WO2012047569A1 - Composés tricycliques accolés inhibiteurs de la cible mammifère de la rapamycine - Google Patents

Composés tricycliques accolés inhibiteurs de la cible mammifère de la rapamycine Download PDF

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WO2012047569A1
WO2012047569A1 PCT/US2011/053199 US2011053199W WO2012047569A1 WO 2012047569 A1 WO2012047569 A1 WO 2012047569A1 US 2011053199 W US2011053199 W US 2011053199W WO 2012047569 A1 WO2012047569 A1 WO 2012047569A1
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alkyl
compound
compounds
inhibitors
heteroaryl
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PCT/US2011/053199
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English (en)
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Zhaoyang Meng
Panduranga Adulla P. Reddy
M. Arshad Siddiqui
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Schering Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel fused tricyclic compounds that are inhibitors of mammalian Target of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP, and are useful in the treatment of cellular proliferative diseases, for example cancer and other proliferative disorders.
  • mTOR mammalian Target of Rapamycin
  • mTOR The mammalian target of rapamycin
  • mTOR is a central regulator of cell growth and proliferation and plays a gatekeeper role in the control of cell cycle progression.
  • mTOR mediates mitgenic signals from P13K/AKT through to the downstream targets S6K1 and 4E-BP1 and to Ser 473 on AKT.
  • Rator-mTOR complex mTORCl
  • mTORCl Rator-mTOR complex
  • S6K1 ribosomal S6 kinase 1
  • 4E-BP1 eukaryotic translation initiation factor 4E-binding protein
  • Rictor-mTOR complex is a rapamycin-insensitive complex that phosphorlates AKT. Although the precise mechanism by which rapamycin inhibitis mTOR function is not well understood, rapamycin partially inhibits mTOR function through mTORCl. Since mTORC2 is involved in the regulation of cell survival and actin cytoskeletal organization in a rapamycin-independent manner, complete inhibition of mTOR function through inhibition of both mTORCl and mTORC2 may lead to a broader spectrum antitumor activity and/or better efficacy than through inhibition of mTORCl alone.
  • the present invention relates to novel fused tricyclic derivatives, that are useful for treating cancer and other cellular proliferative diseases, for treating disorders associated with mTOR activity, and for inhibiting the mTOR kinase.
  • the compounds of the invention may be illustrated by the Formula I:
  • the compounds of this invention are useful in the inhibition of mTOR kinase, and are illustrated by a compound of the formula:
  • W is CR x R y , NR S , or SO m ;
  • Y is CR x R y , NR 6 , 0, C(O) or SO m ;
  • Z is CR x R y , NR 5 , O, C(O) or SO m ;
  • R 1 is hydrogen, halo, -C(0)R 5 , C 1-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Cj-s cycioalkyl, C 3- g cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo, cyano, Ci -6 alkyl, C 1-6 haloalkyl, (CR y R z ) m OR (CR y R z ) ra NR3 ⁇ 4 z , C(0)R y , C(0)OR y , SO m R y , C(0)NR y R z , NR y C(0)R 3 and
  • R 2 is hydrogen, halo, cyano, NR y R z , OR y , Ci -6 alkyl or C ⁇ 6 haloalkyl;
  • R 3 is hydrogen, NR R z , (CR R z ) m OR Q.6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3 _ 8 cycioalkyl, C 3 . 8 cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said cycioalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, Ci -6 alkyl, C J-6 haloalkyl and 0R y ;
  • R 4 is C -8 cycioalkyl, C 3 physically 8 cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said cycioalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C 3-6 alkyl, C 1-6 haloalkyl, (CR y R z ) m OR 0(d -6 haloalkyl), C(0)R y , C(0)OR y , SO m R y and NR y R z ;
  • R 5 is not present, hydrogen, aryl, heteroaryl, heterocyclyl or heterocyclyl(R 6 );
  • R x is hydrogen or C ⁇ alkyl;
  • R y is not present, hydrogen, Cj -6 alkyl or Ci -6 haloalkyl, wherein said alkyl group is optionally substituted with one to three hydroxyl;
  • R z is hydrogen, Ci -6 alkyl or C 1-6 haloalkyl, wherein said alkyl group is optionally substituted with one to three hydroxyl; m is an integer from zero to two;
  • W is CR x R y or NR 5 . In a subclass of the invention, W is CR x R y , In a subclass of the invention, W is NR 5 .
  • X is CR x R y or NR 6 . In a subclass of the invention, X is CR x R y . In a subclass of the invention, X is NR 6 .
  • Y is CR x R or NR 6 or C(O). In a subclass of the invention, Y is CR x R y . In a subclass of the invention, Y is NR 6 . In a subclass of the invention, Y is C(O).
  • Z is CR x R y or NR 5 . In a subclass of the invention, Z is CR x R y . In a subclass of the invention, Z is NR 5 .
  • R 1 is heteroaryl, wherein said heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo, cyano, C 1-6 alkyl, C w haloalkyl, (CR y R z ) m OR y , (CR y R z ) m NR y R z , OR y , C(0)R y , C(0)OR y , SO m R y 5 C(0)NR y R z and NR y R z .
  • R 1 is heteroaryl, wherein said heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo, and Cj-6 alkyl.
  • R 1 is pyridinyl or quinolinyl wherein said pyridinyl and quinolinyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo, Ci_ 6 alkyl and OR y .
  • R 1 is pyridinyl which is substituted with phenyl
  • R 1 is pyridinyl which is substituted with pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, pyridinyl or pyrazinyl, wherein said pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, pyridinyl or pyrazinyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and Ci -6 alkyl.
  • R 1 is pyrazolyl which is optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo, C ⁇ .e alkyl and OR y .
  • R 1 is quinolinyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR y and Ci -6 alkyl.
  • R 1 is quinolinyl, which is optionally substituted with halo.
  • R 2 is hydrogen
  • R is hydrogen
  • R 4 is aryl
  • R 5 is hydrogen, heterocyclyl or heterocyclyl(R 6 ).
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • variable e.g. R.6
  • its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable
  • Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted with one or more substituents” should be taken to be equivalent to the phrase “optionally substituted with at least one substituent” and in such cases another embodiment will have from zero to three substituents.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-Cio as in “Ci-Cio alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • “Ci-Cio alkyl” specifically includes methyl, ethyl, ⁇ -propyl, /-propyl, rc-butyl, i-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl- cyclopentyl, cyclohexyl, and so on.
  • cycloalkyl includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups.
  • cycloalkyl as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
  • haloalkyl means an alkyl radical as defined above, unless otherwise specified, that is substituted with one to five, preferably one to three halogen. Representative examples include, but are not limited to trifiuoromethyl, dichloroethyl, and the like.
  • Alkoxy represents either a cyclic or non-cyclic alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl and cycloalkyl above.
  • alkenyl refers to a non- aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms, unless otherwise specified, containing at least 1 carbon to carbon triple bond. Up to 3 carbon-carbon triple bonds may be present.
  • C2- 6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • substituents may be defined with a range of carbons that includes zero, such as (Co-C6)alkylene-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -CH2PI1, CH(CH3)CH2CH(CH3)Ph, and so on.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • heteroaryl represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, benzimidazolonyl, benzoxazolonyl, quinolinyl, isoquinolinyl, dihydroisoindolonyl,
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 3- to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • heterocyclic is also considered to be synonymous with the terms “heterocycle” and “heterocyclyl” and is understood as also having the definitions set forth herein.
  • Heterocyclyl therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof.
  • heterocyclyl include, but are not limited to the following: azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyi, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazoiyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxooxazolidinyl, oxazolyl, oxazoline, oxopiperazinyl, oxopyrrolidinyl, oxomorpholinyi, isoxazoline, oxet
  • tetrahydrothiopyranyl tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1 ,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin- 2-onyl, pyrrolidinyl, morpholinyl, thiomo ⁇ holinyl, dihydrobenzoimidazolyl,
  • dihydrooxadiazolyl dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazoiyi, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dioxidothiomorpholinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.
  • Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • halo or halogen as used herein is intended to include chloro, fluoro, bromo and iodo.
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • a (Ci -C6)alkyl may be substituted with one, two or three substituents selected from
  • OH oxo
  • halogen alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on.
  • the term "free form” refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of the instant invention.
  • the free form of the specific salt compounds described may be isolated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, txifluoroacetic and the like.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, ⁇ , ⁇ 1 - dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine f trimethylamine tripropylamine, tromethamine and the like.
  • the compound of the present invention is acidic, the term "
  • the compounds of the present invention may potentially be internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • An isolated compound having internally balance charges, and thus not associated with a intermolecular counterion, may also be considered the "free form" of a compound.
  • the compounds of the invention are useful to bind to and/or modulate the activity of mTOR kinase.
  • the compounds of the instant invention inhibit the activity of mTORCl .
  • the compounds of the instant invention inhibit the activity of mTORC2.
  • the compounds of the instant invention inhibit the activity of both mTORCl and mTORC2.
  • modulate means either increasing or decreasing kinase activity of mTOR.
  • the compounds of the instant invention inhibit the kinase activity of mTOR.
  • the kinase activity of mTOR may be modulated in a variety of ways; that is, one can affect the phosphorylation/activation of mTOR either by modulating the initial phosphorylation of the protein or by modulating the autophosphorylation of the other active sites of the protein.
  • the kinase activity of mTOR may be modulated by affecting the binding of a substrate of mTOR phosphorylation.
  • the compounds of the invention are used to treat or prevent cellular
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), autoimmune disease, viral disease, fungal disease, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g. ocular retinopathy), neuronal, alopecia, cardiovascular disease, graft rejection, inflammatory bowel disease, proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like. It is appreciated that in some cases the cells may not be in a hyper- or hypoproliferation state (abnormal state) and still require treatment.
  • the invention herein includes application to cells or individuals which are afflicted or may eventually become afflicted with any one of these disorders or states.
  • the compounds, compositions and methods provided herein are particularly deemed useful for the treatment and prevention of cancer including solid tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc.
  • the instant compounds are useful for treating cancer.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to:
  • sarcoma angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma
  • lipoma teratoma
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma
  • bronchogenic carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma
  • alveolar (bronchiolar) carcinoma bronchial adenoma
  • sarcoma lymphoma
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,
  • Wilm's tumor [nephroblastoma], lymphoma, leukemia,), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:
  • hepatoma hepatocellular carcinoma
  • cholangiocarcinoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • Bone osteogenic sarcoma (osteosarcoma)
  • fibrosarcoma malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,
  • meningiosarcoma meningiosarcoma, gliomatosis
  • brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors
  • spinal cord neurofibroma, meningioma, glioma, sarcoma
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous
  • cystadenocarcinoma unclassified carcinoma] granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes
  • carcinoma carcinoma
  • Hematologic blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis
  • Adrenal glands neuroblastoma.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, in addition to the cancers listed above: Lung: bronchogenic carcinoma (non- small cell lung); Gastrointestinal: rectal, colorectal and colon; Genitourinary tract: kidney (papillary renal cell carcinoma); and Skin: head and neck squamous cell carcinoma.
  • the compounds of the instant invention are useful for treating or preventing cancer selected from: head and neck squamous cell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, gastric cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma.
  • the compounds of the instant invention are useful for treating or preventing cancer selected from: histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma.
  • the compounds of the instant invention are useful for treating cancer selected from: histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, liver cancer, gastric cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma.
  • the compounds of the instant invention are useful for the prevention or modulation of the metastases of cancer cells and cancer.
  • the compounds of the instant invention are useful to prevent or modulate the metastases of ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, gastric cancers, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastoma and sarcomas.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous,
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, macrocrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisoi or alpha- tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of
  • polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol are examples of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of
  • polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol are examples of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the instant invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of cancer being treated; the severity (i.e., stage) of the cancer to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • compounds of the instant invention can be administered in a total daily dose of up to 1000 mg.
  • Compounds of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • Compounds of the instant invention can be administered at a total daily dosage of up to 1000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
  • the administration can be continuous, i.e., every day, or
  • intermittent administration of a compound of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • the compounds of the instant invention may be administered according to any of the schedules described above, consecutively for a few weeks, followed by a rest period.
  • the compounds of the instant invention may be administered according to any one of the schedules described above from two to eight weeks, followed by a rest period of one week, or twice daily at a dose of 100 - 500 mg for three to five days a week.
  • the compounds of the instant invention may be administered three times daily for two consecutive weeks, followed by one week of rest.
  • the instant compounds are also useful in combination with known therapeutic agents and anti-cancer agents.
  • instant compounds are useful in combination with known anti-cancer agents.
  • Combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • the instant compounds are also useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-Co A reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-Co A reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene,
  • LY353381 LY1 17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2- [4- [2-( 1 -piperidiny l)ethoxy] phenyl] -2H- 1 -benzopyran-3 -yl] -phenyl-2 ,2-dimethylpropanoate , 4,4' -dihydroxybenzophenone-2 ,4-dinitropheny 1-hydrazone , and SH646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a- difluoromethylornithine, 1LX23-7553, trans-N ⁇ (4'-hydroxyphenyl) retinaraide, and N-4- carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyI- pyridine)platinum, benzylguanine, glufosfamide, GPXIOO, (trans, trans, trans)-bis-mu-(hexane- l,6
  • hypoxia activatable compound is tirapazamine.
  • proteasome inhibitors include but are not limited to lactacystin and bortezomib.
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3 ⁇ 4'-didehydro-4'-deoxy-8'-norvmcaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237)
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rabitecan, 6-ethoxypropionyl-3 ' ,4 5 -O-exo-benzylidene-chartreusin , 9-methoxy-N,N- dimethyl-5-mtropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fiuoro-2,3- dihydro-9-hydroxy-4-methyl- 1 H, 12H-benzo[de]pyrano [3 ' ,4 ' :b,7] -indolizino [ 1 ,2b]quinoline- 10,13(9H,15H)dione, lurtotecan, 7-[2-( -isopropylarnino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kifl4, inhibitors of Mphosphl and inhibitors of ab6-KIFL.
  • histone deacetylase inhibitors include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med. Chem. 46(24):5097-5116 (2003).
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK- 1 ), inhibitors of bub- 1 and inhibitors of bub-R 1.
  • PLK Polo-like kinases
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and ⁇ 3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2' -fluoromethylene ⁇ 2'-deoxycytidine, N-[5-(2,3-dihydro- benzofuryl)sulfonyl] -N ' -(3 ,4-
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,
  • simvastatin ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239)
  • pravastatin PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589)
  • fluvastatin See U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896)
  • atorvastatin LIPITOR®; see U.S. Pat. Nos.
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314.
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314.
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314.
  • CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl -protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and
  • GGPTase-II geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Fit-
  • VEGF 1 vascular endothelial growth factor 1
  • Flk-l/KDR Flk-l/KDR
  • M P matrix metalloprotease
  • integrin blockers interferon- , interleukin-12
  • pentosan polysulfate cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992);
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)
  • VEGF see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al, Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679- 692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)).
  • TAFIa inhibitors have been described in PCX Publication WO 03/013,526 and U,S, Ser. No. 60/349,925 (filed January 18, 2002).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, fiavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met
  • Further agents include inhibitors of RTKs as described by Bume- Jensen and Hunter, Nature, 411:355- 365, 2001.
  • “Inhibitors of cell proliferation and survival signaling pathway” refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors. Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO
  • Such agents include small molecule inhibitor compounds and antibody antagonists.
  • Specific anti-IGF-lR antibodies include, but are not limited to, dalotuzumab, figitumumab, cixutumumab, SHC 717454, Roche R1507, EMI 64 or Amgen AMG479.
  • the mTOR inhibitors in current clinical development are structural analogs of rapamycin.
  • the mTOR inhibitors of the instant invention include ridaforolimus, temsirolimus, everolimus, a rapamycin-analog and combinations thereof.
  • Ridaforolimus also known as AP 23 73, MK-8669 and deforolimus, is a unique, non-prodrug analog of rapmycin that has antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines. Ridaforolimus has been administered to patients with advanced cancer and is currently in clinical development for various advanced malignancies, including studies in patients with advanced soft tissue or bone sarcomas. Thus far, these trials have demonstrated that ridaforolimus is generally well-tolerated with a predictable and manageable adverse even profile, and possess anti-tumor activity in a broad range of cancers. A description and preparation of ridaforolimus is described in U.S. Patent No. 7,091,213 to Ariad Gene
  • Temsirolimus also known as Torisel®, is currently marketed for the treatment of renal cell carcinoma.
  • a description and preparation of temsirolimus is described in U.S. Patent No. 5,362,718 to American Home Products Corporation, which is hereby incorporated by reference in its entirety.
  • Everolimus also known as Certican® or RAD001, marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmokinetics with fewer side effects than rapamycin (sirolimus). Everolimus has been used in conjunction with microemulsion cyclosporin (Neoral®, Novartis) to increase the efficacy of the immunosuppressive regime.
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat. 5,536,752, U.S. Pat. 5,550,142, U.S. Pat.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4- methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-memyl-3-(3-methyl-2- butenyl)oxiranyl]-l -oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino- l ⁇ [[3,5-dichloro-4-(4-chlorobenzoyl)-phenyl]methyl]-lH-l,2,3-triazole-4- carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ ⁇ ⁇ 3 integrin and the ⁇ ⁇ ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ ⁇ ⁇ 6 > ⁇ 8 > ⁇ 1 ⁇ > ⁇ 2 ⁇ > ⁇ 5 ⁇ ) ⁇ and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ 3, ⁇ ⁇ ⁇ 5, ⁇ * ⁇ , 3 ⁇ 4 ⁇ 8 > ⁇ ⁇ , ⁇ 2 ⁇ > ⁇ 5 ⁇ , 6 ⁇ and «6 ⁇ 4 integrins.
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and 5.
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol 1998; 31 :909-913; J. Biol. Chem. 1999;274:9116-9121; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-01 1, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT- 501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2-benzisoxazol-6- yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example), a uPA/uPAR antagonist
  • the compounds of the instant invention may also be administered in
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • P-gp p-glycoprotein
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • neurokinin- 1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent No
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514
  • the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l -(R)-(3,5- bis(trifluoromethyl)-phenyl)ethoxy)-3 -(S)-(4-fluorophenyl)-4-(3-(5 -oxo- 1 H,4H- 1 ,2,4- triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat No. 5,719,147.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • the compounds of the instant invention may also be administered in
  • inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
  • a compound of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole
  • Arimidex® arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); brefeldin A; busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone
  • doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone ®); dromostanolone propionate (Masterone Injection®);
  • eculizumab injection Soliris®
  • Elliott's B Solution Elliott's B Solution®
  • eltrombopag Promacta®
  • epirubicin Ellence®
  • Epoetin alfa epogen®
  • erlotinib Tarceva®
  • estramustine (Emcyt®); ethinyl estradiol; etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); everolimus tablets (Afmitor®); exemestane (Aromasin®); ferumoxytol (Feraheme Injection®); Filgrastim (Neupogen®); fioxuridine (intraarterial) (FUDR®);
  • fludarabine Fludarabine
  • fluorouracil, 5-FU Adrucil®
  • fulvestrant Faslodex®
  • gefitinib Iressa®
  • gemcitabine Gamzar®
  • gemtuzumab ozogamicin Mylotarg®
  • goserelin acetate Zoladex Implant®
  • goserelin acetate Zoladex®
  • histrelin acetate Histrelin implant®
  • hydroxyurea Hydrea®
  • Ibritumomab Tiuxetan Zevalin®
  • Idamycin® ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); iobenguane 1 123 injection (AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinib tablets (Tykerb®); lenalidomide
  • Mithracin® porfimer sodium (Photofrin®); pralatrexate injection (Folotyn®); procarbazine (Matulane®); quinacrine (Atabrine®); rapamycin; Rasburicase (Elitek®); raloxifene hydrochloride (Evista®); Rituximab (Rituxan®); romidepsin (Istodax®); romiplostim
  • streptozocin Zanosar®
  • sunitinib maleate Sutent®
  • talc Sclerosol®
  • vinorelbine (Navelbine®); vorinostat (Zolinza®); wortmannin; and zoledronate (Zometa®).
  • the scope of the instant invention encompasses the use of the instantly claimed compounds in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a
  • cytotoxic/cytostatic agent an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-y agonist, a PP AR- ⁇ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, an apoptosis inducing agent, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint and any of the therapeutic agents listed above.
  • RTKs receptor tyrosine kinases
  • any one or more of the specific dosages and dosage schedules of the compounds of the instant invention may also be applicable to any one or more of the therapeutic agents to be used in the combination treatment (hereinafter refered to as the
  • the specific dosage and dosage schedule of this second therapeutic agent can further vary, and the optimal dose, dosing schedule and route of administration will be determined based upon the specific second therapeutic agent that is being used.
  • the route of admmistration of the compounds of the instant invention is independent of the route of administration of the second therapeutic agent.
  • the administration for a compound of the instant invention is oral administration.
  • the administration for a compound of the instant invention is intravenous administration.
  • a compound of the instant invention is administered orally or intravenously, and the second therapeutic agent can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a compound of the instant invention and second therapeutic agent may be administered by the same mode of administration, i.e. both agents administered e.g. orally, by IV.
  • a compound of the instant invention by one mode of administration, e.g. oral, and to administer the second therapeutic agent by another mode of administration, e.g. IV or any other ones of the administration modes described hereinabove.
  • the first treatment procedure, administration of a compound of the instant invention can take place prior to the second treatment procedure, i.e., the second therapeutic agent, after the treatment with the second therapeutic agent, at the same time as the treatment with the second therapeutic agent, or a combination thereof.
  • a total treatment period can be decided for a compound of the instant invention.
  • the second therapeutic agent can be administered prior to onset of treatment with a compound of the instant invention or following treatment with a compound of the instant invention.
  • anti-cancer treatment can be administered during the period of administration of a compound of the instant invention but does not need to occur over the entire treatment period of a compound of the instant invention.
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroace1yl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, or an antibody to VEGF.
  • the estrogen receptor modulator is tamoxifen or raloxifene.
  • a method of treating cancer comprises administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy and/or in combination with a compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drag, an inhibitor of cell proliferation and survival signaling, an apoptosis inducing agent, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic and an agent that interferes with a compound selected from: an estrogen receptor modulator
  • Yet another embodiment of the invention is a method of treating cancer that comprises administering a therapeutically effective amount of a compound of Formula I in combination with paclitaxel or trastuzumab.
  • the invention further encompasses a method of treating or preventing cancer that comprises administering a therapeutically effective amount of a compound of Formula I in combination with a COX-2 inhibitor.
  • the instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of Formula I and a compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an
  • antiproliferative agent a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist; an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic and an agent that interferes with a cell cycle checkpoint.
  • a method of treating or preventing a disease in which angiogenesis is implicated which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention.
  • Other inhibitors of MET may also be administered for this method of treatment.
  • Ocular neovascular diseases which may result in certain forms of blindness, are examples of conditions where much of the resulting tissue damage can be attributed to aberrant infiltration of blood vessels in the eye.
  • the undesirable infiltration can be triggered by ischemic retinopathy, such as that resulting from diabetic retinopathy, retinopathy of prematurity, retinal vein occlusions, etc., or by degenerative diseases, such as the choroidal neovascularization observed in age-related macular degeneration.
  • ischemic retinopathy such as that resulting from diabetic retinopathy, retinopathy of prematurity, retinal vein occlusions, etc.
  • degenerative diseases such as the choroidal neovascularization observed in age-related macular degeneration.
  • Inhibiting the growth of blood vessels by administration of the present compounds would therefore prevent the infiltration of blood vessels and prevent or treat diseases where angiogenesis is implicated, such as ocular diseases like retinal vascularization, diabetic retinopathy, age-related macular degeneration, and the like.
  • Routes of systemic administration of the compounds of the present invention described above may be utilized in the treatment of such ocular neovascular diseases.
  • Other routes of ocular administration may also be employed, such as topical, periocular, intravitreal and the like.
  • Intravitreal implants coated with a drug:polymer matrix may also be employed.
  • Ophthalmic pharmaceutical compositions that are adapted for topical administration to the eye may be in the form of solutions, suspensions, ointments, creams or as a solid insert.
  • Ophthalmic formulations of this compound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% of medicament.
  • For a single dose from between 0.01 to 5000 ng, preferably 0.1 to 500 ng s and especially 1 to 100 ng of the compound can be applied to the human eye.
  • Formulations useful for intravitreal administration are similar to saline solutions described previously for intravenous administration.
  • the compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures.
  • the illustrative schemes below are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions of the instant invention hereinabove.
  • NMP N-Methyl-2-pyrrolidone
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • PhNTf 2 N-phenyl bis-trifluoromethanesulfonimide
  • SPA scintillation proximity assay TBAF tetra-n-butylammonium fluoride
  • TMS-CN trimethylsilyl cyanide
  • Substituted pyrazolo[l,5-a]pyrimidine IV is treated with amine R5NH2 and an appropriate base such as NaHC0 3 in an appropriate solvent such as NMP to provide the corresponding displacement intermediate V (General Scheme 2).
  • Intermediate V is brominated by reacting with N-Bromosuccinimide (NBS) in an appropriate solvent or solvent mixture such as DCM, DCM-CH 3 CN and DMF to provide the corresponding bromide intermediate VI.
  • NBS N-Bromosuccinimide
  • Bromide intermediate VI is heated with ethyl 3-(tributylstannyl)acrylate in an appropriate solvent or solvent mixture such as 1,4-dioxane, CH 3 CN or Dioxane-CH 3 CN in the presence of an appropriate catalyst such as Pd(PPh 3 )4 to afford the corresponding unsaturated ester intermediate VII.
  • Unsaturated ester intermediate VII is treated with an appropriate base, such as NaOEt, in an appropriate solvent, such as EtOH, to afford the unsaturated lactam VIII.
  • Bromide intermediate VI is heated with tributyl(vinyl)stannane in an appropriate solvent or solvent mixture such as 1 ,4-dioxane, CH 3 CN or Dioxane-CH 3 CN in the presence of an appropriate catalyst such as Pd(PPh 3 ) 4 to afford the corresponding intermediate IX (General Scheme 4), Intermediate IX is treated with allyl bromide and an appropriate base such as NaH in an appropriate solvent or solvent mixture such DMF to afford the
  • Intermediate X is heated with Grubbs 2 nd catalyst in an appropriate solvent such as toluene to afford intermediate XI.
  • Intermediate XI is first treated with an appropriate acid such as TFA-3 ⁇ 40 and then with TFA-Et 3 SiH to afford intermediate XII.
  • Phenylboro ic acid (37.98 mmol, 4630.9 mg), 3 P0 4 (94.95 mmol, 20129 mg), and PdCl 2 (dppf)-CH 2 Cl 2 (1.58 mmol, 1291 mg) was added to a solution of 2-(6-chloropyridin- 3-yl)acetonitrile (31.65 mmol, 5000 mg) in dioxane (100 mL) and H 2 0 (10 mL). The resulting mixture was stirred at 75°C under argon overnight. The mixture was diluted with H 2 0 and then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with N3 ⁇ 4S0 4 .
  • Step 3 Preparation of 3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-pyrazolon ,5-a]pyrrolo[3,4- d]pyrimidin-8 ⁇ amine
  • Step 4 (R)- 1 -(9-amino-3 -(6-phenylpyridin- 3 -yl)-5 ,6-dihydropyrazolo [ 1 ,5-a]pyrido [4,3- d] pyrimidin-7(8H)-yl)-2-hydroxypropan- 1 -one
  • Step 1 Preparation of pyrazolo[l,5-a]
  • Step 4 Preparation of 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5- a]pyrimidin-7-amine
  • Step 5 Preparation of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[ 1 ,5- a]pyrimidin-7-amine
  • Step 6 Preparation of 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2- (trimethylsilyl)ethoxy)methyl)pyrazolo [ 1 , 5 -a] pyrimidin-7-amine
  • Step 7 Preparation of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6- fluoroquinolin-3 -yl)pyrazol o [ 1 ; 5-a]pyrimidin- 5 -ylamino)piperidine- 1 -carboxylate
  • Step 8 Preparation of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3- (6-£tuoroquinolin-3 -yl)pyrazolo [ 1 , 5 -a] pyr imidin-5 -ylamino)piperidme- 1 -carboxylate
  • Step 9 Preparation of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(3- ethoxy-3-oxoprop- 1 -enyl)-3-(6-fluor quinolin-3-yl)pyrazolo[l ,5-a]pyrimidin-5- ylamino)piperidine- 1 -carboxylate
  • Step 10 Preparation of 9-amino-3-(6-fiuoroquinolin-3-yl)-5-(piperidin-4-yl)pyrazolo[l ,5- a]pyrido[2,3-d]pyrimidin-6(5H)-one
  • Step 1 Preparation of 9-amino-3-(6-fluoroquinolin-3-yl)-5-(piperidin-4-yl)-7,8- dihydropyrazolo[l,5-a pyrido[2 i 3-d]pyrimidin-6(5H)-one
  • Step 1 Preparation of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6- phenylpyridin-3 -yl)-6-vinylpyrazolo [1,5 -a]pyrimidin-5 -ylamino)piperidine- 1 -carboxylate
  • Step 2 Preparation of tert-butyi 4-(aIlyl(7-(bis((2-(trimemylsilyl)ethoxy)methyl)m phenylpyridin-3-yl)-6 ⁇ vinylpyrazolo[l,5-a]pyrimM ⁇
  • Step 3 Preparation of tert-butyi 4-(9-(bis((2-(trimethyIsilyl)ethoxy)methyl)amino)-3-(6- phenylpyridin-3-yl)pyrazolo[l,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)piperidine-l-carboxylate
  • tert-butyl 4-(9-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6- phenylpyridin-3-yl)pyrazolo[l ,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)piperidine-l -carboxylate (97.8 mg, was treated with 80% TFA H 2 0 (5 ml). After stirring at room temperature for 0.5h, the mixture was concentrated and then TFA (1.5 ml) and Et 3 SiH (0.5 ml) were added and the mixture was stirred overnight.
  • 100 mg of (R) ⁇ l-(9-amino-3-(6- phenylpyridin-3-yl)-5 i 6-dihydropyrazolo[l,5-a]pyrido[4,3-d]pyrimidin-7(8H)-yl) ⁇ 2- hydroxypropan-l-one is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.
  • the mTOR assay buffer contains 10 mM hepes (pH 7.4), 50 mM NaCl, 100 BSA, 50 mM B-glycerophosphate, 10 mM MnC12 and 0.5 mM DTT. 20 ng of mTOR enzyme is preincubated with the compound for 10 minutes. 5 ⁇ ATP and 0.1 ⁇ GSTS6K is added. The reaction is incubated for one hour at 30 °C. Anti phospho p70S6K (about 1.7 ng/well) and anti GSTXL665 (1 :1 Ratio with the substrate GSTS6K) are added after incubating. The plates are read at least 2 hours after adding the anti phospho p70S6 and the anti GSTXL665.
  • ICso DETERMINATIONS Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds.
  • Concentration of compound was plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC S o values, the dose- response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis.
  • This in vitro assay utilizes recombinant His-CHKl expressed in the baculovirus expression system as an enzyme source and a biotinylated peptide based on CDC25C as substrate (biotin-RSGLYRSPSMPENLNRPR).
  • SPA beads Amersham, CatJ SPQ0032: 500 mg/vial Add 10 mL of D-PBS to 500 mg of SPA beads to make a working concentration of 50 mg/mL. Store at 4 ⁇ C. Use within 2 week after hydration.
  • Staurosporine 100 ⁇ g: CALBIOCHEM, Cat. # 569397
  • IC n DETERMINATIONS Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds.
  • Concentration of compound was plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC50 values, the dose- response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis.
  • Selected Thiazole Derivatives of the present invention were tested using this assay and provided IC 50 values ranging from about 1 nM to about 5500 nM.
  • BACULOVIRUS CONSTRUCTIONS Cyclin E was cloned into pVL1393 (Pharmingen, La Jolla, California) by PCR, with the addition of 5 histidine residues at the amino-terminal end to allow purification on nickel resin. The expressed protein was approximately 45kDa.
  • CD 2 was cloned into pVL1393 by PCR, with the addition of a haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS). The expressed protein was approximately 34kDa in size.
  • Cyclin E/CDK2 kinase assays can be performed as described below in low protein binding 96-weIl plates (Corning Inc, Corning, New York).
  • Enzyme is diluted to a final concentration of 50 ⁇ g/mL in kinase buffer containing 50mM Tris pH 8.0, 10 mM MgCl 2 l mM DTT, and 0.1 mM sodium orthovanadate.
  • the substrate used in these reactions is a biotinylated peptide derived from Histone HI (from Amersham, UK). The substrate is thawed on ice and diluted to 2 ⁇ in kinase buffer. Test compounds are diluted in 10% DMSO to desirable concentrations. For each kinase reaction, 20 ⁇ , of the 50 ⁇ ⁇ enzyme solution (1 ⁇ g of enzyme) and 20 ⁇ of the 2 ⁇ substrate solution are mixed, then combined with 10 ⁇ of diluted compound in each well for testing.
  • the kinase reaction is initiated by addition of 50 ⁇ of 2 ⁇ ATP and 0.1 ⁇ of 33P-ATP (from Amersham, UK). The reaction iss allowed to run for 1 hour at room temperature, then is stopped by adding 200 ⁇ , of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5mM EDTA, and 5 mg/mL streptavidine coated SPA beads (from Amersham, UK) for 15 minutes. The SPA beads are then captured onto a 96-well GF B filter plate (Packard/Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard/Perkin Elmer Life Sciences.).
  • Nonspecific signals are eliminated by washing the beads twice with 2M NaCl then twice with 2 M NaCl with 1% phosphoric acid.
  • the radioactive signal can then be measured using, for example, a TopCount 96 well liquid scintillation counter (from Packard/Perkin Elmer Life Sciences).
  • ICsn DETERMINATIONS Dose-response curves are plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound is plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC50 values, the dose-response curves are then fitted to a standard sigmoidal curve and IC 50 values can be derived using nonlinear regression analysis.
  • Compounds of the present invention exhibit mTOR IC50 values of about 1 nM to about 5500 nM, CHK1 IC50 values of about 100 nM to about 55000 nM, and CDK2 IC 50 values of about 800 nM to about 30000 nM. In all cases, the compounds are much more selective for mTOR over CHK1 and CDK2.
  • the following table shows the activity data for an illustrative list of compounds of the invention.

Abstract

La présente invention concerne de nouveaux composés tricycliques accolés qui sont des inhibiteurs de kinase de la cible mammifère de la rapamycine (mTOR), également connue sous le nom de FRAP, RAFT, RAPT ou SEP, et sont utiles pour le traitement de troubles de prolifération cellulaire, par exemple du cancer et d'autres troubles de prolifération.
PCT/US2011/053199 2010-09-28 2011-09-26 Composés tricycliques accolés inhibiteurs de la cible mammifère de la rapamycine WO2012047569A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102633803A (zh) * 2012-05-03 2012-08-15 盛世泰科生物医药技术(苏州)有限公司 一种5,7-二氯吡唑并[1,5-a]嘧啶的合成方法
RU2619932C1 (ru) * 2015-11-25 2017-05-22 федеральное государственное бюджетное образовательное учреждение высшего образования "Воронежский государственный университет" (ФГБОУ ВО "ВГУ") ЗАМЕЩЕННЫЕ ПИРАЗОЛО[1,5-а]ПИРИДО[3,4-е]ПИРИМИДИНЫ И ИХ ИСПОЛЬЗОВАНИЕ В КАЧЕСТВЕ ИНГИБИТОРОВ ПРОТЕИНКИНАЗ

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WO2002053565A1 (fr) * 2000-12-28 2002-07-11 Ono Pharmaceutical Co., Ltd. Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif
US20070027156A1 (en) * 2003-09-09 2007-02-01 Hisao Nakai Crf antagonists and heterobicyclic compounds
US20070173519A1 (en) * 2005-03-17 2007-07-26 Teijin Pharma Limited Pyrazolopyrimidine derivatives or pharmaceutically acceptable salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053565A1 (fr) * 2000-12-28 2002-07-11 Ono Pharmaceutical Co., Ltd. Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif
US20070027156A1 (en) * 2003-09-09 2007-02-01 Hisao Nakai Crf antagonists and heterobicyclic compounds
US20070173519A1 (en) * 2005-03-17 2007-07-26 Teijin Pharma Limited Pyrazolopyrimidine derivatives or pharmaceutically acceptable salts thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102633803A (zh) * 2012-05-03 2012-08-15 盛世泰科生物医药技术(苏州)有限公司 一种5,7-二氯吡唑并[1,5-a]嘧啶的合成方法
RU2619932C1 (ru) * 2015-11-25 2017-05-22 федеральное государственное бюджетное образовательное учреждение высшего образования "Воронежский государственный университет" (ФГБОУ ВО "ВГУ") ЗАМЕЩЕННЫЕ ПИРАЗОЛО[1,5-а]ПИРИДО[3,4-е]ПИРИМИДИНЫ И ИХ ИСПОЛЬЗОВАНИЕ В КАЧЕСТВЕ ИНГИБИТОРОВ ПРОТЕИНКИНАЗ

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