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WO2006015263A2 - Lonidamine analogs - Google Patents

Lonidamine analogs 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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WO
WIPO (PCT)
Prior art keywords
group
alkyl
compound
aryl
cor
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PCT/US2005/027092
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French (fr)
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WO2006015263A3 (en
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/en
Publication of WO2006015263A3 publication Critical patent/WO2006015263A3/en

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Classifications

    • 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

Lonidamine analogs are useful in the treatment of cancer and BPH.

Description

LONIDAMINE ANALOGS
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Patent Application No. 60/683,087, filed May 19, 2005; U.S. Patent Application No. 60/661,067, filed March 11, 2005; U.S. Patent Application No. 60/651,705, filed February 9, 2005; U.S. Patent Application No. 60/646,188, filed January 21, 2005; U.S. Patent Application No. 60/599,666, filed August 5, 2004; U.S. Patent Application No. 60/592,833, filed July 29, 2004; and U.S. Patent Application No. 60/592,723, filed July 29, 2004, the contents of each of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Lonidamine (LND), also known as l-(2,4-dichlorobenzyl)-IH-indazole-3-carboxylic acid, 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.
[0003] Combination studies of lonidamine in advanced breast cancer followed this report, particularly studies in combination with epirubicin or doxorubicin. For examples, see Iaffaioli et al, Sep. 1995, Breast Cancer Res. Treat 35(3): 243-8 (phase II trial of high-dose epirubicin, lonidamine, and alpha 2b interferon); Gardin et al., Jan. 1996, Eur J Cancer 32A(I): 176-7 (phase II trial of lonidamine plus epirubicin and cyclophosphamide); Dogliotti et al, Apr. 1996, J Clin Oncol 14(4): 1165-72 (multicenter prospective randomized trial — reports that lonidamine significantly increases the activity of epirubicin); Gebbia et al, Nov. 1997, Anticancer Drugs 8(10): 943-8 (phase II trial of cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer); Amadori et al, Jun. 1998, Breast Cancer Res. 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); Nistico et al, Aug. 1999, Breast Cancer Res. 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). Surprisingly, however, a more recent reference, Berruti et al., \5 Oct. 2002, J. CHn. Oncol. 20(20): 4150-9, reports that, in a phase III study with a factorial design, time to progression in metastatic breast cancer patients treated with epirubicin was not improved by the addition of either cisplatin or lonidamine {see also Berruti et al, Jul.-Aug. 1997, Anticancer Res. 17(4A): 2763-8).
[0004] 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. For examples, 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. 1989, Tumori 75(1): 43-6 (preliminary analysis of lonidamine versus polychemotherapy); Ianniello et al, 1 JuI. 1996, Cancer 78(1): 63-9 (multicenter randomized clinical trial of cisplatin, epirubicin, and vindesine with or without lonidamine); Gridelli et al, Mar. -Apr. 1997, Anticancer Res. 17(2B): 1277-9 (phase II trial of VM-26 plus lonidamine in pretreated small cell lung cancer); Cornelia et al., May 1999, J Clin Oncol 17(5): 1526-34 (phase II randomized trial of cisplatin, gemcitabine, and vinorelbine); DeMarinis et al, May. -Jun. 1999, Tumori 85(3): 177-82 (phase III randomized trial of vindesine and lonidamine in elderly patients); and Portalone et al, Jul.-Aug. 1999, Tumori 85 (4): 239-42 (phase II study with cisplatin, epidoxorubicin, vindesine and lonidamine). [0005] 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. 30 1989, Tumori 75(3):277-9, and Zaniboni et al, Nov.-Dec. 1995, Tumori 81(6):435-7, which describes a phase II study of mitomycin C and lonidamine as second- line therapy); advanced gastric carcinoma (see Barone et al, 15 Apr. 1998, Cancer 82(8): 1460-7, which describes two parallel randomized phase II studies with a 5-fluorouracil-based or a cisplatin-based regimen); malignant glioma (see Carapella et al, May 1989, JNeurooncol 7(l):103-8, and Jul.-Dec. 1990, J Neurosurg Sd. 34(3-4):261-4); 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. 1996, Anticancer Res 16(6B):3865-9; DeLena et al, Oct. 1997, J CHn Oncol 15(10):3208-13, which reports the revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum; and DeLena et al, Feb. 2001, Eur J Cancer 37(3):364-8, which describes a phase II study of paclitaxel, cisplatin and lonidamine); and recurrent papillary carcinomas of the urinary bladder (see the reference Giannotti et al, 1984, Oncology 41 Suppl 1:104-7, which describes treatment results after administration of lonidamine plus adriamycin versus adriamycin alone in adjuvant treatment).
[0006] Lonidamine has been studied as a treatment of Benign Prostatic Hypertrophy or Benign Prostatic Hyperplasia (BPH) (see U.S. Application 10/759,337, incorporated herein by reference). BPH is a disease in which prostate epithelial cells grow abnormally and block urine flow, and currently afflicts more than 10 million adult males in the United States alone and many millions more throughout the rest of the world.
[0007] There remains a need for compounds in addition to lonidamine that are efficacious in the treatment of cancer, either alone or in combination with other anti-cancer agents, and for the treatment of BPH. The present invention meets this need. BRIEF SUMMARY OF THE INVENTION
[0008] 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.
[0009] In one aspect, the present invention provides compounds which are analogs of lonidamine. The compounds of the present invention have the formula (I): the formula (I):
Figure imgf000005_0001
(I) wherein A-B is a 7,5, 6,5 or a 5,5 cyclic ring system, optionally substituted with from one to five V6 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Ci-C8)alkyl, (C1-C6) alkoxy, nitro, acetamido, L^-CO2H, L'-dialkylamino, (Ci-Cs)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl5 (CrC8)heterocyclyl, aryl, heteroaryl; U!-R3, U1 -COR3, U1 -CUNR3R7, U^CU2R3, R4, NR3OR3, NR3-CUR3, N- (CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2, cyano, nitrileoxide, and-NO, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (d-Cs^eterocycloalkyl, a (C3-Cg)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3; R1 is selected from the group consisting of CO2R3, COR4, COCOR3, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH-V5, COCOR4, CON(R3)N=CR3R7, L1- V5, -L1CO2R3, -CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1-(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (Ci-C8)alkylene, (C2-C8)alkenyl, (C2- Cs)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C6) alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Q - C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (C1-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
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, R3, U!-R3, U^COR3, U1 -CUNR3R7, U!-CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3 CU2R3)2, PU(NR3 CUNR3R7)2, NR3(NR3)2j nitrileoxide, and-NO; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, (Ci-C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-
Cs)heterocyclyl, aryl and heteroaryl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or NR3CN;
R5 is H, OH or halogen; R7 is selected from the group consisting of H, (Ci-C8)alkyl, (C,-C6)alkenyl, (C2-
C8)alkynyl, (CrCg)heteroalkyl, (C3-C8)cycloalkyl, (C1-C8)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (d-C8)heterocyclyl or heteroaryl ring;
R8 is H, halo, nitro, cyano, nitrileoxide, -NO, R3, U1 -R3, U1 -COR3, U1 -CUNR3R7, U1- CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3 -PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2;
R31 is aryl or heteroaryl; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 S5 NHSO2R3, CONHSO2R3, and C(=NCN)NH2;
Y is CR8 2, CR8, NR8, S or O;
U is O, S, NR3, NCOR3, or NCONR3R7;
U1 is O or S; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0010] In a second aspect, the present invention provides lonidamine analogs that have improved aqueous solubility and extended pharmacokinetics in vivo.
[0011] hi a third aspect, 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.
[0012] In a fourth aspect, 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.
[0013] hi a fifth aspect, 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.
[0015] These and other aspects and embodiments of the invention are described in more detail in the detailed description and claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 shows the morphology of prostate in a normal mouse.
[0017] Figure 2 shows the morphology of prostate in a mouse treated with 5 mg/kg Compound 1.
[0018] Figure 3 shows the morphology of prostate in a mouse treated with 20 mg/kg Compound 1.
[0019] Figure 4 illustrates a dose dependent reduction in relative right testis weight upon administration of Compound 1.
[0020] Figure 5 illustrates a dose dependent reduction in relative left testis weight upon administration of Compound 1.
[0021] Figure 6 illustrates a dose dependent reduction in relative whole prostate weight upon administration of Compound 1.
[0022] Figure 7 illustrates a dose dependent reduction in relative dorsal prostate weight upon administration of Compound 1.
[0023] Figure 8 illustrates a dose dependent reduction in relative ventral prostate weight upon administration of Compound 1.
[0024] Figure 9 illustrates a dose dependent reduction in absolute ventral prostate weight upon administration of Compound 1.
[0025] Figure 10 illustrates a dose dependent reduction in absolute dorsal prostate weight upon administration of Compound 1.
[0026] Figure 11 illustrates a dose dependent reduction in absolute whole prostate weight upon administration of Compound 1
[0027] Figure 12 illustrates a dose dependent reduction in absolute right testis weight upon administration of Compound 1. [0028] Figure 13 illustrates a dose dependent reduction in absolute left testis weight upon administration of Compound 1.
[0029] Figure 14 illustrates a reduction in absolute ventral prostate weight upon administration of Compound 3.
[0030] Figure 15 illustrates a reduction in absolute dorsal prostate weight upon administration of Compound 3.
[0031] Figure 16 illustrates a reduction in absolute anterior prostate weight upon administration of Compound 3.
[0032] Figure 17 illustrates a reduction in absolute right testis weight upon administration of Compound 3.
[0033] Figure 18 illustrates a reduction in absolute left testis weight upon administration of Compound 3.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The description below is organized into sections for convenience only, and disclosure found in any organizational section is applicable to any aspect of the invention.
Definitions
[0035] The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the chemical and medical arts. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over the definition of the term as generally understood in the art.
[0036] As used herein, the terms "a" or "an" means "at least one" or "one or more."
[0037] As used herein, the term "Alkyl" refer to a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, (Cj-C8)alkyl is meant to include methyl, ethyl, n- propyl, 2-propyl, n- butyl, 2-butyl, tert-butyl, pentyl, and the like. For each of the definitions herein (e.g., alkyl, alkenyl, alkoxy, araalkyloxy), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have six or fewer main chain carbon atoms. (C1-C8) Alkyl may be further substituted with substituents, including for example, hydroxyl, amino, mono or di(C]-C6)alkyl amino, halo, (C2-C6) alkenyl ether, cyano, nitro, ethenyl, ethynyl, (C1-C6) alkoxy, (Ci-C6) alkylthio, acyl, - COOH, -CONH2, mono- or di-(CrC6)alkyl-carboxamido, -SO2NH2, -OSO2-(C] -C6)alkyl, mono or di(Ci-C6) alkylsulfonamido, cyclohexyl, heterocyclyl, aryl and heteroaryl.
[0038] As used herein, the terms "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.
[0039] As used herein, the term " Alkylene" refer to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, (C1-C6)alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
[0040] As used herein, the term "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. For example, (C2-C6)alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.
[0041] As used herein, the term "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. The term "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.
[0042] 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.
[0043] As used herein, the terms "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, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or -(CR'R")n-CONRXRy (where n is an integer from 0 to 5, R' and R" x y are independently hydrogen or alkyl, and R and R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). In one embodiment, Rx and Ry 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.
[0044] As used herein, the terms "Araalkyl" or "Aryl(Ci-Cx)alkyl" refer to the radical -
RXRY where Rx is an alkylene group (having eight or fewer main chain carbon atoms) and
RY is an aryl group as defined above. Thus, "araalkyl" refers to groups such as, for example, benzyl, phenylethyl, 3-(4-nitrophenyl)-2-methylbutyl, and the like. Similarly, "Araalkenyl" means a radical -RXRY where Rx 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.
[0045] As used herein, the term "cyclic ring system" means a single heterocyclyl, cycloalkyl, aryl, or heteroaryl ring or combination of heterocyclyl, cycloalkyl, aryl, or heteroaryl rings as defined herein.
[0046] As used herein, the term "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), -(CR3R") -
COOR (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-CONRXRy x y
(where 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). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2- carboxamidocyclohexenyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
[0047] As used herein, the term "Cycloalkyl-alkyl" means a radical -R XRY wherein Rx 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.
[0048] As used herein, the term "halo" and the term "halogen" when used to describe a substituent, refer to -F, -Cl, -Br and -I.
[0049] As used herein, the term "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. Ry 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. For each of the
W X V Z above, 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., C1-C10) refers to the total number of carbon atoms in the portion of the heteroalkyl
W X V 2 group exclusive of the cyano, -OR , -NR R , or -S(O) R portions. The term "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, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH 2-CH3, -
CH2-CH25-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N- OCH3, and -CH=CH-N(CH3 )-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
For heteroalkylene groups, 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)2R'- represents both -C(O)2R'- and -R5C(O)2.
[0050] As used herein, the term "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-CONRXRy (where n is an integer from O to 5, R' and R" are independently hydrogen or alkyl, and R and R are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl). In one embodiment, Rx and Ry 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, pyrazolopyridinyl, triazolopyridinyl, pyrazolopyrimidinyl, triazolopyrimidinyl, pyrrolotriazinyl, pyrazolotriazinyl, triazolotriazinyl, pyrazolotetrazinyl, hexaaza-indenyl, and heptaaza-indenyl and the derivatives thereof. Unless indicated otherwise, the arrangement of the hetero atoms within the ring may be any arrangement allowed by the bonding characteristics of the constituent ring atoms.
[0051] As used herein, the terms "heterocycle", "heterocyclyl", "heterocycloalkyl" or "cycloheteroalkyl" 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 (where n is an integer from χ y
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). More specifically the term heterocyclyl includes, but is not limited to, pyridyl, tetrahydropyranyl, N- methylpiρeridin-3-yl, N-methylpyrrolidin-3-yl, 2-pyrrolidon-l-yl, furyl, quinolyl, thienyl, benzothienyl, pyrrolidinyl, piperidinyl, morpholmyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, l,l-dioxo-hexahydro-lλ6-thiopyran-4-yl, tetrahydroimidazo [4,5-c] pyridinyl, imidazolinyl, piperazinyl, and piperidin-2-onyl.and the derivatives thereof. The prefix indicating the number of carbon atoms (e.g., C3-C10) refers to the total number of carbon atoms in the portion of the cycloheteroalkyl or heterocyclyl group exclusive of the number of heteroatoms. In one embodiment, Rx and Ry 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.
[0052] As used herein, the terms "Heterocyclylalkyl" or "Cycloheteroalkyl-alkyl" means a radical -RXRV where Rx is an alkylene group and Rv is a heterocyclyl group as defined herein, e.g., tetrahydropyran-2-ylmethyl, 4-(4-substituted-phenyl)piperazin-l-ylmethyl, 3- piperidinylethyl, and the like. [0053] As used herein, the terms "halo" and "halogen" are used interchangeably; the terms "hydroxy" and "hydroxyl" are used interchangeably; and the terms "COOR3" and "CO2R3" are used interchangeably.
[0054] As used herein, the terms "optional" or "optionally" as used throughout the specification mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "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.
[0055] As used herein, the term "Optionally substituted" means a ring which is optionally substituted independently with substituents.
[0056] The above terms (e.g., "alkyl," "aryl" and "heteroaryl"), 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.
[0057] 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', -CO2R', -CONR'R",
-OC(O)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"\ -NR"C(0)2R', -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR\ -S(O)R', -S(O)2R', -S(O) 2NR'R", -NR5S(O)2R", - CN and -NO2, -R', -N3, perfluoro(Ci-C4)alkoxy, and perfmoro(Ci -C4)alkyl, in a number ranging from zero to the total number of open valences on the radical; and where R', R" and R'" are independently selected from hydrogen, Ci _g alkyl, C3.6 cycloalkyl, C2_g alkenyl,
C2_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.
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. For example, -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. [0058] 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-U3-, wherein T and
U3 are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2.
Alternatively, 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. Alternatively, 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)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted Ci -g alkyl.
[0059] For each of the definitions above, the term "di-alkylamino" refers to an amino moiety bearing two alkyl groups that can be the same, or different.
[0060] 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. For example compounds of Formula I would exclude compounds which contain a N-CO2H, NSO2H or NSO3H moiety.
[0061] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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".
[0062] 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).
[0063] "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:
[0064] (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, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
[0065] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
[0066] "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. Representative 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.
[0067] Turning next to the compositions of the invention, 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.
[0068] As used herein, "treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. For purposes of this invention, 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.
[0069] As used herein, "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
[0070] As used herein, "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. For example, as used herein, 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.
[0071] As used herein, 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. Thus, a therapeutically effective amount may be administered in one or more administrations.
[0072] As used herein, 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. Thus, a prophylactically effective amount may be administered in one or more administrations.
Lonidamine analogs
[0073] m another embodiment (GROUP 22), the compounds of the present invention have the formula (I):
Figure imgf000019_0001
(I) wherein A-B is a 7,5, 6,5 or a 5,5 cyclic ring system, optionally substituted with from one to five V6 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Ci-C8)alkyl, (Ci-C6) alkoxy, nitro, acetamido, lΛC02H, iΛdialkylamino, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C!-C8)heterocyclyl, aryl, heteroaryl; U1 -R3, U1 -COR3, U^CUNR3R7, U^CU2R3, R4, NR3OR3, NR3-CUR3, N- (CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3,
CU2RJ, CUNR >3'Rr,7', CUNR'CUR", CUN(CURJ)2, CUNR'CU2RJ, CUN(CU2RJ)2 CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3),, PU(NR3CUNR3R7)2, NR3(NR3)2, cyano, nitrileoxide, and-NO, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Cj-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3;
R1 is selected from the group consisting Of CO2R3, COR4, COCOR3, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, CC=NCN)NH2, -NHCO-V5, -NHNH-V5, COCOR4, CON(R3)N=CR3R7, L1- V5, -L1CO2R3, -CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL'(CO2H)2, COHNL1CCO2H)2 and CONHL1-(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (d-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (CrC4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (C1-C6) alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (C1-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)CyC loalkyl, a (Ci- Cg)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (C1-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, -NO, R3, UJ-R3, U1 -COR3, U1OJNR3R7, U^CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3 CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2, nitrileoxide, and-NO; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, (Ci-C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C1-
C8)heterocyclyl, aryl and heteroaryl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or NR3CN;
R5 is H, OH or halogen;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, (C2-C6)alkenyl, (C2-
C8)alkynyl, (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; or R and R are taken together form a (C1-C8)heterocyclyl or heteroaryl ring;
R8 is H, halo, nitro, cyano, nitrileoxide, -NO, R3, UJ-R3, U^COR3, U^CUNR3R7, U1- CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2; NR3(NR3)2;
R31 is aryl or heteroaryl; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3, CONHSO2R3, and C(=NCN)NH2t
Y is CR8 2, CR8, NR8, S or O;
U is O5 S, NR3, NCOR3, or NCONR3R7; and
U1 is O or S; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0074] In addition to compounds having formula (I) above, the present invention further includes all salts thereof, and particularly, pharmaceutically acceptable salts thereof. Still further, 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. In other embodiments 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. [0075] In one embodiment, 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. In another embodiment, an acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or arylsulfonyl group is part of a cyclic structure. For ease of reference, certain sets of compounds of the invention are referred to as "groups," e.g.,. "Group 1 ". It will be appreciated, however, that no method or composition of the invention is limited to groups to which numbers have been assigned. [0076] In one group of embodiments, (GROUP 1) the compounds of the present invention have the formula (I) with the proviso that the compound is not-lonidamine, tolnidamine,
Figure imgf000022_0001
For convenience, 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. [0077] In another embodiment, the present invention provides compounds of formula (III)
Figure imgf000022_0002
(III) wherein
R1 is selected from the group consisting of COOR3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 and L1 -V5 wherein L1 is selected from the group consisting of,
Figure imgf000023_0001
and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci-C8)heteroalkyl, halogen, hydroxy, (C1-C4) (C1-C6) alkoxy, cyano, nitro, amino, (Ci-C4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3 -C8)cyclo alkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (C] -C4) alkylamino or (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar or CO=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(^NCN)NH2;
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 (C1-C8)alkyl;
R3 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl or (Ci-C8)heterocyclyl, or aryl or heteroaryl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (Ci-C8)alkyl or (Ci-Csjheteroalkyl, (C3-C8)cyclo alkyl or (Ci-C8)heterocyclyl, or aryl or heteroaryl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl;
Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, C-R8, CU, O, NR7 and S; each W6, W7 ; W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or (C1- C8)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (C]-C4) alkylamino and (C1-C4) dialkylamino; Y is CHR8, CR8, NR8, S or O;
R8 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 W1, W4, and W5 are C; W2 and W3 are N; W6 and W7 are CH, Y is
CH2; R6 is Cl; and R1 is not COOR3 or COR4.
[0078] hi another group of embodiments, 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. The sets of compounds having the formulas (a), (b), (c), (d), (e), (f), (g),
(h), and (i) can be referred to as GROUPS A, B, C, D, E, F, G, H, and I, respectively. For convenience, the set of compounds defined by formula (I ) and not including compounds (a)-
(i) as defined below can be referred to as GROUP 2 compounds.
[0079] hi an embodiment the present invention excludes the following compounds:
Figure imgf000024_0001
[0080] Within this embodiment; referring to formula (a)
(i) Rla is selected from the group consisting Of CONHNH2, CONHN(CH3)2, and - CH=CHCO2H; R2a is a group having the formula:
Figure imgf000025_0001
(al) (a2) wherein each R6 independently is a halogen, and nlO is 1 or 2; and
R3a is hydrogen;
(ii) Rla is CO2H;
R2a 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
R3a is hydrogen; iii) Rla is CO2H
R2a is 4-chlorophenyl; and
R3a is chloro, OH, methyl, or OMe; iv) Rla is selected from the group consisting Of CO2Me, CO2Et, -CO-glyceryl, COCH3, CONH2, CH2CO2H, CH2CH2CO2H and
N
N
//
N N--N (a3)
R2a is 4-chlorophenyl, and R3a isH;
(v) Rla is CO2H,
R2a is 2, 4-dichlorophenyl,
R3ais selected from the group consisting of-(OCH3)nio wherein nlo is 1 or 2, chloro, bromo, fluoro, CO2H, and CH2CO2H. [Cheng];
(vi) Rla is -0-PO3H, -0-SO3H, -0-CH2CO2H, 0-CH(CO2H)2, NHCH(CO2H)2, CH2CH(NH2)CO2H, CONHCH(CO2H)2, and CONH(CH2)nii-cyclopropyl wherein nil is O or 1,
R2a is 2, 4-dichlorophenyl, R3ais H; and
(vii) RIa is selected from the group consisting of -COCH3, -SH, -tetrahydrofurfuryl, - CH2CO2H, -CH2CH2CO2H, -H, -CH3, -CH2OH, -NH2, -CN, -tetrazin-2-yl, , O-(CH2)i- 2CO2H, 0-CH2CO2Ci -C4alkyl, -0-PO3H, -0-SO3H, 0-CH(CO2H)2, NHCH(CO2H)2 and CH2CHNH2CO2H;
R2a is selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methylρhenyl, trifluoromethylphenyl, 3- benzoyl, 4-halophenyl, 4-methylsulfonylphenyl, 4-methylphenyl, 4-cyanoρhenyl, 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, 2,6-dimethyl-3-dimethylsulfamoylphenyl, 4- imidazoyl;
R3a is selected from the group consisting of H, 2-dimethylaminoethyl, 5-amino, chloro, bromo, 5-hydroxy, 5-methyl, methoxy, dimethoxy, fluoro, CO2H, CH2CO2H, 5-nitro, 5-acetamido and 7-chloro;
(viii) compounds having the formulae:
Figure imgf000026_0001
(a4) (a5) (ix) compounds having the formula:
Figure imgf000026_0002
wherein R!a is COOH, CONH2, COO CH2CH2OH, COOCH2CHOHCH2OH, or
COOCH(CH2OH)2;
R22a is H or halo,
R20a is halo, Me, methoxy, trifluoromethyl, C0NH2, or methanesulfonyl, and
R21a is H, Me, halo, or a group forming with the benzene ring to which it is attached a naphthyl ring.
[0081] Within this embodiment, referring to formula (b):
Rlb is CO2H;
R2b is phenyl;
R3b is H; [0082] Within this embodiment, referring to formula (c):
(i) Rlc is CH2CONH2;
R2c 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,
R3c is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH2CH2CH2)1-4CO2H, -OCH2-tetraazo-2-yl and -SCH3;
(ii) compounds having the formula:
Figure imgf000027_0001
(cl) when Rlc is COCONH2; R5c and R2c are defined as set forth in Table 2A below; and
R3c is benzyl, then compounds i-xxv, xxvii, xxix, xxxvii, and xxxix are excluded;
R3c is Me, then compound xxvi is excluded;
R3c is H, then compounds i-xxix, xxxviii, and xxxix are excluded;
R3c is -CH2-CO2Me, then compounds i, ii, iv, vi, viii-xxiii, xxiv, xxx-xxxviii, and xxxix are excluded;
R3° is -CH2-CO2Et, then compounds iii, v, and vii are excluded; and R3c is -CH2-CO2H, then compounds i-xxix, xxx-xxxvii, and xxxix are excluded.
Table 2A
Figure imgf000028_0001
(iii) compounds having the following structure
R
Figure imgf000029_0001
(c2)
(a) wherein R23c is CH2CN or tetrazolyl, R5c is ethyl
R20c is 3-chloro; and
(b) R23c is CH2-tetrazolyl, CH2-2-pyridyl, CH2-4-pyridyl, CH2-2-quinolinyl, -(CH2)3- CO2Et, -(CH2)3-CO2H, -(CH2)2-CO2H,
R5c is ethyl;
R20c is 2-phenyl; and
(c) R23c is OCH2CO2H, R5c is ethyl and R20c is H; (d) R23o is Me or H, and
R5c is ethyl when R20c is hydrogen,
R5c is cylopropyl when R20c is 2-phenyl, and
R5c is ethyl when R2Oc is 2-phenyl;
(e) wherein R23c is -(CH2)3-CO2Et or -(CH2)3-CO2H, and
R5c is ethyl when R20° is hydrogen,
R5c is cylopropyl when R20c is 2-phenyl, and
R5c is ethyl when R20c is 2-phenyl;
(f) wherein R23c is -(CH2)2-CO2Et, -(CH2)2-CO2H, -CH2-CO2Et or -CH2-CO2H, R5c is ethyl and R20c is 2-phenyl;
(iii) compounds having the following structure
Figure imgf000030_0001
(c3) wherein R24c is H or Me and R25c is Me. [0083] Within this embodiment, referring to formula (d):
Rld is CH2CONH2;
R2d 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;
R3d is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH2CH2CH2)1-4CO2H, -OCH2-tetraazo-2-yl and -SCH3; [0084] Within this embodiment referring to formula (e):
(i) Rle is CH2CONH2,
R2e 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-butylρhenyl, 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-ρhenylethyl;
R3e is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - 0(CH2CH2CH2)I-4CO2H, -OCH2-tetraazo-2-yl and -SCH3; [0085] Within this embodiment, referring to formula (f):
Rlf is CO2H;
R2f 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;
R3f is H; [0086] Within this embodiment, referring to formula (g): Rlg is CO2Et;
R2g is phenyl;
R3g is H; [0087] Within this embodiment, referring to formula (h):
Rlh is CO2Et or Q=NH)OEt;
R2h is phenyl;
R3h is H, 5-methyl or 7-methyl; [0088] Within this embodiment (Group J), referring to formula (i):
RH is CONHCH2CH2Cl or CONHCH2CH2-piperazin-4-yl;
R2' is benzyl; and
R3i is H.
[0089] hi one embodiment 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. Japan, 1978, 51(l)and :251-6, Caputo, Chemotherapy, 1981, 27(suppl. 2): 107-20, Silvestrini et al, Prog. Med. Chem., 1984, 21, 111-35, Milanesio et al, J. Org. Chem. 2000, 65, 3416- 25, Hagishita et al, J. Med. Chem. 1996, 39, 3636-58, Tapia et al, J. Med. Chem. 1999, 42, 2870-80, U.S. Patent Nos. 4,002,759, 3,895,026, 6,001,865, 5,034398, 3,625,971, 3,470,194, 5,621,002, PCT Appl. titled Prodrugs of Lonidamine and Lonidamine Analogs, Att. Docket No. 021305-002210PC, PCT Appl. No. US2004/0167196, and PCT Pub. No.WO96/03383. [0090] hi another group of embodiments, the compounds of the present invention have the formula (I) with the proviso that the compound does not have the formula:
Figure imgf000031_0001
wherein R1 is -COOH; -CONR3R4, -CONHNR6R7; -COOR5 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 CF3; R3 and R4 may be independently alkyl or hydrogen; R6 and R are usually -H or -CH3; X represents a straight chain or branched chain, saturated or unsaturated hydrocarbon linkage group; Y is-CHR7-; and n is 0 or 1.
[0091] A number of other groups of embodiments are set forth below.
[0092] In any of the above embodiments, Y is NR8. hi other embodiments Y is NH. In other embodiments Y is O. In other embodiments Y is S. hi other embodiments Y is CR8. Y is CR8 2. hi other embodiments Y is CH2.
[0093] hi one embodiment, the present invention provides R8 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Cr Cg)alkyl, (C1-C6) alkoxy, nitro, acetamido, L^CO2H, LΛdialkylamino, (CrC8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; U1- R3, U1 -COR3, U1 -CUNR3R7, U1 -CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3- CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3, SOR3, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2, cyano, nitrileoxide, and-NO, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (CrC^heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3. hi another embodiment, the present invention provides R substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (C1-C8)alkyl, (C!-C8)heteroalkyl, (C2-Cg)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; U1 -R3, R4, NR3- CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (CrC8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3. In another embodiment, the present invention provides R8 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Ci-C8)alkyl, (CrC8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; O-R3, S- R3 , R4, NR3-COR3, NR3-CONR3R7, NR3- CSNR3R7, NR3-C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-Cs)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3. In another embodiment, the present invention provides R8 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe- CONMe2, NH-CSNH2, NH-C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-ATyI, COMe, COEt, COpropy^CO-cyclopropyl, CSNMe2, Q=NMe)NMe2, CONHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, PO(NMe2)2. In another embodiment, the present invention provides R8 selected from the group consisting of hydrogen, (C1-C4) alkyl or (Q-C^heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino, and (Ci-C4) dialkylamino. In another embodiment, 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.
[0094] In other embodiments the present invention provides compounds of Formula I, wherein A-B is a 7,5-fused (C1-C8)CyCHc ring system. In one embodiment the present invention provides compounds of Formula I, wherein A-B is a 6,5-fused (Ci-C8)cyclic ring system, m other embodiments the present invention provides compounds of Formula I, wherein A-B is a 5,5-fused (C1-C8)CyCHc ring system.
[0095] In one embodiment (GROUP 4) the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula IIA:
Figure imgf000034_0001
(IIA) wherein each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 W9 or W12 is independently N, NV6, CO, CS, SO, SO2 or CV6 ; represents a single or double bond;
R1, Y, R2 and V6 are as defined above in formula (I); and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0096] Returning to formula IIA those of skill in the art will appreciate, upon considering the entirety of this disclosure, that the total number of nitrogens in W1 and W3- W9 and W12 will typically not exceed 5, and the substitution pattern of the 5-membered ring is such that none of W1, W3, W4, and W5 is CH or CV6. In one embodiment, all of W6- W9 and W12are independently CV6. hi another embodiment, three of W6-W9 and W12 are independently CV6 and the other is CH or N. In another embodiment, two of W6-W9 and W12 are independently CV6 and the rest are CH or N. In another embodiment, one of W6-W9 and W12 is CV6 and the rest are CH or N.
[0097] hi one embodiment, the present invention provides V6 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Cr C8)alkyl, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci- C8)heterocyclyl, aryl, heteroaryl; U1 -R3, R4, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N- (CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl5 a (C1-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3. hi another embodiment, the present invention provides V6 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Ci-Cg)alkyl, (Ci-Cs)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; O-R3, S- R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3-C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V6 is other than -COOR3. In another embodiment, the present invention provides V6 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH-C(=NH)NH2, N(Me)- C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyl,CO- cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, PO(NMe2)2. hi another embodiment, the present invention provides V6 selected from the group consisting of hydrogen, (Ci-C4) alkyl or (Ci-C4)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (CpC4) alkylamino, and (Ci-C4) dialkylamino. In another embodiment, the present invention provides V6 selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
[0098] In one embodiment (GROUP 5) the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula IIIA:
Figure imgf000035_0001
(IIIA) wherein each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N, NV6, CO, CS, SO, SO2 or CV6 ; represents a single or double bond;
R1, Y, R2 and V6 are as defined above in formula (I); and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0099] Returning to formulas IIIA, those of skill in the art will appreciate, upon considering the entirety of this disclosure, that the total number of nitrogens in W1 and W3-W will typically not exceed 5, and the substitution pattern of the 5-membered ring is such that none of W1, W3, W4, and W5 is CH or CV6. In one embodiment, all of W6- W9 are independently CV6. In another embodiment, three of W6- W9 are independently CV0 and the other is CH or N. In another embodiment, two of W6 -W9 are independently CV6 and the rest are CH or N. In another embodiment, one of W6- W9 is CV6 and the rest are CH or N. In one embodiment, V is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fiuoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
[0100] In another embodiment (GROUP 6), the compounds of the present invention have the formulas IIIB,
Figure imgf000036_0001
(IIIB)
wherein
R1 is selected from the group consisting of COOR3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 CON(R3)N=CR3R7, -L1CO2R3, -CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1 (CO2H)2 and CONHL1 -(C3- C8)cycloalkyl; and L1 -V5 wherein L1 is selected from the group consisting of -C ≡€-, -
Figure imgf000036_0002
V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or (d-C8)heteroalkyl, halogen, hydroxy, (Ci-C4) (Ci-C6) alkoxy, cyano, nitro, amino, (Ci-C4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3-C8)cycloalkyl, a (C1-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci-C4) alkylamino or (C1-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (C1-C4) alkylamino, and (C1-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar and Q=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar or C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(=NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and (Ci- C8)alkyl;
R3 is H, (Ci-Cs)alkyl, (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl or heteroaryl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (d-C8)alkyl, (d-C^heteroalkyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl or heteroaryl;
R and R together are (Q-C^heteroalkyl or heteroaryl;
Ar is aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C8)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, oxo, U^R3, U1 -COR3, (Ci-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R8 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0101] In another embodiment (GROUP 7), the present invention provides compounds of formula IIIA wherein the A-B ring moiety has the following structure
Figure imgf000038_0001
(IIIA) wherein W'-W5 is defined as follows in Table IA:
Table IA
Figure imgf000038_0002
and for each ring B 1-21 as defined above, W6-W9 is defined as follows in Table IB:
Table IB
Figure imgf000038_0003
Figure imgf000039_0002
[0102] In one embodiment (GROUP B), the present invention provides compounds of formulae IIIA and for each ring B 1-21, W6- W9 is defined as follows in Table 1C:
Table 1C
Figure imgf000039_0001
Figure imgf000040_0001
wherein ~^ indicates a single bond to W4 and *- indicates a single bond to W5 and
V6 and U are as defined above.
[0103] In another embodiment (GROUP 9), the present invention provides compounds wherein the C=U bond in the structural formulas in Table 1C is independently replaced with an SO or an SO2 moiety; such as, for example, providing a compound containing the moiety
Figure imgf000041_0001
[0104] In another embodiment (GROUP 10), the compounds of the present invention have the formula IVA
Figure imgf000041_0002
(IVA)
[0105] In one embodiment (GROUP 11), W1 -W5 of formula (IV) are as defined in Table IA above; and for each W1 -W5 as defined above, W6- W8 are defined as follows in Table ID:
Table ID
Figure imgf000041_0003
[0106] In one embodiment (GROUP 12), A-B in formula IVA is selected from the group consisting of:
Figure imgf000042_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
[0107] In another group of embodiments, (GROUP 13), the compounds of the present invention have the formula (HID):
Figure imgf000042_0002
(HID) wherein
R1 is selected from the group consisting of COOR3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 and L1 -V5 wherein L1 is selected from the group consisting of -
C ≡€-, -C(VVC(V3)-,
Figure imgf000042_0003
-NΉCO- and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or
Figure imgf000042_0004
halogen, hydroxy, (C1-C4) (C1-C6) alkoxy, cyano, nitro, amino, (CrC4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-Cg)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci -C4) alkylamino or (C1-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (C1-C4) alkylamino, and (C1-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5S, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar and Q=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 S, NHSO2CR3 3, NHSO2Ar or C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(=NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three Rϋ substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl;
R3 is H, (C1-C8)alkyl or (C1-C8)heteroalkyl, (C3-C8)cycloalkyl or (Ci-C8)heterocyclyl, or aryl or heteroaryl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl or (Ci-Cg)heterocyclyl, or aryl or heteroaryl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl;
Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W is a member selected from the group consisting of N, CR , CO, O, NR and S; each W6, W7 , W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (C1-Ce) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R8 is H, a straight or branched chain (CrC8)alkyl or (CrC8)heteroalkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[0108] In another group of embodiments (GROUP 14), the compounds of the present invention have the formula (HID) of embodiment:
Figure imgf000044_0001
(HID)
when R1 is not selected from the group consisting of COOR3, COR4, CH-CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 and L1 -V5 when L1 is selected from the group consisting of -C sC-, -C(V1H^(V3)-, -C(VV)C(V3V4)-,
Figure imgf000044_0002
-NHCO- and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (d-C8)heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, cyano, nitro, amino, (C1-C4) alkylamino and (C1-C4) dialkylamino or V1 and V3 together form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 S, NHSO2CR3 3, NHSO2Ar or C(^NCN)NH2; and when L1 is - NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(^NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (d-C8)alkyl;
R3 is H, (C1-C8)alkyl or (CrC8)heteroalkyl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (C1-C8)alkyl or (Ci-C8)heteroalkyl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl; Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino and (C1-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R8 is H, a straight or branched chain (Ci-Cs)alkyl or (Ci-C8)heteroalkyl group; represents a single, double or normalized bond.
[0109] hi another group of embodiments, (GROUP 15), the compounds of the present invention have the formula (HID), (HD) or (HE):
Figure imgf000045_0001
wherein in formula (HID):
R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 and iΛv5 wherein L1 is selected from the group consisting of -CsC-, -C(V1^C(V3)-, -C(V1 V2JC(V3V4)-,
Figure imgf000045_0002
-NHCO- and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci-Cs)heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, cyano, nitro, amino, (Ci-C4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3-Cs)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci-C4) alkylamino or (C1-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (C]-C4) alkylamino, and (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar or C(=NCN)NH2; and when L1 is - NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(^NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl;
R3 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (d-C8)alkyl or (Ci-C8)heteroalkyl;
R3 and R7 together are (CrC8)heteroalkyl or heteroaryl;
Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C]-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R8 is H, a straight or branched chain (Ci-C8)alkyl or (Ci -C8)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):
R1 is selected from the group consisting of COOR3, CH=CHCO2R3, COR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 S and, C(=NCN)NH2, and lΛv5 wherein L1 is selected from
the group consisting
Figure imgf000046_0001
-NHCO-, and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj-C4 alkyl or (Ci-C8)heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, cyano, nitro, amino, Cj-C4 alkylamino, and CpC4 dialkylamino or V1 and V3 together form a (C3 -Cs)cyclo alkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, Cj-C4 alkylamino, or Ci-C4 dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, C)-C4 alkylamino, and C1-C4 dialkylamino, then the other is hydrogen or alkyl; V5 is selected from COOR3, COR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar, C(=NCN)NH2; and q is 1-6; with the proviso that in NHSO2CR5S, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is
-NHCO- then V5 is COR4 , NHSO2CR5 3) NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4 and C(=NCN)NH2;
R3 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R7 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl;
R5 is H, OH or halogen;
R6 is halo or a straight or branched chain (C1-C8)alkyl;
Ar is a substituted or unsubstituted aryl or heteroaryl;
Y is CH2, CHR8, CR8, NR8, S or O; and
R is H or a straight or branched chain (Ci-C8)alkyl group; and
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl.
[0110] In another group of embodiments (GROUP 16), the compounds of the present invention have the formula (HID), (HIE), (IID) or (HE):
Figure imgf000048_0001
wherein in formula (HID) and
R1 is selected from the group consisting OfNHSO2Ar, C(=NCN)NH2, and COCOR4;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
R3 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (Ci-Cs)alkyl or (Ci-C8)heteroalkyl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl;
Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (Ci-C4) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R is H, a straight or branched chain (Ci-C8)alkyl or (C]-C8)heteroalkyl group; represents a single, double or normalized bond; and in formula (V):
wherein in formula (HIE) the variables are defined as in embodiment except R1 is not selected from the group consisting of R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3 and CONH2(=NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl;
R3 is H, (CrC8)alkyl or (C,-C8)heteroalkyl; each R4 is a member independently selected from the group consisting Of NR3R7, NHOR3, NHNR3R7 and NHCN;
R5 is H, OH or halogen;
R7 is H or (Ci-C8)alkyl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR , CO, O, and S; each W6, W7, W8 or W9 is independently N, C or CH;
Y is CHR8, NH, or O;
R8 is H or a straight or branched chain (Ci-C8)alkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and in formula (HID) or (HIE):
R1 is selected from the group consisting of COOR3, CH=CHCO2R3, COR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 S and, C(^NCN)NH2, and L1 -V5 wherein L1 is selected from
the group consisting of
Figure imgf000049_0001
-NHCO-, and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C4 alkyl or (C)-C8)heteroalkyl, halogen, hydroxy, (Ci-C4) alkoxy, cyano, nitro, amino, Ci-C4 alkylamino, and Ci-C4 dialkylamino or V1 and V3 together form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V and V is hydroxyl, amino, Ci-C4 alkylamino, or Ci-C4 dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, C1-C4 alkylamino, and CrC4 dialkylamino, then the other is hydrogen or alkyl; V5 is selected from COOR3, COR4, B(OR3)2, SO2R4, NHSO2CR5 3! NHSO2CR3 3, NHSO2Ar, C(=NCN)NH2; and q is 1-6; with the proviso that in NHSO2CR5 3j R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4,
B(OR3)2, SO2R4and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when
L1 Is
-NHCO- then V5 is COR4 , NHSO2CR5 3, NHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4 and
C(=NCN)NH2;
R3 is H, (C1-C8)alkyl or (C1-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R7 is H, (Ci-C8)alkyl or (d-C8)heteroalkyl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl;
R5 is H, OH or halogen;
R6 is halo or a straight or branched chain (C1-C8)alkyl;
Ar is a substituted or unsubstituted aryl or heteroaryl;
Y is CH2, CHR8, CR8, NR8, S or O; and
R is H or a straight or branched chain (C1-Cs)alkyl group; and
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (C1-C8)^yI.
[0111] In another group of embodiments, (GROUP 17), the compounds of the present invention have the formula (HDD):
Figure imgf000050_0001
(HID) wherein R1 is L1 -V5 wherein L1 selected from the group consisting of -C ≡£-,
Figure imgf000050_0002
-NHCO-, and -NHNH- wherein each V1,
V τl5 V , and V is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci-Cg)heteroalkyl, halogen, hydroxy, (Ci-C4) alkoxy, cyano, nitro, amino, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino or V1 and V3 together form a (C3-Cs)cycloalkyl, a (Ci-Cs)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl, or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci-C4) alkylamino, or (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 S wherein R5 is not OH, NHSO2CR3 3, NHSO2Ar, C(^NHCN)NH2;
R2 is an aryl or. heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
R3 is H, (Ci-Cs)alkyl or (Ci-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
Ar is a substituted or unsubstituted aryl or heteroaryl;
R7 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl;
R3 and R7 together are (Ci-C8)heteroalkyl or heteroaryl; each W1, W3, W4, or W5 is independently N or C;
W2 is a member selected from the group consisting of N, NR7, CR5, CO, O, and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (Ci-C4) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S, or O;
R8 is H or a straight or branched chain (Ci-C8)alkyl group; and represents a single, double or normalized bond.
[0112] In another group of embodiments, (GROUP 18), the compounds of the present invention have the formula (HIE) of embodiment:
Figure imgf000052_0001
(HIE) wherein R1 is not CH=CHCO2R3 when
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;
R3 is H5 (Ci-Cs)alkyl or (CrC8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3, NHNR3R7 and NHCN;
R5 is H, OH or halogen;
R7 is H or (Ci-C8)alkyl; each W1, W3, W4 or W5 is independently N or C;
W is a member selected from the group consisting of N, CR , CO, O, and S; each W6, W7, W8 or W9 is independently N, C or CH;
Y is CHR8, NH, or O; and
R8 is H or a straight or branched chain (d-C8)alkyl group; represents a single, double or normalized bond.
[0113] In another group of embodiments, (GROUP 19), the compounds of the present invention have the formula (HIE), (HF) or (IIG):
Figure imgf000052_0002
(HIE) (ΠF) (IIG) wherein in formula (HIE): R! is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3 and C0NH2(=NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl;
R3 is H, (d-C8)alkyl or (Ci-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3, NHNR3R7 and NHCN;
R5 is H, OH or halogen;
R7 is H or (CrC8)alkyl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, and S; each W6, W7 , W8 or W9 is independently N, C or CH;
Y is CHR8, NH, or O;
R8 is H or a straight or branched chain (d-C8)alkyl group; represents a single, double or normalized bond; with the proviso that when
W1, W4, and W5 are C; W2 and W3 are N; W6 and W7 are CH, Y is CH2; R6 is Cl; R1 is not COOR3 or COR4; and the compound does not have the formula selected from the group consisting of:
Figure imgf000053_0001
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and wherein in formula (ITF) and (HG):
R1 is selected from the group consisting of COOR3, CH=CHCO2R3, COR4, B(OR3)2, SO2R4, NHSO2CR5 S and CONH2(^NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl; and
Y is CH2, O, NH, or S.
[0114] In another group of embodiments, (GROUP 20), the compounds of the present invention have the formula (HE), (VI) or (VII):
Figure imgf000054_0001
(HIE) (HF) (IIG) wherein in formula (HIE) R1 is CONH2(^NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl;
R3 is H, (Ci-C8)alkyl or (CrC8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3, NHNR3R7 and NHCN;
R5 is H, OH or halogen;
R7 is H or (Ci-C8)alkyl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, and S; each W6, W7, W8 or W9 is independently N5 C or CH;
Y is CHR8, NH, or O;
R8 is H or a straight or branched chain (d-C8)alkyl group; represents a single, double or normalized bond; with the proviso that when
W1, W4, and W5 are C; W2 and W3 are N; W6 and W7 are CH, Y is CH2; R6 is Cl; R1 is not COOR3 or COR4; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and in formula (IIF) and (IIG):
R1 is selected from the group consisting of COOR3, CH=CHCO2R3, COR4, B(OR3)2, SO2R4, NHSO2CR5 3 and C0NH2(=NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl; and
Y is CH2, O, NH, or S.
Within this group of embodiments, the compounds of the present invention also have the formula (HIE) wherein R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3 and C0NH2(=NHCN);
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (C1-C8)alkyl;
R3 is H, (Ci-C8)alkyl or (d-C8)heteroalkyl; each R4 is NHCN;
R5 is H, OH or halogen;
R7 is H or (CrC8)alkyl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, and S; each W6, W7, W8 or W9 is independently N, C or CH;
Y is CHR8, NH, or O;
R is H or a straight or branched chain (CrC8)alkyl group; represents a single, double or normalized bond; with the proviso that when
W1, W4, and W5 are C; W2 and W3 are N; W6 and W7 are CH, Y is CH2; R6 is Cl; R1 is not COOR3 or COR4; pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. [0115] In another group of embodiments, (GROUP 21), the compounds of the present invention have the formula (HIE):
Figure imgf000056_0001
(HIE) wherein R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, and NHSO2CR5 3;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl;
R3 is H, (Ci-C8)alkyl or (Ci-Cg)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3 and NHNR3R7;
R5 is H, OH or halogen;
R7 is H or (Ci-C8)alkyl; each W1, W3, W4, W5, W6, W7, W8 or W9 is independently N, C or CH;
W2 is a member selected from the group consisting of N, CR5, CO, O, and S;
Y is CHR8, 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
W1, W4, and W5 are C; W2 and W3 are N; W6 and W7 are CH, Y is CH2; R6 is Cl; R1 is not
COOR3 or COR4; and pharmaceutically acceptable salts, solvates, hydrates, tautomer and prodrugs thereof.
[0116] In first another group of embodiments (GROUP 22), the formula:
Figure imgf000056_0002
is a member selected from the group consisting of:
Figure imgf000057_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y and V6 is defined as above.
[0117] In another group of embodiments (GROUP 23), the formula:
Figure imgf000058_0001
is a member selected from the group consisting of:
Figure imgf000058_0002
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y and V6 is defined as above. Within these embodiments, W -W are independently CV6. In another embodiment, three of W6- W9 are independently CV6 and the other is CH or N. In another embodiment, two of W6-W9 are independently CV6 and the rest are CH or N. In another embodiment, one of W6- W9 is CV6 and the rest are CH or N. In one embodiment, V is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
[0118] In another group of embodiments (GROUP 24), the formula:
Figure imgf000059_0001
is a member selected from the group consisting of:
Figure imgf000059_0002
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
[0119] In another group of embodiments, (GROUP 25) the formula:
Figure imgf000059_0003
is a member selected from the group consisting of:
Figure imgf000060_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
[0120] In another embodiment, (GROUP 26) R1 is selected from the group consisting of:
CONHNH2, CONH2, CONHNMe2, CONMe2
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
,CONHNH,
Figure imgf000061_0004
[0121] In another embodiment, (GROUP 27) R1 is selected from the group consisting of:
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
XONHNH,
Figure imgf000062_0004
[0122] Within these embodiments, R1 is a COOR3 or L^CO2R3, wherein L1 is defined as above in formula (I) and R3 is H or (CH2)qNR9R10 and each R9 and R10 is a straight or branched chain (Ci-C8)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.
[0123] In one embodiment, L1 is -CVl=CV3- wherein V1 and V3 together form a (Q- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl, or a heteroaryl ring. In another embodiment the (Q-C^heterocycloalkyl, (C3-Cs)cycloalkenyl, aryl, or heteroaryl ring is a five-membered ring. In another embodiment, the heteroaryl ring contains one or more nitrogen atoms.
[0124] In another embodiment, (GROUP 28) R1 is preferably a COOR3 moiety, and R3 is preferably H or (CH2)nNR9R10 wherein each R9 and R10 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.
[0125] In one embodiment, any R1 and V6 or any two V6 attached to the same, adjacent or within two atoms may be taken together with the atoms with which they are attached to form a (C3-Cg)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring. Within this embodiment, the (C3-Cg)cycloalkyl moiety is selected from the group consisting of cyclopentane, cyclobutane, cyclohexane, and cycloheptane. In a related embodiment, (C3-C8)cycloalkenyl moiety is selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In a related embodiment, the aryl moiety is selected from benzene or naphthalene. In another related embodiment, 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, triazolotriazine, pyrazolotetrazine, hexaaza-indene, and heptaaza-indene and the derivatives thereof . In another related embodiment, the (C]-C8)heterocyclyl moiety is selected from the group consisting of piperidine, tetrahydropyran, N-methylpiperidine, N-methylpyrrolidine, pyrrolidone, tetrahydrofurane, morpholine, pyrrolidine, tetrahydrothiophene, 1,1-dioxo-hexahydro-lλ6- thiopyran, tetrahydroimidazo [4,5-c] pyridine, imidazoline, and piperazine. In another related embodiment, two V6 groups together forms a (Ci-Cs)heterocycle moiety selected from the group consisting of:
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
wherein the straight and wavy lines indicate the point of attachment to the rest of the molecule. In one embodiment the compound is selected from the group consisting of:
Figure imgf000065_0001
[0126] In other embodiments, the present invention provides a compound wherein the R1 group is attached to the A-B ring system such that it is rotationally restricted. In one embodiment W1 (or a sunstituent thereon) taken together with W2 or W6 (or a sunstituent thereon) form a (C3-Cs)cycloalkyl, a (C1-C8) heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring, such as for example
Figure imgf000065_0002
[0127] In one embodiment, W1 taken together with W2 or W6 form a (Ci-C8)heterocycle moiety selected from the group consisting of
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
wherein the straight line indicates the point of attachment to W1 and the wavy line and indicates the points of attachment within two atoms of W1 on the rest of the molecule. In one embodiment the straight line indicates the point of attachment to W2. In another embodiment the straight line indicates the point of attachment to W6.
Figure imgf000067_0001
wherein ring A, W1, W3, Y, and R2 are defined as in formula (II), and each W13, W14 and W 15 is independently selected from the group consisting of N, NV6, CO, CS, SO, SO2 and CV6 wherein V6 is as defined above in formula (I). Within this embodiment, compounds of the present invention have the formulae:
Figure imgf000067_0002
wherein the variables are as defined herein. In another embodiment, compounds of the present invention have the formulae:
Figure imgf000067_0003
wherein the variables are as defined herein. Within the embodiment, compounds of the present invention have the formulae:
Figure imgf000068_0001
wherein R , R and V is as defined above.
[0128] In another embodiment (GROUP 29), compounds of the present invention have the formulae:
Figure imgf000068_0002
wherein W^W6 and W13-W15 is as defined above.
[0129] Within this embodiment, compounds of the present invention have the formulae:
Figure imgf000068_0003
wherein W^W6 and W13-W15 is as defined above and the remaining variables are as defined herein.
Within this embodiment, compounds of the present invention have the formulae:
Figure imgf000069_0001
wherein the variables are as defined herein.
[0130] In another embodiment (GROUP 30), compounds of the present invention have the formulae:
Figure imgf000069_0002
Figure imgf000069_0003
wherein the variables are as defined herein. [0131] In one embodiment, the present invention provides R6 substituents, each independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, -NO, R3, U!-R3, 1/-COR3, U1 -CUNR3R7, U]-CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3- CUNR3R7, N-(OJNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3, SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3 CUNR3R7)2, NR3(NR3)2, nitrileoxide, and-NO, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3- C8)cycloalkenyl, an aryl or a heteroaryl ring. In another embodiment, the present invention provides R6 substituents, each independently selected from the group consisting of halo, nitro, cyano, U1 -R3, R3, R4, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3- CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3- C8)cycloalkyl, a (Q-C^heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring. In another embodiment, the present invention provides R6 substituents, each independently selected from the group consisting of halo, cyano, (Ci-Cg)alkyl, (C1-Cs)heteroalkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (d-C8)heterocyclyl, aryl, heteroaryl; 0-R3, S- R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3-C(=NR3)NR3R7, NR3-CO2R3, NR3- SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (C];-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring. In another embodiment, the present invention provides R substituents, each independently selected from the group consisting of halo, cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH- CSNH2, NH-C(=NH)NH2, N(Me)-C(^NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-S02-Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, CONHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, S03-Aryl, SO2NH2, PO(NMe2)2. In another embodiment, the present invention provides R6 each independently selected from the group consisting of hydrogen, (Ci-C4) alkyl or (Ci-C4)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino. In another embodiment, the present invention provides R6 each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl. In one embodiment, R6 the present invention provides each independently selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡CH and -C ≡C-CH3.
[0132] In one embodiment, R2 has 1 or 2 substituents. In another embodiment, R2 has two R6 substituents. R6 substituents are independently selected from the group consisting of halo and a straight or branched chain (Q-C^alkyl.
In one embodiment, R2 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-C8)alkyl.
[0133] In another embodiment, R2 is selected from the group consisting of
Figure imgf000071_0001
wherein each W10 or W11 is preferably, independently selected from the group consisting of N, C and CH. In this embodiment R6 is preferably halo or a straight or branched chain (C]- C8)alkyl; and the wavy line indicates the point of attachment to the rest of the molecule. Within this embodiment R2 is more preferably phenyl and R6 is preferably independently selected from the group consisting of Cl, Br, or CH3, and more preferably is Cl. [0134] In another embodiment R2 is selected from the group consisting of:
Figure imgf000072_0001
Figure imgf000072_0002
wherein the variables are as defined herein.
[0135] In another embodiment, R3, R7, and R8 are independently selected from the group consisting of: H, -CH3, -CH2CH3,
Figure imgf000073_0001
Figure imgf000073_0002
[0136] In another embodiment, Y is preferably NH, O, CR8 or CHR8. In another embodiment, Y is preferably NH, O, or CHR8. R8 is preferably H.
[0137] In another embodiment, (GROUP 31) compounds preferably have the formula:
Figure imgf000074_0001
Figure imgf000074_0002
wherein R1, R6 and Y are defined as in formula (IIID). Within this embodiment, compounds preferably have the formula:
Figure imgf000074_0003
wherein R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3 and C0NH2(=NHCN); R3 is H, (CrC8)alkyl or (C,-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3, NHNR3R7 and NHCN; R5 is H, OH or halogen; R7 is H or (C1-C8)alkyl; and R6 is halo or a straight or branched chain (C1-C8)alkyl. Within this embodiment, R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, and NHSO2CR5 3; each R is a member independently selected from the group consisting OfNR3R7, NHOR3 and NHNR3R7. Within these embodiments, R6 is preferably independently selected from the group consisting of Cl, Br, or CH3, and more preferably is Cl.
[0138] In another embodiment (GROUP 39), compounds of the present invention have the structure:
Figure imgf000075_0001
wherein R1, R6 and Y are defined as in formulae (I) and (II). Within this embodiment, compounds preferably have the formula:
Figure imgf000075_0002
wherein R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 S and CONH2(=NHCN); R3 is H, (Ci-Cg)alkyl or (C,-C8)heteroalkyl; each R4 is a member independently selected from the group consisting OfNR3R7, NHOR3, NHNR3R7 and NHCN; R5 is H, OH or halogen; R7 is H or (d-C8)alkyl; and R6 is halo or a straight or branched chain (C]-C8)alkyl. Within this embodiment, R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, and NHSO2CR5 3; each R4is a member independently selected from the group consisting OfNR3R7, NHOR3 and NHNR R . Within these embodiments, R is preferably independently selected from the group consisting of Cl, Br, or CH3, and more preferably is Cl. [0139] In another embodiment, (GROUP 32) compounds have the formula:
Figure imgf000076_0001
ein R1, W2, Y, and R6 are defined as in formula (HID). Within this embodiment, R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, C(=NCN)NH2 and L1 -V5; L1 and V5 are defined as above in formula (HID); W2 is N is CR9, R9 is H or halo; Y is CH2, O, NH, or S; and R6 is halo or a straight or branched chain (Q-C^alkyl. Within this embodiment, R1 is COOR3 or - CV^CV^R3. R3 is H or (CH2)nNR10Rn, wherein each R10 and R1 ' is a straight or branched chain (Ci-C8)alkyl, or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered (Ci-C8)heterocyclyl ring system; and the subscript n is an integer of from 1 to 4. In another embodiment, R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3 and C0NH2(=NHCN); W2 is N is CR9, R9 is H or halo; Y is CH2, O, NH, or S; and R6 is halo or a straight or branched chain (C1-Cs)alkyl. Within these embodiments, R1 is preferably selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4 and NHSO2CR5 3. Within this embodiment, R1 is preferably COOR3. R3 is preferably H or (CH^nNR10R11, wherein each R10 and R11 is a straight or branched chain (C1-C8)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. R6 is preferably independently selected from the group consisting of Cl, Br, or CH3, and more preferably is Cl. [0140] In another embodiment, (GROUP 40) the compounds have the formula:
Figure imgf000076_0002
wherein R1, W2, Y, and R6 are defined as in formulae (I) and (II). [0141] In another embodiment (GROUP 33), the compound has the formula:
Figure imgf000077_0001
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH- V5, L1- V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L^CO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1-(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (Ci-Cs)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting
Figure imgf000077_0002
(Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, -NO, (C)-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-Cs)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R9 substituents independently selected from the group consisting of halo and a straight or branched chain (C1-Cg)alkyl; each R3 is a member independently selected from the group consisting of H, (C]- C8)alkyl, (Ci-Cs)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and
NR3CN;
R5 is H, OH or halogen; each V" is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, (Ci-C8)heteroalkyl, (C3- Cg)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (C!-C8)heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8, S or O; and
R8 is H, (Ci-C8)alkyl or (Ci-C8)heteroalkyl. [0142] In another embodiment (GROUP 41), the compound has the formula:
Figure imgf000078_0001
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH- V5, L1- V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L^CO2H)2, -NHL^CO2H)2, COHNL1 (CO2H)2 and CONHL1 -(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (Ci-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl; (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, -NO, (C]-C4)alkylamino and (C1-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (C1-C4) alkylamino or (C1-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R9 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-Cs)alkyl; each R3 is a member independently selected from the group consisting of H, (Cp Cg)alkyl, (CpC8)heteroalkyl, (C3-C8)cycloalkyl, (CpCs)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (CpC8)alkyl, (CpC8)heteroalkyl, (C3- C8)cycloalkyl, (CpCg)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (CpCs)heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8, S or O; and
R8 is H3 (Ci-C8)alkyl or (CpC8)heteroalkyl. [0143] In another embodiment, (GROUP 34) compounds have the formula:
Figure imgf000079_0001
wherein each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡€-CH3; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C ≡€-CO2H, -C ≡C-CONHOH, -C ≡€- CONHNH2, -C ≡e-CONHNMe, -C ≡C-CONHNMe2, -C ≡C-CONMeNH2, -C -C- CONMeNHNe and -C ≡C-CONMeNMe2; with the proviso that when R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C ≡€H and - C ≡C-CH3. Within this embodiment, the compounds have the formula
Figure imgf000080_0001
wherein R6 is hydrogen, F, Br, CN, CF3, CH3, CHMe2, -C s€H, and -C H€-CH3; and
R1 is CO2H, CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2, -CsC-CO2H, -C ≡C-CONHOH, -C ≡C- CONHNH2, -C ≡C-CONHNMe, -C ≡€-C0NHNMe2, -C ≡€-C0NMeNH2, -C ≡€- CONMeNHNe and -C ≡€-C0NMeNMe2. Within this embodiment, the compounds have the formula:
Figure imgf000080_0002
wherein each R6 independently is R6 is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡CH and -C≡€-CH3; R1 is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7. Within this embodiment, the compound has the formula:
Figure imgf000080_0003
wherein R is
Figure imgf000081_0001
In another embodiment (GROUP 42), compounds have the formula:
Figure imgf000081_0002
wherein each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡€-CH3; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C≡C-CO2H, -C ≡C-CONHOH, -C ≡C- CONHNH2, -C ≡C-CONHNMe, -C^-CONHNMe2, -C^-CONMeNH2, -C ≡C- CONMeNHNe and -C ≡€-C0NMeNMe2; with the proviso that when R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C ≡€H and - C ≡€-CH3. Within this embodiment, the compounds have the formula
Figure imgf000081_0003
wherein each R6 independently is R6 is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C≡€-CH3; Ri is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7. Within this embodiment, the compounds has the formula:
Figure imgf000082_0001
wherein R is
Figure imgf000082_0002
[0144] In another embodiment, (GROUP 35), the compounds have the formulas
Figure imgf000082_0003
wherein R1 is CO2H, CH=CHCO2H5 CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2, -C ≡€-CO2H, -C ≡€- CONHOH, -C^-CONHNH2, -C ≡€-CONHNMe, -C =C-CONHNMe2, -C ^-CONMeNH2, C ≡C-CONMeNHNe and -C ≡C-CONMeNMe2;
and V6 is hydrogen, amino, or alkylamino.
In another embodiment, (GROUP 43), the compounds have the formulas
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
wherein R1 is CO2H, CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2, -C ≡C-C02H, -C ≡€- CONHOH, -C ^-CONHNH2, -C ≡€-CONHNMe, -C ^-CONHNMe2, -C sC-CONMeNH2, C ≡€-CONMeNHNe and -C ≡€-CONMeNMe2;
and V6 is hydrogen, amino, or alkylamino.
[0145] In another embodiment(GROUP 36), compounds have the formula:
Figure imgf000084_0001
wherein wherein R1, W2, Y, and R6 are defined as in formula (HID). [0146] In another embodiment (GROUP 44), compounds have the formula:
Figure imgf000084_0002
wherein wherein R » 1 , Λ W17-2 , Y, and R are defined as in formula (HID).
[0147] In another embodiment, (GROUP 37) the compounds have the formula:
Figure imgf000084_0003
wherein R . 1 , r R>2 and Y are as defined above in formula (I). [0148] In one embodiment(GROUP 38), the present invention provides the compounds having the formula selected from the group consisting of:
Figure imgf000085_0001
wherein R3 is phenyl, pyridyl or SO2R7; and V6 is H or NHR3.
In one embodiment (GROUP 45), the present invention provides the compounds having the formula selected from the group consisting of:
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
Figure imgf000086_0004
wherein R3 is phenyl, pyridyl or SO2R7; and V6 is H or NHR3. [0149] Within any of the above embodiments, R1 is L1 -V5 or CO2R3. In another embodiment R1 is C2alkenyl-CO2R3. In another embodiment, R3 is H or (CH2)qNR13 2; each R13 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.
[0150] In another embodiment (GROUP 46), the compound has the formula:
formula:
Figure imgf000087_0001
wherein
R1 is selected from the group consisting of: CO2R3, COR4 , CH=CHCO2R3 and
CONHSO2CR3 3; each R3 is a member independently selected from the group consisting of H, (Ci Cg)alkyl, aryl, (Ci-Cg)heteroalkyl and (Ci-Cg)heterocyclyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7 and NR7NR3R7; each R6 is a member independently selected from the group consisting of H, halo, (Ci
C8)alkyl, and (Ci-C8)heteroalkyl;
R7 is selected from the group consisting of H, (Ci C8)alkyl, (Ci-C8)heteroalkyl, aryl and (Q-
Cδjheterocyclyl; each V is independently a member selected from the group consisting of hydrogen, halo, oxo; cyano, (d-C8)alkyl, (CrC8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-
CONR3R7, NR3-CSNR3R7, NR3-C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3,
CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31,
SO2NR3R7, PO(OR3)2, PS(OR3)2, and PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; the subscript plO is an integer of from 0 to 4;
Y is CH2, NH, S or O; and
W1 and W2 is each C or N.
Within this embodiment, V6 is H. In another embodiment, Wl and W2 are CR5. hi another embodiment, W1 is CR5 and W2 is N. In another embodiment, W1 is N and W2 is CR5. In another embodiment, Y is O. hi another embodiment, Y is S. hi another embodiment, Y is
NH. hi another embodiment, Y is CH2. Within these embodiments, the compound has the formula:
Figure imgf000088_0001
wherein R1 is selected from the group consisting of: CO2R3, COR4, CONHSO2CR3 3; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, aryl,
Figure imgf000088_0002
(Ci-C8)heterocyclyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7,
NR7NR3R7;
R6 is independently selected from the group consisting of H, halo, (Ci-Csjheteroalkyl
R7 is H, (Ci C8)alkyl, (Ci-C8)heteroalkyl, aryl, (Ci-C8)heterocyclyl; and
Y is CH2
[0151] hi another embodiment (GROUP 47), the compound has the formula:
Figure imgf000088_0003
wherein R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH-V5, L1 -V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (d-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (d-C4)alkoxy, cyano, nitro, amino, -NO, (C1-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Cr C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl; pio is 1-4; each V6 is, independently hydrogen, halo, oxo; cyano, (Ci-Cs)alkyl, (Ci- C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C,-C8)heterocyclyl, aryl, heteroaryl; 0-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, CC=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Cr C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo, cyano, (Ci-C8)alkyl, (Ci-Cs)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; 0-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring.; each R3 is a member independently selected from the group consisting of H, (C1- Cg)alkyl, (Ci-Cs)heteroalkyl, (C3-Cs)cycloalkyl, (C]-C8)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (C1-C8)alkyl, (C1-Cg)heteroalkyl, (C3- Cs)cycloalkyl, (Ci-Cs)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (Ci-Cs^eterocyclyl or heteroaryl ring;
Y is CHR8, C(R8)2, NR8, S or O; and
R8 is H, (C1-Cg)alkyl, (CrC8)heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, 0-R3, S-R3, R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(-NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2.
[0152] In another embodiment, (GROUP 48) compounds have the formula:
Figure imgf000090_0001
wherein each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡CH and -C ≡£-CH3; pio is 1-4; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, CH(Me)2, methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-propynyl, 0-Me, O-Et, O-cycloproρyl, O-Aryl, S-Me, S-Et, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COproρyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, CONHQ=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aiyl, SO2NH2, or PO(NMe2)2; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -CsC-CO2H, -C ≡€-CONHOH, -C s€- CONHNH2, -C ≡€-CONHNMe, -C^-CONHNMe2, -C^-CONMeNH2, -Cs€- CONMeNHNe and -C s€-CONMeNMe2; with the proviso that when each V6 is H and R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C ≡€H, and -C ≡€-CH3. Within this embodiment, the compounds have the formula
Figure imgf000091_0001
wherein R6 is hydrogen, F, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡€-CH3; pi O is 1-4; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-ATyI, COMe, COEt, CQprøpyl,CO-cyclσpropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R1 is CO2H, CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe5 CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2, -C≡C-CO2H, -Cs€-CONHOH, -CaC-CONHNH2, -C ≡€-CONHNMe, -C ≡€-CONHNMe2, -C s€-CONMeNH2, -C ≡C-CONMeNHNe and -C MT-CONMeNMe2. [0153] Within this embodiment, the compounds have the formula:
Figure imgf000092_0001
wherein each R5 independently is R6 is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡CH and -C ≡€-CH3; plO is 1-4, each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH- CSNH2, NH-C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and Ri is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN-CR3R7. Within this embodiment, the compound has the formula:
Figure imgf000092_0002
wherein each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-Q=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyLCO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R3 is
Figure imgf000093_0001
[0154] In another embodiment, (GROUP 49) compounds preferably have the formula:
Figure imgf000093_0002
Figure imgf000093_0003
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH-V5, L1 -V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -(C3-C8)cycloalkyl; -
L1 is selected from the group consisting of (CrC8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (Q- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (d-C4)alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (CrC4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl; pio is 1-4; each V6 is, independently hydrogen, halo, oxo; cyano, (Ci-Cg)alkyl, (Cr C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-Cs)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3 -CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo, cyano, (CrCg)alkyl, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring.; each R3 is a member independently selected from the group consisting of H, (C]- C8)alkyl, (d-C^heteroalkyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (C1-C8)alkyl, (Ci-C8)heteroalkyl, (C3- C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (d-C8)heterocyclyl or heteroaryl ring;
Y is CHR8, C(R8)2, NR8, S or O; and
R8 is H, (Q-C^alkyl, (CrC^heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, O-R3, S-R3, R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7,
CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3),,
PO(NR3R7)2.
[0155] Within this embodiment, Y is CH2; each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡£-CH3; pI0 is 1-4;
each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, CH(Me)2, methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-proρynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, MH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C=C-CO2H, -C ≡C-CONHOH, -C ≡€- CONHNH2, -C ≡C-CONHNMe, -C ^-CONHNMe2, -C ≡€-C0NMeNH2, -C ≡£- CONMeNHNe and -C ≡€-C0NMeNMe2; with the proviso that when each V6 is H and R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C -CH, and -C ≡€-CH3.
Within this embodiment, Y is CH ; each R independently is R is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡€-CH3; plO is 1-4, each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH-C(=NH)NH2, N(Me)- C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2- Aryl, COMe1 COEt, COpropyl,CO- cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and Ri is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7. Within this embodiment, R1 is CONHNHR3; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- CO=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropylCO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R3 is
Figure imgf000096_0001
[0156] In another embodiment, (GROUP 50) compounds have the formula:
Figure imgf000096_0002
Figure imgf000096_0003
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH-V5, L1 -V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1-(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (CrC8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (C1- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-Cs)CyC loalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
Pio is 1-4; each V6 is, independently hydrogen, halo, oxo; cyano, (Ci-Cg)alkyl, (C1- C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3 -CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo, cyano, (Ci-Cs)alkyl, (CrC8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring.; each R3 is a member independently selected from the group consisting of H, (Ci- Cs)alkyl, (Ci-Cg)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting of NR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, (Ci-Cs)heteroalkyl, (C3- Cg)cycloalkyl, (Ci-Cs)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (Ci-C8)heterocyclyl or heteroaryl ring;
Y is CHR8, C(R8)2, NR8, S or O; and
R8 is H, (CrCs)alkyl, (Ci-C8)heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, O-R3, S-R3, R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2.
Within this embodiment, Y is CH2; each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡C-CH3; ρ1Q is 1-4; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2- Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, CONHQ=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C^C-CO2H, -C≡G-CONHOH, -C ≡€- CONHNH2, -C ≡C-CONHNMe, -C^-CONHNMe2, -C ^-CONMeNH2, -C ≡€- CONMeNHNe and -C ≡€-C0NMeNMe2; with the proviso that when each V6 is H and R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C E-CH, and -C ≡€-CH3.
Within this embodiment, Y is CH2; each R6 independently is R6 is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C s€H and -C =€-CH3; plO is 1-4, each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH-C(=NH)NH2, N(Me)- C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyl,CO- cyclopropyl, CSNMe2, Q=NMe)NMe2, C0NΗC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R1 is CONHAr, CONH(Py) wherein Py is 2~, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7. Within this embodiment, R1 is CONHNHR3; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Axyl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R3 is
Figure imgf000099_0001
[0157] In another embodiment (GROUP 51), compounds have the formula:
Figure imgf000099_0002
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(^NCN)NH2, -NHCO-V5, -NHNH-V5, L1 -V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, O-L](CO2H)2, -NHL^CO2H)2, COHNL'(CO2H)2 and CONHL1-(C3-Cs)cycloalkyl;
L1 is selected from the group consisting of (C1-Cg)alkylene, (C2-C8)alkenyl, (C2- Cg)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (Ci-C4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (C1-C4)alkoxy, cyano, nitro, amino, -NO, (Q-C^alkylamino and (C1-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (C1- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl; pio is 1-4; each V6 is, independently hydrogen, halo, oxo; cyano, (Ci-Cs)alkyl, (Ci- C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR R )2, or any two V attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from the group consisting of halo, cyano, (Ci-C8)alkyl, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; O-R3, S-R3 , R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2, PO(NR3R7)2, or any two R6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring.; each R3 is a member independently selected from the group consisting of H, (C1- C8)alkyl, (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl, (C]-C8)heterocyclyl, aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, (Ci-C8)heteroalkyl, (C3- C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (Ci-C8)heterocyclyl or heteroaryl ring;
Y is CHR8, C(R8)2, NR8, S or O; and
R8 is H, (d-C8)alkyl, (Ci-C8)heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, O-R3, S-R3, R4, NR3-COR3, NR3-CONR3R7, NR3-CSNR3R7, NR3- C(=NR3)NR3R7, NR3-CO2R3, NR3 -SO2R3, COR3, CO2R3, CSNR3R7, C(=NR3)NR3R7,
CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31, SO2NR3R7, PO(OR3)2, PS(OR3)2,
PO(NR3R7)2.
[0158] Within this embodiment, Y is CH2; each R6 independently is selected from the group consisting of hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡CH and -C -C-CH3; p10 is 1-4; each V5 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, 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, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAC, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2- Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, Q=NMe)NMe2, CONHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C =C-CO2H, -C≡€-CONHOH, -C≡€- CONHNH2, -C ≡€-CONHNMe, -C ≡€-CONHNMe2, -C ≡€-CONMeNH2, -C ≡€- CONMeNHNe and -C ≡C-CONMeNMe2; with the proviso that when each V6 is H and R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C ≡CH and -C s€-CH3.
Within this embodiment, Y is CH2; each R6 independently is R6 is hydrogen, F, Cl, Br, CN, CF3, CH3, CHMe2, -C ≡€H and -C ≡C-CH3; plO is 1-4, each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, CH(Me)2, methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1-propynyl, 3-proρynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH-C(=NH)NH2, N(Me)- C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2- Aryl, COMe, COEt, COpropyl,CO- cyclopropyl, CSNMe2, C(=NMe)NMe2, CONHC(^NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R1 is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7. Within this embodiment, R1 is CONHNHR3; each V6 independently is hydrogen, halo, oxo; cyano, CH3, CH2CH3, CH(Me)2, methoxymethyl, ethoxymethyl, cyclopropyl, cyclobutyl, 2-furanyl, 3-furanyl, ethynyl, 1- propynyl, 3-ρropynyl, O-Me, O-Et, O-cyclopropyl, O-Aryl, S-Me, S-Et, NH2, NHMe, NMe2, NHAc, NHOH, NHNH2, NHNHAc, NH-CONH2, NMe-CONMe2, NH-CSNH2, NH- C(=NH)NH2, N(Me)-C(=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-SO2-Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, CONHC(=NH)H2, SO2Me, SO2Et, SOMe, SOEt, SO3-Aryl, SO2NH2, or PO(NMe2)2; and R3 is
Figure imgf000102_0001
[0159] Within any of the above embodiments, R1 is iΛv5 or CO2R3. In another embodiment R1 is C2alkenyl-CO2R3. In another embodiment, R3 is H or (CH2)qNR13 2; each R13 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.
[0160] Within any of the above embodiments, R6 is independently selected from the group consisting of Cl, Br, or CH3. In another embodiment, each R6 is CL
[0161] Within any of the above embodiments, R6 is independently selected from the group consisting of Cl, Br, or CH3. In another embodiment, each R6 is Cl.
[0162] Still other preferred groups of embodiments are provided in the Examples below.
[0163] Examples of compounds of Formula 1 include:
l-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-acrylic acid;
Figure imgf000102_0002
3-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-acrylic acid:
Figure imgf000102_0003
3-(2,4-Dichloro-benzyl)-benzo[c]thiophene-l-acrylic acid:
Figure imgf000103_0001
3-(2,4-Dichloro-benzyl)-isobenzofuran- 1-acrylic acid:
Figure imgf000103_0002
3-(2,4-Dichloro-benzyl)-2H-isoindole-l-carboxylic acid:
Figure imgf000103_0003
[0164] l-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-carboxylic acid:
Figure imgf000103_0004
[0165] 3-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-l-carboxylic acid:
Figure imgf000104_0001
[0166] 3-(2,4-Dichloro-benzyl)-benzo[c]thioρhene-l-carboxylic acid:
Figure imgf000104_0002
[0167] 3-(2,4-Dichloro-benzyl)-isobenzofuran-l-carboxylic acid:
Figure imgf000104_0003
[0168] 3-(2,4-Dichloro-benzyl)-2H-isoindole-l-carboxylic acid:
Figure imgf000104_0004
[0169] 3-(2,4-Dichloro-benzyl)-benzo[c]thiophene- 1 -carboxylic acid:
Figure imgf000104_0005
l-(4-Chloro-2-methyl-benzyl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-acrylic acid:
Figure imgf000105_0001
1 -(4-Chloro-2-methyl-phenylamino)-2-oxo- 1 ,2-dihydro-cyclohepta[b]pyrrole-3-aclylic acid:
Figure imgf000105_0002
and 1 -(4-Chloro-2-methyl-phenoxy)-2-oxo- 1 ,2-dihydro-cyclohepta[b]pyrrole-3-acrylic acid:
Figure imgf000105_0003
l-(4-Chloro-2-methyl-benzyl)-2-oxo-l,2-dihydro-cyclohepta[b]ρyrrole-3-carboxylic acid:
Figure imgf000105_0004
1 -(4-Chloro-2-methyl-phenylamino)-2-oxo- 1 ,2-dihydro-cyclohepta[b]pyrrole-3 -carboxylic acid:
Figure imgf000106_0001
and l-(4-Chloro-2-methyl-phenoxy)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0002
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000111_0001
wherein R is selected from the group consisting of H, F, Br, CN, CF3, CH3 CHMe2 and -
C ≡C-CH3.
[0170] In another embodiment the compounds of the present invention include all of the compounds of the examples.
MONOCYCLIC EMBODIMENTS
[0171] In another embodiment, compounds of the present invention have the formulae:
Figure imgf000111_0002
wherein the variables are as defined herein.
[0172] In another embodiment, compounds of the present invention have the formulae:
Figure imgf000112_0001
wherein the variables are as defined herein..
ACID BIOISOSTERES
[0173] In one aspect, R1 is a bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof selected from a cyclic 4, 5, or 6 membered heterocycle, arene or heteroerene. In one embodiment, a squaric acid or a derivative thereof is a cyclic 4 membered arene based bioisostere Of CO2H, CONH2, CONHNH2, or a derivative thereof. In one embodiment, the squaric acid derivative can have a formula:
Figure imgf000112_0002
[0174] In another embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof contains a hydroxyl substituted 5 or 6 membered arene or a heteroerene. In another embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof contains in the substituted 5 or 6 membered (C1-C8)heterocycle , arene or a heteroerene a moiety or formula
Figure imgf000113_0001
[0175] In one embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof contains a moiety of formula
Figure imgf000113_0002
wherein the variables are as defined herein.
[0176] In one embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof have a formula selected from the group consisting of:
Figure imgf000113_0003
wherein the variables are as defined herein.
In one embodiment, the present invention provides carboxylic acid bioisosteres: COR3, COCOR3, COCHR3COR3 , COC(R3)2COR3, COCHR3CO2R3 , COC(R3)2CO2R3, COCHR3COR4 , COC(R3)2COR4, COCHR3COCOR3 , COC(R3)2COCOR3, COCHR3COCO2R3 , COC(R3)2COCO2R3, COCHR3COCOR4 , COC(R3)2COCOR4, and CF3. In a related embodiment, the present invention provides carboxylic acid bioisosteres: COCF3,
COCOCH2R3, and COCOCH3.
[0177] 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.
DIMERS
[0178] In one aspect the present invention provides a multimeric-compound containing two or more lonidamine analog moieties. In one embodiment, the lonidamine analogs in the multimeric compound are both joined covalently by R9 substituents. hi one embodiment, the lonidamine analogs in the multimeric compound are both joined covalently by R1 substituents. In one embodiment, the lonidamine analogs in the multimeric compound are both joined covalently by V1 substituents. hi one embodiment, one of the lonidamine analogs in the multimeric compound is joined by one of R9, R1, or V1 substituent and the other lonidamine analogs in the multimeric compound is joined by one of R9, R1, or V1 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.
PRODRUGS
[0179] hi one aspect, the present invention provides prodrugs of lonidamine analogs of formula (I). As used herein, 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. To produce a prodrug, 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.
[0180] In one aspect, the present invention provides prodrugs of lonidamine analogs of formula (I) wherein when R1 represents COOR , and R represents a group of the formula (CR15R16)mNR17R18 wherein each R15 and R16 is independently H, a straight or branched chain (Ci-C8)alkyl, (Ci-C8)heteroalkyl, (Ci-C8)cycloalkyl, or (Ci-C8)heterocyclyl or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered (C1-C8)cycloalkyl or (Q-C^heterocyclyl ring system. Each R17 and R18 is a straight or branched chain (Ci-C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, or (C1- C8)heterocyclyl or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered cycloalkyl or (CrC8)heterocyclyl ring system.
[0181] A number of other groups of embodiments are preferred and are set forth below.
[0182] In a first group of embodiments, R1 is preferably a COOR3 moiety.
[0183] R3 can be a straight or branched chain (C1-C8) alkyl or (Ci-C6) alkoxy, or a three- to eight-membered cycloalkyl or heterocyclyl ring system. For example, R3 can be (CrC6) alkoxymethyl, such as methoxymethyl; (Ci-C6) alkanoyloxymethyl esters such as pivaloyloxymethyl; phthalidyl esters; (C3-C8)cycloalkoxycarbonyloxy(Ci-C6)alkyl such as 1- cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, such as 5-methyl-l,3- dioxolen-2-on-ylmethyl; and (C1-C6)alkoxycarbonyloxyethyl such as 1- methoxycarbonyloxyethyl.
[0184] The subscript m is preferably 2 and each R15 and R16 is preferably independently selected from the group, H, CH3, and a member in which R15 and R16 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,1-dioxo-hexahydro-lΔ6- thiopyran-4-yl or tetrahydropyran-4-yl group.
[0185] The prodrugs of the invention provide for the release of a drug lonidamine and its analogs. An illustrative example discussed below illustrated how a prodrug of the invention can be designed to exhibit increased aqueous solubility and extended pharmacokinetics in vivo.
[0186] In an embodiment of the invention, 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. Following absorption into the bloodstream, 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.
[0187] In one aspect of the invention, 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 R15 and R16 groups. The R15 and R16 groups in the prodrug, as shown in the structure above, 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. Similarly, 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.
[0188] In a preferred embodiment, 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.
[0189] In another aspect of the invention, R4 and R5 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.
[0190] In one aspect, 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." In some embodiments, the prodrug has a higher Vmax 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. In one embodiment, the transporter is expressed in the plasma membranes of epithelial cell lining in the human gut. [0191] In another embodiment, the transporter is expressed in the plasma membranes of epithelial cell lining in the prostate. In one embodiment, 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. In one embodiment, 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). In one embodiment, the transporter is PEPT2, which is expressed in human kidney, brain, lung, liver, and heart. In one embodiment, the transport system is carrier mediated. In a related embodiment, the transport system is receptor mediated.
[0192] In one embodiment, 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. In a related embodiment, the prodrug is selectively taken up by subject's prostate compared to other organs. In another embodiment, 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. In a related embodiment, the prodrug is selectively taken up by prostate epithelial cell as compared to other epithelial cells.
[0193] In one embodiment, 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. In another embodiment, 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.
[0194] In one embodiment, 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).
[0195] In one embodiment, 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
G5-G4-G3-G2-G1, wherein G5 is from 0 to 16 amino acids; G4 is serine, isoleucine, or lysine; G3 is serine or lysine; G2 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).
[0196] In one embodiment, 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.
[0197] In one embodiment, the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is a vitamin or a vitamin precursor, hi one embodiment, 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. In one embodiment, 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. In a related embodiment, the moiety M is α-tocopherol. In another related embodiment, the moiety M is an α-tocopherol-PEG conjugate. In another related embodiment, the moiety M is an α-tocopherol- α,ω-dicarboxylic acid-PEG conjugate. In another related embodiment, the moiety M is an α-tocopherol-succinic acid-PEG conjugate. Various α-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 In one embodiment, the present invention provides a prodrug of lonidamine or a lonidamine analog, wherein the moiety M is a hormone or a hormone precursor.
[0199] In one embodiment, 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. In one embodiment, 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.
[0200] 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.
[0201] Other 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. WO 04/053192, WO 04/052844, WO 04/052841, WO 04/052360, WO 04/041203, WO 04/033655, WO 03/104184, WO 03/099338, WO 03/080588, WO 03/077902, WO 03/065982, WO 03/020214, WO 02/100392, WO 02/100347, WO 02/100344, WO 02/100172, WO 02/44324, WO 02/42414, WO 02/32376, WO 02/28883, WO 02/28882, WO 02/28881, and WO 02/28411. In a related embodiment, 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.
[0202] In another aspect, 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. In some embodiments, 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.
[0203] hi some embodiments, 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. In some embodiments, P2 can be Alanine, Leucine, Tyrosine, Glycine, Serine, 3-Pyridylalanine, or 2-Thienylalanine. In some embodiments, P3 can be Leucine, Phenylalanine, Isoleucine, Alanine, Glycine, Tyrosine, 2-Naphthylalanine, or Serine.
[0204] In some embodiments, 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.
[0205] In some embodiments, 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. In some embodiments, 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 370C. 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.
[0206] 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. For example, dicarboxylic (or a higher order carboxylic) acid or a pharmaceutically acceptable salt thereof may be used as a stabilizing group. In other embodiments, the stabilizing group is not an amino acid. ,
[0207] In another aspect, linker prodrugs of the following formulae are provided:
(X), and
Figure imgf000121_0001
(XI), wherein D is a lonidamine analog of formula (I); Q1 is O or CH2; Zj and Z2 are cleavable linkers; R' is alpha-OH or hydrogen; R" is alpha-OH, beta-OH or hydrogen; W is - CH(CH3)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 CO2H, SO3H, SO2H, -P(O)(OR)(OH), -OP(O)(OR)(OH), and OSO3H wherein R is Ci-C6 alkyl, (C,- Cg)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, or heteroaryl; 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. .
[0208] In another aspect, compounds of the following formulae, and enantiomers and diastereomers thereof, are provided:
Figure imgf000122_0001
wherein R3Hc is alkyl (e.g., C1-C6 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. In one embodiment, R^ is lower alkyl. In one embodiment, when D is covalently attached to a heteroatom in the formula above, then D is a lonidamine analog of formula (I), as defined above.
[0209] Various polyethylene glycol (PEG) moieties and methods for forming prodrugs with them that can be used in or to make compounds of the invention are described in U.S. Patent Nos. 6,608,076; 6,395,266; 6.194.580; 6,153,655; 6,127,355; 6,111,107; 5,965,566; 5,880,131; 5,840,900; 6,011,042 and 5,681,567.
[0210] Various protecting groups and methods for forming prodrugs with them that can be used in or to make compounds of the invention can be adapted from the references Testa et al., Hydrolysis in Drug and Prodrug Metabolism, June 2003, Wiley- VCH, Zurich, 419-534 and Beaumont et al., Curr. Drug Metab. 2003, 4:461-85.
[0211] In another embodiment, 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. In one embodiment, 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. In one embodiment, the cleavable linker has at least one connection with the structure: C*-C(=X*)X*-C* wherein C* is a substituted or unsubstituted methylene group, and X* is S or O. In one embodiment, the cleavable linker has at least one C*-C(=O)O-C* connection. In one embodiment, the cleavable linker has at least one C* -CO=O)S-C* connection. In one embodiment, the cleavable linker has at least one -C(=O)N*-C*-SO2-N* -connection, wherein N* is -NH- or C1-C6 alkylamino. In one embodiment, the cleavable linker is hydrolyzed by an esterase enzyme.
[0212] In one embodiment, 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. In another embodiment, the linker is a substrate for enzymes. See generally Rooseboom et al., 2004, Pharmacol. Rev. 56:53-102.
Synthesis of Lonidamine Analogs
[0213] 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. 65:449-61; Silvestrini, 1981, "Basic and Applied Research in the Study of Indazole Carboxylic Acids" Chemotherapy 27:9-20; Lobl et al., 1981, "Effects of Lonidamine (AF 1890) and its analogues on follicle-stimulating hormone, luteinizing hormone, testosterone and rat androgen binding protein concentrations in the rat and rhesus monkey" Chemotherapy 27:61- 76; and U.S. Patent Nos. 3,895,026 and 6,001,865.
[0214] Synthetic methodology applicable to other lonidamine analogs is generally described in U.S. Pat. No. 6,146,658, PCT app. No. PCT/US05/19350 (filed June 2, 2005); and U.S. provisional application nos. 60/576,968 (filed June 20, 2004) and no. 60/588,694 (filed July 15, 2004), as is administration of polymorphic forms, enantiomeric forms, tautomeric forms, solvates, hydrates, and the like. In one embodiment, the present invention provides novel prodrugs of compounds having formulas (I). Other exemplary prodrug forms of lonidamine and analogs thereof are described in copending PCT App. No.
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. Methods for making lonidamine analogs wherein A-B ring is 2-chloroindole is can be adapted from the reference Andreani et al., Arch. Pharm., Weinheim, 1984, 317: 847-51.
[0215] Methods of synthesizing compounds of the present inventions are generally decribed in Schemes I-XX below. In one embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided as shown in scheme 1 below:
Scheme I
Figure imgf000125_0001
3) Hydrolysis
Figure imgf000125_0002
ii, W2 = CNH2 >ii
[0216] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided as shown in scheme II below:
Scheme II
Figure imgf000125_0003
[0217] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided as shown in scheme III below:
Scheme III
Figure imgf000126_0001
[0218] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided that relate generally to the methodology described in Bermudez et al., J. Med. Chem. 1990, 33:1924, Palacios et al, Tetrahedron 1995, 5i(12):3683-3690 and Okuda et al., J. Org. Chem. 1991, 56, 6024, as shown in schemes IV- IX below:
Scheme IV
Figure imgf000127_0001
Scheme
Scheme
Scheme
Figure imgf000127_0002
VII
Figure imgf000127_0003
Scheme VIII
Figure imgf000127_0004
[0219] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided that relate generally to the methodology described in Tapia et al., J. Med. Chem. 1999, 42: 2870 and Boultadakis et al, Syn. Lett. 2002, S: 1547-1549 as shown in schemes IX- XII below:
Figure imgf000129_0001
Scheme XI
Figure imgf000129_0002
Scheme XII
Figure imgf000129_0003
[0220] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided that relate generally to the methodology described in Selvakumar et al., Tetrahedron Lett. 2002, ¥5(50): 9175-9178 as shown in scheme XIII below:
Figure imgf000130_0001
[0221] In another embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided as shown in scheme XIV below:
Scheme XIV
Figure imgf000130_0002
room-temperature Cl
Y = CH2, NH and O
[0222] In another embodiment of the invention, methods of making lonidamine analogs of formula (I) are provided as shown below:
Scheme XV
Figure imgf000130_0003
Can exist in cis or trans isomers which can be separated by crystallization
Scheme XVI
Figure imgf000130_0004
Carboxyl compound of formula (II) T/US2005/027092
Figure imgf000131_0001
formula (I) of the present invention can be synthesized as shown in several embodiments in schemes I-
XVI above. The conversion of these carboxyl compounds and other presursors to compounds of the present invention having formula I wherein R1 is CH=CH-CO2H are provided hereafter.
[0223] Acrylic acid analogs of the present invention are synthesized from suitable carboxyl precursors as shown below in Scheme XVII:
Scheme XVII
Figure imgf000131_0002
formyl intermediate
[0224] In another embodiment, acrylic acid analogs of the present invention are synthesized from suitable formyl precursors as shown below:
Scheme XVIII
Figure imgf000131_0003
formyl intermediate [0225] In another embodiment the formyl intermediate synthesized in scheme XVII is converted to an acrylic acid analog by employing a Witting Homer or a related carbon carbon double-bond forming reactrion as shown in Schem XIX:
Scheme XIX
Figure imgf000132_0001
formyl intermediate of Scheme XVIII
[0226] In another embodiment, 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 (CH2N2) or alkylsubstituted diazomethane (RaIkCHN2 wherein R^ is a substituted or unsubstituted Cj-C4 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.
Scheme XX
Figure imgf000132_0002
[0227] In another embodiment, 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, Ptθ2-charcoal, Ra-Ni, Wilkinson's catalyst, Li-liquid ammonia depending on the nature of substituents present in the starting compounds.
[0228] In one embodiment, compounds of formula I wherein one of W6- W9 is a carbon atom substituted with a substituted or unsubstituted Ci-C4 alkyl, substituted or unsubstituted (Ci-C4) heteroalkyl, halogen, hydroxy, (C]-C4) alkoxy, amino, cyano, nitro, Ci-C4 alkylamino, and Ci-C4 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:
Figure imgf000133_0001
in scheme VI yields a compound of formula I.
Method of synthesis of compounds of the present invention wherein at least one of W6 -W9 is a heteroatom is provided in the following section. A compound of the present invention wherein W1 -W9 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!-W9 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*-W9 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*-W9 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'-W13 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!-W9 define a Pyrazolo[3,4- bjpyridine mjoiety can be prepared by adapting synthetic procedure described by the reference Misra et al. Bioorg. Med. Chem. Lett., 2003, 13 2405-8. 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,
Figure imgf000134_0001
l 145-54. A compound of the present invention wherein W^-W13 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^W9 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!-W9 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'-W9 define a pyrazolo[453-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^W9 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.
[0229] 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. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like. Alternatively, 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. 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. Alternatively, 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.
[0230] 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.
[0231] In certain embodiments, 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. In one embodiment, 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. In one embodiment the salts are citric acid salts.
[0232] In another embodiment, 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 α-amino acid. Examples of aminoacids include but are limited to glycine, lysine, and arginine. In one embodiment, the cation employed in the base addition salt of lonidamine or a lonidamine analog is sodium, potassium, ammonium, or calcium. In one embodiment, base addition salts of lonidamine and lonidamine analogs are formed employing lysine, glycine, or arginine as a base. In one embodiment, 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. In another embodiment, 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. In one embodiment, 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.
[0233] 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.
[0234] In an embodiment of the invention, 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. Following absorption into the bloodstream, 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.
[0235] In one aspect of the invention, the serum half live of the lonidamine analogs of the present invention are increased in vivo compared to lonidamine.
[0236] In one embodiment, the lonidamine analog is stable enough so that the serum half life of the compound is from about 8 to about 24 hours.
Uses of Lonidamine Analogs
[0237] The 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.
Pharmaceutical Compositions
[0238] For use as a prophylactic, therapeutic or contraceptive agent, a lonidamine analog disclosed herein (including pharmaceutically acceptable salts, solvates, hydrates, and prodrugs) is usually formulated as a pharmaceutical composition comprising the analog and a pharmaceutically-acceptable carrier. The term "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.
[0239] Pharmaceutical 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. For topical or nasal administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0240] Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.); GOODMAN AND GILMAN'S: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 10TH EDITION 2001 by Louis Sanford Goodman et al., McGraw-Hill Professional; PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS 7th Edition Howard C. Ansel, et al., 2004, Lippincott Williams & Wilkins Publishers; PHARMACEUTICAL CALCULATIONS 11th Edition, 2001, by Mitchell J. Stoklosa et al., Lippincott Williams & Wilkins;. PHYSICAL PHARMACY: PHYSICAL CHEMICAL PRINCIPLES IN THE PHARMACEUTICAL SCIENCES 4th Edition by Pilar Bustamante, et al., 1993, Lea & Febiger.
Dosages and Administration [0241] A variety of routes, dosage schedules, and dosage forms are appropriate for administration of pharmaceutical compositions of the invention. Appropriate dosage schedules and modes of administration will be apparent to the ordinarily skilled practitioner upon reading the present disclosure and/or can be determined using routine pharmacological methods and/or methods described herein.
[0242] 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.
[0243] For example, 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. In one embodiment, 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. In another embodiment, 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. In certain other embodiments, an analog is administered in a dose of about 25 to 250 mg. In another embodiment, a dose is about 25 to about 150 mg.
[0244] 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. Cell culture studies are frequently used in the art to optimize dosages, and the assays disclosed herein can be used in determining such doses (e.g., to determine the dose that induces significant apoptosis in prostate epithelial cells but not in other cells, such as, for example, liver cells), hi addition, appropriate dosages of the analogs of the invention can be estimated by comparison to 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).
[0245] For illustration, 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.
Use of Phannaceutical Compositions
Benign Prostatic Hyperplasia (BPH)
[0246] 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. The use of 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(suρρl 7):S27-33] which also provides exemplary dosage regimens and schedules for treatment of BPH.
[0247] In certain embodiments, 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.
Treatment of Cancer
[0248] In another aspect, the invention provides a method for treatment of cancer by administering a therapeutically effective amount of 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, medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilms tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas.
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, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, actinomycin F(I), anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-l- norleucine, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, fludarabine, 6- mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-fluorouracil, tegafur, L- asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin, defofamide, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, fiutamide, gallium nitrate, hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylam in e, urethan, vinblastine and vincristine.
[0249] In one embodiment 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-
51, optionally with the proviso that compounds of any one or more of Groups B-J are excluded.
Prevention of Epithelial Cancer
[0250] In another aspect, the invention provides a method for prevention of cancer by administering a prophylactically effective amount of a compound described hereinabove. In one embodiment, the cancer is prostate cancer. In another embodiment 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.
[0251] 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. In addition, age is a risk factor for developing prostate cancer, with more than 75% percent of prostate cancer diagnosed in men ages 65 or older.
[0252] 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, NBSl or LKBl loci associated with increased susceptibility to epithelial breast cancer; e.g., Dumitrescu et ai, 2005, J Cell. MoI. Med. 9:208-21; or (4) family history of epithelial cancer.
[0253] 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.
[0254] The use of lonidamine for prevention of cancer has been described [see U.S . provisional application No. 60/587,017 and PCT application US05/ , entitled
"Prevention of Cancer" filed July 8, 2004].
[0255] In certain embodiments of the invention, 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 (PIN)
[0256] Prostatic Intraepithelial Neoplasia (PIN) 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
US05/ entitled "Prevention of Cancer" filed July 8, 2005 (Attorney docket No.
021305-002720PC). 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.
[0257] 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. [0258] In certain embodiments of the invention, 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.
[0259] In certain embodiments 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
[0260] Compounds of the invention find use for treatment or prevention of macular degeneration. Macular degeneration (e.g., Age-related Macular Degeneration, AMD) is a degeneration of the cells of the macula, resulting in a loss of function of the portion of the eye responsible for central vision, blurred vision and ultimately blindness. 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). In response to the reduced nutrient flow and hypoxia to RPE and the retina, new blood vessels grow from the deeper choroidal layer up into the RPE layer and in between the RPE and the retina, a process known as choroidal neovascularization (CNV). Leakage from the new vessels damages the retina, leading to visual distortions. New vessels may also grow up into the retina, creating blind spots. In addition, hypoxia inducible factor (e.g., HIF-lalpha) can be over-expressed subadjacent to the retina, which can stimulate growth of new blood vessel. The use of lonidamine to treat macular degeneration is disclosed in commonly assigned copending US provisional application No. 60/639055. Administration of compounds of the invention that inhibit angiogenesis and/or HIF-lalpha expression may be used in macular degeneration therapy.
[0261] In certain embodiments of the invention, 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.
[0262] In certain embodiments 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
[0263] In another aspect, 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.
[0264] In certain embodiments of the invention, 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.
[0265] In certain embodiments 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.
Antispermato genesis
[0266] 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. A New Class of Antispermatogenic Agents," J. Med. Chem. iP:778-83; Silvestrini, 1981, "Basic and Applied Research in the Study of Indazole Carboxylic Acids," Chemotherapy 27:9-20; Lobl et al, 1981, "Effects of Lonidamine (AF 1890) and its analogues on follicle-stimulating hormone, luteinizing hormone, testosterone and rat androgen binding protein concentrations in the rat and rhesus monkey," Chemotherapy 27:61-16; U.S. 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. 65:449-61 Burroughs et al., 2004, "Identification of tissue, cellular, and molecular targets for the new non-hormonal male contraceptive Gamendazole® compared to Lonidamine", Abstract of poster presentation, Future of Male Contraception, Sep 29-Oct 2, Seattle, Washington (see also, www.futureofmalecontraception.com), and Georg et ah, 2004, "Discovery of Gamendazole®: Design, Synthesis, and in vivo Evaluation of an Effective Orally Bioavailable Non-hormonal Male Contraceptive Agent" Abstract of oral presentation, Future of Male Contraception, Sep 29-Oct 2, Seattle, Washington (see also, www.futureofmalecontraception.com) and the lonidamine analogs described herein have similar activities. Accordingly, the compounds described herein may find use as contraceptives.
[0267] In certain embodiments of the invention, 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.
[0268] In certain embodiments, 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.
[0269] In a related use, compounds of the invention can be used to control fertility in animals (e.g., rodents).
Energorytic Activity
[0270] It has been suggested that lonidamine' s anticancer properties result at least in part from a lonidamme-mediated disruption of the mitochondrial membrane, resulting in reduced activity of mitochondria-bound hexokinase and interference with ATP production by the glycolytic pathway and oxidative phosphorylation. See, Floridi et al., 1981, "Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells" Cancer Res. 41 :4661-6; Fanciulli et al., 1996, "Effect of the antitumor drug lonidamine on glucose metabolism of adriamycin-sensitive and -resistant human breast cancer cells" Oncology Research 3:111- 120, and references numbered 15-22 therein; and Gatto, 2002, "Recent studies on lonidamine, the lead compound of the antispermatogenic indazol-carboxylic acids" Contraception 65:277-78. The 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.
[0271] In certain embodiments of the invention, 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.
[0272] In certain embodiments 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.
[0273] Further, 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
July 8, 2004) and related PCT application PCT US05/ (filed July 8, 2005), entitled
"Prevention of Cancer" each of which is incorporated herein by reference.
Biological Activities of Lonidamine Analogs.
[0274] JJQ various embodiments, a pharmaceutical composition of the invention may be any compound described herein. In various embodiments, a pharmaceutical composition of the invention may comprise a compound of Formula I, or compounds of any of Groups 1-45, as described above. In certain embodiments, 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). As is usual in the pharmaceutical arts, 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. 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.
Antiproliferation Assays
[0275] In certain embodiments 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). Numerous cell proliferation assays are known in the art. Suitable assays include the antiproliferation assays described in Examples 6 and 7, below. In some embodiments, a compound is used that has the same or greater antiproliferative activity than does lonidamine. In an aspect, 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. In one embodiment the cell exhibits abnormal or unregulated growth in vivo (e.g., a malignant or benign tumor cell). In one embodiment 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).
Apoptosis assay in cell lines.
[0276] As shown in Example 3 of patent publication US 20040167196, 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. In some methods of the invention, a lonidamine analog has similar apoptosis-inducing activity.
[0277] Also see Example 8, infra, for an apoptosis assay for characterizing analogs.
Apoptosis assay in primary cell cultures. [0278] As shown in Example 3 of patent publication US 20040167196, 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. In some methods of the invention, a lonidamine analog has similar apoptosis-inducing activity is selected. In some embodiments of the invention, 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. In some embodiments of the invention, 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).
HIF-I -alpha expression assays.
[0279] 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. Thus, in some embodiments of the invention, 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.
Hexokinase activity.
[0280] 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.
[0281] Likewise, it is believed that the 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.
[0282] In one embodiment, 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.
[0283] In one embodiment, 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.
In vivo measurements of prostate function.
[0284] 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. See, for example, Narayan and Kurhanewicz, 1992, Prostate Suppl. 4:43- 50; Kurhanewicz et al., 1991, Magnetic Resonance in Medicine 22:404-13 and Thomas et al., 1990, J. Magnetic Resonance 87:610-19, for MRS assays that can be applied for this purpose.
In vivo measurements of prostate size.
[0285] 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.
[0286] Examples 10 and 11, infra, describe assays in mice of the effect of an analog on the prostate.
EXAMPLES
EXAMPLE l
[0287] To a solution of l-(2,4-dichlorobenzyl)-indazole carbonylchloride (see US Pat. No. 3,895,026) in EtOAc was added a solution of aqueous NH2OH. The organic solution was washed with water, volatiles removed in vacuo, and the residue crystallized from acetic acid to yield compound 1.
[0288] Compound 2 was made according to the method described above for compound 1 by reacting 1-benzylindazole carbonylchloride with aqueous NH2OH. Compound 2 was purified from the crude reaction mixture by crystallization from acetic acid.
EXAMPLE 2
[0289] To a solution of l-(2,4-dichlorobenzyl)-indazole carbonylchloride (see US Pat. No. 3,895,026) in EtOAc was added excess aminoethanol (about 10 eq) and stirred for 5 min at rt. The organic portion was washed with water, dilute aqueous HCl, and concentrated in a rotary evaporator to yield a residue which was separated by column chromatography on silica gel using 10-100% EtOAc/hexane as a solvent to yield compound 10.
[0290] Compounds 16 and 17 were synthesized in the same way as provided for compound 10 using l-(2,4-dichlorobenzyl)-indazole carbonylchloride and 1-benzylindazole carbonylchloride, respectively, and substituting hydrazine hydrate for aqueous NH2OH.
EXAMPLE 3
[0291] To a solution of 2-aminopyridine (20 mmol) in pyridine (20 mL) was added l-(2,4- dichlorobenzyl)-indazole carbonylchloride (20 mmol, see US Pat. No. 3,895,026) and stirred for 3 h at rt and concentrated in a rotary evaporator to yield a residue which was separated by column chromatography on silica gel using 10-100% EtOAc/hexane as a solvent to yield compounds 6 and 7.
[0292] Compounds 8 and 9 were synthesized employing the procedure as provided for compound 7 and substituting 2-aminopyridine with 3,4-difluoroaniline and 2-amino thiazole, repectively.
EXAMPLE 4
[0293] To a solution OfMeSO2NH2 (20 mmol) in pyridine (20 nxL) was added l-(2,4- dichlorobenzyl)-indazole carbonylchloride (20 mmol, see US Pat. No. 3,895,026) and stirred for 16 h at rt and concentrated in a rotary evaporator to yield a residue which was separated by column chromatography on silica gel using 10-90% EtOAc/hexane as a solvent to yield compound 4.
EXAMPLE 5
[0294] To a solution of glucuronic acid (5 g) in DMF (20 mL) was added diazabicyloundecane (DBU, 1.1 equivalent) and stirred at rt for 15 min followed by the addition of allyl bromide (1.2 equivalent). The reaction mixture was stirred for 16 h, and concentrated in a rotary evaporator to yield a residue which was separated by column chromatography on silica gel employing 50-100% acetone in toluene to yield allyl glucuronidate:
Figure imgf000151_0001
which was employed in the next reaction as follows.
[0295] To a solution of allyl glucuronate (2 g) and l-(2,4-dichlorobenzyl)- indazolecarboxylic acid (2 equivalent) in THF (120 mL) was added triphenylphosphine (2 equivalent), diisopropyl azodicarboxylate (2 equivalent) and stirred for Ih at rt and volatiles removed in a rotary evaporator. The residue was separated by column chromatography using silica gel and employing 20-70% acetone/toluene as eluent to yield:
Figure imgf000152_0001
1.8 g of which was deprotected using Pd(PPh3)4 (0.1 equivalent) and pyrrolidine (0.56 equivalent) in THF (20 niL) to yield after column chromatographic separation on silica gel employing 0-30% water/MeCN as solvent to yield compound 15 in a 1:1.25 ratio of the a and β isomers.
Figure imgf000152_0002
15
[0296] The compounds 18-22 were synthesized as described in the reference Corsi et al., (supra, see scheme above), hi general, to a solution of indazole-3-carboxylic acid (10 mmol) and sodium hydroxide (20 niL 10% NaOH aq.) was added a benzylic chloride (R2-CH2-C1, 2 equivalent) wherein R2 is
Figure imgf000152_0003
and stirred for 12 Ii at 7O0C. The reaction mixture was then cooled to room-temperature and a white solid obtained was filtered, acidified with HCl (IN), and recrystalized from AcOH to yield pure 18-22 as white solids.
EXAMPLE 6 Antiproliferation assay
[0297] To determine the effect of lonidamine and analogs thereof on cell proliferation, the antiproliferative activity of these compounds was tested in a multi-well Alamar Blue based assay (at 2 h and 3 days). Cell growth in the presence and absence of the test compound (compounds 1-13) was compared, as measured by a fluorescence plate reader at excitation 550 nm and emission 590 run (see Biosource International Inc., Tech Application Notes, Use ofAlamar Blue in the measurement of Cell Viability and Toxicity, Determining IC5o). H460 cells (ATCC HTB-177 (NCI-H40), 4,000 cells/well/200 μϊ) and LNCap cells (ATCC CRL- 1740,6,000 cells/well/200 μl) 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. In the Control group, AlamarBlue was added to the plate at (i) day 0 and (ii) day 3 and measured to establish the control reading. In all the groups, 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 (GI50 (also referred to IC5O herein)) of lonidamine and lonidamine analogs was calculated. The results of the assay are tabulated in Table 3.
Table 3 GI50 (μM) of lonidamine and lonidamine analogs in proliferation assay
Figure imgf000153_0001
Figure imgf000154_0004
wherein compounds 1-15 have the following structure
Figure imgf000154_0001
Figure imgf000154_0002
15 16 17
Figure imgf000154_0003
EXAMPLE 7 Antiproliferation assay
[0298] The effect of lonidamine and analogs thereof on cell proliferation in PWR-IE cells (ATCC CRL-11611) was determined in an antiproliferative assay using PWR-IE cells (5000 cells/well) in Keratinocyte SFM medium (Gibco Products, Invitrogen Corporation, Carlsbad, CA) according to the procedure detailed in Example 2 above. The results of the assay are tabulated in Table 4.
Table 4 [0299] IC50 (μM) of lonidamine and lonidamine analogs in proliferation assay
Figure imgf000155_0002
EXAMPLE 8 BrdU-TUNEL assay
[0300] The effect of compound 1 (as described in Example 1 above) on apoptosis was determined as follows. PWR-IE cells (2 x 105 cells/ml/well) were seeded in a 24 well plate. After 24 h compound 1 was added at various concentrations as tabulated in Table 5. The culture media were removed after 24 h, the cells were rinsed with PBS buffer (200 μL) and incubated (5 min, 370C) with a solution of Guava Viacount CDR in PBS (1 :3 v/v). Media (750 μL) containing at least 5% FBS was added to each well, the cells released by repeated pipeting, centrifuged, and the supernatant aspirated. The cells were resuspended in PBS buffer (150 μL) and fixed by incubating (60 min, 40C) with 4% paraformaldehyde in PBS. The cells were centrifuged, and the supernatant removed to a final volume of 15 μL. The cell pellets were resuspended, followed by dropwise addition of 200 μl of ice-cold ethanol (70%), and the cells incubated at -2O0C at least for 2 hr. The cells were centrifuged, the supernatant removed, washed, and incubated with the DNA labeling mix (370C, 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).
[0301] The effect of compound 1 on apoptosis of LNCaP cells was determined using the same protocol as described in Example 4.
Table 5
Figure imgf000156_0001
As tabulated in Table 4, Compound 1 induces apoptosis in PWRlE cells.
EXAMPLE 9 Cell cycle analysis
[0302] The effect of compound 1 (as described in Example 1 above) on the cell cycle was determined as follows. LNCaP cells (2 x 105 cells/ml/well) were seeded in a 24 well plate. After 24 h, compound 1 was added at various concentrations as tabulated in Table 6. The culture media were removed after 24 h, the cells were trypsinized and centrifuged. The cell pellets were resuspended in lOOμl PBS buffer, after which 300 μl of ice-cold ethanol (96%) added dropwise, and the cells were incubated at 40C for at least 24 hr. The cells were centrifuged and the supernatant was discarded. The cell cycle staining reagent (Guava Technologies, Hayward, CA, USA, 200 μl) 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
Figure imgf000157_0001
a — G0/G1 (Gap 1), phase when cells prepare for cell division cycle b = S phase, DNA synthesis or replication phase c = G2 (Gap 2), phase when cells prepare for mitosis d = M phase, mitosis i.e. cell division phase.
Compound 1 does not have a measurable effect on the cell cycle.
EXAMPLE 10
Mouse studies
[0303] The effect of Compound 1 on the mouse prostate was determined as follows. Compound 1 was orally administered daily for 5 days to male, C57B1/6J mice, (n=5, 6-8 weeks old) 1 at 2, 5, and 20 mg/kg (as a 1% carboxymethylcellulose formulation). The control mice received an equal amount of the vehicle (carboxymethylcellulose). On day 6 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.
EXAMPLE Il
Mouse studies
[0304] The effect of Compound 1 on the mouse prostate was determined as follows. Compound 1 was orally administered daily for 10 days to male, C57B1/6J mice, (n= 8, 6-8 weeks old) at 0.2 0.5, 2, 5, and 20 mg/kg as a 1% carboxymethylcellulose formulation for 10 days. The control mice received an equal amount of the vehicle (carboxymethylcellulose). On day 11 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.
EXAMPLE 12 Mouse studies
[0305] The 10 day effect of Compound 3 on the mouse prostate and its 5 day effect on mouse testis were determined as in Example 11 by using 10 mice per experiment group and the results are illustrated graphically in Figures 14-18.
EXAMPLE 13 Mouse studies
[0306] 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. The results of the study indicated a tolerated dose of Compound 1 in mice of 500 mg/kg/day upon oral dosing for 5 days and a 10 fold higher therapeutic index in mice compared to lonidamine when used for prostate weight reduction.
EXAMPLE 14 In vivo viability and proliferation of mouse prostate cells
Prostate cells harvested from mice treated with 20mg/kg of Compound lwere 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.
[0307] Although the present invention has been described in detail with reference to specific embodiments, those of skill in the art will recognize that modifications and improvements are within the scope and spirit of the invention, as set forth in the claims which follow. All publications and patent documents (patents, published patent applications, and unpublished patent applications) cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description and example, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples are for purposes of illustration and not limitation of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I) :
Figure imgf000160_0001
(I) wherein A-B is a 7,5, 6,5 or a 5,5 cyclic ring system , optionally substituted with from one to five V6 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Ci-C8)alkyl, (Ci-C6) alkoxy, nitro, acetamido, L^CO2H, L'-dialkylamino, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl; U^R3, iΛCOR3, U^CUNR3R7, U^CU2R3, R4, NR3OR3, NR3-CUR3, N- (CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CUR3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO2R3,SOR3, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2, cyano, nitrileoxide, and-NO, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a
(\ 1X heteroaryl ring; with the proviso that V is other than -COOR ;
R1 is selected from the group consisting of CO2R3, COR4, COCOR3, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO- V5, -NHNH- V5, COCOR4, CON(R3)N=CR3R7, L1- V5, -L1CO2R3, - CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, O-Ll(CO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -(C3-C8)cycloalkyl; or may be taken together with a V6 attached to adjacent or within two atoms to form a (C3-C8)cycloalkyl, a (Cr C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; L1 is selected from the group consisting of (Ci-Cs)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (d-C4)alkyl, (Q- C8)heteroalkyl, (C2-C6)alkenyl, (Cz-C3)alkynyl, (C3-C8)cycloalkyl, (Q-C8)heteiOcyclyl, aryl, heteroaryl, halogen, hydroxy, (Cj-C6) alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a (C3-Cg)cycloalkyl, a (Ci- C8)heterocycloalkyl., a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (C1-C4) alkylamino or (C1-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
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, R3, U'-R3, U!-COR3, U^CUNR3R7, U]-CU2R3, R4, NR3OR3, NR3 -CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N- (SO2R3)2, NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3) (NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)i, PU(NR3CUNR3R7)2, NR3(NR3)2, nitrileoxide, and-NO; each R3 is a member independently selected from the group consisting of H, (C] C8)alkyl, (d-C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-
C8)heterocyclyl, aryl and heteroaryl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 OrNR3CN;
R5 is H, OH or halogen;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, (C2-C6)alkenyl, (C2-
C8)alkynyl, (CrCs^eteroalkyL (C3-C8)cycloalkyl, (Ci-C3)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (Ci-C8)heterocyclyl or heteroaryl ring;
R8 is H, halo, nitro, cyano, nitrileoxide, -NO, R3, U^R3, U1 -COR3, U1 -CUNR3R7, U1- CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2, NR3-CUNR3R7, N-(CUNR3R7)2, NR3-CU2R3, N-(CU2R3)2, NR3-SO2R3, N-(SO2R3)^ NR3-SOR3, N-(SOR3)2, NR3-PU2R3, N-(PU2R3)2, NR3-P(=U)(UR3)R3, CU2R3, CUNR3R7, CUNR3CUR3, CUN(CUR3)2, CUNR3CU2R3, CUN(CU2R3)2, CUNR3CUNR3R7, CUN(CUNR3R7)2, SO3R31, SO2NR3R7, SO2NR3CUR3, SO2N(CUR3)2, SO2NR3CU2R3, SO2N(CU2R3)2, SO2NR3CUNR3R7, SO2N(CUNR3R7)2, PU(UR3)2, PU(UR3)(NR3R7), PU(NR3R7)2, PU(NR3COR3)2, PU(NR3CU2R3)2, PU(NR3CUNR3R7)2, NR3(NR3)2;
R31 is aryl or heteroaryl; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3, CONHSO2R3, and C(=NCN)NH2;
Y is CR8 2, CR8, NR8, S or O;
U is O, S, NR3, NCOR3, or NCONR3R7;
U1 is O or S; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; provided that the compound does not have a formula selected from the group consisting of:
Figure imgf000162_0001
wherein in formula (a):
(i) Rla is selected from the group consisting Of CONHNH2, CONHN(CH3)2, and - CH=CHCO2H;
R2a is a group having the formula:
Figure imgf000163_0001
(al) (a2) wherein each R6 independently is a halogen, and nlO is 1 or 2; and
R3a is hydrogen; (ii) Rla is CO2H;
R2a is selected from the group consisting of 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-trifluoromethylphenyl, A- cyanophenyl, 4-phenylsulfonyl-phenyl, 3,4-dichloroρhenyl, 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-chioronaphthylmethyl, 2,4-dimethylρhenyl and 2-methyl-4-chlorophenyl; and
R3a is hydrogen; iii) Rla is CO2H
R2a is 4-chlorophenyl; and R3a is chloro, OH, methyl, or OMe; iv) Rla is selected from the group consisting of CO2Me, CO2Et, -CO-glyceryl, COCH3, CONH2, CH2CO2H, CH2CH2CO2H and
N .
X N // N-N
(a3)
R2a is 4-chlorophenyl, and R3a isH;
(v) Rla is CO2H, R2a is 2, 4-dichlorophenyl,
R3ais selected from the group consisting of-(OCH3)nio wherein nio is 1 or 2, chloro, bromo, fluoro, CO2H, and CH2CO2H. [Cheng];
(vi) Rla is -0-PO3H, -0-SO3H, -0-CH2CO2H, 0-CH(CO2H)2, NHCH(CO2H)2, CH2CH(NH2)CO2H, CONHCH(CO2H)2, and CONH(CH2)nn-cyclopropyl wherein nil is O or 1,
R2a is 2, 4-dichlorophenyl, R3ais H; and
(vii) Rla is selected from the group consisting of -COCH3, -SH, -tetrahydrofurfuryl, - CH2CO2H, -CH2CH2CO2H, -H, -CH3, -CH2OH, -NH2, -CN, -tetrazin-2-yl, , O-(CH2)i. 2CO2H, 0-CH2CO2C1 -C4alkyl, -0-PO3H, -0-SO3H, 0-CH(CO2H)2, NHCH(CO2H)2 and CH2CHNH2CO2H;
R2a is selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl, trifiuorornethylphenyl, 3- benzoyl, 4-halophenyl, 4-methylsulfonylphenyl, 4-methylphenyl, 4-cyanophenyl, 4- 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, 2,6-dimethyl-3-dimethylsulfamoylphenyl, A- imidazoyl;
R3a is selected from the group consisting of H, 2-dimethylaminoethyl, 5 -amino, chloro, bromo, 5-hydroxy, 5-methyl, methoxy, dimethoxy, fluoro, CO2H, CH2CO2H, 5-nitro, 5-acetamido and 7-chloro;
(viii) compounds having the formulae:
Figure imgf000164_0001
(a4) (a5)
(ix) compounds having the formula:
Figure imgf000164_0002
wherein Rla is COOH, CONH2, COO CH2CH2OH, COOCH2CHOHCH2OH, or COOCH(CH2OH)2;
R22a is H or halo,
R20a is halo, Me, methoxy, trifluoromethyl, C0NH2, or methanesulfonyl, and
R21a is H5 Me, halo, or a group forming with the benzene ring to which it is attached a naphthyl ring, in formula (b):
Rlb is CO2H;
R2b is phenyl;
R3b is H; in formula (c):
(i) Rlc is CH2CONH2;
R2c is phenyl, 2-phenyl-phenyl, 2-benzyl-phenyl, 3-chlorophenyl, 3-trifiuorophenyl, 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, 2 -phenyl ethyl,
R3c is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH2CH2CH2)1-4CO2H, -OCH2-tetraazo-2-yl and -SCH3;
(ii) compounds having the formula:
Figure imgf000165_0001
(cl) when Rlc is COCONH2; R5c and R2c are defined below; and
R3c is benzyl, then compounds i-xxv, xxvii, xxix, xxxvii, and xxxix are excluded;
R3c is Me, then compound xxvi is excluded;
R3c is H, then compounds i-xxix, xxxviii, and xxxix are excluded;
R3c is -CH2-CO2Me5 then compounds i, ii, iv, vi, viii-xxiii, xxiv, xxx-xxxviii, and xxxix are excluded;
R3c is -CH2-CO2Et, then compounds iii, v, and vii are excluded; and R >3c is -CH2-CO2H, then compounds i-xxix, xxx-xxxvii, and xxxix are excluded;
Figure imgf000166_0001
(iii) compounds having the following structure
R
Figure imgf000167_0001
(c2)
(a) wherein R23c is CH2CN or tetrazolyl, R5c is ethyl
R20c is 3-chloro; and
(b) R23c is CH2-tetrazolyl, CH2-2-pyridyl, CH2-4-pyridyl, CH2-2-quinolinyl, -(CH2)3- CO2Et5 -(CH2)3-CO2H, -(CH2)2-CO2H,
R5c is ethyl;
R20c is 2-phenyl; and
(c) R23c is OCH2CO2H3 R5c is ethyl and R20c is H;
(d) R230 is Me or H, and
R5c is ethyl when R20c is hydrogen,
R5c is cylopropyl when R2Oc is 2-phenyl, and
R5c is ethyl when R20c is 2-phenyl;
(e) wherein R23c is -(CH2)3-CO2Et or -(CH2)3-CO2H, and
R5c is ethyl when R20c is hydrogen,
R5c is cylopropyl when R20c is 2-phenyl, and
R5c is ethyl when R20c is 2-phenyl;
(f) wherein R23c is -(CH2)2-CO2Et, -(CH2)2-CO2H, -CH2-CO2Et or -CH2-CO2H, R5c is ethyl and R20c is 2-phenyl; (iii) compounds having the following structure
Figure imgf000168_0001
(c3) wherein R24c is H or Me and R25c is Me. in formula (d):
Rld is CH2CONH2;
R2d 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;
R3d is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH2CH2CH2)1-4CO2H, -OCH2-tetraazo-2-yl and -SCH3; in formula (e):
(i) Rle is CH2CONH2,
R2e 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;
R3e is selected from the group consisting of H, methyl, ethyl, t-butyl, cyclopropyl, - O(CH2CH2CH2)1-4CO2H, -OCH2-tetraazo-2-yl and -SCH3; in formula (f):
Rlf is CO2H;
R2f is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2, 5-dichlorophenyl, 2, 6-dichlorophenyl, 3, A- dichlorophenyl and 3,5-dichlorophenyl;
R3f is H; in formula (g):
Rlg is CO2Et;
R2g is phenyl;
R3g is H; in formula (h):
Rlh is CO2Et or C(=NH)OEt;
R2h is phenyl;
R3h is H, 5-methyl or 7-methyl; in formula (i):
R11 is CONHCH2CH2Cl or CONHCH2CH2-piperazin-4-yl;
R2' is benzyl; and R3i is H.
2. A compound of claim 1, wherein A-B is a 7, 5 -fused cyclic ring system.
3. The compound of claim 1 or 2, wherein formula A-B has the formula IIA:
Figure imgf000169_0001
(IIA) wherein each W1, W3, W4 or W5 is independently N or C; W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 W9 or W12 is independently N, NV6, CO, CS, SO, SO2 or CV6 ; represents a single or double bond;
R1, Y, R2 and V6 are as defined above in formula (I); and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. 4. A compound of any one of claims 1-3 having formula (IID) or (IIE):
Figure imgf000170_0001
(IED) (IIE)
5. A compound of claim 1, wherein A-B is a 5, 5-fused cyclic ring system.
A compound of claim 5, wherein formula A-B has the formula IVA:
Figure imgf000170_0002
(IVA)
7. A compound of claim 1, wherein A-B is a 6, 5-fused cyclic ring system.
8. The compound of claim 1 of formula IIIB,
Figure imgf000170_0003
•R2
(EDB) wherein
R1 is selected from the group consisting of COOR3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar, C(^NCN)NH2, COCOR4 CON(R3)N=CR3R7, -L1CO2R3, -CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1-(C3- C8)cycloalkyl; and L1 -V5 wherein L1 is selected from the group consisting of -C ≡€-, -
Figure imgf000171_0001
-NHCO- and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or (Ci-C8)heteroalkyl, halogen, hydroxy, (Ci-C4) (Ci-C6) alkoxy, cyano, nitro, amino, (Ci-C4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3 -Cs)cyclo alkyl, a (Ci-Cg)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci -C4) alkylamino or (C1-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (Ci-C4) alkylamino, and (C1-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar and Q=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar or C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(=NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and (Q- C8)alkyl;
R3 is H, (Ci-C8)alkyl, (CrC8)heteroalkyl, (C3-C8)cycloantyl, (Q-CsOheterocyclyl, aryl or heteroaryl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (Ci-C8)alkyl, (CrC8)heteroalkyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl or heteroaryl;
R3 and R7 together are (CrC8)heteroalkyl or heteroaryl;
Ar is aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7, W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, (C1-C4) alkyl, (Ci-Cs^eteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, oxo, U1 -R3, U^-COR3, (C1-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O; R8 is H, (Ci-Cg)alkyl or (Ci-Cg)heteroalkyl; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
9. The compound of any one of Claims 1, 7, or 8 of formula (HID):
Figure imgf000172_0001
(HID) wherein
R1 is selected from the group consisting of COOR3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar, C(=NCN)NH2, COCOR4 and L1 -V5 wherein L1 is selected from the group consisting of -
(CVV)q
C sC-, -CCV^CCV3)-, -C(VV)C(V3V4)-, -CV-CV3-, -NHCO- and -NHNH- wherein each V1, V2, V3, and V4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or (Ci-C8)heteroalkyl, halogen, hydroxy, (Ci-C4) (C1-C6) alkoxy, cyano, nitro, amino, (C1-C4) alkylamino and (Ci-C4) dialkylamino or V1 and V3 together form a (C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 and V2 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; and if one of V3 and V4 is hydroxyl, amino, (C1-C4) alkylamino, and (Ci-C4) dialkylamino, then the other is hydrogen or alkyl; q is 1-6; V5 is selected from COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2Ar and C(=NCN)NH2; with the proviso that in NHSO2CR5 3, R5 is not OH; when L1 is -NHCO- then V5 is COR4 , NHSO2CR5 3,NHSO2CR3 3, NHSO2Ar or C(=NCN)NH2; and when L1 is -NHNH- then V5 is COOR3, COR4, COCOR4, B(OR3)2, SO2R4, or C(=NCN)NH2;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents that are independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl; R3 is H, (C1-C8)alkyl or (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl or (Ci-C8)heterocyclyl, or aryl or heteroaryl; each R4 is a member independently selected from the group consisting of NR3R7,NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen;
R7 is H, (Ci-Cs)alkyl or (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl or (CrC8)heterocyclyl, or aryl or heteroaryl;
R3 and R7 together are (Ci-Cg)heteroalkyl or heteroaryl;
Ar is a substituted or unsubstituted aryl or heteroaryl; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, CR5, CO, O, NR7 and S; each W6, W7 , W8 or W9 is independently N or CV6 wherein V6 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or (Ci- C8)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (CrC4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8, S or O;
R8 is H, a straight or branched chain (Ci-C8)alkyl or (Ci-C8) heteroalkyl group; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
10. The compound of any one of Claim 1, 7, 8, or 9 wherein the A-B ring system has the following formula:
selected from the group consisting o
Figure imgf000173_0001
Figure imgf000174_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y and V6 is defined as above.
11. The compounds of any one of Claims 1 , 7, and 8 wherein the A-B ring system has the structure
Figure imgf000174_0002
(HIA) wherein W 7-1 - ΛWΪ 7-5 is defined as follows in Table IA: Table IA
Figure imgf000175_0001
and for each ring B 1-21 as defined above, W6- W9 is defined as follows in Table IB:
Table IB
Figure imgf000175_0002
12. The compounds of any one of Claims 1, 7, and 8 wherein the A-B ring system has the structure
Figure imgf000176_0001
(πiA) wherein W'-W5 is defined as follows in Table IA:
Table IA
Figure imgf000176_0002
and for each ring B 1-21 as defined above, W6- W9 is defined as follows in Table 1C: Table 1C
Figure imgf000177_0001
Figure imgf000178_0001
wherein → indicates a single bond to W4 and indicates a single bond to W 5 a „„nd,} Λ VΓ6 and U are as defined above.
13. The compound of any one of preceding claims wherein R1 is selected from the group consisting of:
CONHNH2, CONH2, CONHNMe2, CONMe2
Figure imgf000179_0001
Figure imgf000179_0003
Figure imgf000179_0004
Figure imgf000179_0002
Figure imgf000179_0005
Figure imgf000179_0006
XONHNH5
Figure imgf000179_0007
14. The compound of any one of Claims 1-12 wherein, R1 is a COOR3 or L1 -CO2R3, wherein L1 is defined as above in formula (I) and R3 is H or (CH2)qNR9R10 and each R9 and R10 is a straight or branched chain (Ci-Csjalkyl, 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.
15. The compound of any one of claims 1 — 12 and 14 wherein L1 is -
CV!=CV3-
16. The compound of any one of claims 1-12, 14, and 15 wherein R is - CV^CV^COOR3.
17. The compound of claim 16 wherein V1 and V3 together form a (Ci-Cg) heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl, or a heteroaryl ring.
18. The compound of any one of Claims 1-12, 14 and 15 wherein R1 is COOR3 , wherein R3 is H or (CH2)nNR9R10 wherein each R9 and R10 is a straight or branched chain (C1-Cs)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.
19. The compound of any preceding claim wherein R2 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 (C1-C8)alkyl.
20. The compound of any of the preceding claims wherein R is selected from the group consisting of
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000181_0002
wherein each W10 or Wn is independently selected from the group consisting of N, C, and CH; R9 is halo or a straight or branched chain (Cj-C8)alkyl; and the wavy line indicates the point of attachment to the rest of the molecule.
21. The compound of any of the preceding claims wherein R6 is F, Cl, Br, CN, CF3, CH3, CHMe2, -C≡€H or -C≡€-CH3.
22. The compound any of the preceding claims wherein each R3, R7, and R8 are independently selected from the group consisting of: H, -CH3, -CH2CH3,
Figure imgf000182_0001
Figure imgf000182_0002
23. The compound of any of the preceding claims wherein Y is NR , O, S,
CR* or CHR".
24. The compound of any of the preceding claims wherein Y is NH, O or
S.
25. The compound of any of the preceding claims wherein Y is CHR or
CRS.
26. The compound of claim 25 wherein Y is CH2.
27. The compound of any one of claims 1, 7-9 and 13-15 selected from the group consisting of:
Figure imgf000183_0001
Figure imgf000183_0002
28. The compound of claim 27 selected from the group consisting of:
Figure imgf000183_0003
Figure imgf000184_0001
29. The compound any one of claims 1, 7-9 and 13-15 selected from the group consisting of:
Figure imgf000184_0002
30. The compound of any one of claims 1, 7-9 and 13-26 of formula:
Figure imgf000185_0001
31. The compound of claim 30 wherein R1 is selected from the group consisting Of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 S, CONHSO2CR3 S, C(=NCN)NH2, -NHCO-V5, -NHNH- V5, V- V5 and - L1CO2R3, -CN, -tetrazin-2-yl, -0-L1CO2R3, -0-PO3H, -0-SO3H, 0-L1CCO2H)2, - NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -(C3-C8)cycloalkyl;
L1 is selected from the group consisting of (C1-C8)alkylene, (C2-Cs)alkenyl, (C2- Cs)alkynyl, and (C3-Cg)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V1 is independently selected from the group consisting of (C]-C4)alkyl, (Ci- C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (CrC4)alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (C1-C4) dialkylamino, or any two V1 attached to the same or adjacent atoms maybe taken together with the atoms with which they are attached to form a (C3-Cg)cycloalkyl, a (Cr Cs)heterocycloalkyl, a (C3-Cs)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, CC1-C4) alkylamino or (C1-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R9 substituents independently selected from the group consisting of halo and a straight or branched chain (C1-C8)alkyl; each R3 is a member independently selected from the group consisting of H, (C1- C8)alkyl,
Figure imgf000185_0002
CC3-C8)cycloalkyl,
Figure imgf000185_0003
aryl and heteroaryl; each R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 and NR3CN;
R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3, COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2R3 3, CONHSO2CR3 3 and CC=NCN)NH2; R7 is selected from the group consisting of H, (Ci-Cg)alkyl, (Ci-Cg)heteroalkyl, (C3- C8)cycloalkyl, (Ci-Cg)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (Ci-Cs)heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8, S or O; and
R8 is H, (C1-C8)alkyl or (C]-C8)heteroalkyl.
32. The compound of any one of claims 1, 7-9 and 13-26 having the formula:
Figure imgf000186_0001
wherein
R1 is selected from the group consisting of: CO2R3, COR4 , CH=CHCO2R3 and
CONHSO2CR3 3; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, aryl, (Ci-C8)heteroalkyl and (C1-C8)heterocyclyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7 and NR7NR3R7; each R6 is a member independently selected from the group consisting of H, halo, (Ci
C8)alkyl, and (Ci-C8)heteroalkyl;
R7 is selected from the group consisting of H, (C1 C8)alkyl, (Ci-C8)heteroalkyl, aryl and (Q-
C8)heterocyclyl; each V6 is independently a member selected from the group consisting of hydrogen, halo, oxo; cyano, (CrC8)alkyl, (d-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)cycloalkyl, (C,-C8)heterocyclyl, aryl, heteroaryl; 0-R3, S-R3 , R4, NR3-COR3, NR3-
CONR3R7, NR3-CSNR3R7, NR3-C(=NR3)NR3R7, NR3-CO2R3, NR3-SO2R3, COR3, CO2R3,
CSNR3R7, C(=NR3)NR3R7, CONR3COR3, CONR3C(=NR3)R3, SO2R3,SOR3, SO3R31,
SO2NR3R7, PO(OR3)2, PS(OR3)2, and PO(NR3R7)2, or any two V6 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a
(C3-C8)cycloalkyl, a (Ci-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; the subscript pi 0 is an integer of from 0 to 4; Y is CH2, NH, S or O; and W1 and W2 is each C or N.
33. The compound of claim 32 wherein V6 is H.
34. The compound of claim 33 wherein W1 and W2 are CR5.
35. The compound of claim 33 wherein W1 is CR5 and W2 is N.
36. The compound of claim 33 wherein W1 is N and W2 is CR5.
37. The compound of claim 33 wherein Y is O.
38. The compound of claim 33 wherein Y is S.
39. The compound of claim 33 wherein Y is NH.
40. The compound of claim 33 wherein Y is CH2.
41. The compound of any one of claims 1, 7-9 and 13-26 of formula:
Figure imgf000187_0001
wherein R1 is selected from the group consisting of: CO2R3, COR4, CONHSO2CR3 3; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, aryl, (Q-C^heteroalkyl, (CrC8)heterocyclyl; each R4 is a member independently selected from the group consisting OfNR3R7, NR3OR7,
NR7NR3R7;
R6 is independently selected from the group consisting of H, halo, (C]-C8)heteroalkyl
R7 is H, (C1 C8)alkyl, (CrC8)heteroalkyl, aryl, (Ci-C8)heterocyclyl; and
Y is CH2.
42. The compound of any one of claims 1, 7-9 and 13-26 of formula:
Figure imgf000188_0001
43. The compound of claim 42 wherein wherein each R6 independently is R6 is hydrogen, F, Cl, Br, CN5 CF3, CH3, CHMe2, -C ≡GH and -C -C-CH3; R1 is CONHAr, CONH(Py) wherein Py is 2-, 3-, or 4-pyridyl, CONHSO2R3, and CONHN=CR3R7; and
R1 is CH=CHCO2H, CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH-CHCONHOH, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2; -C sC-CO2H, -C ≡€-CONHOH, -C sC- CONHNH2, -C ≡€-CONHNMe, -C ≡€-C0NHNMe2, -C ≡€-C0NMeNH2, -C -C- CONMeNHNe and -C ≡€-C0NMeNMe2; with the proviso that when R1 is CH=CHCO2H, CONHNH2, or CONHNMe2, then at least one of R6 is CN, CF3, CH3, CHMe2, -C sCH, and - C ≡C-CH3.
44. The compound of claim 43 of formula:
Figure imgf000188_0002
wherein R6 is hydrogen, F, Br, CN, CF3, CH3, CHMe2, -C ≡€H, and -C ≡C-CH3 45. The compound having the formula:
Figure imgf000189_0001
wherein R is
Figure imgf000189_0002
46. The compound having the formula:
Figure imgf000190_0001
Figure imgf000190_0002
Figure imgf000190_0003
Figure imgf000190_0004
Figure imgf000191_0001
wherein R1 is CO2H, CH=CHCO2H5 CONHOH, CONHNH2, CON(Me)NH2, CON(Me)NHMe, CON(Me)NMe2, CONHNHMe, CONHNMe2, CH=CHC0NH0H, CH=CHCONHNH2, CH=CHCON(Me)NH2, CH=CHCON(Me)NHMe, CH=CHCON(Me)NMe2, CH=CHCONHNHMe, CH=CHCONHNMe2, -C ≡€-C02H, -C -C- CONHOH, -C =C-CONHNH2, -C ≡€-CONHNMe, -C ^-CONHNMe2, -C =C-CONMeNH2, - C ≡€-CONMeNHNe and -C ≡€-C0NMeNMe2; and V6 is hydrogen, amino, or alkylamino. 47. The compound of any one of claims 1 , 7-9 and 13-26 having the formula
Figure imgf000192_0001
48. A compound selected from the group consisting of:
Figure imgf000193_0001
wherein R3 is phenyl, pyridyl or SO2R7; and V6 is H or NHR3.
49. A compound selected from the group consisting of:
Figure imgf000194_0001
Figure imgf000194_0002
Figure imgf000194_0003
Figure imgf000194_0004
wherein R3 is phenyl, pyridyl or SO2R7; and V6 is H or NHR3.
50. A compound selected from the group consisting of:
Figure imgf000195_0001
Figure imgf000195_0002
Figure imgf000196_0001
Figure imgf000196_0002
Figure imgf000197_0001
wherein R6 is selected from the group consisting of H, F, Br, CN, CF3, CH3, CHMe2 and C ≡€-CH3.
51. A compound having the formula l-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-acrylic acid;
Figure imgf000197_0002
3-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-acrylic acid:
Figure imgf000197_0003
3-(2,4-Dichloro-benzyl)-benzo[c]thiophene-l-acrylic acid:
Figure imgf000197_0004
3-(2,4-Dichloro-benzyl)-isobenzofuran-l-acrylic acid:
Figure imgf000198_0001
3-(2,4-Dichloro-benzyl)-2H-isoindole-l -carboxylic acid:
Figure imgf000198_0002
l-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-3-carboxylic acid:
Figure imgf000198_0003
3-(2,4-Dichloro-benzyl)-imidazo[l,5-a]pyridine-l-carboxylic acid:
Figure imgf000198_0004
3-(2,4-Dichloro-benzyl)-benzo[c]thiophene- 1 -carboxylic acid:
Figure imgf000198_0005
3-(2,4-Dichloro-benzyl)-isobenzofuran-l-carboxylic acid:
Figure imgf000199_0001
-(2,4-Dichloro-benzyl)-2H-isoindole-l-carboxylic acid:
Figure imgf000199_0002
-(2,4-Dichloro-benzyl)-benzo[c]thiopliene-l -carboxylic acid:
Figure imgf000199_0003
Figure imgf000200_0001
Figure imgf000200_0002
Figure imgf000200_0003
52. The compound of any one.of claims 27-30 wherein R1 is selected from the group consisting of COOR3, COR4, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3S, CC=NCN)NH2 and iΛV5; Y is CH2, O, NH, or S; and R6 is halo or a straight or branched chain (C1-C8)alkyl.
53. The use of a compound of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof (a) for treatment or prevention of a condition selected from cancer, benign prostatic hyperplasia, macular degeneration, and prostatic intraepithelial neoplasia, or for use as an antispermatigenic agent, or
(b) for preparation of a medicament for treatment or prevention of a condition selected from cancer, benign prostatic hyperplasia, macular degeneration, and prostatic intraepithelial neoplasia, or for use as an antispermatigenic agent wherein formula (I) has the structure:
Figure imgf000201_0001
(I) wherein
A-B is a 7,5-, 6,5-, 5,5-cyclic ring system, optionally substituted with from one to five R3 substituents independently selected from the group consisting of amino, halo, oxo; (Q- C8)alkyl, (C1-C6) alkoxy, nitro, acetamido, CO2H, X^CO2H, Xi-dialkylamino, heteroalkyl, (C3-Cs)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1 is selected from the group consisting of CO2R4, COR5, CONR4COR4, CH=CHCO2R4, B(OR4)2, SO2R5, NHSO2CR6 3, NHSO2CR4 3, CONHSO2CR4 3, C(=NCN)NH2, -NHCO-R7, -NHNH-R7, X^R7 and -X1CO2R4, -CN, -tetrazin-2-yl, -O- X1CO2R4, -0-PO3H, -0-SO3H, 0-X^CO2H)2, -NHX^CO2H)2, COHNX^CO2H)2 and CONHX1 -cycloalkyl;
X1 is selected from the group consisting of (CrC8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 wherein each V is independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, (C1-C4)alkoxy, cyano, nitro, amino, -NO, (Ci-C4)alkylamino and (CrC4) dialkylamino, or any two V1 attached to the same or adjacent atoms may be taken together with the atoms with which they are attached to form a cycloalkyl, a heterocycloalkyl, a cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that if one of V1 is hydroxyl, amino, (Ci-C4) alkylamino or (Ci-C4) dialkylamino, then an V1 attached to the same atom is hydrogen or alkyl;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R9 substituents independently selected from the group consisting of halo and a straight or branched chain (Ci-C8)alkyl; each R4 is a member independently selected from the group consisting of H, (C i- Cs)alkyl, heteroalkyl, (C3-Cg)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5 is selected from the group consisting OfNR4R10, NR4OR10, NR10NR4R10 or NR4CN;
R6 is H, OH or halogen; each R7 is a member independently selected from the group consisting of COOR4, COR5, CONR4COR4, COCOR5, B(OR4)2, SO2R5, NHSO2CR6 3, NHSO2CR4 3, CONHSO2CR43, NHSO2R2 and C(=NCN)NH2;
R10 is selected from the group consisting of H, (Ci-Cg)alkyl, heteroalkyl, (C3- Cs)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R4 and R10 are taken together form a heterocyclyl or heteroaryl ring;
Y is CHR11, CR11, NR11, S or O;
R11 is H, (Ci-C8)alkyl or heteroalkyl; represents a single or double bond.
54. The use of a compound of any of Claims 1-43 or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof
(a) for treatment or prevention of a condition selected from cancer, benign prostatic hyperplasia, macular degeneration, and prostatic intraepithelial neoplasia, or for use as an antispermatigenic agent, or
(b) for preparation of a medicament for treatment or prevention of a condition selected from cancer, benign prostatic hyperplasia, macular degeneration, and prostatic intraepithelial neoplasia, or for use as an antispermatigenic agent.
55. The use of a compound of Claim 9 or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof for prevention or treatment of cancer.
56. A method of inhibiting proliferation of a cell comprising contacting the cell with an compound of Claim 9 or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1786424A2 (en) * 2004-08-20 2007-05-23 The University of Kansas Lonidamine analogues and their use in male contraception and cancer treatment
US7501438B2 (en) 2006-07-07 2009-03-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
EP2079703A1 (en) * 2006-11-01 2009-07-22 F. Hoffmann-Roche AG Indazole derivatives useful as l-cpt1 inhibitors
WO2009106982A1 (en) * 2008-02-29 2009-09-03 Pfizer Inc. Indazole derivatives
WO2010017870A1 (en) * 2008-08-14 2010-02-18 Merck Patent Gmbh Bicyclic triazole derivatives for treating tumors
US7691877B2 (en) 2006-02-17 2010-04-06 Pfizer Inc. Pharmaceuticals
WO2010098344A1 (en) 2009-02-25 2010-09-02 第一三共株式会社 Tricyclic pyrazolopyrimidine derivative
EP2336141A2 (en) 2005-06-29 2011-06-22 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2012026433A1 (en) 2010-08-23 2012-03-01 第一三共株式会社 Free crystal of tricyclic pyrazolopyrimidine derivative
WO2012026434A1 (en) 2010-08-23 2012-03-01 第一三共株式会社 Crystal of tricyclic pyrazolopyrimidine derivative
US8158638B2 (en) 2006-09-19 2012-04-17 Daiichi Sankyo Company, Limited Pyrazolopyrimidine derivative
US8431572B2 (en) 2007-06-06 2013-04-30 Merck Patent Gesellschaft Mit Beschrankter Haftung 2-oxo-3-benzylbenzoxazol-2-one derivatives and related compounds as met kinase inhibitors for the treatment of tumours
US8497266B2 (en) 2008-06-18 2013-07-30 Merck Patent Gmbh 3-(3-pyrimidin-2-ylbenzyl)-1,2,4-triazolo[4,3-b]pyridazine derivatives as MET kinase inhibitors
US8557813B2 (en) 2007-12-21 2013-10-15 Merck Patent Gmbh 2-benzylpyridazinone derivatives as met kinase inhibitors
US8580781B2 (en) 2007-07-12 2013-11-12 Merck Patent Gmbh Pyridazinone derivatives
US8586599B2 (en) 2008-12-22 2013-11-19 Merck Patent Gmbh Polymorphic forms of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one dihydrogenphosphate and processes of manufacturing thereof
US8604036B2 (en) 2008-04-21 2013-12-10 Merck Patent Gmbh Pyridazinone derivatives
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
CN106232583A (en) * 2014-02-20 2016-12-14 康奈尔大学 For suppressing the Compounds and methods for of flesh fasciclin
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
WO2017123826A1 (en) * 2016-01-14 2017-07-20 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
WO2017121693A1 (en) 2016-01-15 2017-07-20 Bayer Pharma Aktiengesellschaft Substituted thiazole and thiadiazole amides, and use thereof
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10300051B2 (en) 2014-02-13 2019-05-28 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
EP3564214A1 (en) 2018-05-04 2019-11-06 Universita' Degli Studi G. D Annunzio Chieti - Pescara Indazole derivatives as modulators of the cannabinoid system
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
WO2020069330A3 (en) * 2018-09-28 2020-07-23 Acucela Inc. Inhibitors of vap-1
KR20210014374A (en) * 2019-07-30 2021-02-09 부산대학교 산학협력단 Novel indole derivatives and composition for preventing or treating inflammatory diseases comprising the same
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11866440B2 (en) 2012-08-22 2024-01-09 Cornell University Methods for inhibiting fascin
WO2024109642A1 (en) * 2023-07-28 2024-05-30 常州大学 USE OF BENZOAZACYCLIC COMPOUND AS ALLOSTERIC MODULATOR OF β2-ADRENOCEPTOR
US12037334B2 (en) 2018-09-28 2024-07-16 Acucela Inc. Inhibitors of VAP-1
EP4213839A4 (en) * 2020-09-17 2024-08-07 Escient Pharmaceuticals Inc Modulators of mas-related g-protein receptor x4 and related products and methods

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHENG C.Y. ET AL.: 'Indazole carboxylic acids in male contraception' CONTRACEPTION vol. 65, no. 4, 2002, pages 265 - 268, XP003001053 *

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514463B2 (en) * 2004-08-20 2009-04-07 University Of Kansas Lonidamine analogues and their use in male contraception and cancer treatment
EP1786424A4 (en) * 2004-08-20 2009-11-25 Univ Kansas Lonidamine analogues and their use in male contraception and cancer treatment
EP1786424A2 (en) * 2004-08-20 2007-05-23 The University of Kansas Lonidamine analogues and their use in male contraception and cancer treatment
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
EP2336141A2 (en) 2005-06-29 2011-06-22 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US7691877B2 (en) 2006-02-17 2010-04-06 Pfizer Inc. Pharmaceuticals
US7501438B2 (en) 2006-07-07 2009-03-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
US8158638B2 (en) 2006-09-19 2012-04-17 Daiichi Sankyo Company, Limited Pyrazolopyrimidine derivative
EP2079703A1 (en) * 2006-11-01 2009-07-22 F. Hoffmann-Roche AG Indazole derivatives useful as l-cpt1 inhibitors
JP2010508318A (en) * 2006-11-01 2010-03-18 エフ．ホフマン−ラ ロシュ アーゲー Indazole derivatives useful as L-CPT1 inhibitors
US8431572B2 (en) 2007-06-06 2013-04-30 Merck Patent Gesellschaft Mit Beschrankter Haftung 2-oxo-3-benzylbenzoxazol-2-one derivatives and related compounds as met kinase inhibitors for the treatment of tumours
US8580781B2 (en) 2007-07-12 2013-11-12 Merck Patent Gmbh Pyridazinone derivatives
US9284300B2 (en) 2007-07-12 2016-03-15 Merck Patent Gmbh Pyridazinone derivatives
US8927540B2 (en) 2007-07-12 2015-01-06 Merck Patent Gmbh Pyridazinone derivatives
US9403799B2 (en) 2007-07-12 2016-08-02 Merck Patent Gmbh Pyrimidinyl-pyridazinone derivatives for treating a disease which is influenced by inhibition of met kinase
US8921357B2 (en) 2007-07-12 2014-12-30 Merck Patent Gmbh Pyridazinone derivatives
US9062029B2 (en) 2007-07-12 2015-06-23 Merck Patent Gmbh Pyrimidinyl pyridazinone derivatives
US8658643B2 (en) 2007-07-12 2014-02-25 Merck Patent Gmbh Pyrimidinyl pyridazinone derivatives
US8557813B2 (en) 2007-12-21 2013-10-15 Merck Patent Gmbh 2-benzylpyridazinone derivatives as met kinase inhibitors
US8859547B2 (en) 2007-12-21 2014-10-14 Merck Patent Gmbh Pyridazinone derivatives
WO2009106982A1 (en) * 2008-02-29 2009-09-03 Pfizer Inc. Indazole derivatives
US8604036B2 (en) 2008-04-21 2013-12-10 Merck Patent Gmbh Pyridazinone derivatives
US8497266B2 (en) 2008-06-18 2013-07-30 Merck Patent Gmbh 3-(3-pyrimidin-2-ylbenzyl)-1,2,4-triazolo[4,3-b]pyridazine derivatives as MET kinase inhibitors
AU2009281491B2 (en) * 2008-08-14 2014-02-20 Merck Patent Gmbh Bicyclic triazole derivatives for treating tumors
WO2010017870A1 (en) * 2008-08-14 2010-02-18 Merck Patent Gmbh Bicyclic triazole derivatives for treating tumors
US8435986B2 (en) 2008-08-14 2013-05-07 Merck Patent Gesellschaft Mit Beschrankter Haftung Bicyclic traizole derivatives for treating of tumors
US8586599B2 (en) 2008-12-22 2013-11-19 Merck Patent Gmbh Polymorphic forms of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one dihydrogenphosphate and processes of manufacturing thereof
US8445504B2 (en) 2009-02-25 2013-05-21 Daiichi Sankyo Company, Limited Tricyclic pyrazolopyrimidine derivatives
US8236813B2 (en) 2009-02-25 2012-08-07 Daiichi Sankyo Company, Limited Tricyclic pyrazolopyrimidine derivatives
WO2010098344A1 (en) 2009-02-25 2010-09-02 第一三共株式会社 Tricyclic pyrazolopyrimidine derivative
US8846703B2 (en) 2010-08-23 2014-09-30 Daiichi Sankyo Company, Limited Crystal of a free tricyclic pyrazolopyrimidine derivative
EP2810945A1 (en) 2010-08-23 2014-12-10 Daiichi Sankyo Company, Limited Dihydrochloride salt of a tricyclic pyrazolopyrimidine derivative
US8815880B2 (en) 2010-08-23 2014-08-26 Daiichi Sankyo Company, Limited Crystal of tricyclic pyrazolopyrimidine derivative
WO2012026434A1 (en) 2010-08-23 2012-03-01 第一三共株式会社 Crystal of tricyclic pyrazolopyrimidine derivative
WO2012026433A1 (en) 2010-08-23 2012-03-01 第一三共株式会社 Free crystal of tricyclic pyrazolopyrimidine derivative
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
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US11858929B2 (en) 2014-02-20 2024-01-02 Cornell University Compounds and methods for inhibiting fascin
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US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
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CN108602775B (en) * 2016-01-14 2022-04-29 贝思以色列女会吏医学中心公司 Mast cell modulators and uses thereof
US20190016680A1 (en) * 2016-01-14 2019-01-17 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
US11084789B2 (en) 2016-01-14 2021-08-10 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
CN108602775A (en) * 2016-01-14 2018-09-28 贝思以色列女会吏医学中心公司 Mast cell conditioning agent and application thereof
WO2017121693A1 (en) 2016-01-15 2017-07-20 Bayer Pharma Aktiengesellschaft Substituted thiazole and thiadiazole amides, and use thereof
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
EP3564214A1 (en) 2018-05-04 2019-11-06 Universita' Degli Studi G. D Annunzio Chieti - Pescara Indazole derivatives as modulators of the cannabinoid system
US11512064B2 (en) 2018-08-31 2022-11-29 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
WO2020069330A3 (en) * 2018-09-28 2020-07-23 Acucela Inc. Inhibitors of vap-1
US11787791B2 (en) 2018-09-28 2023-10-17 Acucela Inc. Inhibitors of VAP-1
US12037334B2 (en) 2018-09-28 2024-07-16 Acucela Inc. Inhibitors of VAP-1
KR20210014374A (en) * 2019-07-30 2021-02-09 부산대학교 산학협력단 Novel indole derivatives and composition for preventing or treating inflammatory diseases comprising the same
KR102241064B1 (en) 2019-07-30 2021-04-16 부산대학교 산학협력단 Novel indole derivatives and composition for preventing or treating inflammatory diseases comprising the same
EP4213839A4 (en) * 2020-09-17 2024-08-07 Escient Pharmaceuticals Inc Modulators of mas-related g-protein receptor x4 and related products and methods
WO2024109642A1 (en) * 2023-07-28 2024-05-30 常州大学 USE OF BENZOAZACYCLIC COMPOUND AS ALLOSTERIC MODULATOR OF β2-ADRENOCEPTOR

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