WO2006015191A2 - Multicyclic lonidamine analogs - Google Patents

Multicyclic lonidamine analogs Download PDF

Info

Publication number
WO2006015191A2
WO2006015191A2 PCT/US2005/026929 US2005026929W WO2006015191A2 WO 2006015191 A2 WO2006015191 A2 WO 2006015191A2 US 2005026929 W US2005026929 W US 2005026929W WO 2006015191 A2 WO2006015191 A2 WO 2006015191A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
nhso
alkyl
aryl
cycloalkyl
Prior art date
Application number
PCT/US2005/026929
Other languages
French (fr)
Other versions
WO2006015191A3 (en
Inventor
Mark Matteucci
Photon Rao
Jian-Xin Duan
Original Assignee
Threshold Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Threshold Pharmaceuticals, Inc. filed Critical Threshold Pharmaceuticals, Inc.
Publication of WO2006015191A2 publication Critical patent/WO2006015191A2/en
Publication of WO2006015191A3 publication Critical patent/WO2006015191A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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-spermato genie 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 ah 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).
  • 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
  • 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, IntJRadiat 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. 1996, Anticancer Res 16(6B):3865-9; DeLena et al, Oct. 1997, J Clin
  • 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).
  • 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 a formula selected from the group consisting of:
  • A-B is a 7,5, 6,5 or a 5,5 cyclic ring system , optionally substituted with from one to five V substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (C 1 -C 8 )alkyl, (C 1 -C 6 ) alkoxy, nitro, acetamido, L 1 -CO 2 H, i ⁇ dialkylamino, (C 1 -C 8 )heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )heterocyclyl, aryl, heteroaryl; U 1 -R 3 , U 1 -COR 3 , U ⁇ CUNR 3 R 7 , U ⁇ CU 2 R 3 , R 4 , NR 3 OR 3 ,
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -Cg)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 (C 1 -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 6 ) alkoxy, cyano, nitro, amino, -NO, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to
  • 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, nitro, cyano, nitrileoxide, SO 2 R 3 , SOR 3 , -NO 5 R 3 , U 1 -R 3 , U ⁇ COR 3 , U ⁇ CUNR 3 R 7 , U ⁇ CU 2 R 3 , R 4 ,
  • Y is CHR 8 , CR 8 , NR 8 ,
  • U is O, S, NR 3 , NCOR 3 , or NCONR 3 R 7 ;
  • U 1 is O or S
  • Z is a alkylene or heteroalkylene chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers 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. [0013] In a fifth aspect, the present invention provides methods for synthesizing the compounds of the invention and compounds useful as intermediates in such synthetic methods.
  • the present invention provides pharmaceutical formulations of the compounds of the invention.
  • 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 1 -C 8 )alkyl is meant to include methyl, ethyl, n- propyl, 2-propyl, n- butyl, 2-butyl, tert-butyl, pentyl, and the like.
  • (Ci-C 8 ) Alkyl may be further substituted with substituents, including for example, hydroxyl, amino, mono or di(Ci-C 6 )alkyl amino, halo, (C 2 -C 6 ) alkenyl ether, cyano, nitro, ethenyl, ethynyl, (Ci-C 6 ) alkoxy, (Ci-C 6 ) alkylthio, acyl, - COOH, -CONH 2 , mono- or di-(Ci-C 6 )alkyl-carboxamido, -SO 2 NH 2 , -OSO 2 -(Ci-C 6 )alkyl, mono or di(Ci-C 6 ) alkylsulfonamido, cyclohexyl, heterocyclyl, aryl and heteroaryl.
  • substituents including for example, hydroxyl, amino, mono or di(Ci-C 6 )alkyl
  • 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.
  • (Ci-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,-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-alkylamino, 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, cycloalky
  • 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.
  • Araalkyl or " Aryl(C i -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
  • R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl
  • R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R") n -CONR R
  • 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 w x y one, two or three substituents independently selected from cyano, -OR , -NR R , and -
  • 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-
  • 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 , R , R , and R can be further substituted by amino, fluorine, alkylamino, di- alkylamino, OH or alkoxy.
  • 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 group exclusive of the cyano, -OR , -NR R , or -S(O) R portions.
  • 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.
  • 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).
  • 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 -COOR (where n is an integer from 0 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 0 to 5, R' and R" are
  • 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 -COOR (n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
  • 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- methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, 2-pyrrolidon-l-yl, furyl, quinolyl, thienyl, benzothienyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, l,l-dioxo-hexahydro-l ⁇ 6 -thiopyran-4-yl, tetrahydroimidazo [4,5-c] pyridinyl, imi
  • 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 RY where R x is an alkylene group and RY 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.
  • 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.
  • 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 e.g., "alkyl,” “aryl” and “heteroaryl”
  • aryl and heteroaryl will include both substituted and unsubstituted forms of the indicated radical.
  • substituents for each type of radical are provided below.
  • 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 5 and R" When R 5 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 5 R 5 ' 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)-(CH 2 )q-U 3 -, wherein T and
  • U 3 are independently -NH-, -O-, -CH 2 - 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) 2 NR'- 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 - (CH 2 ) s -X-(CH 2 )t-, where s and t are independently integers of from 0 to 3, and X is -O-, -
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted C ⁇ - ⁇ 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 stereoisomers 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, A- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsul
  • 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.
  • 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.
  • the present invention provides Lonidamine analogs of the formula selected from the group consisting of:
  • 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; (d-C 8 )alkyl, (C 1 -C 6 ) alkoxy, nitro, acetamido, L 1 -CO 2 H, i ⁇ dialkylamino, (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 , U 1 XOR 3 , U 1 XUNR 3 R 7 , U 1 XU 2 R 3 , R 4 , NR 3 OR 3 ,
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -Cg)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, (C 1 -C 6 ) alkoxy, cyano, nitro, amino, -NO, (C 1 -C 4 )alkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1
  • 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, SO 2 R 3 , SOR 3 , -NO, R 3 , U 1 -R 3 , U 1 -COR 3 , U ⁇ CUNR 3 R 7 , U 1 -CU 2 R 3 , R 4 ,
  • 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, (d-C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -
  • R 8 is H, halo, nitro, cyano, nitrileoxide, -NO, R 3 , 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-(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 -SOR 3 , N-(SOR 3 ) 2 , NR 3 -PU 2 R 3 , N-(PU 2 R 3 ) 2 , NR 3 -P( U)(UR 3 )R 3 , CU 2 R 3 , CUNR 3 R 7 , CUNR 3 CUR 3 , CUN(CUR 3 ) 2 , CUNR 3 CU 2 R 3 , CUN(CU 2 R 3 ) 2 , CUNR 3 CUNR 3 R 7 , CUN(CUNR 3 R 7 ) 2
  • R 31 is aryl or heteroaryl; each V 5 is a member independently selected from the group consisting of COOR , COR 4 , CONR 3 COR 3 , COCOR 4 , B(OR 3 ) 2 , SO 2 R 4 , NHSO 2 CR 5 3 , NHSO 2 CR 3 3 , CONHSO 2 CR 3 S , NHSO 2 R 3 , CONHSO 2 R 3 , and C( ⁇ NCN)NH 2 ;
  • Y is CHR 8 , CR 8 , NR 8 ,
  • U is O, S, NR 3 , NCOR 3 , or NCONR 3 R 7 ;
  • U 1 is O or S;
  • Z is a alkylene or heteroalkylene chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
  • the present invention further includes all salts thereof, and particularly, pharmaceutically 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.
  • an amino or alkylamino functionality present in a compound of the present invention can be further substituted with one or more acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl groups, hi another embodiment, an acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or arylsulfonyl group is part of a cyclic structure.
  • the present invention provides compounds of Formula I, II or III, wherein A-B is a 5, 5-fused cyclic ring system.
  • Li one embodiment the present invention provides compounds of Formula I, II or III, wherein A-B is a 6, 5-fused cyclic ring system.
  • the present invention provides compounds of Formula I, II or III, wherein A-B is a 7, 5-fused cyclic ring system.
  • the present invention provides compounds of Formula IVA,
  • W 1 -W 5 of formula (IVA) are as defined in Table IA; and for each W ⁇ -W 5 as defined therein, W 6 -W 8 are defined as follows in Table IB:
  • A-B in formula IVA is selected from the group consisting of:
  • the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula VA:
  • 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 present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula (VIA):
  • W -W is defined as follows in Table IB:
  • the present invention provides compounds of formula VIA, wherein W 6 - W 9 is defined as follows in Table ID:
  • V 6 and U are as defined above.
  • the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula (VIA): wherein 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 present invention provides compounds of formula VIA, wherein
  • V , 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-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 (Ci-Cg)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, (C] -C 4 ) alkylamino or
  • R 3 is H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, (C,-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, (C ! -C 8 )alkyl, (d-C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )heterocyclyl, aryl or heteroaryl;
  • R 3 and R 7 together are (d-C 8 )heteroalkyl or heteroaryl;
  • Ar is 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, (Ci-C 4 ) alkyl, (C 1 -C 8 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino and (Ci-C 4 ) dialkylamino;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (Ci-C 8 )alkyl or (d-C 8 )heteroalkyl; represents a single, double or normalized bond; 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, (Ci- C 8 )alkyl, (Ci-Cs)heteroalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alJcynyl, (C 3 -C 8 )cycloalkyl, (Q- 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)
  • the present invention provides V 6 selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl or (Q-C ⁇ heteroalkyl, halogen, hydroxy, (C 1 -C 6 ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino, and (C 1 -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.
  • the present invention provides compounds of the formula selected from the group consisting of:
  • 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 substituents independently selected from the group consisting of (CrC ⁇ alkyl, heteroalkyl, halogen, hydroxy, (Q-C ⁇ alkoxy, cyano, nitro, amino, (CrC ⁇ alkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • 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; each R 3 is a member independently selected from the group consisting of H, (C 1 - C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (C 1 -C 8 ⁇ UCyI, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; 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, NV 6 , CV 6 , CO, O, and S; each W 6 , W 7 , W 8 or W 9 is independently N or CR 12
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (Ci-C 8 )alkyl or heteroalkyl
  • R 12 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl or heteroalkyl, halogen, hydroxy, (C 1 -C 4 ) alkoxy, amino, cyano, nitro, (Ci-C 4 ) alkylamino, and (Ci-C 4 ) dialkylamino;
  • Z is an alkyl or heteroalkyl chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
  • the present invention provides compounds wherein A-B is a member selected from the group consisting of:
  • R 1 is L 1 -V 5 or CO 2 R 3" .
  • R 1 is selected from the group consisting of:
  • 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 comprises a moiety of the formula:
  • the bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof comprises a moiety having a formula selected from the group consisting of:
  • bioisostere of CO 2 H, CONH 2 , CONHNH 2 , or a derivative thereof have a formula selected from the group consisting of:
  • 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 Chemistiy-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; 47(10); 2706-9; and Hazeldine et al., J Med. Chem., 2002; 45: 3130-7.
  • 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 a straight or branched chain (C 1 -C 8 )alkyl or, if both present on the same substituent, joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript q is an integer of from 1 to 4.
  • the cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl is a five- membered ring.
  • the heteroaryl ring contains one or more nitrogen atoms.
  • R 1 is COOR 3 .
  • R 3 is H or (CH 2 ) n NR 13 2 wherein each R 13 is a (Ci- C 8 )alkyl, or, if both present on the same substituent, may be joined together to form a three- to eight-membered cycloalkyl or 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 -C 8 )cycloalkyl, a (CrC ⁇ heterocycloalkyl, a (C 3 -C 8 )cycloalkenyl, an aryl or a heteroaryl ring.
  • the (C 3 -Cs)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, pyrrolotriazine, pyrazolotriazine,
  • the (C 1 -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 (Q-C ⁇ heterocycle moiety selected from the group consisting of:
  • Y is NR 8 . In other embodiments Y is CR 8 . Y is CHR 8 . In other embodiments Y is CH [0084] In one embodiment, the present invention provides R 8 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Q- Cg)alkyl, (Ci-C 6 ) alkoxy, nitro, acetamido, IJ-CO 2 H, i ⁇ dialkylamino, (Ci-Cs)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'-CU 2 R 3 , R
  • the present invention provides R 8 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Ci-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 R 3 , N-
  • the present invention provides R 8 selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl or (Ci-C 4 )heteroalkyl, halogen, hydroxy, (C]-C O ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino, and (C 1 -C 4 ) dialkylamino.
  • the present invention provides R 8 selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
  • R 2 is selected from the group consisting of pyrroyl, pyrazoyl, imidazoyl, pyridinyl, dihydropyridinyl, pyrazmyl, pyridazinyl, pyrimidinyl and phenyl, optionally substituted with from one to two substituents selected from the group consisting of halo or (Ci-Cg)alkyl.
  • R 2 is selected from the group consisting of
  • each W 10 or W 11 is independently selected from the group consisting of N, C, and CH;
  • R ⁇ is halo or a straight or branched chain (d-CsJalkyl; the wavy line indicates the point of attachment to Y and the straight line indicates a point of attachment to R or Z.
  • R 2 is phenyl or phenylene.
  • PU(NR 3 COR 3 ) 2 , PU(NR 3 CU 2 R 3 ) 2 , PU(NR 3 CUNR 3 R 7 ) 2 , NR 3 (NR 3 ) 2 , nitrileoxide, and-NO, or any two R 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 - Cs)cycloalkenyl, an aryl or a heteroaryl ring.
  • the present invention provides R 6 each independently selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl or (C 1 -C 4 )heteroalkyl, halogen, hydroxy, (Ci-C 6 ) alkoxy, amino, cyano, nitro, (C 1 -C 4 ) alkylamino, and (C 1 -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 ⁇ €-CH 3.
  • R 2 has 1 or 2 substituents.
  • R 2 has two R 6 substituents.
  • each R 6 is independently selected from the group consisting of halo and (Ci-C 8 )alkyl. In another embodiment, R 6 is independently selected from the group consisting of Cl, Br, and CH 3 . hi another embodiment, each R 6 is Cl. [0088] hi one embodiment, R 3 , R 7 , and R 8 are independently selected from the group consisting of: H, -CH 3 , -CH 2 CH 3 ,
  • the compound is selected from the group consisting of:
  • R 6 is, independently Cl or CH 3 ;
  • W 1 is N or C
  • W 9 is N or CR 6 ;
  • W 2 is a member selected from the group consisting of N, CR 5 , NR 7 and CO; each W 10 is independently, NH, CH 2 , O, or S; represents a single, double or normalized bond; and the subscript p is an integer of from 0 to 2.
  • L 1 is selected from the group consisting of (C 1 -C 8 )alkylene, (C 2 -Cs)alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, heteroalkyl, halogen, hydroxy, (d-C 4 )alkoxy, cyano, nitro, amino, (Q-GOalkylamino and (C 1 -C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ; and R 8 is H, (C r C 8 )alkyl or heteroalkyl;
  • W 1 is N or C
  • W 9 is N or CR 6 ;
  • W 11 is independently O or CH 2 ; and the subscript p is an integer of from 0 to 2.
  • the compound have the formula:
  • R 1 is selected from the group consisting of CO 2 R 3 , COR 4 , CONR 3 COR 3 ,
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -C 8 )alkenyl, (C 2 -
  • V 1 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (d-C 4 )alkoxy, cyano, nitro, amino, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (d-C 4 )alkoxy, cyano, nitro, amino, (Ci-C 4 )al
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (Ci-C 8 )alkyl or heteroalkyl
  • W 9 is N or CR 6 ;
  • W 10 is independently O or CH 2 ; and the subscript p is an integer of from O to 2.
  • the com ound has the formula:
  • R 1 is selected from the group consisting of CO 2 R 3 , COR 4 , CONR 3 COR 3 ,
  • 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 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (C 1 -C ⁇ aIkOXy, cyano, nitro, amino, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci-
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 OrNR 3 CN;
  • R 5 is H, OH or halogen; each V 5 is a member independently selected from the group consisting of COOR 3 , COR 4 , CONR 3 COR 3 , COCOR 4 , B(OR 3 ) 2 , SO 2 R 4 , NHSO 2 CR 5 3 , NHSO 2 CR 3 3 , CONHSO 2 CR 3 3 , NHSO 2 R 3 and C( ⁇ NCN)NH 2 ;
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (C 1 -C 8 )alkyl or heteroalkyl
  • W 1 is N or C
  • W 2 is a member selected from the group consisting of N, CR 5 , NR 7 and CO
  • W 9 is N, CR 6 or CH;
  • W 10 is independently O or CH 2 ; and the subscript
  • R 1 is selected from the group consisting of CO 2 R 3 , COR 4 , CONR 3 COR 3
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci-
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR 8 , CR 8 , NR 8 ; and
  • R 8 is H, (C 1 -C 8 )alkyl or heteroalkyl
  • W 9 is N, CR 6 or CH;
  • W 10 is independently O or CH 2 ; and the subscript p is an integer of from O to 2.
  • the compound is selected from the group consisting of:
  • L 1 is selected from the group consisting of (C 1 -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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, (d-C 4 )alkylamino and (C]-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (C 1 -
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 KR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - Cg)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR 8 , CR 8 , KR 8 ; and
  • R 8 is H, (C 1 -C 8 )alkyl or heteroalkyl
  • W 9 is N, CR 6 or CH; •
  • W 10 is independently O or CH 2 ; and the subscript p is an integer of from O to 2.
  • the compound has the formula: wherein
  • L 1 is selected from the group consisting of (Q-C ⁇ alkylene, (C 2 -Cs)alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (C 1 -C 4 )alkoxy, cyano, nitro, amino, (Q-GOalkylamino and (C]-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH 3 ; each R 3 is
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-C 8 )alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R and R are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (CrC 8 )alkyl or heteroalkyl; W 1 is N or C; with the proviso that if W 1 is N then R 1 is not CO 2 H;
  • W 9 is N, CR 6 or CH;
  • W 2 is a member selected from the group consisting of N, CR 5 , and CO;
  • W 10 is NH, CH 2 , O, or S; and represents a single, double or normalized bond.
  • the compound has the formula:
  • 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 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, (C 1 -C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci-
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 OrNR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-Cs)alkyl, heteroalkyl, (C 3 - Cg)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (d-C 8 )alkyl or heteroalkyl
  • W 1 is N or C
  • W is a member selected from the group consisting of N, CR , NR and CO;
  • W 9 is N, CR 6 or CH;
  • W 10 is NH, CH 2 , O, or S; and represents a single, double or normalized bond.
  • the compound has the formula:
  • 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 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, cyano, nitro, amino, (C 1 -C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (Ci-C 8 )alkyl or heteroalkyl; the subscript p is an integer of from O to 2;
  • W 1 is N or C
  • W 2 is a member selected from the group consisting of N, CR 5 , NR 7 and CO;
  • W 9 is N, CR 6 or CH;
  • W 10 is NH, CH 2 , O, or S; and represents a single, double or normalized bond.
  • the compound has the formula:
  • L 1 is selected from the group consisting of (Ci-C 8 )alkylene, (C 2 -Cs)alkenyl, (C 2 - C 8 )alkynyl, and (C 3 -C 8 )cycloalkylene, optionally substituted with from one to fourteen V 1 substituents independently selected from the group consisting of (C]-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R b substituents independently selected from Cl
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-Cs)alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (C 1 -C 8 )alkyl or heteroalkyl; the subscript p is an integer of from O to 2; W 1 is N or C;
  • W is a member selected from the group consisting of N, CR , NR and CO;
  • W 9 is N, CR 6 or CH;
  • W 10 is NH, CH 2 , O, or S; and represents a single, double or normalized bond.
  • R 1 is X 1 -R 7 or CO 2 R 4 .
  • R 1 is C 2 alkenyl-CO 2 R 4 .
  • R 4 is H or (CH 2 ) q NR 13 2 ; each R 13 is independently (C 1 -C 8 )alkyl, or, if both present on the same substituent may be joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
  • R 6 is independently Cl, Br, or CH 3 . In another embodiment, R 6 is Cl.
  • the compound is selected from the group consisting of: 3-(4-Chloro-3H-inden-l-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
  • 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 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, (Ci-C 4 )alkoxy, cyano, nitro, amino, (Ci-C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (Ci-
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • Y is CHR 8 , CR 8 , NR 8 ; and R 8 is H, (C 1 -C 8 )alkyl or heteroalkyl;
  • W 10 is NH, CH 2 , O, or S.
  • the compound is selected from the group consisting of:
  • R 1 is selected from the group consisting of CO 2 R 3 , COR 4 , CONR 3 COR 3 ,
  • V 1 substituents independently selected from the group consisting of (Ci-C 4 )alkyl, heteroalkyl, halogen, hydroxy, cyano, nitro, amino, (C 1 -C 4 )alkylamino and (Ci-C 4 ) dialkylamino, or any two V 1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
  • R 2 is an aryl or heteroaryl group, optionally substituted with from one to three R 6 substituents independently selected from Cl or CH 3 ; each R 3 is a member independently selected from the group consisting of H, (C 1 - C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from the group consisting OfNR 3 R 7 , NR 3 OR 7 , NR 7 NR 3 R 7 or NR 3 CN;
  • R 7 is selected from the group consisting of H, (Ci-Cg)alkyl, heteroalkyl, (C 3 - C 8 )cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 and R 7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
  • Y is CHR 8 , CR 8 , NR 8 ;
  • R 8 is H, (Ci-C 8 )alkyl or heteroalkyl
  • W 10 is NH, CH 2 , O, or S; with the proviso that in compound
  • R 1 is not CO 2 H.
  • the compound is selected from the group consisting of:
  • Lonidamine analogs can be prepared by known synthetic methods and the teaching herein. Synthesis of lonidamine is described in U.S. Patent No. 3,895,026. Synthesis of lonidamine analogs, including tolnidamine (TND), has also been described ⁇ see, e.g., Corsi et al, 1976, "l-Halobenzyl-lH-Indazole-S-Carboxylic Acids. A New Class of Antispermatogenic Agents", J. Med. Chem. iP:778-83; Cheng et al, 2001, "Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis" Biol. Reprod.
  • 60/586,934 entitled “Tertiary amine prodrugs of lonidamine and analogs” (filed July 8, 2004) and “Prodrugs of lonidamine and analogs” (filed Nov 1, 2004).
  • Other exemplary lonidamine analogs are described in U.S. provisional application nos. 60/599,666 and 60/592,723, entitled “Heterocyclic Lonidamine Analogs" (filed Aug 5, 2004 and July 29, 2004 respectively); 60,599,664 and 60/592,677, entitled “Multicyclic Lonidamine Analogs” (filed Aug 5, 2004 and July 29 Aug 05, 2004 respectively) and provisional application entitled Lonidamine Analogs (filed Jan 21, 2005).
  • Syntheses of ester prodrugs of the lonidamine analog compounds 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 presences of an inert base, such as triethyl amine, 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 recrystalization 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 commercially available. Non-commercially available starting materials can be synthesized via 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 acid addition salts are citric acid salt.
  • 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.
  • amino acids include, but are not 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 an amine (wherein the amine is defined as above).
  • one equivalent of an amine is mixed with one equivalent of lonidamine or a lonidamine analog in water. The mixture is stirred 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 when in a base addition salt one component is lonidamine, the base is other than arginine or glycine.
  • the base addition salt of lonidamine and arginine is not administered intravenously to rats.
  • the base addition salt of lonidamine and glycine is not administered intravenously to normal dogs.
  • 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 thai 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 [0124] 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.
  • compositions 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.
  • 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(suppl 7):S27-33] which also provides exemplary dosage regimens and schedules for treatment of BPH.
  • 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,
  • 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.
  • 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;
  • PSA prostate specific antigen
  • 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), HEXIMl (ovarian epithelial cancer), FL J20267 (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.
  • 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
  • HGPIN high grade
  • LGPIN low grade
  • 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 Biochern. Suppl. 16H:10-9. Patients diagnosed as having HGPIN have an increased likelihood of developing prostate cancer within 10 years.
  • 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.
  • 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
  • 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 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.
  • 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-Indazole 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.
  • the subject when used in humans, 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).
  • Energolvtic Activity It has been suggested that lonidamine's anticancer properties result at least in part from a lonidamine-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.
  • 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.
  • the patient is not also under treatment for BPH or cancer, hi 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, hi various embodiments, a pharmaceutical composition of the invention may comprise a compound of Formula I, or compounds of any of Groups 1-38, 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.
  • 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.
  • 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 mM).
  • 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
  • an energolytic agent reduces HIF-I -alpha expression (prevents HIF-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.
  • 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 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, BiolReprod. 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.
  • 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.
  • 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.
  • the antiproliferative activity of the compounds of the invention is 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 is compared, as measured by a fluorescence plate reader at excitation 550 nm and emission 590 nm (see Biosource International Inc., Tech Application Notes, Use of Alamar Blue in the measurement of Cell Viability and Toxicity, Determining IC 50 ).
  • H460 cells ATCC HTB- 177 (NCI-H40), 4,000 cells/well/200 ⁇ ) and LNCap cells (ATCC CRL- 1740,6,000 cells/well/200 ⁇ l) are seeded in a 96 well plate in RPMI medium (Invitrogen Corporation, Carlsbad, CA). After 24 hours, these plates are divided into 3 groups - Control group, 2h treatment group and 3 day treatment group. A test compound is added to each plate in the treatment groups (2h and 3 day) at a various concentration. In the 2h treatment group, after 2h the cells are rinsed to remove the test compound and incubated for 3 days, followed by staining with AlamarBlue.
  • the cells in the 3 day treatment group are incubated for 3 days, followed by staining with AlamarBlue.
  • AlamarBlue is 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 is 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 5O (also referred to IC 50 herein)) of lonidamine and lonidamine analogs is calculated.
  • GI 5O also referred to IC 50 herein
  • EXAMPLE 4 BrdU-TUTSfEL assay The effect of the compounds of the invention on apoptosis is determined as follows. PWR-IE cells (2 x 10 5 cells/ml/well) are seeded in a 24 well plate. After 24 h the test compound is added at various concentrations. The culture media are removed after 24 h, the cells are rinsed with PBS buffer (200 ⁇ L) and incubated (5 min, 37 0 C) with a solution of Guava Viacount CDR in PBS (1:3 v/v). Media (750 ⁇ L) containing at least 5% FBS is added to each well, the cells released by repeated pipeting, centrifuged, and the supernatant aspirated.
  • the cells are resuspended in PBS buffer (150 ⁇ L) and fixed by incubating (60 min, 4 0 C) with 4% paraformaldehyde in PBS.
  • the cells are centrifuged, and the supernatant removed to a final volume of 15 ⁇ L.
  • the cell pellets are 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 are centrifuged, the supernatant removed, washed, and incubated with the DNA labeling mix (37 0 C, 60 min).
  • the cells are 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 effect of the test compound on apoptosis of LNCaP cells is determined using the same protocol as described above.
  • the effect of a compound of the invention on the cell cycle is determined as follows.
  • LNCaP cells (2 x 10 5 cells/ml/well) are seeded in a 24 well plate. After 24 h, the test compound is added at various concentrations. The culture media are removed after 24 h, the cells are trypsinized and centrifuged. The cell pellets are resuspended in lOO ⁇ l PBS buffer, after which 300 ⁇ l of ice-cold ethanol (96%) added dropwise, and the cells are incubated at 4 0 C for at least 24 hr. The cells are centrifuged and the supernatant is discarded.
  • the cell cycle staining reagent (Guava Technologies, Hayward, CA, USA, 200 ⁇ l) is added to each well. The cells are shielded from light and incubated at room temperature for 30 min. The samples are analyzed (Guava PCA-96 instrument, Cytosoft software, Guava Technologies, 25801 Industrial Boulevard, Hayward CA 94545-2991, USA).
  • the effect of a compound of the invention on the mouse prostate is determined as follows.
  • the control mice received an equal amount of the vehicle (carboxymethylcellulose).
  • the mice are sacrificed and the entire prostate and the individual lobes (e.g., the dorsal lobe and the ventral lobe) are weighed to measure absolute weights. Relative weights of prostate and individual lobes are 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 are calculated by dividing the absolute weight by the total weight of the mouse.
  • the effect of a compound of the invention on the mouse prostate is determined as follows.
  • the control mice received an equal amount of the vehicle (carboxymethylcellulose).
  • the mice are sacrificed and the left and right testes, the entire prostate and the individual prostatic lobes (e.g., the dorsal lobe and the ventral lobe) are weighed to measure absolute weights. Relative weights of entire prostate and individual lobes are 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 are calculated by dividing the absolute weight by the total weight of the mouse.
  • Relative weights of the left and right testis are calculated by dividing the corresponding absolute weights by the total weights of the mouse.
  • Prostate cells harvested from mice treated with a compound of the invention are assayed by the TUNEL assay as described above.
  • the prostate cells are 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention provides lonidamine analogs as well as methods of treating cancer and BPH.

Description

MULTICYCLIC LONIDAMINE ANALOGS
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Patent Application No. 60/651,671, filed February 9, 2005, U.S. Patent Application No. 60/599,664, filed August 5, 2004, and U.S. Patent Application No. 60/592,677, filed July 29, 2004, the contents 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-spermato genie 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 ah, 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, 15 Oct. 2002, J. Clin. 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, IntJRadiat 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, J Neurooncol 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 Clin
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 a formula selected from the group consisting of:
Figure imgf000005_0001
(I) (II) (III) wherein wherein A-B is a 7,5, 6,5 or a 5,5 cyclic ring system , optionally substituted with from one to five V substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (C1-C8)alkyl, (C1-C6) alkoxy, nitro, acetamido, L1 -CO2H, iΛdialkylamino, (C1 -C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C1 -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, 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 (CrC^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, 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; or may be taken together with a V6 attached to adjacent or within two atoms to form a (C3-Cg)cycloalkyl, a (C1- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
L1 is selected from the group consisting of (Ci-C8)alkylene, (C2-Cg)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 (C1-C4)alkyl, (C1- 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, (Ci-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 R6 substituents independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, SO2R3, SOR3, -NO5 R3, U1 -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)2, PU(NR3CUNR3R7)2, NR32(NR32)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, (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, (C,-C6)alkenyl, (C2-
C8)alkynyl, (Ci-Cg)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)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, 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 3, NHSO2R3, CONHSO2R3, and C(=NCN)NH2;
Y is CHR8, CR8, NR8,
U is O, S, NR3, NCOR3, or NCONR3R7;
U1 is O or S;
Z is a alkylene or heteroalkylene chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
[0010] hi 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] hi 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] In 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.
DETAILED DESCRIPTION OF THE INVENTION [0016] 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
[0017] 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.
[0018] As used herein, the terms "a" or "an" means "at least one" or "one or more."
[0019] 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, (C1-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. (Ci-C8) Alkyl may be further substituted with substituents, including for example, hydroxyl, amino, mono or di(Ci-C6)alkyl amino, halo, (C2-C6) alkenyl ether, cyano, nitro, ethenyl, ethynyl, (Ci-C6) alkoxy, (Ci-C6) alkylthio, acyl, - COOH, -CONH2, mono- or di-(Ci-C6)alkyl-carboxamido, -SO2NH2, -OSO2-(Ci-C6)alkyl, mono or di(Ci-C6) alkylsulfonamido, cyclohexyl, heterocyclyl, aryl and heteroaryl.
[0020] 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.
[0021] 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, (Ci-C6)alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
[0022] 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, (C,-C6)alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.
[0023] 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.
[0024] 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.
[0025] 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-alkylamino, 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.
[0026] As used herein, the terms " Araalkyl" or " Aryl(C i -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.
[0027] 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.
[0028] 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), -(CR'R")n-
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-CONR R
(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.
[0029] 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.
[0030] As used herein, the term "halo" and the term "halogen" when used to describe a substituent, refer to -F, -Cl, -Br and -I.
[0031] As used herein, the term "Heteroalkyl" means an alkyl radical as defined herein with w x y one, two or three substituents independently selected from cyano, -OR , -NR R , and -
Z
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-
Z 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 , 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 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..
[0032] 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-COOR (where n is an integer from 0 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 0 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. [0033] 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-COOR (n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
X V cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R")n-CONR R (where n is an integer from x 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- methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, 2-pyrrolidon-l-yl, furyl, quinolyl, thienyl, benzothienyl, pyrrolidinyl, piperidinyl, morpholinyl, 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.
[0034] As used herein, the terms "Heterocyclylalkyl" or "Cycloheteroalkyl-alkyl" means a radical — RXRY where Rx is an alkylene group and RY is a heterocyclyl group as defined herein, e.g., tetrahydropyran-2-ylmethyl, 4-(4-substituted-phenyl)piperazin-l-ylmethyl, 3- piperidinylethyl, and the like.
[0035] 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. [0036] 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.
[0037] As used herein, the term "Optionally substituted" means a ring which is optionally substituted independently with substituents.
[0038] 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 aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below.
[0039] 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)NR5R", -NR"C(O)R\ -NR'-C(0)NR"R"', -NR"C(0)2R\ -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR5, -S(O)R', -S(O)2R', -S(O) 2NR'R", -NR5S(O)2R", - CN and -NO2, -R', -N3, perfluoro(Ci-C4)alkoxy, and perfluoro(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"5 are independently selected from hydrogen, C\_ 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 R5 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, -NR5R5' 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.
[0040] 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 C\-β alkyl.
[0041] 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.
[0042] 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.
[0043] 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". [0044] The compounds of this invention may exist in stereoisomers 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).
[0045] "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:
[0046] (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, A- 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
[0047] (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.
[0048] "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.
[0049] 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.
[0050] As used herein, "treating" a condition or patient refers to talcing 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.
[0051] 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).
[0052] 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.
[0053] 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.
[0054] 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
[0055] hi one aspect, the present invention provides Lonidamine analogs of the formula selected from the group consisting of:
Figure imgf000018_0001
(I) (II) (III) wherein 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; (d-C8)alkyl, (C1-C6) alkoxy, nitro, acetamido, L1 -CO2H, iΛdialkylamino, (Ci-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; U1 -R3, U1XOR3, U1XUNR3R7, U1XU2R3, 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(CURJ)2, SO2NRXU2R', SO2N(CU2RJ)2, SO2NR CUNR 3-3-RD 7', > 3T> 7N SO2N(CUNR'R')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 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; or may be taken together with a V6 attached to adjacent or within two atoms to form a (C3-Cg)cycloalkyl, a (Cj- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring;
L1 is selected from the group consisting of (Ci-C8)alkylene, (C2-Cg)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, (C1-C6) alkoxy, cyano, nitro, amino, -NO, (C1-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 (Q- 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;
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, SO2R3, SOR3, -NO, R3, U1 -R3, U1 -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, NR32(NR32)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-C3)alkynyl, (C3-C8)cycloalkyl, (Ci-
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, (d-C8)alkyl, (C2-C6)alkenyl, (C2-
C8)alkynyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (Ci-Cs)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (C1-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 COOR , COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 S, NHSO2R3, CONHSO2R3, and C(^NCN)NH2;
Y is CHR8, CR8, NR8,
U is O, S, NR3, NCOR3, or NCONR3R7;
U1 is O or S; Z is a alkylene or heteroalkylene chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
[0056] In addition to compounds having formulas I, II, or III above, the present invention further includes all salts thereof, and particularly, pharmaceutically 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.
[0057] In one embodiment, an amino or alkylamino functionality present in a compound of the present invention can be further substituted with one or more acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl groups, hi another embodiment, an acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or arylsulfonyl group is part of a cyclic structure.
[0058] A number of other groups of embodiments are preferred and are set forth below.
[0059] hi one embodiment the present invention provides compounds of Formula I, II or III, wherein A-B is a 5, 5-fused cyclic ring system. Li one embodiment the present invention provides compounds of Formula I, II or III, wherein A-B is a 6, 5-fused cyclic ring system. hi other embodiments the present invention provides compounds of Formula I, II or III, wherein A-B is a 7, 5-fused cyclic ring system.
[0060] In one embodiment the present invention provides compounds of Formula IVA,
Figure imgf000021_0001
(IVA)
wherein W1 -W5 of formula (IVA) are as defined in Table IA; and for each W^-W5 as defined therein, W6-W8 are defined as follows in Table IB:
Table IA
Figure imgf000021_0002
Figure imgf000022_0002
[0061] In one embodiment, A-B in formula IVA is selected from the group consisting of:
Figure imgf000022_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
[0062] In one embodiment, the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula VA:
Figure imgf000023_0001
(VA) 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. [0063] In one embodiment, the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula (VIA):
Figure imgf000023_0002
(VIA) wherein W1 -W5 is defined as follows in Table 1C:
Table 1C
Figure imgf000023_0003
Figure imgf000024_0001
and for each ring B 1-20 as defined above, W -W is defined as follows in Table IB:
Table IB
Figure imgf000024_0002
[0064] In one embodiment, the present invention provides compounds of formula VIA, wherein W6- W9 is defined as follows in Table ID:
Table ID
Figure imgf000025_0001
Figure imgf000026_0001
wherein ""^ indicates a single bond to W and *• indicates a single bond to W5 and
V6 and U are as defined above.
[0065] In another embodiment, the present invention provides compounds wherein the C=U bond in the structural formulas in Table ID is independently replaced with an SO or an SO2 moiety, such as, for example, providing a compound containing the moiety
Figure imgf000027_0001
[0066] In one embodiment, the present invention provides compounds of formula I, wherein the cyclic ring system A-B has the formula (VIA): 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.
[0067] In one embodiment, the present invention provides compounds of formula VIA, 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 ≡€-,
Figure imgf000027_0002
-NHCO- and -NHNH- wherein each V , 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-C8)cycloalkyl, 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, (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;NHSO2CR33, 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-C8)alkyl, (Ci-C8)heteroalkyl, (C3-C8)cycloalkyl, (C,-C8)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, (C!-C8)alkyl, (d-C8)heteroalkyl, (C3-C8)cycloalkyl, (C1-C8)heterocyclyl, aryl or heteroaryl;
R3 and R7 together are (d-C8)heteroalkyl or heteroaryl;
Ar is 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, (Ci-C4) alkyl, (C1-C8)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino and (Ci-C4) dialkylamino;
Y is CHR8, CR8, NR8;
R8 is H, (Ci-C8)alkyl or (d-C8)heteroalkyl; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[0068] Returning to formulas IVA, VA and VIA, 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. In 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.
[0069] In one embodiment, the present invention provides V6 substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (Ci- C8)alkyl, (Ci-Cs)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alJcynyl, (C3-C8)cycloalkyl, (Q- 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 (Ci-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 V substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (C1-C8)alkyl, (C1-C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (d-CsOheterocyclyl, 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 V6 attached to the same or adj acent 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 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, 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- Me9 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-SO2Me3 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, (C1-C4) alkyl or (Q-C^heteroalkyl, halogen, hydroxy, (C1-C6) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino, and (C1-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.
[0070] In one embodiment the present invention provides compounds of the formula selected from the group consisting of:
Figure imgf000030_0001
(VIB) (VIC) (VID) wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR6 3, NHSO2CR3 3, CONHSO2CR3 3,
C(=NCN)NH2, -NHCO-V5, -NHNH- V5, V-V5 and -L1CO2R3, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-L^CO2H)2, -NHL^CO2H)2, COHNLVCO2H)2 and CONHL1 -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 substituents independently selected from the group consisting of (CrC^alkyl, heteroalkyl, halogen, hydroxy, (Q-C^alkoxy, cyano, nitro, amino, (CrC^alkylamino and (C1-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or 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 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, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R2 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (C1-C8^UCyI, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; each W1, W3, W4 or W5 is independently N or C;
W2 is a member selected from the group consisting of N, NV6, CV6, CO, O, and S; each W6, W7, W8 or W9 is independently N or CR12
Y is CHR8, CR8, NR8;
R8 is H, (Ci-C8)alkyl or heteroalkyl;
R12 is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C4) alkyl or heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino;
Z is an alkyl or heteroalkyl chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
[0071] In any of the embodiments, the present invention provides compounds wherein A-B is a member selected from the group consisting of:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000032_0002
wherein the solid line indicates the point of attachment to' R1 and the wavy line indicates the point of attachment to Y.
[0072] In any of the above embodiments, R1 is L1 -V5 or CO2R3". In other embodiments, R1 is selected from the group consisting of:
CONHNH2, CONH2, CONHNMe2, CONMe2
Figure imgf000033_0001
Figure imgf000033_0002
[0073] 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 imgf000034_0001
wherein the wavy line indicates the point of attachment to the rest of the molecule. [0074] 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 comprises a moiety of the formula:
Figure imgf000034_0002
wherein the wavy line indicates the point of attachment to the rest of the molecule.
[0075] In one embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof comprises a moiety having a formula selected from the group consisting of:
Figure imgf000034_0003
wherein the variables are as defined herein. [0076] In one embodiment, the bioisostere of CO2H, CONH2, CONHNH2, or a derivative thereof have a formula selected from the group consisting of:
Figure imgf000035_0001
wherein the variables are as defined herein. [0077] 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 Chemistiy-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; 47(10); 2706-9; and Hazeldine et al., J Med. Chem., 2002; 45: 3130-7.
[0078] In any of the above embodiments, R1 is L1 -V5 or CO2R3". In other embodiments, R1 is -C2alkenyl-CO2R3;R3 is H or (CH2)qNR13 2; each R13 is independently a straight or branched chain (C1-C8)alkyl or, if both present on the same substituent, joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript q is an integer of from 1 to 4.
[0079] In one embodiment, L1 is -CR14=CR15- wherein R14 and R15 together form a cycloalkyl, a heterocycloalkyl, a cycloalkenyl, an aryl, or a heteroaryl ring. Within this embodiment the cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl is a five- membered ring. In another embodiment, the heteroaryl ring contains one or more nitrogen atoms.
[0080] In other embodiments R1 is COOR3.
[0081] In any of the above embodiments, R3 is H or (CH2)nNR13 2 wherein each R13 is a (Ci- C8)alkyl, or, if both present on the same substituent, may be joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript n is an integer of from 1 to 4. [0082] 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-C8)cycloalkyl, a (CrC^heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring. Within this embodiment, the (C3-Cs)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, pyrrolotriazine, pyrazolotriazine, triazolotriazine, pyrazolotetrazine, hexaaza-indene, and heptaaza-indene and the derivatives thereof . In another related embodiment, the (C1-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 (Q-C^heterocycle moiety selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
wherein the straight and wavy lines indicate the point of attachment to the rest of the molecule.
[0083] In any of the above embodiments, Y is NR8. In other embodiments Y is CR8. Y is CHR8. In other embodiments Y is CH [0084] In one embodiment, the present invention provides R8 substituents, each independently selected from the group consisting of hydrogen, amino, halo, oxo; (Q- Cg)alkyl, (Ci-C6) alkoxy, nitro, acetamido, IJ-CO2H, iΛdialkylamino, (Ci-Cs)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (Ci-C8)heterocyclyl, aryl, heteroaryl; U1- 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, 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 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, (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)cycloalkyl, a (C1-C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V is other than -COOR . In another embodiment, the present invention provides R substituents, each independently selected from the group consisting of hydrogen, halo, oxo; cyano, (CrC8)alkyl, (Q-Csøheteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (d-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-Cg)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; with the proviso that V is other than -COOR . In another embodiment, the present invention provides R 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, Mi2, 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, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=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 (Ci-C4)heteroalkyl, halogen, hydroxy, (C]-CO) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino, and (C1-C4) dialkylamino. In another embodiment, the present invention provides R8 selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, amino, methylamino, dimethylamino, ethylamino, methoxy, and hydroxyl.
[0085] In any of the above embodiments, R2 is selected from the group consisting of pyrroyl, pyrazoyl, imidazoyl, pyridinyl, dihydropyridinyl, pyrazmyl, pyridazinyl, pyrimidinyl and phenyl, optionally substituted with from one to two substituents selected from the group consisting of halo or (Ci-Cg)alkyl. In other embodiments, R2 is selected from the group consisting of
Figure imgf000039_0001
Figure imgf000039_0002
wherein each W10 or W11 is independently selected from the group consisting of
Figure imgf000039_0003
N, C, and CH; Rδ is halo or a straight or branched chain (d-CsJalkyl; the wavy line indicates the point of attachment to Y and the straight line indicates a point of attachment to R or Z. In other embodiments, R2 is phenyl or phenylene.
[0086] In one embodiment, the present invention provides R6 substituents, each independently selected from the group consisting of halo, nitro, cyano, nitrileoxide, -NO, R3, U1 -R3, iΛCOR3, 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, 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, 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- Cs)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, U^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- Cs)cycloalkyl, a (Q-Cs^eterocycloalkyl, 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, (d-C8)alkyl, (C1-C8)heteroalkyl, (C2-
C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C1-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 (Ci-C8)heterocycloalkyl, a (C3-Cs)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, 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)-Q=NMe)NMe2, NH-CO2Me, NH-SO2Me, NH-S02-Aryl, COMe, COEt, COpropyl,CO-cyclopropyl, CSNMe2, C(=NMe)NMe2, C0NHC(=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, (C1-C4) alkyl or (C1-C4)heteroalkyl, halogen, hydroxy, (Ci-C6) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino, and (C1-C4) dialkylamino. hi 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. hi 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 ≡€-CH3. [0087] hi one embodiment, R2 has 1 or 2 substituents. hi another embodiment, R2 has two R6 substituents. In one embodiment, each R6 is independently selected from the group consisting of halo and (Ci-C8)alkyl. In another embodiment, R6 is independently selected from the group consisting of Cl, Br, and CH3. hi another embodiment, each R6 is Cl. [0088] hi one embodiment, R3, R7, and R8 are independently selected from the group consisting of: H, -CH3, -CH2CH3,
Figure imgf000042_0001
Figure imgf000042_0002
In one embodiment, the compound is selected from the group consisting of:
Figure imgf000042_0003
wherein;
R6 is, independently Cl or CH3;
W1 is N or C;
W9 is N or CR6; W2 is a member selected from the group consisting of N, CR5, NR7 and CO; each W10 is independently, NH, CH2, O, or S; represents a single, double or normalized bond; and the subscript p is an integer of from 0 to 2.
[0090] In one embodiment, the
Figure imgf000043_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONfflλcycloalkyl;
L1 is selected from the group consisting of (C1-C8)alkylene, (C2-Cs)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (C1-C4)alkyl, heteroalkyl, halogen, hydroxy, (d-C4)alkoxy, cyano, nitro, amino, (Q-GOalkylamino and (C1-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or NR3CN; R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR3,
COR4, C COONNRR33CCOORR33,, C COOCCOORR44,, B B((OORR33))22,, S SOO22RR4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and R8 is H, (CrC8)alkyl or heteroalkyl;
W1 is N or C;
W9 is N or CR6;
W11 is independently O or CH2; and the subscript p is an integer of from 0 to 2. [0091] In one embodiment, the compound have the formula:
Figure imgf000044_0001
wherein
R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3,
CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NΗSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH- V5, L1- V5 and -L1CO2R4, -CN, -tetrazin-2-yl, -O-
L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and
CONHL^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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (d-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 S, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (Ci-C8)alkyl or heteroalkyl;
W9 is N or CR6;
W10 is independently O or CH2; and the subscript p is an integer of from O to 2. [0092] hi one embodiment, the com ound has the formula:
Figure imgf000045_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONfflΛcycloalkyl;
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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (C1-C^aIkOXy, cyano, nitro, amino, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 OrNR3CN;
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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(^NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (C1-C8)alkyl or heteroalkyl;
W1 is N or C;
W2 is a member selected from the group consisting of N, CR5, NR7 and CO
W9 is N, CR6 or CH;
W10 is independently O or CH2; and the subscript
[0093] In on
Figure imgf000046_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X^CO2H)2, -NHL^CO2H)2, COHNLVCO2H)2 and CONffiλcycloalkyl; 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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (CrC4)alkoxy, cyano, nitro, amino, (d-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
Cs)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 S, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and
R8 is H, (C1-C8)alkyl or heteroalkyl;
W9 is N, CR6 or CH;
W10 is independently O or CH2; and the subscript p is an integer of from O to 2. [0094] In one embodiment, the compound is selected from the group consisting of:
Figure imgf000047_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and COKfflλcycloalkyl;
L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (d-C4)alkylamino and (C]-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7KR3R7 or NR3CN;
R5 is H, OH or halogen; each V is a member independently selected from the group consisting of COOR , COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, KHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- Cg)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, KR8; and
R8 is H, (C1-C8)alkyl or heteroalkyl;
W9 is N, CR6 or CH; •
W10 is independently O or CH2; and the subscript p is an integer of from O to 2.
[0095] In one embodiment, the compound has the formula:
Figure imgf000049_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 -L1 CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL^cycloalkyl;
L1 is selected from the group consisting of (Q-C^alkylene, (C2-Cs)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (C1-C4)alkoxy, cyano, nitro, amino, (Q-GOalkylamino and (C]-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R and R are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (CrC8)alkyl or heteroalkyl; W1 is N or C; with the proviso that if W1 is N then R1 is not CO2H;
W9 is N, CR6 or CH;
W2 is a member selected from the group consisting of N, CR5, and CO; and
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond.
[0096] In one embodiment, the compound has the formula:
Figure imgf000050_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONfflλcycloalkyl;
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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (C1-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 OrNR3CN;
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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-Cs)alkyl, heteroalkyl, (C3- Cg)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (d-C8)alkyl or heteroalkyl;
W1 is N or C;
W is a member selected from the group consisting of N, CR , NR and CO;
W9 is N, CR6 or CH;
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond.
[0097] In one embodiment, the compound has the formula:
Figure imgf000051_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X^CO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL^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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy,
Figure imgf000051_0002
cyano, nitro, amino, (C1-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (C1-C8)alkyl, heteroalkyl, (C3-
C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (Ci-C8)alkyl or heteroalkyl; the subscript p is an integer of from O to 2;
W1 is N or C;
W2 is a member selected from the group consisting of N, CR5, NR7 and CO;
W9 is N, CR6 or CH;
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond.
[0098] In one embodiment, the compound has the formula:
Figure imgf000052_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHlΛcycloalkyl;
L1 is selected from the group consisting of (Ci-C8)alkylene, (C2-Cs)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (C]-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three Rb substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-Cs)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (C1-C8)alkyl or heteroalkyl; the subscript p is an integer of from O to 2; W1 is N or C;
W is a member selected from the group consisting of N, CR , NR and CO;
W9 is N, CR6 or CH;
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond. [0099] In any of the above embodiments, R1 is X1 -R7 or CO2R4. In another embodiment, R1 is C2alkenyl-CO2R4. In another embodiment, R4 is H or (CH2)qNR13 2; each R13 is independently (C1-C8)alkyl, or, if both present on the same substituent may be joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
[0100] In any of the above embodiments R6 is independently Cl, Br, or CH3. In another embodiment, R6 is Cl.
[0101] In another embodiment, the compound is selected from the group consisting of: 3-(4-Chloro-3H-inden-l-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000054_0001
3-(4-Chloro-benzofuran-3-yl)-2-oxo-2,3-diliydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000054_0002
3-(4-Chloro-lH-indol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000054_0003
3-(4-Chloro-benzo[b]thiophen-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000055_0001
3-(5-Chloro-3H-inden-l-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxy amide:
Figure imgf000055_0002
3-(6-Chloro-benzofuran-3-yl)-2-oxo-2,3-dihydiO-benzoimidazole-l-carboxylic acid hydroxy amide:
Figure imgf000055_0003
3-(6-Chloro-lH-indol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000055_0004
3-(6-Chloro-benzo[b]thiophen-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000056_0001
1 -(5-Chloro-3H-inden- 1 -yl)- lH-indazole-3-carboxylic acid:
Figure imgf000056_0002
l^ό-Chloro-benzofuran-S-yty-lH-indazole-S-carboxylic acid:
Figure imgf000056_0003
l-(6-Chloro-lH-indol-3-yl)-lH-indazole-3-carboxylic acid:
Figure imgf000056_0004
l-(6-Chloro-benzo[b]thiophen-3-yl)-lH-indazole-3-carboxylic acid:
Figure imgf000057_0001
[0102] In one embodiment, group consisting of:
Figure imgf000057_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL^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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-Cg)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and R8 is H, (C1-C8)alkyl or heteroalkyl;
W10 is NH, CH2, O, or S. [0103] In another embodiment, the compound is selected from the group consisting of:
Figure imgf000058_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL^cycloalkyl; L1 is selected from the group consisting of (C1-Cg)alkylene, (C2-C8)alkenyl, (C2-
C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy,
Figure imgf000058_0002
cyano, nitro, amino, (C1-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or NR3CN; R5 is H, OH or halogen; each V5 is a member independently selected from the group consisting of COOR , COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2;
R7 is selected from the group consisting of H, (Ci-Cg)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (Ci-C8)alkyl or heteroalkyl;
W10 is NH, CH2, O, or S; with the proviso that in compound
Figure imgf000059_0001
R1 is not CO2H.
[0104] In one embodiment, the compound is selected from the group consisting of:
l-(7-Chloro-3H-inden-l-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000059_0002
l-(4-Chloro-benzofuran-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000060_0001
l-(-Chloro-benzo[b]thiophen-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000060_0002
l-(5-Chloro-3H-inden-l-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000060_0003
l-(6-Chloro-benzofuran-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000061_0001
l-(6-Chloro-benzo[b]thiophen-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000061_0002
[0105] In other groups of embodiments, the following compounds are provided in the Examples below.
Synthesis of Lonidamine Analogs
[0106] Lonidamine analogs can be prepared by known synthetic methods and the teaching herein. Synthesis of lonidamine is described in U.S. Patent No. 3,895,026. Synthesis of lonidamine analogs, including tolnidamine (TND), has also been described {see, e.g., Corsi et al, 1976, "l-Halobenzyl-lH-Indazole-S-Carboxylic Acids. A New Class of Antispermatogenic Agents", J. Med. Chem. iP: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).
[0107] Synthetic methodology relevant to the preparation of other Lonidamine analogs in accordance with the methods of the invention is generally described in U.S. Pat. No. 6,146,658 and U.S. provisional application no. 60/576,968 (filed June 20, 2004) and U.S. provisional application 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), (II) and (III). Other exemplary prodrug forms of lonidamine are described in U.S. provisional application no. 60/586,934, entitled "Tertiary amine prodrugs of lonidamine and analogs" (filed July 8, 2004) and "Prodrugs of lonidamine and analogs" (filed Nov 1, 2004). Other exemplary lonidamine analogs are described in U.S. provisional application nos. 60/599,666 and 60/592,723, entitled "Heterocyclic Lonidamine Analogs" (filed Aug 5, 2004 and July 29, 2004 respectively); 60,599,664 and 60/592,677, entitled "Multicyclic Lonidamine Analogs" (filed Aug 5, 2004 and July 29 Aug 05, 2004 respectively) and provisional application entitled Lonidamine Analogs (filed Jan 21, 2005).
[0108] Collot et al, Tetrahedron Lett. 200, 41 (47):9053-9058; Ballard et al, Tetrahedron Lett. 1989, 30(18): 2345; and Tapia et al, J. Med. Chem. 1999, 42: 2870 et a\. describe methods which can be used in the synthesis of compounds of the invention in accordance with the teaching herein. The compounds of the present invention can be synthesized according to methods provided below.
[0109] In one embodiment of the invention, methods for making lonidamine analogs of formula (I) are provided as shown in Schemes 1-4 below:
Figure imgf000063_0001
111
Scheme 2
Figure imgf000063_0002
VIl VlIl
Scheme 4
Figure imgf000063_0003
[0110] Thus in Schemes 1 and 4, compound i or ix can be converted to compound ii and x, respectively, by using any of a variety of coupling reagents. Examples of such coupling reagents include, but are not limited to, Pd2dba3 or Pd(PPh3)4, PdCl2(PPh3)2 or Pd(OAc)2 in combination with Cs2CO3, NaOCMe3, NaHCO3 or NEt3; or CuI or Cu(OAc)2 in DMF. [0111] In another embodiment of the invention, a method for making lonidamine analogs of formula (I) is provided as shown in scheme 5 below:
Scheme 5
[0112] In another embodiment of the invention, a method for making lonidamine analogs of formula (I) is provided as shown in scheme 6 below:
Scheme 6
Figure imgf000064_0002
[0113] In another embodiment of the invention, a method for making lonidamine analogs of formula (II) is provided as shown in scheme 7 below:
Scheme 7
Figure imgf000064_0003
[0114] In another embodiment of the invention, a method for making lonidamine analogs of formula (III) is provided as shown in scheme 8 below:
Figure imgf000065_0001
Figure imgf000065_0003
Figure imgf000065_0002
[0115] In another embodiment of the invention, a method for making lonidamine analogs is provided in commonly assigned copending patent application PCT US 05/ entitled
"Lonidamine analogs" filed July 29, 2005 (Attorney docket No. 021305-002810PC).
[0116] Syntheses of ester prodrugs of the lonidamine analog compounds 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 presences of an inert base, such as triethyl amine, 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 recrystalization 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.
[0117] Suitable starting materials are commercially available. Non-commercially available starting materials can be synthesized via 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.
[0118] 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 acid addition salts are citric acid salt.
[0119] 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 amino acids include, but are not 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 an amine (wherein the amine is defined as above). In one embodiment, one equivalent of an amine is mixed with one equivalent of lonidamine or a lonidamine analog in water. The mixture is stirred 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, when in a base addition salt one component is lonidamine, the base is other than arginine or glycine. 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.
[0120] 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.
[0121] 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 thai 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.
[0122] 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.
[0123] In a preferred 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 [0124] 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 [0125] 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.
[0126] 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.
[0127] 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. Dosafies and Administration
[0128] 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.
[0129] 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.
[0130] 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. hi 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.
[0131] 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).
[0132] 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 Pharmaceutical Compositions Benign Prostatic Hyperplasia (BPH)
[0133] 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(suppl 7):S27-33] which also provides exemplary dosage regimens and schedules for treatment of BPH.
Treatment of Cancer [0134] 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.
[0135] 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(l), 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, flutaniide, 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"-trichlorotriethylamine, urethan, vinblastine and vincristine. Prevention of Epithelial Cancer
[0136] 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. In 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.
[0137] 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.
[0138] 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), HEXIMl (ovarian epithelial cancer), FL J20267 (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 al., 2005, J. Cell. MoI. Med. 9:208-21; or (4) family history of epithelial cancer.
[0139] 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.
[0140] 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] .
Prostatic Intraepithelial Neoplasia (PEST)
[0141] 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 Biochern. Suppl. 16H:10-9. Patients diagnosed as having HGPIN have an increased likelihood of developing prostate cancer within 10 years.
[0142] 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.
[0143] 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
[0144] 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). hi 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.
[0145] 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 [0146] 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.
[0147] 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.
Antispermatogenesis
[0148] 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. 29:778-83; 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 27:61-76; U.S. Patent 6,001,865 entitled "3 -Substituted 1 -Benzyl- lH-Indazole 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 al., 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.
[0149] 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.
[0150] In an related use, compounds of the invention can be used to control fertility in animals (e.g., rodents).
Energolvtic Activity [0151] It has been suggested that lonidamine's anticancer properties result at least in part from a lonidamine-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.
[0152] hi certain embodiments the patient is not also under treatment for BPH or cancer, hi certain embodiments the patient has not previously been treated for BPH or cancer.
[0153] 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. hi various embodiments, a pharmaceutical composition of the invention may be any compound described herein, hi various embodiments, a pharmaceutical composition of the invention may comprise a compound of Formula I, or compounds of any of Groups 1-38, as described above. In certain embodiments, compounds of one, more than one, or all of Groups A-I are excluded.
[0154] 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 [0155] 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. 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.
[0156] 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.
[0157] Also see Example 8, infra, for an apoptosis assay for characterizing analogs.
Apoptosis assay in primary cell cultures.
[0158] 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 mM).
HIF-I -alpha expression assays.
[0159] 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 HIF-I -alpha expression (prevents HIF-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.
[0160] 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.
[0161] 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, BiolReprod. 64:1500-8; Lohiya et al, 1991, 43:485- 96.
[0162] 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.
[0163] 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. [0164] 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.
[0165] 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.
EXAMPLES
EXAMPLE 1 [0166] SYNTHETIC EXAMPLES
[0167] The following example provides methods for synthesizing compounds of the present invention
[0168] -chloronitrobenzene is reacted with diethyl malonate and sodium hydride in THF followed by reductive cyclization employing Pd-C and hydrogen in MeoH, and double alkylation of the cyclized product with 3,4-(dibromomethyl)benzene employing K2CO3 in DMF to yield a multicyclic compound of the present invention as shown in the Scheme below
Figure imgf000080_0001
[0169] Tertiarybutyl indazole-3-carboxylate is reacted with benzofuran-3-boronic acid employing Cu(OAc)2 and Pd(PPh3)4 in DMF to yield a multicyclic compound of the present invention as shown in the scheme below:
Figure imgf000080_0002
EXAMPLE 2 Antiproliferation assay
19 [0170] To determine the effect of the compounds of the invention on cell proliferation, the antiproliferative activity of the compounds of the invention is 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 is compared, as measured by a fluorescence plate reader at excitation 550 nm and emission 590 nm (see Biosource International Inc., Tech Application Notes, Use of Alamar Blue in the measurement of Cell Viability and Toxicity, Determining IC50). H460 cells (ATCC HTB- 177 (NCI-H40), 4,000 cells/well/200 μ\) and LNCap cells (ATCC CRL- 1740,6,000 cells/well/200 μl) are seeded in a 96 well plate in RPMI medium (Invitrogen Corporation, Carlsbad, CA). After 24 hours, these plates are divided into 3 groups - Control group, 2h treatment group and 3 day treatment group. A test compound is added to each plate in the treatment groups (2h and 3 day) at a various concentration. In the 2h treatment group, after 2h the cells are rinsed to remove the test compound and incubated for 3 days, followed by staining with AlamarBlue. The cells in the 3 day treatment group are incubated for 3 days, followed by staining with AlamarBlue. In the Control group, AlamarBlue is 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 is 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 (GI5O (also referred to IC50 herein)) of lonidamine and lonidamine analogs is calculated.
EXAMPLE 3 Antiproliferation assay
[0171] The effect of the compounds of the invention on cell proliferation in PWR-IE cells (ATCC CRL-11611) is 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.
EXAMPLE 4 BrdU-TUTSfEL assay [0172] The effect of the compounds of the invention on apoptosis is determined as follows. PWR-IE cells (2 x 105 cells/ml/well) are seeded in a 24 well plate. After 24 h the test compound is added at various concentrations. The culture media are removed after 24 h, the cells are 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 is added to each well, the cells released by repeated pipeting, centrifuged, and the supernatant aspirated. The cells are resuspended in PBS buffer (150 μL) and fixed by incubating (60 min, 40C) with 4% paraformaldehyde in PBS. The cells are centrifuged, and the supernatant removed to a final volume of 15 μL. The cell pellets are 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 are centrifuged, the supernatant removed, washed, and incubated with the DNA labeling mix (370C, 60 min). The cells are 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 effect of the test compound on apoptosis of LNCaP cells is determined using the same protocol as described above.
EXAMPLE 5 Cell cycle analysis
[0173] The effect of a compound of the invention on the cell cycle is determined as follows. LNCaP cells (2 x 105 cells/ml/well) are seeded in a 24 well plate. After 24 h, the test compound is added at various concentrations. The culture media are removed after 24 h, the cells are trypsinized and centrifuged. The cell pellets are resuspended in lOOμl PBS buffer, after which 300 μl of ice-cold ethanol (96%) added dropwise, and the cells are incubated at 40C for at least 24 hr. The cells are centrifuged and the supernatant is discarded. The cell cycle staining reagent (Guava Technologies, Hayward, CA, USA, 200 μl) is added to each well. The cells are shielded from light and incubated at room temperature for 30 min. The samples are analyzed (Guava PCA-96 instrument, Cytosoft software, Guava Technologies, 25801 Industrial Boulevard, Hayward CA 94545-2991, USA).
EXAMPLE 6 Mouse studies
[0174] The effect of a compound of the invention on the mouse prostate is determined as follows. The compound is 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 are sacrificed and the entire prostate and the individual lobes (e.g., the dorsal lobe and the ventral lobe) are weighed to measure absolute weights. Relative weights of prostate and individual lobes are 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 are calculated by dividing the absolute weight by the total weight of the mouse.
[0175] The absolute entire prostate and relative entire prostate weights reduced in the test groups compared to the control group. The histomorphology of the prostate is also analyzed and compared to that of the control or untreated prostate.
EXAMPLE 7 Mouse studies
[0176] The effect of a compound of the invention on the mouse prostate is determined as follows. The test compound is 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 are sacrificed and the left and right testes, the entire prostate and the individual prostatic lobes (e.g., the dorsal lobe and the ventral lobe) are weighed to measure absolute weights. Relative weights of entire prostate and individual lobes are 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 are calculated by dividing the absolute weight by the total weight of the mouse. Relative weights of the left and right testis are calculated by dividing the corresponding absolute weights by the total weights of the mouse.
EXAMPLE 8 In vivo viability and proliferation of mouse prostate cells
[0177] Prostate cells harvested from mice treated with a compound of the invention are assayed by the TUNEL assay as described above. The prostate cells are 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. %*#
[0178] 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 the formula selected from the group consisting of: 1
Figure imgf000085_0001
(I) (II) (III) 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; (d-C8)alkyl, (C1-C6) alkoxy, nitro, acetamido, lΛC02H, iΛdialkylamino, (C1- C8)heteroalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C1-C8)heterocyclyl, aryl, heteroaryl; U1 -R3, iΛCOR3, U1 -CUMt3R7, U1 -CU2R3, R4, NR3OR3, NR3-CUR3, N-(CUR3)2,
Figure imgf000085_0002
NR -CU2R', N-(CU2RJ)2, NR -SO2R", N-(SO2RJ)2, NR - ORJ, N-(SORJ)2, NR -PU2R', N-(PU2RJ)2, NR 3 - 1P3/ >3τ) 7
S (—= TU)(URJ)RJ, CURJ, CU2R"5, CUNR'R', 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,
>3π7\ > 3r,7 3r>7Λ
PU(URJ)(NR'R'), PU(NRJR')2, PU(NRJCOR')2, PU(NRXU2RO2, PU(NRJCUNRJR')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- Cs)cycloalkyl, a (C1-Cg)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, 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, -NHL1 (CO2H)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 (C1- C8)heterocycloalkyl, a (C3-C8)cycloalkenyl, an aryl or a heteroaryl ring; 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 V wherein each V1 is independently selected from the group consisting of (C]-C4)alkyl, (Q- 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, (CrC4)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; 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, SO2R3, SOR3, -NO, R3, U^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, 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, NR32(NR32)2, nitrileoxide, and-NO; each R3 is a member independently selected from the group consisting of H, (Ci C8)alkyl, (C1-C8)heteroalkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (d- C8)heterocyclyl, aryl and heteroaryl; each R is a member independently selected from the group consisting of NR R , 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, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C1-C8)heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a (C1-C8)heterocyclyl or heteroaryl ring; R8 is H, halo, nitro, cyano, nitrileoxide, -NO, R3, U^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)2j 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 CHR8, CR8, NR8, U is O, S, NR3, NCOR3, or NCONR3R7; U1 is O or S; Z is a alkylene or heteroalkylene chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single or double bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
2. A compound of claim 1, wherein A-B is a 5, 5-fused cyclic ring system.
3. A compound of claim 1, wherein A-B is selected from the group consisting of:
Figure imgf000087_0001
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
4. A compound of claim 1, wherein A-B is a 7, 5-fused cyclic ring system.
5. A compound of claim 1, wherein the cyclic ring system A-B has the formula VA:
Figure imgf000088_0001
(VA) 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.
6. A compound of claim 1, wherein A-B is a 6, 5-fused cyclic ring system.
7. A compound of claim 1, wherein A-B is a 6, 5-fused cyclic ring system of formula (VIA):
Figure imgf000088_0002
(VIA) 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.
8. A compound of claim 1, 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-,
Figure imgf000089_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-C8)cycloalkyl, a (C]-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, 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 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; 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 (C1- C8)alkyl; R3 is H, (Ci-C8)alkyl, (CrC8)heteroalkyl, (C3-C8)cycloalkyl, (Ci-C8)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, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (CrC8)heterocyclyl, aryl or heteroaryl; R3 and R7 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, (Ci-C4) alkyl, (Ci-C^heteroalkyl, halogen, hydroxy, (C1-C6) alkoxy, amino, cyano, nitro, (C1-C4) alkylamino and (C1-C4) dialkylamino; Y is CHR8, CR8, NR8; R8 is H, (C1-C8)aUcyl or (d-C^heteroalkyl; represents a single, double or normalized bond; and
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
9. A compound of the formula selected from the group consisting of:.
Figure imgf000090_0001
(W) (V) (VI) wherein R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR6 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- L1 (CO2H)2, -NH L1CCO2H)2, COHN L1CCO2H)2 and CONHL1 -cycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (C1-C4)alkyl, heteroalkyl, halogen, hydroxy, (C1-C4)alkoxy, cyano, nitro, amino, (Q-GOalkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or 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 and a straight or branched chain (C1-Cs)alkyl; each R3 is a member independently selected from the group consisting of H, (C i- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of NR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R2 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; each W1, W3, W4 or W5 is independently N or C; W2 is a member selected from the group consisting of N, NV6, CV6, CO, O, and S; each W6, W7, W8 or W9 is independently N or CR12 Y is CHR8, CR8, NR8; R8 is H, (Ci-C8)alkyl or heteroalkyl; R12 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C4) alkyl or heteroalkyl, halogen, hydroxy, (C1-C4) alkoxy, amino, cyano, nitro, (Ci-C4) alkylamino, and (Ci-C4) dialkylamino; Z is an alkyl or heteroalkyl chain, saturated or unsaturated, which in combination with the remainder of the molecule is joined to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; represents a single, double or normalized bond; and pharmaceutically acceptable salts, solvates, hydrates, tautomers and prodrugs thereof.
10. The compound of any one of claims 1, 7- 9 wherein A-B is a member selected from the group consisting of:
Figure imgf000092_0001
Figure imgf000092_0002
wherein the solid line indicates the point of attachment to R1 and the wavy line indicates the point of attachment to Y.
11. The compound of any one of claims of the preceding claims wherein R1 is selected from the group consisting of:
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0003
Figure imgf000093_0004
Figure imgf000093_0005
Figure imgf000093_0006
12. The compound of any one of claims of the preceding claims wherein R1 is COOR3.
13. The compound of any one of claims of the preceding claims wherein R3 is H or (CH2)HNR13 2 wherein each R13 is a (d-C8)alkyl, or, if both present on the same substituent, may be joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
14. The compound of any one of claims of the preceding claims wherein Y is NR8
15. The compound of any one of claims 1-13 wherein Y is CR .
16. The compound of any one of claims 1-13 wherein Y is CHR8.
17. The compound of claim 16 wherein Y is CH.
18. The compound of any of the preceding claims wherein R 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 (Ci-Cs)alkyl.
19. The compound of any of the preceding claims wherein R is selected from the group consisting of
Figure imgf000094_0001
wherein each W10 or W11 is independently selected from the group consisting of N, C, and CH; R6 is halo or a straight or branched chain (Ci-C8)alkyl; the wavy line indicates the point of attachment to Y and the straight line indicates a point of attachment to R6 or Z.
20. The compound of any of the preceding claims wherein R2 is phenyl or phenylene.
21. The compound of any of the preceding claims wherein each R6 is independently selected from the group consisting of Cl, Br, and CH3.
22. The compound of any of the preceding claims wherein each R6 is Cl.
23. The compound of any of the preceding claims wherein each R3, R7, and R8 are independently selected from the group consisting of: H, -CH3, -CH2CH3,
Figure imgf000096_0001
Figure imgf000096_0002
24. The compound of claim 1 selected from the group consisting of:
Figure imgf000096_0003
wherein;
R6 is, independently Cl or CH3;
W1 is N or C;
W9 is N or CR6; W2 is a member selected from the group consisting of N, CR5, NR7 and CO; each W10 is independently, NH, CH2, O, or S; represents a single, double or normalized bond; and the subscript p is an integer of from 0 to 2.
25. The compound of claim 1
Figure imgf000097_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -cycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-Cg)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy,
Figure imgf000097_0002
cyano, nitro, amino, (C1-C4)aUcylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R and R are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (C1-C8)alkyl or heteroalkyl; W1 is N or C; W9 is N or CR6; W11 is independently O or CH2; and
the subscript p is an integer of from 0 to 2.
26. The compound of claim 1 having the formula:
Figure imgf000098_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL^cycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-Cs)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (C]-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (C]-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci- C8)alkyl, heteroalkyl, (C3-Cg)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 S, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (CrC8)alkyl or heteroalkyl;
W9 is N or CR6;
W11 is CH2 or O; and the subscript p is an integer of from O to 2.
27. The compound of claim 1 having the formula:
Figure imgf000099_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 -L1CO2R4, -CN, -tetrazin-2-yl, -0- L1CO2R3, -0-PO3H, -0-SO3H, 0-X^CO2H)2, -NHL^CO2H)2, COHNL^CO^z and CONHL^cycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy,
Figure imgf000099_0002
cyano, nitro, amino, (C1-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 S, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (d-C8)alkyl or heteroalkyl; W1 is N or C; W2 is a member selected from the group consisting of N, CR5, NR7 and CO W9 is N, CR6 or CH; W10 is independently O or CH2; and
the subscript p is an integer of from O to 2.
28. The compound of claim 1 selected from the group consisting of:
Figure imgf000100_0001
R1 is selected from the group consisting Of CO2 3
Figure imgf000100_0002
R^, / C~I/OΎRΓ» 44,
CH=CHCO O22RR-3, B(OR3)2, SO2R4, NHSO2CR5 S, NHSO2CR3 3, CONHSO2CR3 3, C(=NCN)NH2, -NHCO-V5, -NHNH- V5, L1- V5 and -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -cycloalkyl; L1 is selected from the group consisting of (Ci-Cs)alkylene, (C2-Cg)alkenyl, (C2- C8)alkynyl, and (C3-Cs)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (Ci~C4)alkylamino and (C]-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (Ci-C8)alkyl or heteroalkyl; W9 is N or CR6; W10 is independently O or CH2; and the subscript p is an integer of from O to 2.
29. The compound of claim 1 having the formula:
Figure imgf000102_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONfflλcycloalkyl; 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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (C1-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci - C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (C1-C8)alkyl, heteroalkyl, (C3- Cg)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R and R are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (Ci-C8)alkyl or heteroalkyl; W9 is N, CR6 or CH;
W2 is a member selected from the group consisting of N, CR5, and CO; and
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond.
30. The compound of claim 1 wherein the compound has the formula:
Figure imgf000103_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHL1 -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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Ci-C4)alkoxy, cyano, nitro, amino, (CrC^alkylamino and (C1-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or NR3CN;
R5 is H, OH or halogen; each V is a member independently selected from the group consisting of COOR , COR4, CONR3COR3, COCOR4, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (Ci-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring;
Y is CHR8, CR8, NR8; and
R8 is H, (Ci-C8)alkyl or heteroalkyl;
W1 is N or C;
W2 is a member selected from the group consisting of N, CR5, NR7 and CO;
W9 is N, CR6 or CH;
W10 is NH, CH2, O, or S; and represents a single, double or normalized bond.
31. The compound of claim 1 wherein compound has the formula:
Figure imgf000104_0001
wherein R1 is selected from the group consisting of CO2R3, COR4, CONR3COR3, CH=CHCO2R3, B(OR3)2, SO2R4, NHSO2CR5 3, NHSO2CR3 3, CONHSO2CR3 3j C(=NCN)NH2, -NHCO-V5, -NHNH- V5, L1- V5 and -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONfflλcycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (CrC4)alkoxy, cyano, nitro, amino, (CrC^alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci - C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting OfNR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(^NCN)NH2; R7 is selected from the group consisting of H, (C1-C8)alkyl, heteroalkyl, (C3- Cs)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (C1 -C8)alkyl or heteroalkyl; the subscript p is an integer of from O to 2; W1 is N or C; W is a member selected from the group consisting of N, CR , NR and CO; W9 is N, CR6 or CH; W10 is NH, CH2, O, or S; and
represents a single, double or normalized bond.
32. The of:
Figure imgf000105_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X^CO2H)2, -NHL^CO2H)2, COHNL^CO2H)2 and CONHL^cycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (Q-GOalkoxy, cyano, nitro, amino, (d-C4)alkylamino and (Ci-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (C1- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of NR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (C1-C8)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (C1-C8)alkyl or heteroalkyl;
W10 is NH, CH2, O, or S.
33. The compound of claim 29 that is selected from the group consisting of: 3-(4-Chloro-3H-inden- 1 -yl)-2-oxo-2,3-dihydro-benzoimidazole- 1 -carboxylic acid hydroxyamide:
Figure imgf000106_0001
3-(4-Chloro-benzofuran-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l -carboxylic acid hydroxyamide:
Figure imgf000107_0001
3-(4-Chloro-lH-indol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxy amide:
Figure imgf000107_0002
3 -(4-Cliloro-benzo [b]thiophen-3-yl)-2-oxo-2,3 -dihydro-benzoimidazole- 1 -carboxylic acid hydroxyamide:
Figure imgf000107_0003
34. The compound of claim 29 that is selected from the group consisting of: 3-(5-Chloro-3H-inden-l-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000108_0001
3-(6-Chloro-benzofuran-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000108_0002
3-(6-Chloro-lH-indol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000108_0003
3-(6-Chloro-benzo[b]thiophen-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-l-carboxylic acid hydroxyamide:
Figure imgf000108_0004
l-(5-Chloro-3H-inden-l-yl)-lH-indazole-3-carboxylic acid:
Figure imgf000109_0001
^(ό-Chloro-benzofuran-S-y^-lH-indazole-S-carboxylic acid:
Figure imgf000109_0002
l^β-Chloro-lH-indol-S-yty-lH-indazole-S-carboxylic acid:
Figure imgf000109_0003
^(ό-Chloro-benzotbJtliiophen-S-y^-lH-indazole-S-carboxylic acid:
Figure imgf000109_0004
35. The compound of claim 1 selected from the group consisting of:
Figure imgf000110_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1 (CO2H)2 and CONHL1 -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 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (C1-C^aIkOXy, cyano, nitro, amino, (CrC^alkylamino and (C1-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring;
R2 is an aryl or heteroaryl group, optionally substituted with from one to three R6 substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci-
C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting of NR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(=NCN)NH2; R7 is selected from the group consisting of H, (d-Cs^lkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (C1 -C8)alkyl or heteroalkyl; W10 is NH, CH2, O, or S; with the proviso that in compound
Figure imgf000111_0001
R1 is not CO2H.
36. The compound of claim 1 wherein the compound is selected from the group consisting of:
Figure imgf000111_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 -L1CO2R4, -CN, -tetrazin-2-yl, -O- L1CO2R3, -0-PO3H, -0-SO3H, 0-X1CCO2H)2, -NHL1CCO2H)2, COHNL1CCO2H)2 and CONHlλcycloalkyl; L1 is selected from the group consisting of (C1-C8)alkylene, (C2-C8)alkenyl, (C2- C8)alkynyl, and (C3-C8)cycloalkylene, optionally substituted with from one to fourteen V1 substituents independently selected from the group consisting of (Ci-C4)alkyl, heteroalkyl, halogen, hydroxy, (d-C4)alkoxy, cyano, nitro, amino, (Ci-C4)alkylamino and (C1-C4) dialkylamino, or any two V1 attached to adjacent atoms may taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, or heteroaryl ring; R is an aryl or heteroaryl group, optionally substituted with from one to three R substituents independently selected from Cl or CH3; each R3 is a member independently selected from the group consisting of H, (Ci- C8)alkyl, heteroalkyl, (C3-C8)cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of NR3R7, NR3OR7, NR7NR3R7 or 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, NHSO2CR3 3, CONHSO2CR3 3, NHSO2R3 and C(-NCN)NH2; R7 is selected from the group consisting of H, (Ci-Cg)alkyl, heteroalkyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, heteroaryl; or R3 and R7 are taken together form a cycloalkylene, heterocyclyl or heteroaryl ring; Y is CHR8, CR8, NR8; and R8 is H, (Ci-C8)alkyl or heteroalkyl;
W10 is NH, CH2, O, or S.
37. The compound of any of the preceding claims wherein each R1 is L1- V5 or CO2R3.
38. The compound of any of the preceding claims wherein R1 is C2alkenyl- CO2R3.
39. The compound of any of the preceding claims wherein R3 is H or (CH2)qNR13 2; each R13 is independently (Ci-C8)alkyl, or, if both present on the same substituent may be joined together to form a three- to eight-membered cycloalkyl or heterocyclyl ring system; and the subscript n is an integer of from 1 to 4.
40. The compound of any of the preceding claims wherein each R6 is independently Cl, Br, or CH3.
41. The compound of any of the preceding claims wherein R is Cl.
42. The compound of claim 35 that is selected from the group consisting of: l-(7-Chloro-3H-inden-l-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000113_0001
l-(4-Chloro-benzofuran-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000113_0002
l-(-Chloro-benzo[b]thiophen-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000113_0003
l-(5-Chloro-3H-inden-l-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000114_0001
l-(6-Chloro-benzofuran-3-yl)-2-oxo-l,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000114_0002
1 -(6-Chloro-benzo[b]thiophen-3-yl)-2-oxo- 1 ,2-dihydro-cyclohepta[b]pyrrole-3-carboxylic acid:
Figure imgf000114_0003
43. A method of inhibiting proliferation of a cell comprising contacting the cell with an compound of claims 1-42 or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
44. The use of a compound of any of claims 1 -42 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.
45. A method for treating cancer, said method comprising administering to a mammal a therapeutically effective amount of a compound of claims 1 -42 to a human subj ect in need of such treatment.
46. A method for treating benign prostatic hypertrophy (BPH) comprising administering a therapeutically effective amount of a compound of claims 1-42 to a human subj ect in need of such treatment.
47. A method for reducing a symptom associated with BPH comprising administering a compound of claims 1-42 to a human subject exhibiting the symptom.
48. A method of reducing prostate size in a human subject, comprising administering a therapeutically effective amount of a compound of claims 1 -42 to the subj ect.
49. A method for prophylaxis of BPH comprising administering a prophylactically effective amount a compound of claims 1-42 to a human subject.
PCT/US2005/026929 2004-07-29 2005-07-29 Multicyclic lonidamine analogs WO2006015191A2 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US59267704P 2004-07-29 2004-07-29
US60/592,677 2004-07-29
US59966404P 2004-08-05 2004-08-05
US60/599,664 2004-08-05
US65167105P 2005-02-09 2005-02-09
US60/651,671 2005-02-09

Publications (2)

Publication Number Publication Date
WO2006015191A2 true WO2006015191A2 (en) 2006-02-09
WO2006015191A3 WO2006015191A3 (en) 2006-11-09

Family

ID=35787857

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/026929 WO2006015191A2 (en) 2004-07-29 2005-07-29 Multicyclic lonidamine analogs

Country Status (2)

Country Link
TW (1) TW200605885A (en)
WO (1) WO2006015191A2 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139499A1 (en) * 2006-05-31 2007-12-06 Aprea Ab Compounds for use as a medicament
EP2336141A2 (en) 2005-06-29 2011-06-22 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
CN102786463A (en) * 2012-07-02 2012-11-21 浙江金伯士药业有限公司 Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester
US8394819B2 (en) 2009-02-24 2013-03-12 Merck Sharp & Dohme Corp. Indole derivatives as CRTH2 receptor antagonists
US8492374B2 (en) 2009-04-29 2013-07-23 Industrial Technology Research Institute Azaazulene compounds
CN108440538A (en) * 2018-05-04 2018-08-24 上海工程技术大学 New pyrrole and imidazole derivative and preparation method thereof and purposes
CN108659003A (en) * 2018-04-14 2018-10-16 刘建 A kind of preparation method of pharmaceutical composition that treating canker sore
EP3564214A1 (en) 2018-05-04 2019-11-06 Universita' Degli Studi G. D Annunzio Chieti - Pescara Indazole derivatives as modulators of the cannabinoid system

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313138B1 (en) * 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313138B1 (en) * 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2336141A2 (en) 2005-06-29 2011-06-22 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2007139499A1 (en) * 2006-05-31 2007-12-06 Aprea Ab Compounds for use as a medicament
US8394819B2 (en) 2009-02-24 2013-03-12 Merck Sharp & Dohme Corp. Indole derivatives as CRTH2 receptor antagonists
US9023864B2 (en) 2009-02-24 2015-05-05 Merck Sharp & Dohme Corp. Indole derivatives as CRTH2 receptor antagonists
US8492374B2 (en) 2009-04-29 2013-07-23 Industrial Technology Research Institute Azaazulene compounds
CN102786463A (en) * 2012-07-02 2012-11-21 浙江金伯士药业有限公司 Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester
CN108659003A (en) * 2018-04-14 2018-10-16 刘建 A kind of preparation method of pharmaceutical composition that treating canker sore
CN108659003B (en) * 2018-04-14 2021-01-26 上海朝晖药业有限公司 Preparation method of compound for treating oral ulcer
CN108440538A (en) * 2018-05-04 2018-08-24 上海工程技术大学 New pyrrole and imidazole derivative and preparation method thereof and purposes
EP3564214A1 (en) 2018-05-04 2019-11-06 Universita' Degli Studi G. D Annunzio Chieti - Pescara Indazole derivatives as modulators of the cannabinoid system
CN108440538B (en) * 2018-05-04 2021-03-16 上海工程技术大学 Novel pyrroloimidazole derivative and preparation method and application thereof

Also Published As

Publication number Publication date
WO2006015191A3 (en) 2006-11-09
TW200605885A (en) 2006-02-16

Similar Documents

Publication Publication Date Title
WO2006015263A2 (en) Lonidamine analogs
US20070043057A1 (en) Lonidamine analogs
US20070015771A1 (en) Lonidamine analogs
CN111163771B (en) Use of pyrimidopyrimidinones as SIK inhibitors
CN107922431B (en) HPK1 inhibitors and methods of use thereof
BR112021002327A2 (en) 6-(4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decan-8-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3h) derivatives -one and related compounds as ptpn11(shp2) inhibitors for cancer treatment
EP3567035B1 (en) N-substituted 2,5-dioxo-azoline compounds for use in the treatment of cancer
RU2686323C2 (en) Novel compounds and compositions for inhibition of fasn
WO2006015191A2 (en) Multicyclic lonidamine analogs
ES2435997T3 (en) Aminopyrimidines useful as protein kinase inhibitors
JP7050093B2 (en) Substituted 5- and 6-membered heterocyclic compounds, methods of preparation thereof, combinations of agents and their use
JP2008520719A (en) Tubulin-binding anticancer agents and their prodrugs
JP2016505596A (en) PRMT5 inhibitors and uses thereof
JP2016505597A (en) PRMT5 inhibitors and uses thereof
JP2019505541A (en) Carboxamide derivatives useful as RSK inhibitors
CA3138197A1 (en) Anti-cancer nuclear hormone receptor-targeting compounds
CN113717156B (en) EGFR inhibitor, preparation method and application thereof
US20190070154A1 (en) New methods of use for an anti-diarrhea agent
JP2021185193A (en) Indenyl compound, pharmaceutical composition and medical use thereof
CA3118400A1 (en) Pyridinone-based epigenetic modifiers and uses thereof
US20190084988A1 (en) Wdr5 inhibitors and modulators
WO2017106520A1 (en) Compounds, compositions and methods of treating cancer
AU2014366436A1 (en) Fluorophenyl pyrazol compounds
US11987579B2 (en) Niclosamide analogues and therapeutic use thereof
BR112019022331A2 (en) METHODS OF USE FOR BENZOTRIAZOL DERIVATIVES TRISUBSTITUTED AS INHIBITORS OF DI-HYDRO-OROTATE OXYGENASE

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase