9 define a pyrrolo[l,2- c]pyrimidine can be prepared by adapting synthetic procedure described by the reference Minguez et al., J. Org. Chem. 1999, 64, 7788-801.
  • a compound of the present invention wherein W*-W 9 define a pyrrolo[2,3-d]pyrimidin-2,4-dione and more particularly a 6- chloropyrrolo[2,3-d]pyrimidin-2,4-dione can be prepared by adapting synthetic procedure described by the reference Edstrom et al., Tetrahedron Lett., 1996, 37(6):759-62.
  • a compound of the present invention wherein W*-W 9 define a 2-chloroindole can be prepared by adapting synthetic procedure described by the reference Engqvist et al. Eur. J. Org. Chem. 2004, 2589-92.
  • a compound of the present invention wherein W'-W 13 define a thieno[2,3- b]indole moiety and more particularly a rotationally restricted lonidamine analog thieno[2,3- b]indole-2-carboxylate and a thieno[2,3-b]indole-2-carboxamide moiety can be prepared by adapting synthetic procedure described by the reference Engqvist et al., Eur. J. Org. Chem. 2004, 2589-92.
  • a compound of the present invention wherein W ! -W 9 define a Pyrazolo[3,4- bjpyridine mjoiety can be prepared by adapting synthetic procedure described by the reference Misra et al. Bioorg.
  • a compound of the present invention wherein W -W define a rotationally restricted lonidamine analog containing a pyridazinoindole moiety can be prepared by adapting synthetic procedure described by the reference Guven et al, Tetrahedron 1993, l 145-54.
  • a compound of the present invention wherein W ⁇ -W 13 define a rotationally restricted lonidamine analog containing a triazolobenzimidazole moiety can be prepared by adapting synthetic procedure described by the reference Reddy et al., Indian J. Chem., 1992, 31B:191-2.
  • a compound of the present invention wherein W ⁇ W 9 define a pyrano[2,3-c]pyrazoles and pyrano[2,3- c]pyrazole-6(l-H)-one moiety can be prepared by adapting synthetic procedure described by the reference Ueda et al, Chem. Pharm. Bull, 1981, 129(72):3522-8.
  • a compound of the present invention wherein W ! -W 9 define a pyrazolo[3,4-d]pyridazine moiety can be prepared by adapting synthetic procedure described by the reference Kaji et al, Chem. Pharm. Bull, 1984, 32(77):4437-46.
  • a compound of the present invention wherein W'-W 9 define a pyrazolo[4 5 3-e][l,2,4]triazene moiety can be prepared by adapting synthetic procedure described by the reference Rykowski et al, Heterocycles, 2000, 53(10): 2175-81.
  • a compound of the present invention wherein W ⁇ W 9 define an imidazo[l,5-b]triazine[l,2,4] moiety can be prepared by adapting synthetic procedure described by the reference Guerret et al, Bull. Chem. Soc. France, 1974, (7-8): 1453-4.
  • Syntheses of ester prodrugs of the invention may start with the free carboxylic acid of a lonidamine analog.
  • the free acid is activated for ester formation in an aprotic solvent and then reacted with a free alcohol group in the presence of an inert base, such as triethylamine, to affect ester formation, producing the prodrug.
  • Activating conditions for the carboxylic acid include forming the acid chloride using oxalyl chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by evaporation.
  • aprotic solvents include, but are not limited to methylene chloride, tetrahydrofuran, and the like.
  • activations can be performed in situ by using reagents such as BOP (benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorolphosphate) and the like (see Nagy et al, Proc. Natl Acad. Sci. 90: 6373-6376, 1993) followed by reaction with the free alcohol.
  • BOP benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorolphosphate
  • Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chloride; evaporation of the organic solvent layer; and recrystallization from a solvent, such as ethanol, which has been acidified with an acid, such as HCl or acetic acid.
  • the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by evaporation.
  • Suitable starting materials are reported in the art (see e.g. Kirshchke et al, Tet. Lett., 4281-4284 (1986); Corisii et al,. J. Med. Chem. 778-783 (1976). Other starting materials are commercially available. Non-commercially available starting materials can be synthesized in via standard literature procedures. Such procedures can be identified via literature search tools such as SciFinder from the American Chemical Society or Beilstein, available from MDL Software.
  • the lonidamine analog is provided in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include addition salts with acids, as well as the salts with bases.
  • suitable acids for the formation of acid addition salts are, for example, mineral acids, such as hydrochloric, hydrobromic, sulphuric or phosphoric acid, or organic acids, such as organic sulphonic acids, for example, benzenesulphonic, 4-toluenesulphonic or methanesulphonic acid, and organic carboxylic acids, such as acetic, lactic, palmitic, stearic, malic, maleic, fumaric, tartaric, ascorbic or citric acid.
  • Acid salts of the tertiary amine moiety confer increased aqueous solubility.
  • the salts are citric acid salts.
  • suitable bases for the formulation of base addition salts of lonidamine and lonidamine analogs are a primary amine, a secondary amine, a tertiary amine, an amino acid, or a naturally occurring ⁇ -amino acid.
  • aminoacids include but are limited to glycine, lysine, and arginine.
  • the cation employed in the base addition salt of lonidamine or a lonidamine analog is sodium, potassium, ammonium, or calcium.
  • base addition salts of lonidamine and lonidamine analogs are formed employing lysine, glycine, or arginine as a base.
  • one equivalent of an amine (wherein amine is as described above) is mixed with one equivalent of lonidamine or a lonidamine analog in water. The mixture is shaken or sonicated to yield a homogenous solution of the base addition salt of lonidamine or a lonidamine analog in water.
  • one equivalent lonidamine or a lonidamine analog is mixed in water with one equivalent of a metal hydroxide, oxide, bicarbonate, or carbonate wherein the metal comprises sodium, potassium, or calcium resulting in the formation of the metal salt of lonidamine or the analog.
  • the base addition salt of lonidamine and arginine is not administered intravenously to rats. In another embodiment, the base addition salt of lonidamine and glycine is not administered intravenously to normal dogs. In one embodiment, when in a base addition salt one component is lonidamine, the base is other than arginine or glycine.
  • the compounds of the invention are lonidamine analogs, including prodrug forms of the analogs.
  • Certain prodrugs of the invention should exhibit, relative to lonidamine, increased aqueous solubility and extended pharmacokinetics in vivo.
  • the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7.5. Any amines having a pKa within 1 unit of 7.5 are suitable alternatives amines for this purpose.
  • the amine may be provided by the amine of a morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine.
  • the basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood.
  • the prodrug moiety is cleaved by esterases that are naturally present in the serum to release the active agent lonidamine or the lonidamine analog. More strongly basic amines, such as trialkyl derivatives with no heteroatom substitutions, will be nearly completely protonated under physiological conditions and will not be as efficiently absorbed.
  • the serum half live of the lonidamine analogs of the present invention are increased in vivo compared to lonidamine.
  • the lonidamine analog is stable enough so that the serum half life of the compound is from about 8 to about 24 hours.
  • lonidamine analogs described herein are suitable for any use contemplated for lonidamine, and in particular may be used for any as prophylactic, therapeutic and contraceptive agents. Exemplary pharmaceutical uses are described below. Other uses of the analogs of the invention include control of rodents.
  • a lonidamine analog disclosed herein is usually formulated as a pharmaceutical composition comprising the analog and a pharmaceutically-acceptable carrier.
  • pharmaceutically acceptable carrier is art- recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
  • Pharmaceutical preparations for oral use can be obtained through combining active compounds with solid excipient and, optionally, other compounds.
  • Pharmaceutical formulations suitable for parenteral administration may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the dose, schedule and duration of administration of the analog will depend on a variety of factors. The primary factor, of course, is the choice of a specific analog. Other important factors include the age, weight and health of the subject, the severity of symptoms, if any, the subject's medical history, co-treatments, goal (e.g., prophylaxis or prevention of relapse), preferred mode of administration of the drug, the formulation used, patient response to the drug, and the like.
  • an analog can be administered at a dose in the range of about 0.1 mg to about 100 mg of the analog per kg of body weight of the patient to be treated per day, optionally with more than one dosage unit being administered per day, and typically with the daily dose being administered on multiple consecutive days.
  • an analog is administered in a dose in the range of about 0.1 mg to about 5 mg per kg of body weight of the patient to be treated per day.
  • an analog is administered in a dose in the range of about 0.2 mg to about 1 mg per kg of body weight of the patient to be treated.
  • an analog is administered in a dose of about 25 to 250 mg.
  • a dose is about 25 to about 150 mg.
  • Guidance concerning administration is provided by prior experience using the analog for a different indication (e.g., lonidamine administered to treat cancer is administered in 150 mg or 300 mg doses three times a day for a period of about a month) and from new studies in humans (e.g., lonidamine administered to treat BPH has been administered in 150 mg doses once a day for a period of about a month) and other mammals.
  • a different indication e.g., lonidamine administered to treat cancer is administered in 150 mg or 300 mg doses three times a day for a period of about a month
  • new studies in humans e.g., lonidamine administered to treat BPH has been administered in 150 mg doses once a day for a period of about a month
  • other mammals e.g., lonidamine administered to treat cancer is administered in 150 mg or 300 mg doses three times a day for a period of about a month
  • lonidamine in terms of (a) bioavailability and (b) biological activity.
  • Biological activity can be determined using assays such as, but not limited to, those described hereinbelow.
  • Preferred lonidamine analog are from 1- to 1000-fold as effective than lonidamine in a bioassay (e.g., as an anti-spermatogenic agent).
  • a therapeutically or prophylactically effective dose of an analog can be administered daily or once every other day or once a week to the patient. Controlled and sustained release formulations of the analogs may be used. Generally, multiple administrations of the analog are employed. For optimum treatment benefit, the administration of the prophylactically effective dose may be continued for multiple days, such as for at least five consecutive days, and often for at least a week and often for several weeks or more. In one embodiment, the analog is administered once (qday), twice (bid), three times (tid), or four times (qid) a day or once every other day (qod) or once a week (qweek), and treatment is continued for a period ranging from three days to two weeks or longer.
  • the invention provides a method for treatment or prophylaxis of benign prostatic hyperplasia (BPH) by administering a therapeutically effective or prophylactically effective amount of a compound described herein.
  • BPH benign prostatic hyperplasia
  • lonidamine for treatment or prophylaxis of BPH has been described [see, e.g., U.S. patent application no. 10/759,337 published as US 20040167196; also see the reference Ditonno et al., 2005, Rev. Urol. 7(su ⁇ l 7):S27-33] which also provides exemplary dosage regimens and schedules for treatment of BPH.
  • a compound of one or more of the following Groups as described hereinabove is administered for prevention or treatment of BPH: Group 2, or any of Groups 3-51, with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the invention provides a method for treatment of cancer by administering a therapeutically effective amount of a compound described herein.
  • a compound described herein The use of lonidamine for treatment of cancer has been described.
  • Cancers that can be treated using analogs of the invention include leukemia, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia,
  • Analogs disclosed herein may be administered alone or in combination with other anti-cancer agents and other drugs (see PCT publication WO2004/064734 for a description of combination therapies using lonidamine).
  • Other anticancer agents that can be used in combination with the analogs of the invention include busulfan, improsulfan, piposulfan, benzodepa, carboquone, 2-deoxy-D-glucose, meturedepa, uredepa, altretamine, imatinib, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, n
  • a compound of one or more of the following Groups as described hereinabove is administered for treatment of cancer: Group 2, or any of Groups 3-
  • the invention provides a method for prevention of cancer by administering a prophylactically effective amount of a compound described hereinabove.
  • the cancer is prostate cancer.
  • the cancer is breast cancer, hi other embodiments the cancer is an epithelial cell cancer.
  • Candidates for prophylasis using the compounds of the invention are individuals at increased risk (compared to the general population) for developing cancer.
  • Indicators of increased risk for developing prostate cancer can include (1) abnormal results from a digital rectal examination or prostate imaging, (2) elevated prostate specific antigen (PSA) levels such as greater than about 2 ng/ml (e.g., greater than about 2 ng/ml but less than about 8 ng/ml), (3) rising PSA, (4) expression of prostate cancer-susceptibility markers (see e.g., WO9514772, WO9845436; WO9837418, WO987093; WO9403599; WO9839446, WO9845435 and US Pat. No. 5,665,874; US Pat. No. 6,902,892); (5) genetic predisposition to developing prostate cancer; and (6) familial history of prostate cancer.
  • age is a risk factor for developing prostate cancer, with more than 75% percent of prostate cancer diagnosed in men ages 65 or older.
  • Indicators of increased risk for developing breast or other epithelial cancers can include (1) abnormal physical examination results (e.g., abnormal breast examination results) or abnormal results from an X-ray, ultrasonographic or other procedure, (2) detection of epithelial cancer-susceptibility markers [e.g., CA-125 (epithelial cancer), HER2 (breast cancer), Topoisomerase II alpha (ovarian epithelial cancer), Werner helicase interacting protein (ovarian epithelial cancer), HEXEvll (ovarian epithelial cancer), FLJ20267 (ovarian epithelial cancer), Deadbox protein-5 (ovarian epithelial cancer), Kinesin-like 6 (ovarian epithelial cancer), p53 (ovarian epithelial cancer) and NY-ESO-I (ovarian epithelial cancer)]; (3) genetic predisposition to developing epithelial cancer (Tor example, polymorphic BRCAl, BRCA2, p53, PTEN, ATM, NBS
  • Candidates for adminsitration of lonidamine analogs for prevention of cancer are individuals not diagnosed or under treatment for cancer (e.g., lung, breast, prostate, brain, ovarian, epithelial cell or other cancer) and, in the case of men not under treatment for BPH. In some embodiments the subject has not previously been treated for BPH or cancer.
  • cancer e.g., lung, breast, prostate, brain, ovarian, epithelial cell or other cancer
  • the subject has not previously been treated for BPH or cancer.
  • a compound of one or more of the following Groups as described hereinabove is administered for prevention of cancer: Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • Prostatic Intraepithelial Neoplasia is characterized by abnormal cellular proliferation within the prostatic ducts, ductules and acini. Treatment of PIN using lonidamine is disclosed in commonly assigned copending patent application PCT
  • PIN can be characterized as high grade (HGPIN) or low grade (LGPIN)- HGPIN is associated with the progressive development of abnormalities in the normal prostatic epithelium, leading to a cancerous condition. See, e.g., Bostwick, 1992, J. Cell Biochem. Suppl. 16H:10-9. Patients diagnosed as having HGPIN have an increased likelihood of developing prostate cancer within 10 years.
  • HGPIN high grade
  • LGPIN low grade
  • the invention provides a method for treating an patient diagnosed with HGPIN by administering a therapeutic amount of a lonidamine analogs disclosed hereinabove.
  • the invention also provides a method for treating an patient diagnosed with LGPIN by administering a therapeutic amount of a lonidamine analogs disclosed hereinabove.
  • PIN is usually diagnosed by needle biopsy , but can be diagnosed by any method known to the skilled artisan and accepted in the medical community.
  • a compound of Formula I optionally with the proviso that compounds of any one or more of Groups B-J are excluded, or one or more of the following Groups as described hereinabove is administered for treatment of PIN: Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the patient is not also under treatment for BPH or cancer. In certain embodiments the patient has not previously been treated for BPH or cancer.
  • Macular degeneration e.g., Age-related Macular Degeneration, AMD
  • AMD Age-related Macular Degeneration
  • the early stages of the disease are associated with reduced nutrient flow, including oxygen, to the retina and diseased and healthy retinal pigment epithelial cells (RPE).
  • RPE retinal pigment epithelial cells
  • CNV choroidal neovascularization
  • hypoxia inducible factor e.g., HIF-lalpha
  • HIF-lalpha hypoxia inducible factor
  • a compound of Formula I optionally with the proviso that compounds of any one or more of Groups B-J are excluded, or one or more of the following Groups as described hereinabove is administered for treatment of macular degeneration: Group 1, Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the patient is not also under treatment for BPH or cancer. In certain embodiments the patient has not previously been treated for BPH or cancer.
  • Antiangio genesis is not also under treatment for BPH or cancer.
  • the invention provides a method for inhibition of angiogenesis- related endothelial cell functions by administering a therapeutically or prophylactically effective amount of a compound described herein.
  • Lonidamine has been reported to inhibition of angiogenesis-related endothelial cell functions. See commonly assigned copending US provisional application No. 60/639055. Also see Del Bufalo et al, 2004, “Lonidamine causes inhibition of angiogenesis-related endothelial cell functions.” Neoplasia 6:513-22.
  • a compound of Formula I optionally with the proviso that compounds of any one or more of Groups B-J are excluded, or one or more of the following Groups as described hereinabove is administered to inhibit angiogenesis in a tissue of a subject: Group 1, Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the patient is not also under treatment for BPH or cancer. In certain embodiments the patient has not previously been treated for BPH or cancer.
  • Lonidamine was initially developed as a male contraceptive based on its antispermatogenic activity (see, e.g., Cheng et al., 2001, Biol. Reprod. 65:449-61 and U.S. Patent 6,001,865).
  • Compounds of the invention with similar activity find use as antispermatogenics (e.g., contraceptives or antifertility agents) in mammals, such as rodents, humans and nonhuman primates.
  • Lonidamine and certain lonidamine analogs have been reported to have antispermatogenic activity (see Corsi et al., 1976, "1-Halobenzyl-lH- Indazole-3-Carboxylic Acids.
  • Patent 6,001,865 entitled “3-Substituted 1 -Benzyl- lH-tndazole Derivatives As Antifertility Agents”; Cheng et ah, 2001, “Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis," Biol. Reprod.
  • a compound of Formula I with the proviso that compounds of Groups A and B are excluded and optionally with the proviso that compounds of any one or more of Groups C-J are excluded, or one or more of the following Groups as described hereinabove is administered to inhibit angiogenesis in a tissue of a subject: Group 1, Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the subject when used in humans, the subject is not under treatment for BPH or cancer. In certain embodiments the subject has not previously been treated for BPH or cancer.
  • compounds of the invention can be used to control fertility in animals (e.g., rodents).
  • lonidamine analogs described herein may be administered to reduce activity of mitochondria-bound hexokinase and/or interfere with ATP production by the glycolytic pathway and oxidative phosphorylation in a cell. Accordingly, these compounds may be used to treat any condition for which such reduction in ATP production is desirable in a cell or tissue.
  • a compound of Formula I with the proviso that compounds of Groups A and B are excluded and optionally with the proviso that compounds of any one or more of Groups C-J are excluded, or one or more of the following Groups as described hereinabove is administered to inhibit angiogenesis in a tissue of a subject: Group 1, Group 2, or any of Groups 3-51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
  • the patient is not also under treatment for BPH or cancer. In certain embodiments the patient has not previously been treated for BPH or cancer.
  • the lonidamine analogs of the invention can be administered in treatment methods described in the following U.S. patent applications: U.S. patent application no. 10/759,337 (filed January 16, 2004); U.S. provisional application nos. 60,592,883, entitled “Methods and Agents for Treatment of Benign Prostatic Hypertrophy” (filed July 29, 2004) and 60/661,067 (filed March 11, 2005); U.S. provisional application no. 60/587,017 (filed
  • a pharmaceutical composition of the invention may be any compound described herein.
  • a pharmaceutical composition of the invention may comprise a compound of Formula I, or compounds of any of Groups 1-45, as described above.
  • compounds of one, more than one, or all of Groups A-I are excluded.
  • Lonidamine analogs best suited for use as pharmaceutcal agents are those with biological activity and low toxicity (low therapeutic index).
  • not every structural analog of a compound is pharmacologically active. Active forms can be identified by routine screening of analogs for the activity of the parent compound.
  • a variety of assays and tests can be used to assess pharmacological activity of analogs of the invention, including in vitro assays, such as those described below and elsewhere herein, in vivo assays of prostate function (including citrate production and ATP production) in humans, non-human primates and other mammals, in vivo assays of prostate size in humans, non-human primates and other mammals, and/or clinical studies.
  • in vitro assays such as those described below and elsewhere herein
  • in vivo assays of prostate function including citrate production and ATP production
  • non-human primates and other mammals in vivo assays of prostate size in humans, non-human primates and other mammals, and/or clinical studies.
  • the activity of a lonidamine analog of interest in any of the assays described below can be compared with that of lonidamine to provide guidance concerning dosage schedules for the compound, and other information.
  • the compounds of the invention have antiproliferative activity (i.e., addition of the compound interfere with or reduce the rate or extent of proliferation of mammalian cells in vitro, ex vivo, or in vivo).
  • antiproliferative activity i.e., addition of the compound interfere with or reduce the rate or extent of proliferation of mammalian cells in vitro, ex vivo, or in vivo.
  • Numerous cell proliferation assays are known in the art. Suitable assays include the antiproliferation assays described in Examples 6 and 7, below.
  • a compound is used that has the same or greater antiproliferative activity than does lonidamine.
  • the invention provides a method for inhibiting proliferation of a mammalian cell by contacting the cell with an compound of the invention. The compound and cell can be contacted in vivo or in vitro. In one embodiment the cell is cultured.
  • the cell exhibits abnormal or unregulated growth in vivo (e.g., a malignant or benign tumor cell).
  • the cell is an epithelial cell or epidermal cell (e.g., a skin cell of a subject with a proliferative skin disease such as psoriasis or contact dermatitis).
  • lonidamine induces apoptosis in cell lines derived from human prostate cells.
  • the induction of apoptosis is significantly greater in LNCaP cells (ATCC NO. CLR- 1740), a prostate-derived cell line that is citrate-producing, than in PC3 cells (ATCC NO. CLR- 1435), a prostate-derived cell line that is citrate-oxidizing, consistent with the susceptibility of the citrate-producing prostate cells to metabolic inhibitors such as lonidamine.
  • a lonidamine analog has similar apoptosis-inducing activity.
  • Example 8 Also see Example 8, infra, for an apoptosis assay for characterizing analogs.
  • lonidamine induces apoptosis in primary cultures of human prostate epithelial cells.
  • the induction of apoptosis is significantly greater in primary cultures of prostate epithelial cells than in primary cultures of human prostate stromal cells, consistent with the susceptibility of citrate-producing prostate cells to metabolic inhibitors such as lonidamine.
  • a lonidamine analog has similar apoptosis-inducing activity is selected.
  • a lonidamine analog that induces apoptosis in primary cultures of prostate epithelial cells to a significantly greater degree than in primary cultures of human prostate stromal cells is used.
  • the lonidamine analog does not significantly induce apoptosis in stromal cells, hi some embodiments of the invention, induction of apoptosis by the lonidamine analog is at least 2-fold greater in epithelial cells than in stromal cells (and sometimes at least 4-fold greater, sometimes at 10-fold greater, and sometimes at least 20-fold greater) when assayed at the concentration of analog at which the difference in the level of apoptosis in the two cell lines is greatest (provided that the concentration of analog used in the assay is not greater than 1 niM).
  • Example 2 of patent publication US 20040167196 suggests that lonidamine reduced HIF-I -alpha expression/accumulation (measured in the nuclear fraction) in cells cultured under conditions of hypoxia by almost 2-fold at 200 micromolar and by more than 5 fold (i.e., more than 10-fold) at higher lonidamine concentrations.
  • an energolytic agent reduces HEF-I -alpha expression (prevents HDF-I -alpha accumulation) in LNCaP cells cultured under hypoxic conditions by at least about 2-fold, at least about 5-fold or at least about 10-fold compared to culture in the absence of lonidamine.
  • lonidamine As discussed above, and without intending to be bound to any specific mechanism, the effects of lonidamine on the prostate may be mediated, at least in part, by its effects on mitochondria and mitochondrial hexokinase activity in secretory epithelial cells. Accordingly, some lonidamine analogs useful in the methods of the present invention have hexokinase inhibitory activity as great or greater than that of lonidamine. Assays for hexokinase activity are known in the art. See Fanciulli et al., 1996, Oncology Research 3:111-120; Floridi et al., 1981, Cancer Res. 41:4661-6. Antispermatogenic activity.
  • antispermatogenic activity of lonidamine results, at least in part, from energolytic effects in germ cells.
  • Some lonidamine analogs useful in the present invention have antispermatogenic activity as great, or greater, than that of lonidamine.
  • Assays for antispermatogenic activity are known in the art. See, e Contraception. g., Grima et al., 2001, Biol Reprod. 64:1500-8; Lohiya et al., 1991, 43:485- 96.
  • the present invention provides a lonidamine analog for therapeutic or prophylactic use (e.g., therapy or prophylaxis of BPH or cancer) as an antispermatogenic agent wherein said lonidamine analog is 1-1000 fold more effective than lonidamine as a male contraceptive or an anti-spermatogenic agent.
  • the present invention provides a lonidamine analog containing an acrylic acid moiety for therapeutic or prophylactic use (e.g., therapy or prophylaxis of BPH or cancer) or as an antispermatogenic agent wherein said lonidamine analog is 1-1000 fold more effective than lonidamine as a male contraceptive or an anti-spermatogenic agent.
  • the effect of a compound on prostate function, and, in particular, on respiration, can be assessed by monitoring prostate tissue metabolism following administration of the compound.
  • Some lonidamine analogs useful in the present invention will detectably reduce ATP, citrate, and/or lactate production by the prostate in animals (including humans, non- human primates and other mammals).
  • ATP, citrate, and/or lactate levels can be monitored directly and/or indirectly in vivo using techniques of magnetic resonance spectroscopy (MRS) or other methods.
  • MRS magnetic resonance spectroscopy
  • the effect of a compound on prostate size can be assessed following administration of the compound using standard methods (for example, ultrasonography or digital rectal examination, for humans, and ultrasonography and/or comparison of organ weight in animals).
  • Assays can be conducted in humans or, more usually, in healthy non-human animals or in monkey, dog, rat, or other animal models of BPH (see, Jeyaraj et al., 2000, J Androl. 21:833-41; Lee et al., 1998, Neurourol Urodyn.17:55-69 and Mariotti et al., 1982, J Urol. 127:795-7),
  • Some lonidamine analogs useful in the present invention will detectably reduce prostate size in such assays and animal models.
  • Compound 2 was made according to the method described above for compound 1 by reacting 1-benzylindazole carbonylchloride with aqueous NH 2 OH. Compound 2 was purified from the crude reaction mixture by crystallization from acetic acid.
  • H460 cells ATCC HTB-177 (NCI-H40), 4,000 cells/well/200 ⁇ ) and LNCap cells (ATCC CRL- 1740,6,000 cells/well/200 ⁇ l) were seeded in a 96 well plate in RPMI medium (Invitrogen Corporation, Carlsbad, CA). After 24 hours, these plates were divided into 3 groups - Control group, 2h treatment group and 3 day treatment group. A test compound was added to each plate in the treatment groups (2h and 3 day) at a concentration as tabulated in Table 1 (in 50 ml of medium). In the 2h treatment group, after 2h the cells were rinsed to remove the test compound and incubated for 3 days, followed by staining with AlamarBlue.
  • the cells in the 3 day treatment group were incubated for 3 days, followed by staining with AlamarBlue.
  • AlamarBlue was added to the plate at (i) day 0 and (ii) day 3 and measured to establish the control reading.
  • the capacity of the cells to proliferate was measured 6 hours after addition of AlamarBlue by a fluorescence plate reader at excitation 550 nm and emission 590 nm and the 50% growth inhibitory concentration (GI 50 (also referred to IC 5O herein)) of lonidamine and lonidamine analogs was calculated.
  • GI 50 also referred to IC 5O herein
  • the cells were resuspended in PBS buffer (150 ⁇ L) and fixed by incubating (60 min, 4 0 C) with 4% paraformaldehyde in PBS. The cells were centrifuged, and the supernatant removed to a final volume of 15 ⁇ L. The cell pellets were resuspended, followed by dropwise addition of 200 ⁇ l of ice-cold ethanol (70%), and the cells incubated at -2O 0 C at least for 2 hr. The cells were centrifuged, the supernatant removed, washed, and incubated with the DNA labeling mix (37 0 C, 60 min).
  • the cells were washed, incubated (30 min) with anti-BrdU staining mix, washed again and analyzed on a Guava PCA-96 system (Guava Technologies, 25801 Industrial Boulevard, Hayward CA 94545-2991, USA).
  • the cell cycle staining reagent (Guava Technologies, Hayward, CA, USA, 200 ⁇ l) was added to each well. The cells were shielded from light and incubated at room temperature for 30 min. The samples were analyzed (Guava PCA-96 instrument, Cytosoflt software, Guava Technologies, 25801 Industrial Boulevard, Hayward CA 94545-2991, USA) as tabulated below. Table 6
  • Compound 1 does not have a measurable effect on the cell cycle.
  • the control mice received an equal amount of the vehicle (carboxymethylcellulose).
  • the mice were sacrificed and the entire prostate and the individual lobes (e.g., the dorsal lobe and the ventral lobe) were weighed to measure absolute weights. Relative weights of prostate and individual lobes were calculated by dividing the absolute weight by the total weight of the mouse.
  • Relative weights of the entire prostate, the dorsal prostate, and the ventral prostate were calculated by dividing the absolute weight by the total weight of the mouse. Both the absolute entire prostate and relative entire prostate weights reduced in the 5 and 20 mg/kg groups compared to the control group. The histomorphology of the prostate was also analyzed and compared to that of the control or untreated prostate as illustrated in Figures 1- 3, showing upon administration of Composition 1. The results show a dose-dependent disorganization of the epithelial cells in animals receiving Compound 1.
  • the control mice received an equal amount of the vehicle (carboxymethylcellulose).
  • the mice were sacrificed and the left and right testes, the entire prostate and the individual prostatic lobes (e.g., the dorsal lobe and the ventral lobe) were weighed to measure absolute weights. Relative weights of entire prostate and individual lobes were calculated by dividing the corresponding absolute weight by the total weight of the mouse.
  • Relative weights of the entire prostate, the dorsal prostate, and the ventral prostate were calculated by dividing the absolute weight by the total weight of the mouse.
  • Relative weights of the left and right testis were calculated by dividing the corresponding absolute weights by the total weights of the mouse. The results are tabulated in Figures 4-13 and show upon administration of Compound 1 a dose dependent reduction in prostate weight.
  • mice The tolerance of mice to compound 1 was determined by treating CD-I mice daily with a single oral dose of compound 1 at 100, 200, and 500 mg/kg for 5 days. The mice were observed for a total of eight days and then euthanized.
  • the toxico logical end-points in this study were standard clinical observations such as changes in movement, breathing, food consumption, mortality and decreased body weight.
  • Prostate cells harvested from mice treated with 20mg/kg of Compound l were assayed by the TUNEL assay ⁇ e.g., see Example 8).
  • the prostate cells were more apoptotic as determined by the TUNEL assay and showed greater cell cycle inhibition as determined by immunohistochemistry of the S phase related proliferating cell nuclear antigen (PCNA assay) with respect to vehicle.
  • PCNA assay S phase related proliferating cell nuclear antigen

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Abstract

La présente invention a trait à des analogues de lonidamine utiles dans le traitement du cancer et de l'hypertrophie bénigne de la prostate.
PCT/US2005/027092 2004-07-29 2005-07-29 Analogues de lonidamine WO2006015263A2 (fr)

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