US20110059976A1 - Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors - Google Patents

Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors Download PDF

Info

Publication number
US20110059976A1
US20110059976A1 US12/843,105 US84310510A US2011059976A1 US 20110059976 A1 US20110059976 A1 US 20110059976A1 US 84310510 A US84310510 A US 84310510A US 2011059976 A1 US2011059976 A1 US 2011059976A1
Authority
US
United States
Prior art keywords
compound
alkyl
aryl
heteroaryl
heteroalkyl
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US12/843,105
Inventor
Johan D. Oslob
Jiang Zhu
Kenneth Barr
Jennifer Cossrow
Brian Raimundo
Hiroko Tanaka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen MA Inc
Viracta Therapeutics Inc
Original Assignee
Sunesis Pharmaceuticals Inc
Biogen Idec MA 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 Sunesis Pharmaceuticals Inc, Biogen Idec MA Inc filed Critical Sunesis Pharmaceuticals Inc
Priority to US12/843,105 priority Critical patent/US20110059976A1/en
Publication of US20110059976A1 publication Critical patent/US20110059976A1/en
Assigned to SUNESIS PHARMACEUTICALS, INC. reassignment SUNESIS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OSLOB, JOHAN D., ZHU, JIANG, COSSROW, JENNIFER, BARR, KENNETH, RAIMUNDO, BRIAN, TANAKA, HIROKO
Assigned to SUNESIS PHARMACEUTICALS, INC., BIOGEN IDEC MA INC. reassignment SUNESIS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIOGEN IDEC MA INC., SUNESIS PHARMACEUTICALS, INC.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/04Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D475/00Heterocyclic compounds containing pteridine ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D475/00Heterocyclic compounds containing pteridine ring systems
    • C07D475/06Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Definitions

  • Protein kinases play a critical role in this regulatory process.
  • a partial non-limiting list of such kinases includes ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie.sub.1, tie.sub.2, TRK,
  • MAPK mitogen activated protein kinase
  • protein kinases have been implicated as targets in central nervous system disorders (such as Alzheimer's), inflammatory disorders (such as psoriasis), bone diseases (such as osteoporosis), atheroscleroses, restenosis, thrombosis, metabolic disorders (such as diabetes) and infectious diseases (such as viral and fungal infections).
  • One of the most commonly studied pathways involving kinase regulation is cellular signalling from receptors at the cell surface to the nucleus.
  • This pathway includes a cascade of kinases in which members of the Growth Factor receptor Tyrosine Kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulin receptor), deliver signals through phosphorylation to other kinases such as Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase families.
  • Each of these kinases is represented by several family members which play related, but functionally distinct roles.
  • the loss of regulation of the growth factor signalling pathway is a frequent occurrence in cancer as well as other disease states.
  • the signals mediated by kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle.
  • Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs).
  • CDKs cyclin dependent kinases
  • the regulation of CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits.
  • a further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit.
  • the coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities.
  • both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/CDK2 whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase. It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer.
  • Raf protein kinases are key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells.
  • Activated cell surface receptors activate ras/rap proteins at the inner aspect of the plasmamembrane which in turn recruit and activate Raf proteins.
  • Activated Raf proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2.
  • activated MEKs catalyse phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK).
  • a variety of cytoplasmic and nuclear substrates of activated MAPK are known which directly or indirectly contribute to the cellular response to environmental change.
  • Three distinct genes have been identified in mammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformic variants that result from differential splicing of mRNA are known.
  • Inhibitors of Raf kinases have been suggested for use in disruption of tumor cell growth and hence in the treatment of cancers, e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer and pancreatic and breast carcinoma; and also in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth.
  • cancers e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer and pancreatic and breast carcinoma
  • disorders associated with neuronal degeneration resulting from ischemic events including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth.
  • the present invention provides novel compounds having the structure:
  • A-B together represent one of the following structures:
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
  • protein kinase e.g., RAF
  • the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit RAF activity.
  • the invention provides pharmaceutical compositions comprising an inventive compound and optionally further comprising an additional therapeutic agent.
  • the additional therapeutic agent is an agent for the treatment of cancer.
  • the present invention provides methods for inhibiting kinase activity (e.g., RAF) activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of the invention.
  • the present invention provides methods for treating any disorder involving RAF activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • FIG. 1 depicts exemplary compound concentration experiments in mouse plasma (solid lines) and tumor tissue (dashed lines) at 1, 3, 8, 16, and 24 hours following a single oral dose of 25 (blue), 50 (red), or 100 (green) mg/kg compound X.
  • FIG. 2 depicts exemplary western analysis of WM-266-4 xenograft tumor tissue.
  • Tumors were excised and proteins extracted at 3, 8, and 16 hours following a single oral dose containing vehicle alone (lanes 1 and 2) or 100 (lanes 3 and 4), 50 (lanes 5 and 6), or 25 (lanes 7 and 8) mg/kg compound X.
  • ERK and phospho-ERK levels were then assessed by Western blot analysis
  • FIG. 3 depicts exemplary growth rates of WM-266-4 melanoma tumor xenografts in mice treated for two weeks with 25, 50, or 100 mg/kg QD compound X, 50 mg/kg BID compound X, 10 mg/kg QD Camptosar, or dosing vehicle alone.
  • the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above.
  • substituents include, but are not limited to aliphatic; heteroaliphatic; alicyclic; heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 —; or -GR G1 wherein G is —O—, —S—, —NR G2 —, —C( ⁇ O)—, —S( ⁇ O)—, —SO 2 —, —C( ⁇ O)O—, —C( ⁇ O)NR G2
  • stable preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties.
  • alkyl includes straight and branched alkyl groups.
  • alkyl encompass both substituted and unsubstituted groups.
  • lower alkyl is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms.
  • the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1-20 or 2-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-10 or 2-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 or 2-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-6 or 2-6 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-4 or 2-4 aliphatic carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • alicyclic refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups.
  • alicyclic is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
  • Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, cyclopropyl, cyclobutyl, —CH 2 -cyclobutyl, cyclopentyl, —CH 2 -cyclopentyl-n, cyclohexyl, —CH 2 -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
  • cycloalkyl refers specifically to cyclic alkyl groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, heteroaliphatic or heterocyclic moieties, may optionally be substituted.
  • An analogous convention applies to other generic terms such as “cycloalkenyl”, “cycloalkynyl” and the like.
  • heteroaliphatic refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom.
  • a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, i.e., in place of carbon atoms.
  • a 1-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain refers to a C 1-6 aliphatic chain wherein at least one carbon atom is replaced with a nitrogen atom, and wherein any one or more of the remaining 5 carbon atoms may be replaced by an oxygen, sulfur, nitrogen, phosphorus or silicon atom.
  • a 1-atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain refers to —NH— or —NR— where R is aliphatic, heteroaliphatic, acyl, aromatic, heteroaromatic or a nitrogen protecting group.
  • Heteroaliphatic moieties may be branched or linear unbranched. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, any of the substituents described above.
  • heteroalicyclic refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein.
  • heterocyclic refers to a non-aromatic 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • aromatic moiety refers to stable substituted or unsubstituted unsaturated mono- or polycyclic hydrocarbon moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity.
  • aromatic moieties include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl.
  • heteroaromatic moiety refers to stable substituted or unsubstituted unsaturated mono-heterocyclic or polyheterocyclic moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity.
  • heteroaromatic moieties include, but are not limited to, pyridyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.
  • aromatic and heteroaromatic moieties may be attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety and thus also include moieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic, -(aliphatic)heteroaromatic, -(heteroaliphatic)heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(alkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties.
  • aliphatic e.g., alkyl
  • heteroaliphatic e.g., heteroalkyl
  • moieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic, -(aliphatic)heteroaromatic, -(hetero
  • aromatic or heteroaromatic moieties and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” are interchangeable.
  • Substituents include, but are not limited to, any of the previously mentioned substituents resulting in the formation of a stable compound.
  • aryl refers to aromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two rings satisfying the Huckel rule for aromaticity, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • heteroaryl refers to heteroaromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety.
  • heteroaryl refers to a cyclic unsaturated radical having from about five to about ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • Substituents for aryl and heteroaryl moieties include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom (“alkoxy”) or through a sulfur atom (“thioalkyl”).
  • the alkyl group contains about 1-20 aliphatic carbon atoms.
  • the alkyl group contains about 1-10 aliphatic carbon atoms.
  • the alkyl group contains about 1-8 aliphatic carbon atoms.
  • the alkyl group contains about 1-6 aliphatic carbon atoms.
  • the alkyl group contains about 1-4 aliphatic carbon atoms.
  • alkoxy groups include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • thioalkyl groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • amine refers to a group having the structure —N(R X ) 2 wherein each occurrence of R X is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or the R X groups, taken together, may form a heterocyclic moiety.
  • alkylamino refers to a group having the structure —NHR X wherein R X is alkyl, as defined herein.
  • aminoalkyl refers to a group having the structure H 2 NR X —, wherein R X is alkyl, as defined herein.
  • the alkyl group contains about 1-20 or 2-20 aliphatic carbon atoms.
  • the alkyl group contains about 1-10 or 2-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 or 2-8 aliphatic carbon atoms.
  • the alkyl group contains about 1-6 or 2-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 or 2-4 aliphatic carbon atoms.
  • alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
  • halo and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • halogenated denotes a moiety having one, two, or three halogen atoms attached thereto.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • acyloxy does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —OC(O)R X , wherein R X is a substituted or unsubstituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • acyl does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —C(O)R X , wherein R X is a substituted or unsubstituted, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • amino does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —C( ⁇ NR X )R Y , wherein R X is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and R Y is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • C 1-6 alkylene refers to a substituted or unsubstituted, linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence “ ⁇ ” at both ends of the radical.
  • C 2-6 alkenylene refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence “ ⁇ ” at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.
  • aliphatic As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups.
  • cycloalkyl used alone or as part of a larger moiety, encompass both substituted and unsubstituted groups.
  • isolated when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.
  • pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
  • Pharmaceutically acceptable derivatives thus include among others pro-drugs.
  • a pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
  • An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest.
  • Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
  • RAF-mediated disease or “RAF-mediated condition”, as used herein, means any disease or other deleterious condition in which RAF is known to play a role.
  • the terms “RAF-mediated disease” or “RAF-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an RAF inhibitor. Such conditions include, without limitation, colon, breast, gastric, ovarian, lung, brain, larynx, cervical, renal, lymphatic system, genitourinary tract (including bladder and prostate), stomach, bone, lymphoma, melanoma, glioma, papillary thyroid, neuroblastoma, and pancreatic cancer.
  • RAF-mediated disease means any disease or other deleterious condition or disease in which RAF is known to play a role.
  • diseases or conditions include, without limitation, cancers such as colon and breast cancer.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • preventing means that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disease, disorder or condition at the time of administration, but who would normally be expected to develop the disease, disorder or condition or be at increased risk for the disease, disorder or condition.
  • the compounds of the invention will slow the development of disease symptoms, delay the onset of disease, or prevent the individual from developing the disease at all.
  • preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • biological sample refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
  • the biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid.
  • the biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g.
  • the biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ.
  • Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
  • Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
  • biological samples may be from any animal, plant, bacteria, virus, yeast, etc.
  • the term animal refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig).
  • An animal may be a transgenic animal or a human clone.
  • the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
  • the present invention provides RAF inhibitors.
  • Compounds of this invention include those generally set forth above and described specifically herein, and are illustrated in part by the various classes, subgenera and species disclosed herein. Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
  • the compounds of the invention include compounds of the general formula (I) as further defined below:
  • A-B together represent one of the following structures:
  • n is an integer from 0-4 as valency permits
  • R 1 and R 2 are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
  • R 3 is hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
  • R 4 is hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; or is absent when is a double bond;
  • L 1 is —O—, —S—, —NR L1A — or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L1B —, —NR L1A NR L1B C( ⁇ O)—, —NR L1A C( ⁇ O)—, —NR L1A CO 2 —, —NR L1A C( ⁇ O)NR L1B —, —S( ⁇ O)—, —SO 2 —, —NR L1A SO 2 —, —SO 2 NR L1A —, —NR L1
  • L 2 is absent, —O—, —S—, —NR L2A —, a heteroalicyclic or heteroaromatic moiety, or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L2A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L2A —, —NR L1A NR L2B —, —NR L2A NR L2B C( ⁇ O)—, —NR L2A C( ⁇ O)—, —NR L2A CO 2 —, —NR L2A C( ⁇ O)NR L2B —, —S( ⁇ O)—, —SO 2 —, —NR L2A SO 2 —,
  • Y is an carbocyclic, heterocyclic, aryl or heteroaryl moiety
  • Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety.
  • L 1 is —Oalkyl-, —N(R)alkyl-, —Salkyl-, —Oalkenyl-, —N(R)alkenyl-, or —Salkenyl-, wherein R is hydrogen, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl or (heterocyclyl)alkyl; and R 2 is —NR 2A R 2B wherein R 2A is hydrogen or alkyl; and R 2B is optionally substituted heteroaryl, heterocyclyl or aryl.
  • L 1 is —N(R L1 )—, wherein R L1 is hydrogen or C 1-6 alkyl; n is 0-3; R 1 is —(CR 1A CR 1B ) q X(CR 1A CR 1B ) t wherein X is absent, —N(R 1C )—, —NH—, —O—, —C( ⁇ O)—, —N(R 1C )C( ⁇ O)—, —C( ⁇ O)N(R 1C )—, —C( ⁇ O)(cis or trans alkenyl)-, —N(R 1C )C( ⁇ O)(cis or trans alkenyl)-, —C( ⁇ O)alkynyl-, —N(R 1C )C( ⁇ O)alkynyl-, —N(R 1C )C( ⁇ O)alkynylN(R 1C
  • R v is optionally substituted phenyl or an optionally substituted 4- to 6-membered heterocyclic ring, wherein said heterocyclic group is optionally fused to an optionally substituted benzene or C 5-8 cycloalkyl group; and R w is halogen, cyano, nitro, —OCF 3 , —CF 3 , hydroxy, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C( ⁇ O)R u , —C( ⁇ O)OR u , —OC( ⁇ O)R u , —NR u C( ⁇ O)R s , —NR u S( ⁇ O) 2 NR s R 3 , —NR u C( ⁇ O)NR s R 3 , —NR u C( ⁇ O)OR s , —C( ⁇ O)
  • R 3 is not an aryl or heteroaryl moiety.
  • the present invention defines particular classes of compounds which are of special interest.
  • one class of compounds of special interest includes compounds of formula (I A ):
  • Another class of compounds of special interest includes compounds of formula (I B ):
  • Another class of compounds of special interest includes compounds of formula (I C ):
  • Another class of compounds of special interest includes compounds of formula (I D ):
  • Another class of compounds of special interest includes compounds of formula (I E ):
  • Another class of compounds of special interest includes compounds of formula (I F ):
  • W 1 is —O—, —S—, —N(R W1 )—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk 1 is a C 1-6 alkylene or C 2-6 alkenylene moiety.
  • Another class of compounds of special interest includes compounds of formula (I G ):
  • W 1 is —O—, —S—, —N(R W1 )—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk 1 is a C 1-6 alkylene or C 2-6 alkenylene moiety.
  • Another class of compounds of special interest includes compounds of formula (I H ):
  • W 2 and W 3 are independently absent, —O— or —N(R W )—, where R W is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic.
  • subclasses of the foregoing classes include subclasses of the foregoing classes in which:
  • each occurrence of R 1 is independently hydrogen, halogen, —CN, —NO 2 , —C( ⁇ O)R 1A , —C( ⁇ O)OR 1A , —C( ⁇ O)NR 1A R 1B , —S( ⁇ O) 2 R 1C , —P( ⁇ O)(R 1C ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R 1A and R 1B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl; where
  • each occurrence of R 1 is independently hydrogen, halogen, —NO 2 , —CN, —C( ⁇ O)OR 1A , —S( ⁇ O) 2 R 1C , —P( ⁇ O)(R 1C ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl; wherein R 1A is hydrogen or C 1-6 alkyl; and each occurrence of R 1C is independently C 1-6 alkyl;
  • each occurrence of R 1 is independently hydrogen, halogen, —NO 2 , —CN, C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkylamino, diC 1-5 alkylamino, aminoC 1-5 alkyl, C 1-5 alkylaminoC 1-5 alkyl or diC 1-5 alkylaminoC 1-5 alkyl;
  • R 1 is F
  • n is 1 and R 1 is as defined in any one of subsets i)-iii) above;
  • R 2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
  • R 2 is C 1-3 alkyl or C 1-3 alkoxy
  • R 2 is methyl or —CF 3 ;
  • R 2 is halogen
  • xi) R 2 is hydrogen
  • R 3 is hydrogen, —C( ⁇ O)R 1A , —C( ⁇ O)OR 1A , —C( ⁇ O)NR 1A R 1B , —S( ⁇ O) 2 R 1C , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R 1A and R 1B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)
  • R 3 is hydrogen, —C( ⁇ O)R 1A , lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl; wherein R 1A is hydrogen, or lower alkyl, aryl, or heteroaryl;
  • R 3 is hydrogen or lower alkyl
  • R 3 is hydrogen or methyl
  • R 3 is hydrogen
  • L 1 is a 2-8 atom heteroaliphatic linker having at least one N, O or S atom in the heteroaliphatic main chain;
  • L 1 is a 2-8 atom heteroaliphatic linker having at least one N or O atom in the heteroaliphatic main chain;
  • L 1 is a 2-8 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
  • L 1 is —W 1 -Alk 1 -; wherein W 1 is —O—, —S—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk 1 is a C 1-6 alkylene or C 2-6 alkenylene moiety;
  • L 1 is —W 1 -Alk 1 -; wherein W 1 is —O—, —S—, —N(R W1 )—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)—,
  • L 1 is —W 1 -Alk 1 -; wherein W 1 is —O—, —S—, —N(R W1 )—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—,
  • L 1 is —O-Alk 1 -; wherein Alk 1 is a substituted or unsubstituted C 1-2 alkylidene chain;
  • L 1 is —O-cyclopropyl-
  • L 1 is —O—CH 2 CH 2 —;
  • L 1 is —O—CH(R L1C )—, wherein R L1C is hydrogen or lower alkyl;
  • L 1 is —O—CH 2 —;
  • L 1 is —O—CH(Me)-;
  • L 1 is —NR W1 -Alk 1 -; wherein R W1 is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 2-6 alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —S( ⁇ O)—, —SO 2 —, —O—, —S—, or —NR L1A —; wherein
  • R L1A is hydrogen or lower alkyl
  • L 1 is —NR W1 -Alk 1 -; wherein R W1 is hydrogen or lower alkyl; and Alk 1 is a substituted or unsubstituted C 1-2 alkylidene chain;
  • L 1 is —NH-cyclopropyl-
  • L 1 is —NH—CH 2 CH 2 —;
  • L 1 is —NH—CH(R L1C )—, wherein R L1C is hydrogen or lower alkyl;
  • L 1 is —NH—CH 2 —;
  • L 1 is —NH—CH(Me)—
  • L 1 is —C( ⁇ O)-Alk 1 -; wherein Alk 1 is a substituted or unsubstituted C 2-6 alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —S( ⁇ O)—, —SO 2 —, —O—, —S—, or —NR L1A —; wherein R L1A is hydrogen or lower alkyl;
  • xl) L 1 is —C( ⁇ O)-Alk 1 -; wherein Alk 1 is a substituted or unsubstituted C 1-2 alkylidene chain;
  • L 1 is —C( ⁇ O)-cyclopropyl-
  • L 1 is —C( ⁇ O)—CH 2 CH 2 —;
  • L 1 is —C( ⁇ O)—CH(R L1C )—, wherein R L1C is hydrogen or lower alkyl;
  • xliv) L 1 is —C( ⁇ O)—CH 2 —;
  • L 1 is —C( ⁇ O)—CH(Me)—;
  • L 1 is —C( ⁇ O)NR W1 -Alk 1 -; wherein R W1 is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 2-6 alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —S( ⁇ O)—, —SO 2 —, —O—, —S—, or —NR L1A —;
  • R L1A is hydrogen or lower alkyl
  • L 1 is —C( ⁇ O)NR W1 -Alk 1 -; wherein R W1 is hydrogen or lower alkyl; and Alk 1 is a substituted or unsubstituted C 1-2 alkylidene chain;
  • L 1 is —C( ⁇ O)NH-cyclopropyl-
  • L 1 is —C( ⁇ O)NH—CH 2 CH 2 —;
  • L 1 is —C( ⁇ O)NH—CH(R L1C )—, wherein R L1C is hydrogen or lower alkyl;
  • L 1 is —C( ⁇ O)NH—CH 2 —;
  • L 1 is —C( ⁇ O)NH—CH(Me)—;
  • Y is a saturated or unsaturated cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • Y is a saturated or unsaturated monocyclic cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • Y is a saturated or unsaturated 5- to 6-membered monocyclic cyclic ring
  • Y is an unsaturated 5-membered monocyclic cyclic ring system comprising one or more heteroatoms selected from S, N and O;
  • Y is an unsaturated 6-membered monocyclic cyclic ring system comprising one or more heteroatoms selected from S, N and O;
  • Y is a cycloalkyl, cycloalkenyl, heterocylic, aryl or heteroaryl moiety
  • Y is a 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocylic, 6-membered aryl or 6-membered heteroaryl moiety;
  • Y is one of:
  • each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Y3 , —SR Y3 , —NR Y2 R Y3 , —SO 2 NR Y2 R Y3 , —C( ⁇ O)NR Y2 R Y3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Y3 , —N(R Y2 )C( ⁇ O)R Y3 , wherein each occurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom
  • Y is one of:
  • Y is one of:
  • R Y1 is hydrogen, halogen or lower alkyl
  • Y is one of:
  • Y is one of:
  • L 2 is absent, —O—, —S—, —NR L2A —, a heterocyclic or heteroaryl moiety, or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L2A —, —NR L2A NR L2B , —NR L2A NR L2B C( ⁇ O)—, —NR L2A C( ⁇ O)—, —NR L2A CO 2 —, —NR L2A C( ⁇ O)NR L2B —, —S( ⁇ O)—, —SO 2 —, —NR L2A SO 2 —, —NR
  • L 2 is a 2-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
  • L 2 is —O—, —S—, —NR L2A —, —C( ⁇ O)NR L2A , —OC( ⁇ O)NR L2A —, —NR L2A NR L2B , —NR L2A NR L2B C( ⁇ O)—, —NR L2A C( ⁇ O)—, —NR L2A C( ⁇ O)O—, —NR L2A C( ⁇ O)NR L2B —, —NR L2A SO 2 —, —SO 2 NR L2A —, —NR L2A NR L2B —, or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C
  • L 2 is —O—, —S—, —NR L2A —, —C( ⁇ O)NR L2A —, —OC( ⁇ O)NR L2A —, —NR L2A NR L2B —, —NR L2A NR L2B C( ⁇ O)—, —NR L2A C( ⁇ O)—, —NR L2A CO 2 —, —NR L2A C( ⁇ O)NR L2B —, —NR L2A SO 2 —, —SO 2 NR L2A —, —NR L2A SO 2 NR L2B —, or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—,
  • L 2 is —O—, —S—, —NR L2A —, —C( ⁇ O)NR L2A —, —NR L2A C( ⁇ O)—, —OC( ⁇ O)NR L2A —, —NR L2A CO 2 —, or —NR L2A C( ⁇ O)NR L2B —, wherein each occurrence of R L2A and R L2B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • L 2 is —C( ⁇ O)NR L2A —, —NR L2A C( ⁇ O)—, or —NR L2A C( ⁇ O)NR L2B —, wherein each occurrence of R L2A and R L2B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • L 2 is —C( ⁇ O)NH—, —NHC( ⁇ O)—, —OC( ⁇ O)NH—, —NHC( ⁇ O)O— or —NHC( ⁇ O)NH—;
  • L 2 is —C( ⁇ O)NH—
  • L 2 is —NHC( ⁇ O)—
  • L 2 is —NHC( ⁇ O)NH—
  • L 2 is a saturated or unsaturated 5- to 6-membered monocyclic cyclic ring
  • L 2 is a 5- to 6-membered heterocyclic moiety
  • L 2 is a 5-membered heterocyclic moiety
  • L 2 is a 6-membered heterocyclic moiety
  • L 2 is a 5-membered heterocyclic moiety comprising one or more nitrogen atoms
  • L 2 is a 5-membered unsaturated heterocyclic moiety comprising one or more nitrogen atoms
  • L 2 is one of:
  • each occurrence of R L2A is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR L2C , —SR L2C , —NR L2B R L2C , —SO 2 NR L2B R L2C , —C( ⁇ O)NR L2B R L2C , halogen, —CN, —NO 2 , —C( ⁇ O)OR L2C , —N(R L2B )C( ⁇ O)R L2C , wherein each occurrence of R L2B and R L2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R L2B and R L2C taken together with the nitrogen atom
  • L 2 is one of:
  • L 2 is:
  • L 2 is:
  • lxxxix Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety;
  • xc) Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety
  • xci) Z is one of:
  • R Z1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl;
  • xcii) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety;
  • xciii) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety;
  • R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 , —SO 2 R Z4 , —C( ⁇ O)N(R Z2 ) 2 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z2 , —N(R Z2 )C( ⁇ O)R Z3 or —N(R Z2 )SO 2 R
  • xciv) Z is one of:
  • each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C( ⁇ O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z3 , —N(R Z2 )C( ⁇ O)R Z3 , wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the
  • xcv) Z is one of:
  • xcvi) Z is one of:
  • R Z1 is independently hydrogen, halogen, lower alkyl or lower haloalkyl
  • R Z2 and R Z3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2 and R Z3 taken together with the nitrogen atom to which they are attached for a 5-6 membered heterocyclic ring
  • R Z4 is lower alkyl or lower haloalkyl
  • xcvii) Z is one of:
  • R Z1 is independently halogen, lower alkyl or lower haloalkyl
  • xcviii) Z is one of:
  • X is halogen
  • R Z1 is substituted or unsubstituted lower alkyl
  • R Z2 is hydrogen, halogen or substituted or unsubstituted lower alkyl
  • xcix) Z is one of:
  • c) Z is an optionally substituted bicyclic heterocycle
  • ci) Z is a moiety having one of the following structures:
  • each “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 , —SO 2 R Z4 , —C( ⁇ O)N(R Z2 ) 2 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z2 , —N(R Z2 )C( ⁇ O)R Z3 or —N(R Z2 )SO 2
  • cii) Z is a moiety having one of the following structures:
  • each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C( ⁇ O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z3 , —N(R Z2 )C( ⁇ O)R Z3 , wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached
  • ciii) L 2 is absent and Z is an optionally substituted bicyclic heterocycle
  • each “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 , —SO 2 R Z4 ; wherein C( ⁇ O)N(R Z2 ) 2 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z2 , —N(R Z2 )C( ⁇ O)R Z3 or —N(R Z2 )SO 2
  • each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C( ⁇ O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Z3 , —N(R Z2 )C( ⁇ O)R Z3 , wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached
  • L 2 is absent and Z is a moiety having one of the following structures:
  • each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 ; —SO 2 R Z4 , —C( ⁇ O)N(R Z2 ) 2 ; halogen, —CN, —NO 2 , —C( ⁇ O)OR Z2 , —N(R Z2 )C( ⁇ O)R Z3 or —N(R Z2 )SO 2 R Z4 ; wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any
  • L 2 is absent and Z is a moiety having one of the following structures:
  • each occurrence of R Z1 is independently hydrogen, halogen, lower alkyl, lower heteroalkyl, lower haloalkyl, aryl, heteroaryl, —OR Z2 , —SR Z2 or —N(R Z2 ) 2 ; wherein each occurrence of R Z2 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of R Z2 , taken together with the nitrogen atom to which they are attached (e.g., N(R Z2 ) 2 ), form a substituted or unsubstituted heterocyclic moiety;
  • L 2 is absent and Z is a moiety having one of the following structures:
  • R Z1 is independently halogen, lower alkyl or lower haloalkyl
  • X is halogen and R Z1 is halogen, lower alkyl or lower haloalkyl;
  • R Z1 is lower alkyl
  • R Z2 is —CX 3 or lower alkyl
  • X is halogen
  • X is F or Cl
  • R is —CF 3 or tert-butyl
  • R 4 is a substituent that enhances water solubility of the compound
  • R 4 is hydrogen, —CN, —OR 4A , —SR 4A , —NR 4A R 4B , —C( ⁇ O)R 4A , —C( ⁇ O)OR 4A , —C( ⁇ O)NR 4A R 4B , —C( ⁇ NR 4A )R 4B , —C( ⁇ NR 4A )OR 4B , —C( ⁇ NR 4A )NR 4B R 4C , —S( ⁇ O) 2 R 4D , —P( ⁇ O)(R 4D ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(
  • R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; each of which bearing a polar substitutent selected from the group consisting of: —OR 4A , —SR 4A , —NR 4A R 4B , —C( ⁇ O)OR 4A , —C( ⁇ O)NR 4A R 4B , —C( ⁇ NR 4A )R 4B , —C( ⁇ NR 4A )OR 4B , —C( ⁇ NR 4A )NR 4B R 4C , —S( ⁇ O) 2 R 4D and —P(
  • R 4 is C 1-6 alkylNR 4 R 4B , wherein each occurrence of R 4A and R 4B is independently hydrogen or C 1-6 alkyl; or taken together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring;
  • R 4 has the structure:
  • p is an integer from 1-6;
  • X is O , NR 4A or C(R 4A ) 2 ; wherein each occurrence of R 4A is independently hydrogen or lower alkyl; and/or
  • R 4 has the structure:
  • cxx represents a single bond
  • cxxi represents a double bond
  • any one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated and any one or more occurrences of aryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.
  • the invention encompasses any and all compounds of R 2 , R 3 , R 4 , L 1 , L 2 , Y formula I generated by taking any possible permutation of variables n, R 1 , and Z, and other variables/substituents (e.g., R L1 , R L2 , R Y1 , R Z1 etc.) as further defined for R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , Y and Z, described in i) through cxxi) above.
  • variables/substituents e.g., R L1 , R L2 , R Y1 , R Z1 etc.
  • an exemplary combination of variables described in i) through cxxi) above includes those compounds of Formula I wherein:
  • n 1;
  • R 1 is hydrogen, halogen, —NO 2 , —CN, —C( ⁇ O)OR 1A , —S( ⁇ O) 2 R 1C , —P( ⁇ O)(R 1C ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl;
  • R 1A is hydrogen or C 1-6 alkyl; and each occurrence of R 1C is independently C 1-6 alkyl;
  • R 2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
  • R 3 is hydrogen, —C( ⁇ O)R 1A , lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl;
  • R 1A is hydrogen, or lower alkyl, aryl, or heteroaryl
  • R 4 is a substituent that enhances water solubility of the compound
  • L 1 is —W 1 -Alk 1 -; wherein W 1 is —O—, —S—, —N(R W1 )—, —C( ⁇ O)—, —N(R W1 )C( ⁇ O) or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC(
  • L 2 is —C( ⁇ O)NR L2A —, —OC( ⁇ O)NR L2A —, —NR L2A NR L2B —, —NR L2A NR L2B C( ⁇ O)—, —NR L2A C( ⁇ O)—, —NR L2A C( ⁇ O)O—, —NR L2A C( ⁇ O)NR L2B —, —NR L2A SO 2 —, —SO 2 NR L2A —, —NR L2A SO 2 NR L2B —, or a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L2A —, —OC( ⁇ O)
  • Y is a saturated or unsaturated cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety.
  • n, R 1 , R 4 , L 1 , L 2 , Y and Z are as defined generally and in classes and subclasses herein.
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A
  • C 1-6 alkyl moiety may be substituted or unsubstituted.
  • C 1-6 alkyl moiety may be substituted or unsubstituted.
  • the C 1-6 alkyl moiety is a substituted or unsubstituted C 1-2 alkyl moiety.
  • the C 1-6 alkyl moiety is —CH 2 —.
  • the C 1-6 alkyl moiety is —CH(R L1 )—; wherein R L1 is lower alkyl. In certain embodiments, R L1 is methyl.
  • n, R 1 , R 4 , L 1 , Y and Z are as defined generally and in classes and subclasses herein;
  • G 2 is absent, O or NR G2 ; and
  • R W3 and R G2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
  • -G 2 C( ⁇ O)N(R W3 )— is —C( ⁇ O)NH—, —OC( ⁇ O)NH—, or —NHC( ⁇ O)NH—. In certain embodiments, -G 2 C( ⁇ O)N(R W3 )— is —C( ⁇ O)NH—.
  • n, R 1 , R 4 , L 1 , L 2 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-2; and J 1 , J 2 and J 3 are independently O, S, N, NR Y1 or CR Y1 ; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Y3 , —SR Y3 , —NR Y2 R Y3 , —SO 2 NR Y2 R Y3 , —C( ⁇ O)NR Y2 R Y3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Y3 , —N(R Y2 )C( ⁇ O)R Y3 , wherein each occurrence of R Y2 and R Y3 is
  • the 5-membered ring having the structure:
  • n, R 1 , R 4 , L 1 , L 2 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; and J 4 , J 5 and J 6 are independently N or CR Y1 ; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Y3 , —SR Y3 , —NR Y2 R Y3 , —SO 2 NR Y2 R Y3 , —C( ⁇ O)NR Y2 R Y3 , halogen, —CN, —NO 2 , —C( ⁇ O)OR Y3 , —N(R Y2 )C( ⁇ O)R Y3 , wherein each occurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower hetero
  • R 1 , R 4 , L 2 and Z are as defined generally and in classes and subclasses herein;
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and
  • Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —
  • the 5-membered ring having the structure:
  • n, R 1 , R 4 , L 1 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; J 1 , J 2 and J 3 are independently O, S, N, NR Y1 or CR Y1 ; J 4 , J 5 and J 6 are independently N or CR Y1 ; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Y3 , —SR Y3 , —NR Y2 R Y3 , —SO 2 NR Y2 R Y3 , —C( ⁇ O)NR Y2 R Y3 , halogen, —CN, —C( ⁇ O)OR Y3 , —N(R Y2 )C( ⁇ O)R Y3 , wherein each occurrence of R
  • the 5-membered ring having the structure:
  • -G 2 C( ⁇ O)N(R W3 )— is —C( ⁇ O)NH—, —OC( ⁇ O)NH—, or —NHC( ⁇ O)NH—. In certain embodiments, -G 2 C( ⁇ O)N(R W3 )— is —C( ⁇ O)NH—.
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A
  • the 5-membered ring having the structure:
  • —N(R W3 )C( ⁇ O)G 2 - is —NHC( ⁇ O)—, —NHC( ⁇ O)O—, or —NHC( ⁇ O)NH—.
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A
  • the 6-membered ring having the structure:
  • —N(R W3 )C( ⁇ O)G 2 - is —NHC( ⁇ O)—, —NHC( ⁇ O)O—, or —NHC( ⁇ O)NH—.
  • R 1 , R 4 , L 1 and Y are as defined generally and in classes and subclasses herein;
  • the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S;
  • m is an integer from 0-6; and each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 , —SO 2 R Z4 , —C( ⁇ O)N(R Z2 ) 2 , halogen, —CN, —NO 2 , —C( ⁇ O )OR Z
  • L 2 is absent and Z is a moiety having one of the following structures:
  • each occurrence of R Z1 is independently hydrogen, halogen, lower alkyl, lower heteroalkyl, lower haloalkyl, aryl, heteroaryl, —OR Z2 , —SO Z2 or —N(R Z2 ) 2 ; wherein each occurrence of R Z2 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of R Z2 , taken together with the nitrogen atom to which they are attached (e.g., N(R Z2 ) 2 ), form a substituted or unsubstituted heterocyclic moiety.
  • L 2 is absent and Z is a moiety having one of the following structures:
  • R Z1 is halogen, lower alkyl or lower haloalkyl; and R Z2 is —CX 3 or lower alkyl.
  • R Z1 is —CF 3 or tert-butyl.
  • X is F or Cl.
  • R Z2 is —CF 3 or tert-butyl.
  • L 2 is absent and Z is a moiety having one of the following structures:
  • R is —CF 3 or tert-butyl.
  • n, R 1 and R 4 are as defined generally and in classes and subclasses herein;
  • Z is an aryl, heteroaryl or heterocyclic moiety;
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
  • Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L
  • the compounds have the structure:
  • R Z1 is halogen or lower alkyl
  • X is halogen and R L1 is lower alkyl.
  • R Z1 is Cl or methyl.
  • R L1 is methyl.
  • n, R 1 and R 4 are as defined generally and in classes and subclasses herein;
  • Z is an aryl, heteroaryl or heterocyclic moiety;
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
  • Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L
  • the compounds have the structure:
  • R Z1 is halogen or lower alkyl
  • X is halogen and R L1 is lower alkyl.
  • R Z1 is Cl or methyl.
  • R L1 is methyl.
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L
  • the compounds have the structure:
  • R Z1 is lower alkyl, lower diaminoalkyl or lower alkyl and R L1 is lower alkyl.
  • R Z1 is lower haloalkyl.
  • R Z1 is —CF 3 .
  • R L1 is methyl.
  • W 1 is —O—, —N(R W1 )—, —C( ⁇ O)— or —C( ⁇ O)N(R W1 )—, where R W1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1 is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C( ⁇ O)—, —CO 2 —, —C( ⁇ O)C( ⁇ O)—, —C( ⁇ O)NR L1A —, —OC( ⁇ O)—, —OC( ⁇ O)NR L1A —, —NR L1A NR L
  • the compounds have the structure:
  • R Z1 is lower alkyl or lower alkyl and R L1 is lower alkyl.
  • R Z1 is lower alkyl.
  • R Z1 is t-Bu.
  • R L1 is methyl.
  • —W 1 -Alk 1 - is —NH—C 1-6 alkyl-, —O—C 1-6 alkyl-, —C( ⁇ O)—C 1-6 alkyl- or —C( ⁇ O)NH—C 1-6 alkyl-; wherein the C 1-6 alkyl moiety may be substituted or unsubstituted.
  • the C 1-6 alkyl moiety is a substituted or unsubstituted C 1-2 alkyl moiety.
  • the C 1-6 alkyl moiety is —CH 2 —.
  • the C 1-6 alkyl moiety is —CH(R L1 )—; wherein R L1 is lower alkyl.
  • R L1 is methyl.
  • n is 1 and R 1 is hydrogen, halogen, heterocyclyl, aryl or heteroaryl. In certain exemplary embodiments, n is 0.
  • R Z1 is hydrogen, halogen, lower alkyl or lower haloalkyl.
  • m is 1 and R Z1 is halogen, lower alkyl or lower haloalkyl.
  • n is 0, 1 or 2. In certain embodiments, n is 0.
  • Z is one of the following structures:
  • R Z1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl.
  • Z is one of the following structures:
  • X is halogen
  • R Z1 is substituted or unsubstituted lower alkyl
  • R Z2 is hydrogen, halogen or substituted or unsubstituted lower alkyl.
  • Z is one of the following structures:
  • L 2 is absent and Z is a moiety having one of the following structures:
  • R Z1 is lower alkyl; X is halogen; and R Z2 is —CX 3 or lower alkyl.
  • L 2 is absent and Z is a moiety having one of the following structures:
  • X is F or Cl
  • L 2 is absent and Z is a moiety having one of the following structures:
  • R is —CF 3 or tert-butyl
  • R 4 is a substituent that enhances water solubility of the compound. In certain embodiments, R 4 has the structure:
  • R 4 has the structure:
  • inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.
  • certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers.
  • this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
  • Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention.
  • different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques.
  • the present invention provides novel compounds, specifically compounds having the following general structure:
  • A-B together represent one of the following structures:
  • R 1 , R 2 , R 3 , L 1 , L 2 , Y and Z are as defined in classes and subclasess herein.
  • LG 1 is a suitable leaving group and L 1A is adapted to displace LG 1 upon reaction with pyrido pyrimidinone (1).
  • the methodology may be used to generate inventive compounds of the general formula (I B ):
  • W 1 is —O—, —S— or —N(R W1 )— wherein R W1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk 1 is a C 1-6 alkylene or C 2-6 alkenylene moiety.
  • prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities.
  • prodrug moieties of interest include those that can be attached to group —NH 2 .
  • prodrug moieties include the following:
  • the present invention encompasses any prodrug form of the compounds described herein. Although certain other exemplary prodrug moieties generated from the inventive compounds amino group are detailed herein, it will be appreciated that the present invention is not intended to be limited to these prodrug moieties; rather, a variety of additional prodrug moieties can be readily identified by a person skilled in the relevant art.
  • the present invention provides compounds that are inhibitors of protein kinases (e.g., RAF kinase), and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to melanoma, leukemia, or cancers such as colon, breast, gastric, ovarian, lung, brain, larynx, cervical, renal, lymphatic system, genitourinary tract (including bladder and prostate), stomach, bone, lymphoma, melanoma, glioma, papillary thyroid, neuroblastoma, and pancreatic cancer.
  • melanoma e.g., leukemia
  • cancers such as colon, breast, gastric, ovarian, lung, brain, larynx, cervical, renal, lymphatic system, genitourinary tract (including bladder and prostate), stomach, bone, lymphoma, melanoma, glioma, papillary thyroid, neuroblastoma, and pancreatic cancer.
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • Compounds of the present invention may additionally be useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the areas of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.
  • Blood vessel proliferative disorders include arthritis and restenosis.
  • Fibrotic disorders include hepatic cirrhosis and atherosclerosis.
  • Mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies.
  • Metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a RAF kinase.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having protease inhibitory activity.
  • the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.
  • compounds of this invention were assayed for their ability to inhibit protein kinases, more specifically RAF.
  • compounds of this invention which are of particular interest include those which:
  • compounds of the invention are RAF kinase inhibitors. In certain exemplary embodiments, inventive compounds are RAF inhibitors. In certain exemplary embodiments, inventive compounds have Cell IC 50 values ⁇ 100 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 75 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 50 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 25 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 10 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 7.5 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 5 ⁇ M.
  • inventive compounds have Cell IC 50 values ⁇ 2.5 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 1 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 800 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 600 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 500 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 300 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 200 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 100 nM.
  • a method for the treatment or lessening the severity of an RAF-mediated disease or condition comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof.
  • an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of an RAF-mediated disease or condition.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of an RAF-mediated disease or condition. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as inhibitors of protein kinases.
  • the compounds and compositions of the invention are RAF kinase inhibitors, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of RAF kinase is implicated in the disease, condition, or disorder.
  • the disease, condition, or disorder may also be referred to as “RAF-mediated disease” or disease symptom.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of RAF kinase is implicated in the disease state.
  • the activity of a compound utilized in this invention as an RAF kinase inhibitor may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated RAF. Alternate in vitro assays quantitate the ability of the inhibitor to bind to RAF. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/RAF, complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with RAF bound to known radioligands.
  • RAF kinase means a measurable change in RAF activity between a sample comprising said composition and a RAF kinase and an equivalent sample comprising RAF kinase in the absence of said composition.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as “appropriate for the disease, or condition, being treated”.
  • therapies or anticancer agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine
  • alkylating drugs mechlorethamine,
  • agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation.
  • These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations
  • Another aspect of the invention relates to inhibiting RAF activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of RAF kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention.
  • the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • kits are especially suited for the delivery of solid oral forms such as tablets or capsules.
  • Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • placebo dosages, or calcium dietary supplements can be included to provide a kit in which a dosage is taken every day.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • Compound 1.4 Compound 1.3 (664 mg, 2.92 mmol), PdCl 2 (CH 3 CN) 2 (38.1 mg, 0.147 mmol), rac-BINAP (90.7 mg, 0.146 mmol), Et 3 N (610 ⁇ l, 4.38 mmol) and anhydrous methanol (30 mL) were added to a bomb. Carbon monoxide was purged three times and then the bomb was filled with CO to 50 psi. The reaction mixture was heated in an oil bath at 100° C. overnight. After cooling the reaction mixture, excess CO was vented. Solvents were removed under reduced pressure and the crude material was loaded directly onto a silica gel column.
  • Compound 3 was prepared according to Example 1 except for using compound 3.6 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Compound 4 is prepared according to Example 1 except for using 4.4 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Compound 5.2 A pressure vessel was charged with compound 5.1 (126 mg, 0.56 mmol) and a saturated solution of ammonia in ethanol (10 mL). The vessel was sealed and the reaction mixture was stirred at room temperature for 15 hours, whereupon the reaction mixture was concentrated. Compound 5.2 (138 mg, >100%) was isolated as a yellow solid, contaminated with inorganic salts.
  • Compound 5 is prepared according to Example 1 except for using compound 5.3 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Compound 6 is prepared according to Example 1 except for using compound 6.4 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Compound 7 is prepared according to Example 1 except for using compound 7.2 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • the cooled sodium ethoxide suspension was diluted with ethyl ether (200 mL), then the addition funnel was charged with ethyl chloroacetate (35.3 mL, 330 mmol, 1.0 equiv), ethyl formate (27.0 mL, 330 mmol, 1.0 equiv), and ethyl ether (25 mL).
  • ethyl chloroacetate/ethyl formate mixture was added slowly over 2.5 hours, and the resultant pale yellow suspension was stirred at room temperature overnight.
  • the reaction mixture was cooled to 0° C., and H 2 O (150 mL) was gradually added.
  • the aqueous layer was acidified to pH 3 with aqueous 1 N HCl (300 mL), and extracted with ether (6 ⁇ 80 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the brownish-red crude oil was purified by distillation under reduced pressure to afford compound 13.2 as a colorless oil (33 g, 68%; lit. boiling point 60° C. @ 12 ton).
  • Compound 19 is prepared according to Example 1 except for using compound 19.1 instead of compound 1.11.
  • Example 1 which is prepared according to Example 1 for making compound 1.15 except for using compound 13.4 instead of compound 1.12 and for using 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Compound 26 was prepared according to Example 1 for making compound 1.15 except for using compound 26.4 instead of compound 1.11.
  • Compound 28 was prepared according to Example 1 except for using compound 28.3 instead of compound 1.13.
  • Example 28 which are prepared according to Example 28 except for using compound 13.4 instead of compound 1.12 and for using an amine of the formula H 2 NZ instead of 3,4-diaminobenzotrifluoride for making compound 1.15.
  • Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Compound 32.1 is prepared according to the procedure for compound 1.11 except for using proparyl alcohol instead of compound 1.10.
  • Compound 32.2 is prepared according to the procedure for compound 28.3 except for using compound 32.1 instead of compound 1.12.
  • Compound 32 is prepared according to Example 1 except for using compound 32.2 instead of 1.13.
  • Example 2 which are prepared according to Example 1 for making compound 1.15 except for using compound 32.2 instead of compound 1.13 and for using an amine of the formula H 2 NZ instead of 3,4-diaminobenzotrifluoride.
  • Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Compound 37.1 is prepared according to the procedure to prepare compound 33.3 except for using compound 1.11 instead of compound 33.2.
  • Compound 37.5 is prepared according to Example 1 for making compound 1.12 except that compound 37.4 is used instead of compound 1.11.
  • Compound 37 is prepared according to Example 1 for making compound 1.13 except for using compound 37.5 instead of compound 1.12.
  • Compound 39 is prepared according to Example 37 except for using compound 39.1 instead of compound 37.4.
  • Compound 45.5 is prepared according to Example 1 except for using compound 45.4 instead of compound 1.7.
  • Compound 47.1 is prepared according to Example 1 except for using compound 45.4 instead of compound 1.7, Boc-glycine aldehyde instead of compound 1.9, and a diamine of the formula
  • Compound 47 is prepared according to Example 45 for making compound 45 except for using compound 47.1 instead of compound 45.5.
  • Compound 48.1 is prepared according to Example 1 for making compound 1.15 except for using compound 45.4 instead of compound 1.7, compound 13.4 instead of compound 1.12 and 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Compound 48 is prepared according to Example 45 for making compound 45 except for using compound 48.1 instead of compound 45.5.
  • Compound 51.1 is prepared according to Example 1 except for using compound 49 instead of compound 1.7, Boc-glycine aldehyde instead of compound 1.9, and a diamine of the formula
  • Compound 51 is prepared according to Example 45 for making compound 45 except for using compound 51.1 instead of compound 45.5.
  • Compound 53.1 is prepared according to Example 1 for making compound 1.15 except for using compound 49 instead of compound 1.7, compound 13.4 instead of compound 1.12 and 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Compound 52 is prepared according to Example 45 for making compound 45 except for using compound 52.1 instead of compound 45.5.
  • Compound 53.3 is prepared according to Example 1 for making compound 1.4 except for using compound 53.2 instead of compound 1.3.
  • Compound 53.4 is prepared according to Example 1 except for using compound 53.3 instead of compound 1.6.
  • Compound 55.1 is prepared according to Example 53 for making compound 55.1 except for using methylamine instead of 2,4,6-trimethoxybenzylamine.
  • Compound 55.4 is prepared according to Example 1 for making compound 1.4 except for using compound 55.3 instead of compound 1.3.
  • Compound 55 Compound 55 is prepared according to Example 53 except for using compound 55.4 instead of compound 53.3.
  • WM-266-4 human melanoma cells ATCC #CRL-1676; V600D Raf B
  • matrigel BD Biosciences
  • test compound suspended in dosing vehicle (1/3/6 DMSO/PEG400/saline) was administered by a single oral gavage.
  • Treated mice were then sacrificed at 1, 3, and 8 hours post dosing and terminal endpoints (plasma drug concentration, tumor drug concentration, and tumor levels of phosphorylated ERK) were collected.
  • FIG. 1 shows the plasma and tumor concentration of an illustrative compound of the invention.
  • Tumor levels of phosphorylated ERK were assessed by first grinding freshly harvested tumor samples in liquid nitrogen and then reconstituting the ground tissue in cell extraction buffer (10 mM Tris HCl pH7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 20 mM Na 4 P 2 O 7 , 2 mM Na 4 VO 4 , 1% Triton X-100, 10% Glycerol, 0.1% SDS) containing freshly added phosphatase and protease inhibitors (1:100 of 100 mM PMSF, Sigma Phosphatase Inhibitor Cocktail I (Cat #P-2850), and Sigma Phosphatase Inhibitor Cocktail II (Cat #P-5726), and 1:1000 of Sigma Protease Inhibitor Cocktail (Cat #P-2714)).
  • cell extraction buffer 10 mM Tris HCl pH7.4, 100 mM NaCl, 1 mM EDTA, 1
  • FIG. 2 shows the tumor levels of phosphorylated ERK treated with an illustrative compound of the invention.
  • FIG. 3 shows the tumor growth rate curves for mice treated with an illustrative compound of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Endocrinology (AREA)
  • Transplantation (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)

Abstract

The present invention provides compounds having the formula:
Figure US20110059976A1-20110310-C00001
    • wherein A-B together represent one of the following structures:
Figure US20110059976A1-20110310-C00002
and
    • n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.

Description

    PRIORITY
  • The present application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application Nos. 60/635,644 filed Dec. 13, 2004 and 60/636,740 filed Dec. 16, 2004; The entire contents of each of these applications are incorporated herein by reference.
  • BACKGROUND OF THE INVENTION
  • Cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death. Protein kinases play a critical role in this regulatory process. A partial non-limiting list of such kinases includes ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie.sub.1, tie.sub.2, TRK, Yes and Zap70. In mammalian biology, such protein kinases comprise mitogen activated protein kinase (MAPK) signalling pathways. MAPK signalling pathways are inappropriately activated by a variety of common disease-associated mechanisms such as mutation of ras genes and deregulation of growth factor receptors (Magnuson et al., Seminars in Cancer Biology; 1994 (5), 247-252).
  • Additionally, protein kinases have been implicated as targets in central nervous system disorders (such as Alzheimer's), inflammatory disorders (such as psoriasis), bone diseases (such as osteoporosis), atheroscleroses, restenosis, thrombosis, metabolic disorders (such as diabetes) and infectious diseases (such as viral and fungal infections).
  • One of the most commonly studied pathways involving kinase regulation is cellular signalling from receptors at the cell surface to the nucleus. One example of this pathway includes a cascade of kinases in which members of the Growth Factor receptor Tyrosine Kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulin receptor), deliver signals through phosphorylation to other kinases such as Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase families. Each of these kinases is represented by several family members which play related, but functionally distinct roles. The loss of regulation of the growth factor signalling pathway is a frequent occurrence in cancer as well as other disease states.
  • The signals mediated by kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle. Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs). The regulation of CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits. A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/CDK2 whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase. It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer.
  • Raf protein kinases are key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells. Activated cell surface receptors activate ras/rap proteins at the inner aspect of the plasmamembrane which in turn recruit and activate Raf proteins. Activated Raf proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2. In turn, activated MEKs catalyse phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK). A variety of cytoplasmic and nuclear substrates of activated MAPK are known which directly or indirectly contribute to the cellular response to environmental change. Three distinct genes have been identified in mammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformic variants that result from differential splicing of mRNA are known.
  • Inhibitors of Raf kinases have been suggested for use in disruption of tumor cell growth and hence in the treatment of cancers, e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer and pancreatic and breast carcinoma; and also in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth.
  • Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as RAF inhibitors.
  • SUMMARY OF THE INVENTION
  • As discussed above, there remains a need for the development of novel therapeutic agents and agents useful for treating disorders mediated by RAF. In certain embodiments, the present invention provides novel compounds having the structure:
  • Figure US20110059976A1-20110310-C00003
  • wherein A-B together represent one of the following structures:
  • Figure US20110059976A1-20110310-C00004
  • and
  • n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
  • In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit RAF activity. In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound and optionally further comprising an additional therapeutic agent. In yet other embodiments, the additional therapeutic agent is an agent for the treatment of cancer.
  • In yet another aspect, the present invention provides methods for inhibiting kinase activity (e.g., RAF) activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of the invention. In still another aspect, the present invention provides methods for treating any disorder involving RAF activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • BRIEF DESCRIPTION OF THE DRAWING
  • FIG. 1 depicts exemplary compound concentration experiments in mouse plasma (solid lines) and tumor tissue (dashed lines) at 1, 3, 8, 16, and 24 hours following a single oral dose of 25 (blue), 50 (red), or 100 (green) mg/kg compound X.
  • FIG. 2 depicts exemplary western analysis of WM-266-4 xenograft tumor tissue. Tumors were excised and proteins extracted at 3, 8, and 16 hours following a single oral dose containing vehicle alone (lanes 1 and 2) or 100 (lanes 3 and 4), 50 (lanes 5 and 6), or 25 (lanes 7 and 8) mg/kg compound X. ERK and phospho-ERK levels were then assessed by Western blot analysis
  • FIG. 3 depicts exemplary growth rates of WM-266-4 melanoma tumor xenografts in mice treated for two weeks with 25, 50, or 100 mg/kg QD compound X, 50 mg/kg BID compound X, 10 mg/kg QD Camptosar, or dosing vehicle alone.
  • DEFINITIONS
  • It is understood that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above. Examples of substituents include, but are not limited to aliphatic; heteroaliphatic; alicyclic; heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3—; or -GRG1 wherein G is —O—, —S—, —NRG2—, —C(═O)—, —S(═O)—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)—, —OC(═O)O—, —OC(═O)NRG2—, —NRG2C(═O)NRG3—, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NRG2)—, —C(═NRG2)O—, —C(═NRG2)NRG3—, —OC(═NRG3)—, —NRG2C(═NRG3)—, —NRG2SO2—, —NRG2SO2NRG3—, or —SO2NRG2—, wherein each occurrence of RG1, RG2 and RG3 independently includes, but is not limited to, hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • The term “aliphatic”, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term “alkyl” includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms.
  • In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1-20 or 2-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-10 or 2-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 or 2-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-6 or 2-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-4 or 2-4 aliphatic carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • The term “alicyclic”, as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “alicyclic” is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, cyclopropyl, cyclobutyl, —CH2-cyclobutyl, cyclopentyl, —CH2-cyclopentyl-n, cyclohexyl, —CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
  • The term “cycloalkyl”, as used herein, refers specifically to cyclic alkyl groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, heteroaliphatic or heterocyclic moieties, may optionally be substituted. An analogous convention applies to other generic terms such as “cycloalkenyl”, “cycloalkynyl” and the like.
  • The term “heteroaliphatic”, as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, i.e., in place of carbon atoms. Thus, a 1-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain, as used herein, refers to a C1-6aliphatic chain wherein at least one carbon atom is replaced with a nitrogen atom, and wherein any one or more of the remaining 5 carbon atoms may be replaced by an oxygen, sulfur, nitrogen, phosphorus or silicon atom. As used herein, a 1-atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain refers to —NH— or —NR— where R is aliphatic, heteroaliphatic, acyl, aromatic, heteroaromatic or a nitrogen protecting group. Heteroaliphatic moieties may be branched or linear unbranched. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, any of the substituents described above.
  • The term “heteroalicyclic”, “heterocycloalkyl” or “heterocyclic”, as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term “heterocyclic” refers to a non-aromatic 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • Additionally, it will be appreciated that any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • In general, the term “aromatic moiety”, as used herein, refers to stable substituted or unsubstituted unsaturated mono- or polycyclic hydrocarbon moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of aromatic moieties include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl.
  • In general, the term “heteroaromatic moiety”, as used herein, refers to stable substituted or unsubstituted unsaturated mono-heterocyclic or polyheterocyclic moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of heteroaromatic moieties include, but are not limited to, pyridyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.
  • It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein, may be attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety and thus also include moieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic, -(aliphatic)heteroaromatic, -(heteroaliphatic)heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(alkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases “aromatic or heteroaromatic moieties” and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substituents resulting in the formation of a stable compound.
  • In general, the term “aryl” refers to aromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two rings satisfying the Huckel rule for aromaticity, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Similarly, the term “heteroaryl” refers to heteroaromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, the term “heteroaryl”, as used herein, refers to a cyclic unsaturated radical having from about five to about ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • Substituents for aryl and heteroaryl moieties include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • The terms “alkoxy” (or “alkyloxy”), and “thioalkyl” as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom (“alkoxy”) or through a sulfur atom (“thioalkyl”). In certain embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms. Examples of alkoxy groups, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • The term “amine” refers to a group having the structure —N(RX)2 wherein each occurrence of RX is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or the RX groups, taken together, may form a heterocyclic moiety.
  • The term “alkylamino” refers to a group having the structure —NHRX wherein RX is alkyl, as defined herein. The term “aminoalkyl” refers to a group having the structure H2NRX—, wherein RX is alkyl, as defined herein. In certain embodiments, the alkyl group contains about 1-20 or 2-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 or 2-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 or 2-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 or 2-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 or 2-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
  • The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • The term “halogenated” denotes a moiety having one, two, or three halogen atoms attached thereto.
  • The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • The term “acyloxy”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —OC(O)RX, wherein RX is a substituted or unsubstituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • The term “acyl”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —C(O)RX, wherein RX is a substituted or unsubstituted, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • The term “imino”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure —C(═NRX)RY, wherein RX is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and RY is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
  • The term “C1-6alkylene”, as used herein, refers to a substituted or unsubstituted, linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence “−” at both ends of the radical.
  • The term “C2-6alkenylene”, as used herein, refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence “−” at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.
  • As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”, “heteroaromatic”, “aryl”, “heteroaryl” and the like, used alone or as part of a larger moiety, encompass both substituted and unsubstituted groups.
  • As used herein, the term “isolated”, when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.
  • The phrase, “pharmaceutically acceptable derivative”, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
  • The term “RAF-mediated disease” or “RAF-mediated condition”, as used herein, means any disease or other deleterious condition in which RAF is known to play a role. The terms “RAF-mediated disease” or “RAF-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an RAF inhibitor. Such conditions include, without limitation, colon, breast, gastric, ovarian, lung, brain, larynx, cervical, renal, lymphatic system, genitourinary tract (including bladder and prostate), stomach, bone, lymphoma, melanoma, glioma, papillary thyroid, neuroblastoma, and pancreatic cancer. The term “RAF-mediated disease”, as used herein, means any disease or other deleterious condition or disease in which RAF is known to play a role. Such diseases or conditions include, without limitation, cancers such as colon and breast cancer.
  • The term “treating” or “treated”, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.
  • The term “preventing” as used herein means that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disease, disorder or condition at the time of administration, but who would normally be expected to develop the disease, disorder or condition or be at increased risk for the disease, disorder or condition. In certain embodiments, the compounds of the invention will slow the development of disease symptoms, delay the onset of disease, or prevent the individual from developing the disease at all. In certain embodiments, preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease.
  • As used herein the term “biological sample” includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. For example, the term “biological sample” refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated). The biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes. Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). An animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
  • DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION
  • As noted above, there has been increasing interest in recent years in the development of protein kinase inhibitors, particularly RAF inhibitors, as therapeutic agents for the treatment of diseases/conditions involving protein kinase-mediated events. In one aspect, the present invention provides RAF inhibitors.
  • Compounds of this invention include those generally set forth above and described specifically herein, and are illustrated in part by the various classes, subgenera and species disclosed herein. Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
  • 1) General Description of Compounds of the Invention
  • In certain embodiments, the compounds of the invention include compounds of the general formula (I) as further defined below:
  • Figure US20110059976A1-20110310-C00005
  • and pharmaceutically acceptable derivatives thereof;
  • wherein A-B together represent one of the following structures:
  • Figure US20110059976A1-20110310-C00006
  • Figure US20110059976A1-20110310-P00001
    represents a single or double bond as valency permits;
  • n is an integer from 0-4 as valency permits;
  • R1 and R2 are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
  • R3 is hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
  • R4 is hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; or is absent when
    Figure US20110059976A1-20110310-P00001
    is a double bond;
  • L1 is —O—, —S—, —NRL1A— or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • L2 is absent, —O—, —S—, —NRL2A—, a heteroalicyclic or heteroaromatic moiety, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL2A—, —OC(═O)—, —OC(═O)NRL2A—, —NRL1ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(═O)NRL2B—, —S(═O)—, —SO2—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, —O—, —S—, or —NRL2A—; wherein each occurrence of RL2A and RL2B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • Y is an carbocyclic, heterocyclic, aryl or heteroaryl moiety; and
  • Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety.
  • In certain embodiments, the following groups do not occur simultaneously as defined: A-B together represent
  • Figure US20110059976A1-20110310-C00007
  • L1 is —Oalkyl-, —N(R)alkyl-, —Salkyl-, —Oalkenyl-, —N(R)alkenyl-, or —Salkenyl-, wherein R is hydrogen, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl or (heterocyclyl)alkyl; and R2 is —NR2AR2B wherein R2A is hydrogen or alkyl; and R2B is optionally substituted heteroaryl, heterocyclyl or aryl.
  • In certain embodiments, the following groups do not occur simultaneously as defined: L1 is —N(RL1)—, wherein RL1 is hydrogen or C1-6alkyl; n is 0-3; R1 is —(CR1ACR1B)qX(CR1ACR1B)t wherein X is absent, —N(R1C)—, —NH—, —O—, —C(═O)—, —N(R1C)C(═O)—, —C(═O)N(R1C)—, —C(═O)(cis or trans alkenyl)-, —N(R1C)C(═O)(cis or trans alkenyl)-, —C(═O)alkynyl-, —N(R1C)C(═O)alkynyl-, —N(R1C)C(═O)alkynylN(R1C)—, —N(R1C)C(═O)N(R1C)—, —N(R1C)S(═O)j—, —S(═O)jN(R1C)— or —S(═O)j—; and —Y-L2-Z together represent a moiety having the structure:
  • Figure US20110059976A1-20110310-C00008
  • wherein p is 0-4; Rv is optionally substituted phenyl or an optionally substituted 4- to 6-membered heterocyclic ring, wherein said heterocyclic group is optionally fused to an optionally substituted benzene or C5-8cycloalkyl group; and Rw is halogen, cyano, nitro, —OCF3, —CF3, hydroxy, C3-8cycloalkyl, C1-6alkoxy, C1-10alkyl, C2-6alkenyl, C2-6alkynyl, —C(═O)Ru, —C(═O)ORu, —OC(═O)Ru, —NRuC(═O)Rs, —NRuS(═O)2NRsR3, —NRuC(═O)NRsR3, —NRuC(═O)ORs, —C(═O)NRsR3, —NRsR3, —S(═O)2NRsR3, —S(═O)jC1-6alkyl-, —(CRw1Rw2)t(C6-10aryl)-, —(CRw1Rw2)t(4 to 10 membered heterocyclic)-, —(CRw1Rw2)qC(═O)(CRw1Rw2)t(C6-10aryl)-, —(CRw1Rw2)qC(═O)(CRw1Rw2)t(4 to 10 membered heterocyclic)-, —(CRw1Rw2)qC(═O)(CRw1Rw2)t(C6-10aryl)-, —(CRw1Rw2)qO(CRw1Rw2)t(4 to 10 membered heterocyclic)-, —(CRw1Rw2)qS(═O)j(CRw1Rw2)t(C6-10aryl)- or —(CRw1Rw2)qS(═O)j(CRw1Rw2)t(4 to 10 membered heterocyclic)-; wherein j is 0-2; and q and t are independently 0-5.
  • In certain embodiments, A-B together represent
  • Figure US20110059976A1-20110310-C00009
  • and R3 is not an aryl or heteroaryl moiety.
  • In certain embodiments, the present invention defines particular classes of compounds which are of special interest. For example, one class of compounds of special interest includes compounds of formula (IA):
  • Figure US20110059976A1-20110310-C00010
  • Another class of compounds of special interest includes compounds of formula (IB):
  • Figure US20110059976A1-20110310-C00011
  • Another class of compounds of special interest includes compounds of formula (IC):
  • Figure US20110059976A1-20110310-C00012
  • Another class of compounds of special interest includes compounds of formula (ID):
  • Figure US20110059976A1-20110310-C00013
  • Another class of compounds of special interest includes compounds of formula (IE):
  • Figure US20110059976A1-20110310-C00014
  • Another class of compounds of special interest includes compounds of formula (IF):
  • Figure US20110059976A1-20110310-C00015
  • wherein W1 is —O—, —S—, —N(RW1)—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk1 is a C1-6alkylene or C2-6alkenylene moiety.
  • Another class of compounds of special interest includes compounds of formula (IG):
  • Figure US20110059976A1-20110310-C00016
  • wherein W1 is —O—, —S—, —N(RW1)—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk1 is a C1-6alkylene or C2-6alkenylene moiety.
  • Another class of compounds of special interest includes compounds of formula (IH):
  • Figure US20110059976A1-20110310-C00017
  • wherein W2 and W3 are independently absent, —O— or —N(RW)—, where RW is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic.
  • A number of important subclasses of each of the foregoing classes deserve separate mention; these subclasses include subclasses of the foregoing classes in which:
  • i) each occurrence of R1 is independently hydrogen, halogen, —CN, —NO2, —C(═O)R1A, —C(═O)OR1A, —C(═O)NR1AR1B, —S(═O)2R1C, —P(═O)(R1C)2, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R1A and R1B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R1C is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
  • ii) each occurrence of R1 is independently hydrogen, halogen, —NO2, —CN, —C(═O)OR1A, —S(═O)2R1C, —P(═O)(R1C)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl; wherein R1A is hydrogen or C1-6alkyl; and each occurrence of R1C is independently C1-6alkyl;
  • iii) each occurrence of R1 is independently hydrogen, halogen, —NO2, —CN, C1-5alkyl, C1-5alkoxy, C1-5alkylamino, diC1-5alkylamino, aminoC1-5alkyl, C1-5alkylaminoC1-5alkyl or diC1-5alkylaminoC1-5alkyl;
  • iv) at least one occurrence of R1 is F;
  • v) each occurrence of R1 is hydrogen;
  • vi) n is 1 and R1 is as defined in any one of subsets i)-iii) above;
  • vii) R2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
  • viii) R2 is C1-3alkyl or C1-3alkoxy;
  • ix) R2 is methyl or —CF3;
  • x) R2 is halogen;
  • xi) R2 is hydrogen;
  • xii) R3 is hydrogen, —C(═O)R1A, —C(═O)OR1A, —C(═O)NR1AR1B, —S(═O)2R1C, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R1A and R1B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R1C is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
  • xiii) R3 is hydrogen, —C(═O)R1A, lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl; wherein R1A is hydrogen, or lower alkyl, aryl, or heteroaryl;
  • xiv) R3 is hydrogen or lower alkyl;
  • xv) R3 is hydrogen or methyl;
  • xvi) R3 is hydrogen;
  • xvii) L1 is a 2-8 atom heteroaliphatic linker having at least one N, O or S atom in the heteroaliphatic main chain;
  • xviii) L1 is a 2-8 atom heteroaliphatic linker having at least one N or O atom in the heteroaliphatic main chain;
  • xix) L1 is a 2-8 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
  • xx) L1 is —W1-Alk1-; wherein W1 is —O—, —S—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk1 is a C1-6alkylene or C2-6alkenylene moiety;
  • xxi) L1 is —W1-Alk1-; wherein W1 is —O—, —S—, —N(RW1)—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • xxii) L1 is —W1-Alk1-; wherein W1 is —O—, —S—, —N(RW1)—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, lower alkyl, C3-6cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • xxiii) Compounds of subset xx) above wherein W1 is S;
  • xxiv) Compounds of subset xx) above wherein W1 is O or NRW1;
  • xxv) Compounds of subset xx) above wherein W1 is —C(═O)— or —C(═O)N(RW1)—;
  • xxvi) L1 is —O-Alk1-; wherein Alk1 is a substituted or unsubstituted C1-2alkylidene chain;
  • xxvii) L1 is —O-cyclopropyl-;
  • xxviii) L1 is —O—CH2CH2—;
  • xxix) L1 is —O—CH(RL1C)—, wherein RL1C is hydrogen or lower alkyl;
  • xxx) L1 is —O—CH2—;
  • xxxi) L1 is —O—CH(Me)-;
  • xxxii) L1 is —NRW1-Alk1-; wherein RW1 is hydrogen, lower alkyl, C3-6cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C2-6alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —S(═O)—, —SO2—, —O—, —S—, or —NRL1A—; wherein
  • RL1A is hydrogen or lower alkyl;
  • xxxiii) L1 is —NRW1-Alk1-; wherein RW1 is hydrogen or lower alkyl; and Alk1 is a substituted or unsubstituted C1-2alkylidene chain;
  • xxxiv) L1 is —NH-cyclopropyl-;
  • xxxv) L1 is —NH—CH2CH2—;
  • xxxvi) L1 is —NH—CH(RL1C)—, wherein RL1C is hydrogen or lower alkyl;
  • xxxvii) L1 is —NH—CH2—;
  • xxxviii) L1 is —NH—CH(Me)—;
  • xxxix) L1 is —C(═O)-Alk1-; wherein Alk1 is a substituted or unsubstituted C2-6alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —S(═O)—, —SO2—, —O—, —S—, or —NRL1A—; wherein RL1A is hydrogen or lower alkyl;
  • xl) L1 is —C(═O)-Alk1-; wherein Alk1 is a substituted or unsubstituted C1-2alkylidene chain;
  • xli) L1 is —C(═O)-cyclopropyl-;
  • xlii) L1 is —C(═O)—CH2CH2—;
  • xliii) L1 is —C(═O)—CH(RL1C)—, wherein RL1C is hydrogen or lower alkyl;
  • xliv) L1 is —C(═O)—CH2—;
  • xlv) L1 is —C(═O)—CH(Me)—;
  • xlvi) L1 is —C(═O)NRW1-Alk1-; wherein RW1 is hydrogen, lower alkyl, C3-6cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C2-6alkylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —S(═O)—, —SO2—, —O—, —S—, or —NRL1A—;
  • wherein RL1A is hydrogen or lower alkyl;
  • xlvii) L1 is —C(═O)NRW1-Alk1-; wherein RW1 is hydrogen or lower alkyl; and Alk1 is a substituted or unsubstituted C1-2alkylidene chain;
  • xlviii) L1 is —C(═O)NH-cyclopropyl-;
  • xlix) L1 is —C(═O)NH—CH2CH2—;
  • l) L1 is —C(═O)NH—CH(RL1C)—, wherein RL1C is hydrogen or lower alkyl;
  • li) L1 is —C(═O)NH—CH2—;
  • lii) L1 is —C(═O)NH—CH(Me)—;
  • liii) Y is a saturated or unsaturated cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • liv) Y is a saturated or unsaturated monocyclic cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • lv) Y is a saturated or unsaturated 5- to 6-membered monocyclic cyclic ring;
  • lvi) Y is an unsaturated 5-membered monocyclic cyclic ring system comprising one or more heteroatoms selected from S, N and O;
  • lvii) Y is an unsaturated 6-membered monocyclic cyclic ring system comprising one or more heteroatoms selected from S, N and O;
  • lviii) Y is a cycloalkyl, cycloalkenyl, heterocylic, aryl or heteroaryl moiety;
  • lix) Y is a 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocylic, 6-membered aryl or 6-membered heteroaryl moiety;
  • lx) Y is one of:
  • Figure US20110059976A1-20110310-C00018
  • wherein q is an integer from 0 to 3; each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
  • lxi) Y is one of:
  • Figure US20110059976A1-20110310-C00019
  • wherein q and RY1 are as defined directly above;
  • lxii) Y is one of:
  • Figure US20110059976A1-20110310-C00020
  • wherein q is 0-3; and RY1 is hydrogen, halogen or lower alkyl;
  • lxiii) Y is one of:
  • Figure US20110059976A1-20110310-C00021
  • lxiv) Y is one of:
  • Figure US20110059976A1-20110310-C00022
  • lxv) Y is:
  • Figure US20110059976A1-20110310-C00023
  • lxvi) Y is:
  • Figure US20110059976A1-20110310-C00024
  • lxvii) Y is:
  • Figure US20110059976A1-20110310-C00025
  • lxviii) L2 is absent, —O—, —S—, —NRL2A—, a heterocyclic or heteroaryl moiety, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL2A—, —NRL2ANRL2B, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(═O)NRL2B—, —S(═O)—, —SO2—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, —O—, —S—, or —NRL2A—; wherein each occurrence of RL2A and RL2B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • lxix) L2 is a 2-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
  • lxx) L2 is —O—, —S—, —NRL2A—, —C(═O)NRL2A, —OC(═O)NRL2A—, —NRL2ANRL2B, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2AC(═O)O—, —NRL2AC(═O)NRL2B—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ANRL2B—, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL2A—, —OC(═O)—, —OC(═O)NRL2A—, —NRL2ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(O)NRL2B—, —S(═O)—, —SO2—, —NRL2A—SO2, —SO2NRL2A—, —NRL2ASO2NRL2B—, —O—, —S—, or —NRL2A—; wherein each occurrence of RL2A and RL2B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • lxxi) L2 is —O—, —S—, —NRL2A—, —C(═O)NRL2A—, —OC(═O)NRL2A—, —NRL2ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(═O)NRL2B—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL2A—, —OC(═O)—, —OC(═O)NRL2A—, —NRL2ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(═O)NRL2B—, —S(═O)—, —SO2—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, —O—, —S—, or —NRL2A—; wherein each occurrence of RL2A and RL2B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • lxxii) L2 is —O—, —S—, —NRL2A—, —C(═O)NRL2A—, —NRL2AC(═O)—, —OC(═O)NRL2A—, —NRL2ACO2—, or —NRL2AC(═O)NRL2B—, wherein each occurrence of RL2A and RL2B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • lxxiii) L2 is —C(═O)NRL2A—, —NRL2AC(═O)—, or —NRL2AC(═O)NRL2B—, wherein each occurrence of RL2A and RL2B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • lxxiv) L2 is —C(═O)NH—, —NHC(═O)—, —OC(═O)NH—, —NHC(═O)O— or —NHC(═O)NH—;
  • lxxv) L2 is —C(═O)NH—;
  • lxxvi) L2 is —NHC(═O)—;
  • lxxvii) L2 is —NHC(═O)NH—;
  • lxxviii) L2 is absent;
  • lxxix) L2 is a saturated or unsaturated 5- to 6-membered monocyclic cyclic ring;
  • lxxx) L2 is a 5- to 6-membered heterocyclic moiety;
  • lxxxi) L2 is a 5-membered heterocyclic moiety;
  • lxxxii) L2 is a 6-membered heterocyclic moiety;
  • lxxxiii) L2 is a 5-membered heterocyclic moiety comprising one or more nitrogen atoms;
  • lxxxiv) L2 is a 5-membered unsaturated heterocyclic moiety comprising one or more nitrogen atoms;
  • lxxxv) L2 is one of:
  • Figure US20110059976A1-20110310-C00026
  • wherein q is an integer from 0 to 3; each occurrence of RL2A is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORL2C, —SRL2C, —NRL2BRL2C, —SO2NRL2BRL2C, —C(═O)NRL2BRL2C, halogen, —CN, —NO2, —C(═O)ORL2C, —N(RL2B)C(═O)RL2C, wherein each occurrence of RL2B and RL2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RL2B and RL2C taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
  • lxxxvi) L2 is one of:
  • Figure US20110059976A1-20110310-C00027
  • wherein q, RL2A and RL2B are as defined directly above;
  • lxxxvii) L2 is:
  • Figure US20110059976A1-20110310-C00028
  • lxxxviii) L2 is:
  • Figure US20110059976A1-20110310-C00029
  • lxxxix) Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety;
  • xc) Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety;
  • xci) Z is one of:
  • Figure US20110059976A1-20110310-C00030
  • wherein each occurrence of RZ1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl;
  • xcii) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety;
  • xciii) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety;
  • Figure US20110059976A1-20110310-C00031
  • wherein the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; the “Het” moiety represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2, —SO2RZ4, —C(═O)N(RZ2)2, halogen, —CN, —NO2, —C(═O)ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
  • xciv) Z is one of:
  • Figure US20110059976A1-20110310-C00032
    Figure US20110059976A1-20110310-C00033
  • wherein m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ1, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
  • xcv) Z is one of:
  • Figure US20110059976A1-20110310-C00034
  • xcvi) Z is one of:
  • Figure US20110059976A1-20110310-C00035
  • wherein each occurrence of RZ1 is independently hydrogen, halogen, lower alkyl or lower haloalkyl; RZ2 and RZ3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or RZ2 and RZ3 taken together with the nitrogen atom to which they are attached for a 5-6 membered heterocyclic ring; and RZ4 is lower alkyl or lower haloalkyl;
  • xcvii) Z is one of:
  • Figure US20110059976A1-20110310-C00036
  • wherein each occurrence of RZ1 is independently halogen, lower alkyl or lower haloalkyl;
  • xcviii) Z is one of:
  • Figure US20110059976A1-20110310-C00037
  • wherein X is halogen; RZ1 is substituted or unsubstituted lower alkyl; and RZ2 is hydrogen, halogen or substituted or unsubstituted lower alkyl;
  • xcix) Z is one of:
  • Figure US20110059976A1-20110310-C00038
  • c) Z is an optionally substituted bicyclic heterocycle;
  • ci) Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00039
  • wherein the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2, —SO2RZ4, —C(═O)N(RZ2)2, halogen, —CN, —NO2, —C(═O)ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
  • cii) Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00040
    Figure US20110059976A1-20110310-C00041
    Figure US20110059976A1-20110310-C00042
    Figure US20110059976A1-20110310-C00043
    Figure US20110059976A1-20110310-C00044
    Figure US20110059976A1-20110310-C00045
    Figure US20110059976A1-20110310-C00046
    Figure US20110059976A1-20110310-C00047
    Figure US20110059976A1-20110310-C00048
    Figure US20110059976A1-20110310-C00049
    Figure US20110059976A1-20110310-C00050
  • wherein m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ1, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
  • ciii) L2 is absent and Z is an optionally substituted bicyclic heterocycle;
  • civ) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00051
  • wherein the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2, —SO2RZ4; wherein C(═O)N(RZ2)2, halogen, —CN, —NO2, —C(═O)ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
  • cv) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00052
    Figure US20110059976A1-20110310-C00053
    Figure US20110059976A1-20110310-C00054
    Figure US20110059976A1-20110310-C00055
    Figure US20110059976A1-20110310-C00056
    Figure US20110059976A1-20110310-C00057
    Figure US20110059976A1-20110310-C00058
    Figure US20110059976A1-20110310-C00059
  • wherein m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ1, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
  • cvi) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00060
  • wherein m is an integer from 0-4; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2; —SO2RZ4, —C(═O)N(RZ2)2; halogen, —CN, —NO2, —C(═O)ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
  • cvii) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00061
  • wherein each occurrence of RZ1 is independently hydrogen, halogen, lower alkyl, lower heteroalkyl, lower haloalkyl, aryl, heteroaryl, —ORZ2, —SRZ2 or —N(RZ2)2; wherein each occurrence of RZ2 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety;
  • cviii) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00062
  • wherein RZ1 is independently halogen, lower alkyl or lower haloalkyl;
  • cix) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00063
  • wherein X is halogen and RZ1 is halogen, lower alkyl or lower haloalkyl;
  • cx) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00064
  • wherein RZ1 is lower alkyl; RZ2 is —CX3 or lower alkyl; and X is halogen;
  • cxi) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00065
  • wherein X is F or Cl;
  • cxii) L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00066
  • wherein R is —CF3 or tert-butyl;
  • cxiii) R4 is a substituent that enhances water solubility of the compound;
  • cxiv) R4 is hydrogen, —CN, —OR4A, —SR4A, —NR4AR4B, —C(═O)R4A, —C(═O)OR4A, —C(═O)NR4AR4B, —C(═NR4A)R4B, —C(═NR4A)OR4B, —C(═NR4A)NR4BR4C, —S(═O)2R4D, —P(═O)(R4D)2, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R4A, R4B and R4C are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R4D is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
  • cxv) R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; each of which bearing a polar substitutent selected from the group consisting of: —OR4A, —SR4A, —NR4AR4B, —C(═O)OR4A, —C(═O)NR4AR4B, —C(═NR4A)R4B, —C(═NR4A)OR4B, —C(═NR4A)NR4BR4C, —S(═O)2R4D and —P(═O)(R4D)2, wherein each occurrence of R4A, R4B and R4C is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring; and each occurrence of R4D is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
  • cxvi) R4 is C1-6alkylNR4R4B, wherein each occurrence of R4A and R4B is independently hydrogen or C1-6alkyl; or taken together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring;
  • cxvii) R4 has the structure:
  • Figure US20110059976A1-20110310-C00067
  • wherein p is an integer from 1-6; X is O , NR4A or C(R4A)2; wherein each occurrence of R4A is independently hydrogen or lower alkyl; and/or
  • cxviii) R4 has the structure:
  • Figure US20110059976A1-20110310-C00068
  • cxix) R4 is absent;
  • cxx)
    Figure US20110059976A1-20110310-P00001
    represents a single bond; and/or
  • cxxi)
    Figure US20110059976A1-20110310-P00001
    represents a double bond.
  • It will be appreciated that for each of the classes and subclasses described above and herein, any one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated and any one or more occurrences of aryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.
  • The reader will also appreciate that any and all possible combinations of the variables described in i)-through cxxi) above (e.g., R1, R2, R3, R4, L1, L2, Y and Z, among others) are considered part of the invention. Thus, the invention encompasses any and all compounds of R2, R3, R4, L1, L2, Y formula I generated by taking any possible permutation of variables n, R1, and Z, and other variables/substituents (e.g., RL1, RL2, RY1, RZ1 etc.) as further defined for R1, R2, R3, R4, L1, L2, Y and Z, described in i) through cxxi) above.
  • For example, an exemplary combination of variables described in i) through cxxi) above includes those compounds of Formula I wherein:
  • Figure US20110059976A1-20110310-P00001
    represents a single bond;
  • n is 1;
  • R1 is hydrogen, halogen, —NO2, —CN, —C(═O)OR1A, —S(═O)2R1C, —P(═O)(R1C)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl;
  • wherein R1A is hydrogen or C1-6alkyl; and each occurrence of R1C is independently C1-6alkyl;
  • R2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
  • R3 is hydrogen, —C(═O)R1A, lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl;
  • wherein R1A is hydrogen, or lower alkyl, aryl, or heteroaryl;
  • R4 is a substituent that enhances water solubility of the compound;
  • L1 is —W1-Alk1-; wherein W1 is —O—, —S—, —N(RW1)—, —C(═O)—, —N(RW1)C(═O) or —C(═O)N(RW1)—, where RW1 is hydrogen, lower alkyl, C3-6cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
  • L2 is —C(═O)NRL2A—, —OC(═O)NRL2A—, —NRL2ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2AC(═O)O—, —NRL2AC(═O)NRL2B—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL2A—, —OC(═O)—, —OC(═O)NRL2A—, —NRL2ANRL2B—, —NRL2ANRL2BC(═O)—, —NRL2AC(═O)—, —NRL2ACO2—, —NRL2AC(═O)NRL2B—, —S(═O)—, —SO2—, —NRL2ASO2—, —SO2NRL2A—, —NRL2ASO2NRL2B—, —O—, —S—, or —NRL2A—; wherein each occurrence of RL2A and R2B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
  • Y is a saturated or unsaturated cyclic ring system optionally comprising one or more heteroatoms selected from S, N and O;
  • Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety.
  • Other exemplary combinations are illustrated by compounds of the following subgroups:
  • I. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00069
  • wherein n, R1, R4, L1, L2, Y and Z are as defined generally and in classes and subclasses herein.
  • II. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00070
  • wherein n, R1, R4, L2, Y and Z are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl. In certain embodiments, n is 0.
  • In certain embodiments,
  • Figure US20110059976A1-20110310-C00071
  • has one of the structures below:
  • Figure US20110059976A1-20110310-C00072
  • wherein the C1-6alkyl moiety may be substituted or unsubstituted.
  • In certain embodiments,
  • Figure US20110059976A1-20110310-C00073
  • has the structure below:
  • Figure US20110059976A1-20110310-C00074
  • wherein the C1-6alkyl moiety may be substituted or unsubstituted.
  • In certain embodiments, for compounds of formulae (a), (b), (c) and (d), the C1-6alkyl moiety is a substituted or unsubstituted C1-2alkyl moiety. In certain exemplary embodiments, the C1-6alkyl moiety is —CH2—. In certain other exemplary embodiments, the C1-6alkyl moiety is —CH(RL1)—; wherein RL1 is lower alkyl. In certain embodiments, RL1 is methyl.
  • III. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00075
  • wherein n, R1, R4, L1, Y and Z are as defined generally and in classes and subclasses herein; G2 is absent, O or NRG2; and RW3 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
  • In certain embodiments, -G2C(═O)N(RW3)— is —C(═O)NH—, —OC(═O)NH—, or —NHC(═O)NH—. In certain embodiments, -G2C(═O)N(RW3)— is —C(═O)NH—.
  • IV. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00076
  • wherein n, R1, R4, L1, L2 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-2; and J1, J2 and J3 are independently O, S, N, NRY1 or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.
  • In certain embodiments, in compounds of this subclass, the 5-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00077
  • has one of the following structures:
  • Figure US20110059976A1-20110310-C00078
  • V. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00079
  • wherein n, R1, R4, L1, L2 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; and J4, J5 and J6 are independently N or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.
  • In certain embodiments, in compounds of this subclass, the 6-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00080
  • has the structure:
  • Figure US20110059976A1-20110310-C00081
  • VI. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00082
  • Figure US20110059976A1-20110310-C00083
  • wherein Cy is
  • n, R1, R4, L2 and Z are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NRY1 or CRY1; J4, J5 and J6 are independently N or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.
  • In certain embodiments, in compounds of this subclass, the 5-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00084
  • has one of the following structures:
  • Figure US20110059976A1-20110310-C00085
  • In certain embodiments, in compounds of this subclass, the 6-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00086
  • has the structure:
  • Figure US20110059976A1-20110310-C00087
  • VII. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00088
      • wherein Cy is
  • Figure US20110059976A1-20110310-C00089
  • wherein n, R1, R4, L1 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NRY1 or CRY1; J4, J5 and J6 are independently N or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, O or NRG2; and RW3 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
  • In certain embodiments, in compounds of this subclass, the 5-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00090
  • has one of the following structures:
  • Figure US20110059976A1-20110310-C00091
  • In certain embodiments, in compounds of this subclass, the 6-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00092
  • has the structure:
  • Figure US20110059976A1-20110310-C00093
  • In certain embodiments, -G2C(═O)N(RW3)— is —C(═O)NH—, —OC(═O)NH—, or —NHC(═O)NH—. In certain embodiments, -G2C(═O)N(RW3)— is —C(═O)NH—.
  • VIII. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00094
  • wherein n, R1, R4 and Z are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NRY1 or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, O or NRG2; and RW3 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
  • In certain embodiments, the 5-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00095
  • has one of the following structures:
  • Figure US20110059976A1-20110310-C00096
  • In certain embodiments, —N(RW3)C(═O)G2- is —NHC(═O)—, —NHC(═O)O—, or —NHC(═O)NH—.
  • IX. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00097
  • wherein n, R1, R4 and Z are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; q is an integer from 0-3; J4, J5 and J6 are independently N or CRY1; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORY3, —SRY3, —NRY2RY3, —SO2NRY2RY3, —C(═O)NRY2RY3, halogen, —CN, —NO2, —C(═O)ORY3, —N(RY2)C(═O)RY3, wherein each occurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, O or NRG2; and RW3 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
  • In certain embodiments, the 6-membered ring having the structure:
  • Figure US20110059976A1-20110310-C00098
  • has one of the following structures:
  • Figure US20110059976A1-20110310-C00099
  • In certain embodiments, —N(RW3)C(═O)G2- is —NHC(═O)—, —NHC(═O)O—, or —NHC(═O)NH—.
  • X. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00100
  • wherein L2 is absent and Z is:
  • Figure US20110059976A1-20110310-C00101
  • n, R1, R4, L1 and Y are as defined generally and in classes and subclasses herein; the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2, —SO2RZ4, —C(═O)N(RZ2)2, halogen, —CN, —NO2, —C(═O )ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring.
  • In certain embodiments, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00102
  • wherein each occurrence of RZ1 is independently hydrogen, halogen, lower alkyl, lower heteroalkyl, lower haloalkyl, aryl, heteroaryl, —ORZ2, —SOZ2 or —N(RZ2)2; wherein each occurrence of RZ2 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety.
  • In certain embodiments, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00103
  • wherein X is halogen, RZ1 is halogen, lower alkyl or lower haloalkyl; and RZ2 is —CX3 or lower alkyl. In certain exemplary embodiments, RZ1 is —CF3 or tert-butyl. In certain exemplary embodiments, X is F or Cl. In certain exemplary embodiments, RZ2 is —CF3 or tert-butyl.
  • In certain embodiments, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00104
  • wherein R is —CF3 or tert-butyl.
  • XI. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00105
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; Z is an aryl, heteroaryl or heterocyclic moiety; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl.
  • XII. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00106
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ4, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl.
  • In certain embodiments, the compounds have the structure:
  • Figure US20110059976A1-20110310-C00107
  • wherein RZ1 is halogen or lower alkyl, X is halogen and RL1 is lower alkyl. In certain exemplary embodiments, RZ1 is Cl or methyl. In certain exemplary embodiments, RL1 is methyl.
  • XIII. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00108
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; Z is an aryl, heteroaryl or heterocyclic moiety; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A≦, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl.
  • XIV. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00109
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ4, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl.
  • In certain embodiments, the compounds have the structure:
  • Figure US20110059976A1-20110310-C00110
  • wherein RZ1 is halogen or lower alkyl, X is halogen and RL1 is lower alkyl. In certain exemplary embodiments, RZ1 is Cl or methyl. In certain exemplary embodiments, RL1 is methyl.
  • XV. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00111
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, SO2—, —NRL1ASO2—, —SO2—, —SO2NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; the “D” cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each “Het” moiety independently represents a fully or partially saturated or unsaturated 5-membered ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —ORZ2, —SRZ2, —N(RZ2)2, —SO2N(RZ2)2, —SO2RZ4, —C(═O)N(RZ2)2, halogen, —CN, —NO2, —C(═O)ORZ2, —N(RZ2)C(═O)RZ3 or —N(RZ2)SO2RZ4; wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring.
  • XVI. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00112
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, SO2—, —NRL1ASO2—, —SO2—, —SO2NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ4, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl.
  • In certain embodiments, the compounds have the structure:
  • Figure US20110059976A1-20110310-C00113
  • wherein RZ1 is lower alkyl, lower diaminoalkyl or lower alkyl and RL1 is lower alkyl. In certain exemplary embodiments, RZ1 is lower haloalkyl. In certain exemplary embodiments, RZ1 is —CF3. In certain exemplary embodiments, RL1 is methyl.
  • XVII. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):
  • Figure US20110059976A1-20110310-C00114
  • wherein n, R1 and R4 are as defined generally and in classes and subclasses herein; W1 is —O—, —N(RW1)—, —C(═O)— or —C(═O)N(RW1)—, where RW1 is hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, SO2—, —NRL1ASO2—, —SO2—, —SO2NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; m is an integer from 0 to 3; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ4, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl.
  • In certain embodiments, the compounds have the structure:
  • Figure US20110059976A1-20110310-C00115
  • wherein RZ1 is lower alkyl or lower alkyl and RL1 is lower alkyl. In certain exemplary embodiments, RZ1 is lower alkyl. In certain exemplary embodiments, RZ1 is t-Bu. In certain exemplary embodiments, RL1 is methyl.
  • In certain embodiments, for compounds of subclasses VI, VIII, IX and XI-XVII above, —W1-Alk1- is —NH—C1-6alkyl-, —O—C1-6alkyl-, —C(═O)—C1-6alkyl- or —C(═O)NH—C1-6alkyl-; wherein the C1-6alkyl moiety may be substituted or unsubstituted. In certain embodiments, the C1-6alkyl moiety is a substituted or unsubstituted C1-2alkyl moiety. In certain exemplary embodiments, the C1-6alkyl moiety is —CH2—. In certain other exemplary embodiments, the C1-6alkyl moiety is —CH(RL1)—; wherein RL1 is lower alkyl. In certain embodiments, RL1 is methyl.
  • In certain embodiments, for compounds of subclasses XII-XVII above, n is 1 and R1 is hydrogen, halogen, heterocyclyl, aryl or heteroaryl. In certain exemplary embodiments, n is 0.
  • In certain embodiments, for compounds of subclasses XII-XVII above, RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RZ1 is halogen, lower alkyl or lower haloalkyl.
  • In certain embodiments, for compounds of subclasses I-XVII above, n is 0, 1 or 2. In certain embodiments, n is 0.
  • In certain embodiments, for compounds of subclasses I-XI above, Z is one of the following structures:
  • Figure US20110059976A1-20110310-C00116
  • wherein each occurrence of RZ1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl.
  • In certain embodiments, for compounds of subclasses I-XI above, Z is one of the following structures:
  • Figure US20110059976A1-20110310-C00117
  • wherein X is halogen; RZ1 is substituted or unsubstituted lower alkyl; and RZ2 is hydrogen, halogen or substituted or unsubstituted lower alkyl.
  • In certain embodiments, for compounds of subclasses I-XI above, Z is one of the following structures:
  • Figure US20110059976A1-20110310-C00118
  • In certain embodiments, for compounds of subclasses I-XI above, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00119
  • wherein RZ1 is lower alkyl; X is halogen; and RZ2 is —CX3 or lower alkyl.
  • In certain embodiments, for compounds of subclasses I-XI above, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00120
  • wherein X is F or Cl;
  • In certain embodiments, for compounds of subclasses I-XI above, L2 is absent and Z is a moiety having one of the following structures:
  • Figure US20110059976A1-20110310-C00121
  • wherein R is —CF3 or tert-butyl;
  • In certain embodiments, for compounds of subclasses I-XVII above, R4 is a substituent that enhances water solubility of the compound. In certain embodiments, R4 has the structure:
  • Figure US20110059976A1-20110310-C00122
  • wherein p is an integer from 1-6; X is O, NR4A or C(R4A)2; wherein each occurrence of R4A is independently hydrogen or lower alkyl. In certain exemplary embodiments, R4 has the structure:
  • Figure US20110059976A1-20110310-C00123
  • It will also be appreciated that for each of the subgroups I-XVII described above, a variety of other subclasses are of special interest, including, but not limited to those classes described above i)-cxxi) and classes, subclasses and species of compounds described above and in the examples herein.
  • Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.
  • Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
  • Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • 2) Synthetic Overview:
  • The practitioner has a well-established literature of pyrido-pyrimidinone, pyrimido-pyrimidinone and dihydro pteridinone chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention, including compounds containing the various R1, R2 and R3 substituents and L1, L2, Y and Z moieties.
  • The various patent documents and other references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates. Certain cited patent documents also contain information on formulation, uses, and administration of such compounds which may be of interest. For example, guidance may be found in U.S. Patent Publication Nos.: US 2004/0142945 and US 2003/0114671; and International Application No.: WO 98/08846.
  • Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof.
  • As described above, the present invention provides novel compounds, specifically compounds having the following general structure:
  • Figure US20110059976A1-20110310-C00124
  • and pharmaceutically acceptable derivatives thereof;
  • wherein A-B together represent one of the following structures:
  • Figure US20110059976A1-20110310-C00125
  • and
  • n, R1, R2, R3, L1, L2, Y and Z are as defined in classes and subclasess herein.
  • In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of formula (I) are provided, embodiments of said methods being depicted generally in Scheme A:
  • Figure US20110059976A1-20110310-C00126
  • where LG1 is a suitable leaving group and L1A is adapted to displace LG1 upon reaction with pyrido pyrimidinone (1).
  • In certain embodiments, the methodology may be used to generate inventive compounds of the general formula (IB):
  • Figure US20110059976A1-20110310-C00127
  • wherein W1 is —O—, —S— or —N(RW1)— where RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk1 is a C1-6alkylene or C2-6alkenylene moiety.
  • In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of Formula (IB) wherein W1 is —C(═O)N(RW1)—, where RW1 is as defined above, are provided, embodiments of said methods being depicted generally in Scheme
  • B:
  • Figure US20110059976A1-20110310-C00128
  • Numerous suitable prodrug moieties, and information concerning their selection, synthesis and use are well known in the art. Examples of prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities. For instance, prodrug moieties of interest include those that can be attached to group —NH2. Examples of such prodrug moieties include the following:
  • Figure US20110059976A1-20110310-C00129
  • The present invention encompasses any prodrug form of the compounds described herein. Although certain other exemplary prodrug moieties generated from the inventive compounds amino group are detailed herein, it will be appreciated that the present invention is not intended to be limited to these prodrug moieties; rather, a variety of additional prodrug moieties can be readily identified by a person skilled in the relevant art.
  • 3) Pharmaceutical Compositions
  • As discussed above, the present invention provides compounds that are inhibitors of protein kinases (e.g., RAF kinase), and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to melanoma, leukemia, or cancers such as colon, breast, gastric, ovarian, lung, brain, larynx, cervical, renal, lymphatic system, genitourinary tract (including bladder and prostate), stomach, bone, lymphoma, melanoma, glioma, papillary thyroid, neuroblastoma, and pancreatic cancer. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • Compounds of the present invention may additionally be useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the areas of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. Blood vessel proliferative disorders include arthritis and restenosis. Fibrotic disorders include hepatic cirrhosis and atherosclerosis. Mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies. Metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.
  • It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a RAF kinase.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • Uses of Compounds and Pharmaceutically Acceptable Compositions Research Uses
  • According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having protease inhibitory activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.
  • In certain exemplary embodiments, compounds of this invention were assayed for their ability to inhibit protein kinases, more specifically RAF.
  • Thus, in one aspect, compounds of this invention which are of particular interest include those which:
      • are inhibitors of protein kinases;
      • exhibit the ability to inhibit RAF kinase;
      • are useful for treating mammals (e.g., humans) or animals suffering from an RAF-mediated disease or condition, and for helping to prevent or delay the onset of such a disease/condition;
      • exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability).
  • In certain embodiments, compounds of the invention are RAF kinase inhibitors. In certain exemplary embodiments, inventive compounds are RAF inhibitors. In certain exemplary embodiments, inventive compounds have CellIC50 values ≦100 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦75 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦50 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦25 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦10 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦7.5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦2.5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦1 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦800 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦600 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦500 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦300 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦200 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦100 nM.
  • In yet another aspect, a method for the treatment or lessening the severity of an RAF-mediated disease or condition is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of an RAF-mediated disease or condition. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of an RAF-mediated disease or condition. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.
  • The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
  • The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • As described generally above, the compounds of the invention are useful as inhibitors of protein kinases. In one embodiment, the compounds and compositions of the invention are RAF kinase inhibitors, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of RAF kinase is implicated in the disease, condition, or disorder. When activation of RAF kinase is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as “RAF-mediated disease” or disease symptom. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of RAF kinase is implicated in the disease state.
  • The activity of a compound utilized in this invention as an RAF kinase inhibitor, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated RAF. Alternate in vitro assays quantitate the ability of the inhibitor to bind to RAF. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/RAF, complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with RAF bound to known radioligands.
  • The term “measurably inhibit”, as used herein means a measurable change in RAF activity between a sample comprising said composition and a RAF kinase and an equivalent sample comprising RAF kinase in the absence of said composition.
  • It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”.
  • For example, other therapies, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (CNI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov/cder/cancer/druglistframe—See Appendix).
  • Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
  • The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Another aspect of the invention relates to inhibiting RAF activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of RAF kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Treatment Kit
  • In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • EQUIVALENTS
  • The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof; in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.
  • The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.
  • EXEMPLIFICATION
  • The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds, are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.
  • Example 1
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00130
  • which is prepared according to Scheme A and the protocol below.
  • Figure US20110059976A1-20110310-C00131
    Figure US20110059976A1-20110310-C00132
  • Compound 1.1. To DMF (64 mL) at 0° C. was added POCl3 (200 mL) dropwise. After 1 hour, 2,4-dihydroxypyrimidine (50 g, 446 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then at 110° C. for 3 hours. After cooling to room temperature the solution was poured into ice water portion wise, being careful to keep the mixture from becoming excessively exothermic. The mixture was extracted with ether (8×); the combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo to provide compound 1.1 (58.6 g, 75%) as a pale yellow solid.
  • Compound 1.2. To compound 1.1 (19.5 g, 111 mmol) in toluene (220 mL) was added NH3 (27 mL, 7N in MeOH) and the reaction mixture was heated to 60° C. After 1 hour, a second aliquot of NH3/MeOH (18 mL) was added and stirring continued for an additional 45 minutes. The mixture was cooled and concentrated in vacuo. The solid was portioned between EtOAc, H2O using a small amount of MeOH to help dissolve. The aqueous layer was extracted with EtOAc (5×); the combined organic layer was extracted with H2O, dried over Na2SO4, and concentrated to yield compound 1.2 (19 g) that was used without further purification.
  • Compound 1.3. To compound 1.2 (˜19 g, ˜111 mmol) in CH3CN (300 mL) was added (diethoxy-phosphoryl)-acetic acid ethyl ester (28.3 g, 122 mmol), LiCl (9.24 g, 220 mmol), and Et3N (18.2 mL, 130 mmol). After 7 hours, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×); the combined organic layer was extracted with H2O, dried over Na2SO4, and concentrated in vacuo to provide a brown solid. The resulting solid was suspended in toluene and then filtered to give compound 1.3 (15.6 g, 62% from compound 1.1).
  • Compound 1.4. Compound 1.3 (664 mg, 2.92 mmol), PdCl2(CH3CN)2 (38.1 mg, 0.147 mmol), rac-BINAP (90.7 mg, 0.146 mmol), Et3N (610 μl, 4.38 mmol) and anhydrous methanol (30 mL) were added to a bomb. Carbon monoxide was purged three times and then the bomb was filled with CO to 50 psi. The reaction mixture was heated in an oil bath at 100° C. overnight. After cooling the reaction mixture, excess CO was vented. Solvents were removed under reduced pressure and the crude material was loaded directly onto a silica gel column. Eluent: hexanes/ethyl acetate (1:1→1:2→1:3→1:4→0:100). Ester 1.4 (557 mg, 78%) was obtained as an approximately 1:1 mixture of ethyl and methyl esters. This compound was further purified by recrystallization from chloroform-hexanes (Final yield: 329 mg, 1.35 mmol, 46%).
  • Compound 1.5. To compound 1.4 (30 mg, 0.12 mmol) in ethyl acetate/methanol (2 mL, 1:1) was added Pd on carbon (10%, wet, 8.5 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) at room temperature. After one hour, more Pd/C (9.5 mg) was added and the solution was stirred for an additional 4 hours. The reaction mixture was filtered over a pad of silica gel and celite and rinsed thoroughly with methanol. Removal of the solvent at reduced pressure provided compound 1.5 (30 mg, 100%).
  • Compound 1.6. To compound 1.5 (506 mg, 2 mmol), Et3N in a sealed tube was added ethanol (5 mL). The reaction mixture was warmed to 80° C. and stirred for 4 hours. After cooling to room temperature, the volatiles were removed in vacuo. The resulting material was suspended in ether/hexanes, filtered, and washed with hexanes to provide compound 1.6.
  • Compound 1.7. Compound 1.6 (540 mg, <2.61 mmol) was suspended in THF (9 mL) at room temperature. Lithium hydroxide (1 M aqueous solution, 3 mL, 3 mmol) was added. The reaction mixture becomes clear and after stirring for several hours solid precipitates. More lithium hydroxide (0.5 mL of 1 M solution) was added and the reaction mixture was stirred one more hour. The solvents were removed and the crude reaction mixture was suspended in CH2Cl2. The crude product was filtered and washed thoroughly with CH2Cl2 until all the color was removed. The solid was collected and 3N—HCl (1.18 mL) was added. The compound was filtered, rinsed with a minimal amount of ethanol, and then rinsed with CH2Cl2 to provide compound 1.7 (238 mg) as a white solid.
  • Compound 1.8. To Boc-D-alanine (100 g, 0.53 mol) in CH2Cl2 (2 L) was added O,N-dimethyl-hydroxylamine hydrochloride (55.2 g, 0.57 mol), EDC (106.7 g, 0.56 mol), HOBT (75.6 g, 0.56 mol), and Et3N (157 mL, 1.12 mol). The reaction mixture was stirred for 60 hours and then partitioned between CH2Cl2 and H2O. The organic layer was washed with 1N HCl, 3×H2O, and then dried over Na2SO4. Concentration of the organic layer provided compound 1.8 (110 g, 90%) as a white solid.
  • Compound 1.9. To compound 1.8 (16.23 g, 70 mmol) in CH2Cl2/THF (350 mL, 4:1) at −78° C. was added lithium aluminum hydride (75 mL, 75 mmol, 1.0 M in THF), dropwise, over 45 minutes. After 1 hour at −78° C., the reaction was quenched with aqueous NaHSO4 (110 mL, 110 mmol, 1M solution). The solution was stirred vigorously at room temperature for 1 hour and then partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layer was extracted with brine, dried over NaHSO4 and concentrated to give compound 1.9 (13.9 g), which was used without further purification.
  • Compound 1.10. To compound 1.9 in MeOH (550 mL) was added K2CO3 (20.7 g, 150 mmol) and (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (14.4 g, 75 mmol). After 1.5 hours, the reaction mixture was concentrated in vacuo. Purification by silica gel:chromatography (9:1 hexanes/ethyl acetate) provided compound 1.10 (7.1 g, 60% over two steps) as a white solid.
  • Compound 1.11. To compound 1.10 (6.7 g, 39.6 mmol) and 2-chloro-2-hydroxyiminoacetic acid ethyl ester (18.1 g, 120 mmol) in DMF at 90° C. (120 mL) was added Et3N (16.8 mL, 120 mmol) dropwise over 1 hour. The reaction mixture was stirred for 30 minutes, cooled to room temperature, and then concentrated in vacuo. The residue was dissolved in ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate (2×); the combined organic layer was extracted with 1N HCl, dried over NaHSO4, and concentrated in vacuo. Purification by silica gel chromatography (6:1→3:1 hexanes/ethyl acetate) provided compound 1.11 (8.45 g, 75%).
  • Compound 1.12. Hydrogen chloride in dioxane (4M solution, 10 mL) was added to compound 1.11 (1.49 g, 5.25 mmol) at room temperature and stirred for 2 hours. Solvent was removed under reduced pressure and the remaining reaction mixture was azeotroped with benzene (1×). Ethyl acetate and saturated sodium bicarbonate solution was added and the product was extracted with ethyl acetate (3×). Solid sodium chloride was added to the aqueous layer and the product was extracted with ethyl acetate. The combined ethyl acetate layers were dried with anhydrous sodium sulfate. Removal of the solvent under reduced pressure afforded compound 1.12 (968 mg), which was used in the next step without further purification.
  • Compound 1.13. Compound 1.12 (968 mg, 5.25 mmol), compound 1.7 (917 mg, 4.75 mmol) and PyAOP (2.98 g, 5.72 mmol) were dissolved in DMF (15 mL) at room temperature. Diisopropylethylamine (2.1 mL, 12.1 mmol) was added and the reaction mixture was stirred overnight. Ethyl acetate and water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×); the combined organic layer was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude product was purified using silica gel column chromatography (hexanes/ethyl acetate: 1:1→100% ethyl acetate -3→3:1 ethyl acetate:dichloromethane). The obtained product was further purified by recrystallization from ethyl acetate to give compound 1.13 (1.26 g, 3.51 mmol, 74%). The filtrate was purified again using silica gel chromatography followed by recrystallization to afford additional compound 1.13 (143 mg, 0.40 mmol, 8%).
  • Compound 1.14. To compound 1.13 (1.26 g, 3.51 mmol) was added THF (11 mL) and lithium hydroxide (1N aqueous solution, 3.68 mL, 3.68 mmol). The reaction was stirred at room temperature for 3 hours. Additional lithium hydroxide (1 mL, 1 mmol) was added and the reaction was stirred overnight. After removal of THF under reduced pressure, HCl (3N aqueous solution) was added until no additional precipitates formed. The product was filtered and rinsed thoroughly with 3N—HCl. After drying under reduced pressure overnight, compound 1.14 (765 mg, 2.31 mmol, 66%) was obtained.
  • Compound 1.15. To compound 1.14 (248 mg, 0.75 mmol) in DMF (3 mL) was added 3,4-diaminobenzotrifluoride (158 mg, 0.9 mmol), EDC (170 mg, 0.9 mmol), HOBT (122 mg, 0.9 mmol) and Et3N (0.14 mL, 1.0 mmol). The reaction mixture was stirred overnight and then partitioned between CH2Cl2 and 1N HCl. The aqueous layer was extracted with ethyl acetate (2×); the combined organic layers were extracted with 1N HCl, dried over NaHSO4, and concentrated in vacuo to provide compound 1.15.
  • Compound 1. The residue was heated in AcOH (3 mL) at 80° C. for 1.5 hours. After cooling, the reaction mixture was concentrated and then purified by silica gel chromatography to provide compound 1 (158 mg, 45%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.64 (d, J=6.85 Hz, 3H), 2.57 (t, J=7.58 Hz, 2H), 3.30 (t, J=7.58 Hz, 2H), 5.44 (m, 1H), 7.04 (s, 1H), 7.60 (d, J=8.80 Hz, 1H), 7.81 (d, J=8.80 Hz, 1H), 8.00 (s, 1H), 8.75 (s, 1H), 9.51 (d, J=8.31 Hz, 1H), 11.14 (s, 1H). LCMS: m/z: 472.
  • Example 2
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00133
  • These compounds are prepared according to Example 1 except for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00134
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines and their resulting compounds are shown in Table 1.
  • TABLE 1
    Figure US20110059976A1-20110310-C00135
    Final Compound
    Figure US20110059976A1-20110310-C00136
    Figure US20110059976A1-20110310-C00137
    Figure US20110059976A1-20110310-C00138
    Figure US20110059976A1-20110310-C00139
    Figure US20110059976A1-20110310-C00140
    Figure US20110059976A1-20110310-C00141
    Figure US20110059976A1-20110310-C00142
    Figure US20110059976A1-20110310-C00143
    Figure US20110059976A1-20110310-C00144
    Figure US20110059976A1-20110310-C00145
    Figure US20110059976A1-20110310-C00146
    Figure US20110059976A1-20110310-C00147
    Figure US20110059976A1-20110310-C00148
    Figure US20110059976A1-20110310-C00149
    Figure US20110059976A1-20110310-C00150
    Figure US20110059976A1-20110310-C00151
    Figure US20110059976A1-20110310-C00152
    Figure US20110059976A1-20110310-C00153
    Figure US20110059976A1-20110310-C00154
    Figure US20110059976A1-20110310-C00155
    Figure US20110059976A1-20110310-C00156
    Figure US20110059976A1-20110310-C00157
    Figure US20110059976A1-20110310-C00158
    Figure US20110059976A1-20110310-C00159
    Figure US20110059976A1-20110310-C00160
    Figure US20110059976A1-20110310-C00161
    Figure US20110059976A1-20110310-C00162
    Figure US20110059976A1-20110310-C00163
    Figure US20110059976A1-20110310-C00164
    Figure US20110059976A1-20110310-C00165
    Figure US20110059976A1-20110310-C00166
    Figure US20110059976A1-20110310-C00167
    Figure US20110059976A1-20110310-C00168
    Figure US20110059976A1-20110310-C00169
    Figure US20110059976A1-20110310-C00170
    Figure US20110059976A1-20110310-C00171
    Figure US20110059976A1-20110310-C00172
    Figure US20110059976A1-20110310-C00173
    Figure US20110059976A1-20110310-C00174
    Figure US20110059976A1-20110310-C00175
    Figure US20110059976A1-20110310-C00176
    Figure US20110059976A1-20110310-C00177
  • Example 3
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00178
  • which is prepared according to Scheme B and the protocol below.
  • Figure US20110059976A1-20110310-C00179
  • Compound 3.1. To an oven dried 250 mL three neck flask equipped with a reflux condenser and a 50 mL addition funnel, 5.00 g (217 mmol, 1.1 eq.) of sodium metal and toluene (27 mL) were added. The flask was placed in an oil bath (120° C.) and EtOH (16 mL, 283 mmol, 1.2 eq. to Na) was added dropwise through the addition funnel. The reaction mixture was refluxed for 3 hours after the addition, and by that time a thick suspension had formed. After cooling, ether (136 mL) was added resulting in an off-white suspension. A mixture of ethyl formate (15.3 mL, 189 mmol, 1 eq.) and ethyl acetate (18.5 mL, 180 mmol, 1 eq.) was added dropwise. After stirring at room temperature for 3 days, all solvent was removed under reduced pressure, and compound 3.1 was used without further purification.
  • Compound 3.2. To t-butyl amidine hydrochloride salt (1.38 g, 10.1 mmol) in 5% NaOH/H2O (w/v) (17 mL) was added compound 3.1 (2.76 g, 20.0 mmol, 2 eq.). The reaction mixture was stirred overnight and then acidified to pH=5 with conc. HCl. The solution was extracted with chloroform (3×); the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel column chromatography eluting with hexanes and ethyl acetate to provide compound 3.2 (0.82 g, 53%).
  • Compound 3.3. In a microwave vessel, compound 3.2 (123 mg, 0.81 mmol) was added to a solution containing concentrated H2SO4 (0.8 mL) and 70% HNO3 (0.8 mL). The reaction mixture was stirred in the microwave at 140° C. for 10 minutes and then at 150° C. for 10 minutes. The reaction was quenched by addition of ice. Solid NaHCO3 was added until pH˜5 was reached and compound 3.3 was extracted with chloroform (5×). The organic layer was dried over anhydrous sodium sulfate. After removal of the solvent, the crude compound 3.3 was directly used in the next step. Yield: 115 mg (0.584 mmol, ˜72%).
  • Compound 3.4. Compound 3.3 (115 mg, 0.584 mmol) and POCl3 (1 mL) were stirred at reflux for 3 hours. After removal of excess POCl3 under reduced pressure, ice was added and the product was extracted with chloroform. After drying with anhydrous sodium sulfate and removal of the solvent, crude compound 3.4 (110 mg) was obtained and used without further purification.
  • Compound 3.5. Compound 3.4 was dissolved in MeOH (1 mL) and ammonium hydroxide solution (1.5 mL) was added. The reaction mixture was stirred overnight. After removal of excess ammonia and MeOH, the mixture was extracted with chloroform. After drying with anhydrous sodium sulfate and removal of the solvent, compound 3.5 (89 mg, ˜78%) was obtained and used without further purification.
  • Compound 3.6. To compound 3.5 (89 mg, 0.46 mmol) in MeOH (3 mL) was added 10% Pd/C (wet) (10.3 mg). The reaction was put under an atmosphere of H2 and stirred for 2 hours. The reaction mixture was filtered through a pad of celite and rinsed thoroughly with MeOH. Removal of MeOH afforded compound 3.6 (76 mg, ˜100%) which was used without further purification.
  • Compound 3. Compound 3 was prepared according to Example 1 except for using compound 3.6 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Example 4
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00180
  • which was prepared according to Scheme C and the protocol below.
  • Figure US20110059976A1-20110310-C00181
  • Compound 4.1. 1,1-bis(methylthio)-2-nitroethylene (3.0 g, 18 mmol) in NH3/MeOH (30 mL, 7M) was heated to 50° C. After 18 hours, the reaction mixture was concentrated to obtain an orange solid. Crude product 4.1 (2.42 g, 23 mmol, ˜100%) was used in the next step without further purification.
  • Compound 4.2. Pinacolone (6.2 mL, 50 mmol) and C-methoxy-N,N,N′,N′-tetramethyl-methanediamine (10 mL) were heated to 110° C. under N2. After 18 hours, the reaction mixture was concentrated. The crude product was purified by distillation under reduced pressure to afford 4.2 (4.2 g, 53%) as a yellow crystalline solid.
  • Compound 4.3. Compound 4.1 (0.40 g, 2.9 mmol) and compound 4.2 (0.45 g, 2.9 mmol) in AcOH/EtOH (5 ml, 1:4) were stirred at reflux for 16 hours. The reaction mixture cooled and then concentrated. To the residue was added aqueous sodium hydroxide (1 N) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×); the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (100:0→9:1 hexanes/ethyl acetate) to afford compound 4.3 (320 mg, 56%).
  • Compound 4.4. To compound 4.3 (60 mg, 0.31 mmol) in methanol/ethyl acetate (2 mL, 1:1) at room temperature was added palladium on carbon (10 mg, 10%, wet) and the reaction mixture was put under an atmosphere of hydrogen (balloon). After 4 hours, the reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (100:0419:1 hexanes/ethyl acetate) to afford 4.4 (45 mg, 88%).
  • Compound 4. Compound 4 is prepared according to Example 1 except for using 4.4 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Example 5
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00182
  • which was prepared according to Scheme D and the protocol below.
  • Figure US20110059976A1-20110310-C00183
  • Compound 5.1. To a cooled (0° C.) mixture of fuming sulfuric acid (3.2 mL) and aqueous hydrogen peroxide (50%, 1.6 mL) was added a solution of 3-amino-2-chloro-6-(trifluoromethyl)pyridine (304 mg, 1.55 mmol) in conc. sulfuric acid (4 mL). The reaction was slowly warmed to 25° C. and stirred 20 hours, whereupon the reaction mixture was poured into ice water. The mixture was neutralized with aqueous ammonium hydroxide, and then extracted with ethyl acetate (5×10 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated to afford compound 5.1 (126 mg, 36%) as a yellow solid that was used without further purification.
  • Compound 5.2. A pressure vessel was charged with compound 5.1 (126 mg, 0.56 mmol) and a saturated solution of ammonia in ethanol (10 mL). The vessel was sealed and the reaction mixture was stirred at room temperature for 15 hours, whereupon the reaction mixture was concentrated. Compound 5.2 (138 mg, >100%) was isolated as a yellow solid, contaminated with inorganic salts.
  • Compound 5.3. To compound 5.2 (138 mg, <0.67 mmol) in methanol/ethyl acetate (10 mL, 1:1) at room temperature was added palladium on carbon (36 mg, 10%, wet) and the reaction mixture was placed under an atmosphere of hydrogen (balloon). After 1.5 hours, the reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate and methanol. The solvent was removed under reduced pressure to afford diamine 5.3 (149 mg, >100%) as a yellow film, which was used without further purification.
  • Compound 5. Compound 5 is prepared according to Example 1 except for using compound 5.3 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Example 6
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00184
  • which was prepared according to Scheme E and the protocol below.
  • Figure US20110059976A1-20110310-C00185
  • Compound 6.1. 4-Hydroxy-2-(trifluoromethyl)pyridine was prepared according to the reported procedure (Tyvorskii, V. I.; Bobrov, D. N. Chemistry of Heterocyclic Compounds 1997 33 (8), 1138-1139). To a cooled (0° C.) solution of 4-hydroxy-2-(trifluoromethyl)pyridine (651 mg, 3.99 mmol) in conc. sulfuric acid (1.6 mL) was added fuming sulfuric acid. Fuming nitric acid (4 mL) was added dropwise over 15 minutes, the pressure vessel was sealed tightly. The reaction mixture was heated to 120° C. and stirred 8 hours, whereupon the reaction mixture was cooled to room temperature and poured into ice water. The mixture was brought to pH=1 by addition of 10 M aqueous sodium hydroxide, then extracted with ethyl acetate (5×40 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated to afford compound 6.1 (570 mg, 69%) as a viscous yellow oil that was used without further purification.
  • Compound 6.2. A mixture of compound 6.1 (570 mg, 2.74 mmol), phosphorus pentachloride (900 mg, 4.11 mmol, 1.5 equiv), and phosphorus oxychloride (0.38 mL, 4.11 mmol, 1.5 equiv) was heated to 80° C. and stirred 11 hours. After cooling to room temperature, the reaction mixture was transferred to ice cold water and the mixture was extracted with dichloromethane (4×40 mL). The combined organic layers were washed with sat'd aqueous NaHCO3 (50 mL), water (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 6.2 (512 mg, 83%) was isolated as a yellow oil that was used without further purification.
  • Compound 6.3. A pressure vessel was charged with compound 6.1 (512 mg, 0.51 mmol) and a saturated solution of ammonia in ethanol (15 mL). The vessel was sealed and the reaction mixture was stirred at room temperature for 1.5 hours, whereupon the reaction mixture was concentrated. Compound 6.3 (538 mg, >100%) was isolated as an orange solid, contaminated with inorganic salts.
  • Compound 6.4. To compound 6.3 (538 mg, <2.6 mmol) in methanol/ethyl acetate (25 mL, 1.5:1) at room temperature was added palladium on carbon (total 245 mg, 10%, wet) portionwise over the course of the reaction. The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 27 hours. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate and methanol. The solvent was removed under reduced pressure to afford diamine 6.3 (457 mg, >100%) as a yellow film, which was used without further purification.
  • Compound 6. Compound 6 is prepared according to Example 1 except for using compound 6.4 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Example 7
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00186
  • which was prepared according to Scheme F and the protocol below.
  • Figure US20110059976A1-20110310-C00187
  • Compound 7.1. A mixture of 5-chloro-2-nitro-4-(trifluoromethyl)aniline (101.5 mg, 0.42 mmol), potassium carbonate (59.0 mg, 0.43 mmol), and dimethylamine (2 M/THF, 220 μL, 0.44 mmol) in DMF (150 μL) was heated in the microwave at 100° C. for 15 minutes, then at 120° C. for 20 minutes. The reaction mixture was concentrated and the crude residue was purified using silica gel column chromatography (5410-320% EtOAc/hexanes) to afford compound 7.1 (61.7 mg, 59%) as a yellow solid.
  • Compound 7.2. To compound 7.1 (61.7 mg, 0.248 mmol) in methanol/ethyl acetate (8 mL, 5:3) at room temperature was added palladium on carbon (20 mg, 10%, wet) and the reaction mixture was placed under an atmosphere of hydrogen (balloon). After 2 hours, the reaction mixture was filtered through a pad of celite and the celite pad was washed with methanol and ethyl acetate. The solvent was removed under reduced pressure to afford diamine
  • 7.2 (48 mg, 88%) as a brown film, which was used without further purification.
  • Compound 7. Compound 7 is prepared according to Example 1 except for using compound 7.2 instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15).
  • Example 8
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00188
  • which is prepared according to Example 1 except for using Boc-propargyl amine instead of compound 1.10.
  • Example 9
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00189
  • These compounds are prepared according to Example 1 except for using Boc-propargyl amine instead of compound 1.10 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00190
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 10
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00191
  • which was prepared according to Scheme G and the protocol below.
  • Figure US20110059976A1-20110310-C00192
  • Compound 10.1. Compound 1.9 (2.08 g, <12 mmol), hydroxylamine hydrochloride (852 mg, 12.3 mmol, 1.03) and pyridine (9 mL) were stirred in methanol (45 mL) at room temperature overnight. After evaporation of the solvent, water was added and the product was extracted with methylene chloride three times. The organic layer was dried over anhydrous sodium sulfate. Solvent was removed and pumped overnight to remove pyridine. The crude material, compound 10.1, was used directly in the next reaction. Yield: 2.12 g (<11.3 mmol, 94%).
  • Compound 10.2. To compound 10.1 (2.12 g, <11.3 mmol) dissolved in 56 mL DMF was added NCS (1.51 g, 11.3 mmol) and the reaction was heated to 60° C. for one hour. After cooling the reaction mixture to 0° C., propynoic acid ethyl ester (2.3 mL, 22.7 mmol) was added all at once. Triethylamine (1.65 mL, 11.8 mmol) in DMF (13 mL) was added to the reaction mixture via an addition funnel over 15 minutes. The reaction mixture was stirred for another 10 minutes. Water (70 mL) and ethyl acetate (50 mL) was added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water and then with brine, and dried over anhydrous sodium sulfate. After removal of the solvent, the crude product, compound 10.2, was purified using silica gel column chromatography. The product eluted with a gradient of hexanes:ethyl acetate (5:1) to (4:1). Yield: 1.7 g (5.98 mmol, 50% from compound 1.9).
  • Compound 10. Compound 10 was prepared according to Example 1 except for using compound 10.2 instead of compound 1.11.
  • Example 11
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00193
  • These compounds are prepared according to Example 1 except for using compound 10.2 instead of compound 1.11 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00194
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 12
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00195
  • These compounds are prepared according to Example 1 except for using Boc-glycine aldehyde instead of compound 1.9, compound 10.2 instead of compound 1.11, and diamine of the formula
  • Figure US20110059976A1-20110310-C00196
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 13
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00197
  • These compounds are prepared according to Scheme H and the protocol below.
  • Figure US20110059976A1-20110310-C00198
  • Compound 13.1. To a suspension of Z-D-alanine-NH2 (4.98 g, 22.4 mmol) in dioxane (23 mL) was added Lawesson's reagent (4.98 g, 12.3 mmol, 0.55 equiv). The reaction mixture was heated to 60° C. and stirred for 30 minutes, then cooled to room temperature and stirred an additional 24 hours, whereupon the reaction mixture was concentrated in vacuo. The residue was diluted with a 1:1 mixture of saturated aqueous NaHCO3:H2O (100 mL), then additional saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL). After separation of the phases, the aqueous phase was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (10→25→50→60% EtOAc/hexanes) afforded compound 13.1 (4.75 g, 90%) as a white solid. LCMS: m/z: 239 (M+1).
  • Compound 13.2. A flame-dried 1 L 3-neck round bottom flask equipped with an addition funnel and a condenser was charged with dry toluene (45 mL). Sodium metal chunks (8.34 g, 363 mmol, 1.1 equiv) were added, and the mixture was heated to reflux (bath temp. 115° C.). Dry absolute ethanol (30 mL) was added slowly by addition funnel over 30 minutes. The reaction mixture was stirred at 115° C. for an addition 2 hours, then cooled to room temperature. The cooled sodium ethoxide suspension was diluted with ethyl ether (200 mL), then the addition funnel was charged with ethyl chloroacetate (35.3 mL, 330 mmol, 1.0 equiv), ethyl formate (27.0 mL, 330 mmol, 1.0 equiv), and ethyl ether (25 mL). The ethyl chloroacetate/ethyl formate mixture was added slowly over 2.5 hours, and the resultant pale yellow suspension was stirred at room temperature overnight. The reaction mixture was cooled to 0° C., and H2O (150 mL) was gradually added. After separation of the phases, the aqueous layer was acidified to pH 3 with aqueous 1 N HCl (300 mL), and extracted with ether (6×80 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The brownish-red crude oil was purified by distillation under reduced pressure to afford compound 13.2 as a colorless oil (33 g, 68%; lit. boiling point 60° C. @ 12 ton).
  • Compound 13.3. To a solution of compound 13.1 (1.00 g, 4.2 mmol) in DMF (15 mL) was added compound 13.2 (3.5 g, 5.0 equiv). The reaction mixture was heated to 50° C. and stirred for 3 days, monitoring by LC-MS. After cooling to room temperature, the reaction mixture was diluted with ether (50 mL) then washed with saturated aqueous NaHCO3 (3×100 mL). The combined aqueous washes were extracted with ether (4×25 mL), and the extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (10-20-50% ethyl acetate/hexanes) afforded compound 13.3 (0.81 g, 56%) as a viscous pale yellow oil. LCMS: m/z: 335 (M+1).
  • Compound 13.4. To thiazole 13.3 (0.20 mmol) in TFA (2.5 mL) was added thioanisole (0.25 mL, 2.0 mmol, 10.0 equiv). After stirring at room temperature overnight, the reaction was judged to be complete by LC-MS analysis. The reaction mixture was concentrated in vacuo (using high vac), diluted with EtOAc (30 mL), and washed with saturated aqueous NaHCO3 (3×50 mL). The combined aqueous washes were extracted with EtOAc (3×25 mL), and the extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford amine 13.4, which was used without further purification.
  • Compound 13. Compound 13 is prepared according to Example 1 except for using 13.4 instead of compound 1.12.
  • Example 14
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00199
  • These compounds are prepared according to Example 1 except for using compound 13.4 instead of compound 1.12 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00200
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 15
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00201
  • where RL1A is as described previously. These compounds are prepared according to Example 13except for using
  • Figure US20110059976A1-20110310-C00202
  • instead of Z-D-alanine-NH2 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00203
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 16
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00204
  • which is prepared according to Scheme I and the protocol below.
  • Figure US20110059976A1-20110310-C00205
  • Compound 16.1. To a suspension of Z-D-alanine-NH2 (2.0 g, 8.88 mmol) in toluene (35 mL) was added chlorocarbonyl sulfenyl chloride (1.5 mL, 17.8 mmol, 2 equiv). The reaction mixture was heated to 100° C. and stirred for 4.5 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (10420% EtOAc/hexanes) to afford compound 16.1 (2.1 g, 84%) as a pale yellow solid.
  • Compound 16.2. To a solution of compound 16.1 (2.1 g, 7.5 mmol) in o-dichlorobenzene (15 mL) was added ethyl propiolate (3.0 mL, 30 mmol, 4.0 equiv). The reaction mixture was heated to 150° C. and stirred for 3 days, monitoring by LC-MS. After cooling to room temperature, the reaction mixture was diluted with ether (50 mL) then washed with saturated aqueous NaHCO3 (3×100 mL). The combined aqueous washes were extracted with ether (4×25 mL), and the extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (10-20-50% ethyl acetate/hexanes) afforded compound 16.2 (0.81 g, 56%) as a viscous pale yellow oil. LCMS: m/z: 335 (M+1).
  • Compound 16.3. To a solution of compound 16.2 (1.0 g, 3.0 mmol) in THF (22.5 mL) was added a solution of lithium hydroxide (180 mg, 7.5 mmol, 2.5 equiv) in water (7.5 mL). The reaction was stirred at room temperature for 19 hours, whereupon 1N aqueous HCl was added until a pH of 1 was achieved. The mixture was extracted with ethyl acetate (3×50 mL), and the organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford acid 16.3 (890 mg, 97%) as a brown residue that was used without further purification.
  • Compound 16.4. Compound 16.3 (119 mg, 0.39 mmol), 3,4-diaminobenzotrifluoride (75 mg, 0.43 mmol, 1.1 equiv) and HATU (177 mg, 0.47 mmol, 1.2 equiv) were dissolved in DMF (3.5 mL) at room temperature. Triethylamine (0.14 mL, 0.97 mmol, 2.5 equiv) was added and the reaction was stirred for 4.5 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and water (25 mL) the layers were separated. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford compound 16.4 (111 mg, 62%) as a brown residue that was used without further purification.
  • Compound 16.5. Compound 16.4 was heated in AcOH (1 mL) at 80° C. for 1 hour. After cooling, the reaction mixture was concentrated and then purified by silica gel chromatography (30% EtOAc/hexanes) to provide compound 16.5 (71 mg, 67%) as an off-white solid.
  • Compound 16.6. To compound 16.5 (71.0 mg, 0.16 mmol) in TFA (2.0 mL) was added thioanisole (0.2 mL, 1.6 mmol, 10.0 equiv). After stirring at room temperature for 17 hours, the reaction mixture was concentrated in vacuo (using high vac), diluted with EtOAc (15 mL), and washed with saturated aqueous NaHCO3 (2×20 mL). The combined aqueous washes were extracted with EtOAc (3×15 mL), and the extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford amine 16.6, was used without further purification in the next step.
  • Compound 16. Compound 16.6 (55 mg, 0.17 mmol, 1.15 equiv), compound 1.7 (28 mg, 0.146 mmol) and PyAOP (91 mg, 0.18 mmol, 1.2 equiv) were dissolved in DMF (2 mL) at room temperature. Diisopropylethylamine (64 μL, 0.37 mmol, 2.5 equiv) was added and the reaction was stirred for 21 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and water (25 mL) the layers were separated. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (80-100% EtOAc/hexanes) to afford compound 16 (53 mg, 72%) as a white powder.
  • Example 17
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00206
  • These compounds are prepared according to Example 16 except for using diamine of the formula
  • Figure US20110059976A1-20110310-C00207
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 16.4). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 18
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00208
  • where RL1A is as previously described. These compounds are prepared according to Example 16 except for using
  • Figure US20110059976A1-20110310-C00209
  • instead of Z-D-alanine-NH2 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00210
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 16.4). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 19
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00211
  • which is prepared according to Scheme J and the protocol below.
  • Figure US20110059976A1-20110310-C00212
  • Compound 19.1. Compound 1.10 (283 mg, 1.67 mmol, 1 eq.) and ethyl diazoacetate (208 μL, 2.01 mmol, 1.2 eq.) were dissolved in benzene (0.85 mL) at room temperature. The reaction was microwaved at 140° C. for 80 minutes. The reaction mixture was directly loaded onto a silica gel column. The product was purified using hexanes:ethyl acetate (3:1→2:1→33:2) which afforded 19.1 (208 mg (0.735 mmol, 44%).
  • Compound 19. Compound 19 is prepared according to Example 1 except for using compound 19.1 instead of compound 1.11.
  • Example 20
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00213
  • which is prepared according to Example 1 except for using compound 19.1 instead of compound 1.11 and for using diamine of the formula
  • Figure US20110059976A1-20110310-C00214
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 21
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00215
  • which is prepared according to Example 1 for making compound 1.15 except for using compound 13.4 instead of compound 1.12 and for using 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Example 22
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00216
  • where Z is as previously described. These compounds are made according to Example 21 except for using an amine of the formula H2NZ instead of 3-methoxy-4-trifluoromethylaniline. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • TABLE 2
    H2NZ Final Compound
    Figure US20110059976A1-20110310-C00217
    Figure US20110059976A1-20110310-C00218
    Figure US20110059976A1-20110310-C00219
    Figure US20110059976A1-20110310-C00220
    Figure US20110059976A1-20110310-C00221
    Figure US20110059976A1-20110310-C00222
    Figure US20110059976A1-20110310-C00223
    Figure US20110059976A1-20110310-C00224
    Figure US20110059976A1-20110310-C00225
    Figure US20110059976A1-20110310-C00226
    Figure US20110059976A1-20110310-C00227
    Figure US20110059976A1-20110310-C00228
    Figure US20110059976A1-20110310-C00229
    Figure US20110059976A1-20110310-C00230
    Figure US20110059976A1-20110310-C00231
    Figure US20110059976A1-20110310-C00232
    Figure US20110059976A1-20110310-C00233
    Figure US20110059976A1-20110310-C00234
    Figure US20110059976A1-20110310-C00235
    Figure US20110059976A1-20110310-C00236
    Figure US20110059976A1-20110310-C00237
    Figure US20110059976A1-20110310-C00238
    Figure US20110059976A1-20110310-C00239
    Figure US20110059976A1-20110310-C00240
    Figure US20110059976A1-20110310-C00241
    Figure US20110059976A1-20110310-C00242
    Figure US20110059976A1-20110310-C00243
    Figure US20110059976A1-20110310-C00244
    Figure US20110059976A1-20110310-C00245
    Figure US20110059976A1-20110310-C00246
    Figure US20110059976A1-20110310-C00247
    Figure US20110059976A1-20110310-C00248
    Figure US20110059976A1-20110310-C00249
    Figure US20110059976A1-20110310-C00250
    Figure US20110059976A1-20110310-C00251
    Figure US20110059976A1-20110310-C00252
    Figure US20110059976A1-20110310-C00253
    Figure US20110059976A1-20110310-C00254
    Figure US20110059976A1-20110310-C00255
    Figure US20110059976A1-20110310-C00256
    Figure US20110059976A1-20110310-C00257
    Figure US20110059976A1-20110310-C00258
    Figure US20110059976A1-20110310-C00259
    Figure US20110059976A1-20110310-C00260
    Figure US20110059976A1-20110310-C00261
    Figure US20110059976A1-20110310-C00262
    Figure US20110059976A1-20110310-C00263
    Figure US20110059976A1-20110310-C00264
    Figure US20110059976A1-20110310-C00265
    Figure US20110059976A1-20110310-C00266
    Figure US20110059976A1-20110310-C00267
    Figure US20110059976A1-20110310-C00268
  • Example 23
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00269
  • where Z is as previously described. These compounds are made according to Example 1 for making compound 1.15 except for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 24
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00270
  • where RL1A and Z are as previously described. These compounds are made according to Example 1 for making compound 1.15 except for using
  • Figure US20110059976A1-20110310-C00271
  • instead of
  • Figure US20110059976A1-20110310-C00272
  • and for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 25
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00273
  • where Z is as previously described. These compounds are made according to Example 1 for making compound 1.15 except for using compound 19.1 instead of compound 1.11 and for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 26
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00274
  • which is prepared according to Scheme K and the protocol below.
  • Figure US20110059976A1-20110310-C00275
  • Compound 26.1. To 5-methyl-thiophene-2-carboxylic acid (2.5 g, 17.6 mmol) in CH2Cl2 and MeOH (50 mL, 4:1) was added (trimethylsilyl)diazomethane (9.24 mL, 18.5 mmol, 2.0 M in hexanes) slowly at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Removal of the solvents under reduced pressure provided compound 26.1 (17.95 mmol, 98%) as a white solid. The crude product was used for next step without purification.
  • Compound 26.2. A mixture of compound 26.1, NBS (6.26 g, 35.2 mmol) and AIBN (0.03 g, 0.18 mmol) in CCl4 (20 mL) was heated to 80° C. for 2 hours, then cooled to room temperature, filtered, washed with cold CH2Cl2/CCl4 (1:1). The filtrate was concentrated to provide compound 26.2 as major product (90%) and was used in the next step without purification.
  • Compound 26.3. A mixture of compound 26.2 (41 g, 176 mmol) and sodium azide (22.9 g, 352 mmol) in acetonitrile (150 mL) was stirred at 60° C. for 4 hours. The reaction mixture was cooled and filtered. Removal of the solvent under reduced pressure provided compound 26.3, which was used without additional purification.
  • Compound 26.4. To a solution of compound 26.3 (˜176 mmol) in AcOH (100 mL) at 0° C. was added Zn dust (23 g, 352 mmol) in several portions. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was filtered through a pad of celite, and concentrated. The residue was stirred in 4 N HCl overnight during which time the product precipitated. Filtration of the reaction mixture provided the amine HCl salt (24.9 g, 68% from compound 26.2).
  • A portion of the amine HCl salt (3.13 g, 15.1 mmol) and di-tert-butoxycarbonyl anhydride (3.63 g, 16.9 mmol) were dissolved in CH2Cl2 (30 mL) at room temperature. Triethylamine (5.3 mL, 38.0 mmol) was added and the reaction mixture was stirred for 2 hours. Water was added and the aqueous layer was extracted with chloroform (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide compound 26.4 (3.54 g, 13.0 mmol, 86%).
  • Compound 26. Compound 26 was prepared according to Example 1 for making compound 1.15 except for using compound 26.4 instead of compound 1.11.
  • Example 27
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00276
  • where Z is as previously described. These compounds are prepared according to Example 1 for making compound 1.15 except for using compound 26.4 instead of compound 1.11 and for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 28
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00277
  • which is prepared according to Scheme L and the protocol below.
  • Figure US20110059976A1-20110310-C00278
  • Compound 28.1. To compound 1.4 (1.5 g, 6.6 mmol) in MeOH (60 mL) was added 5% rhodium on alumina (0.8 g). The reaction mixture was stirred vigorously at 45° C. under an atmosphere of nitrogen for 48 hours. The solution was filtered through celite which was then washed with ethyl acetate. Concentration of the filtrate provided compound 28.1 (1.6 g, ˜100%) which was used without additional purification.
  • Compound 28.2. To a sealed tube was added compound 28.1 (˜1.6 g, 6.6 mmol), triethylamine (1.4 mL, 10 mmol) and ethanol (40 mL). The reaction mixture was heated at 80° C. for 6 hours, cooled, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous HCl (0.5 N). The aqueous layer was extracted with ethyl acetate (2×); the combined organic layer was washed with H2O and saturated NaHCO3, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography to provide compound 28.2 (0.6 g, 50% over two steps).
  • Compound 28.3. To compound 28.2 (91 mg, 0.5 mmol) and compound 1.12 (92 mg, 0.5 mmol) in NMP (1.5 mL) was added triethylamine 0.084 mL, 0.6 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 30 minutes. The mixture was partitioned between ethyl acetate and H2O followed by extraction with ethyl acetate (3×) and then brine. The combined organic layer was dried over Na2SO4 and concentrated. Purification of the crude material by silica gel chromatography provided compound 28.3 (50 mg, 31%).
  • Compound 28. Compound 28 was prepared according to Example 1 except for using compound 28.3 instead of compound 1.13.
  • Example 29
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00279
  • which are prepared according to Example 28 except for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00280
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines and their resulting compounds are shown in Table 1.
  • Example 30
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00281
  • which are prepared according to Example 28 except for using compound 13.4 instead of compound 1.12 and for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00282
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines and their resulting compounds are shown in Table 1.
  • Example 31
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00283
  • which are prepared according to Example 28 except for using compound 13.4 instead of compound 1.12 and for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride for making compound 1.15. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 32
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00284
  • which are prepared according to Scheme M and the protocol below.
  • Figure US20110059976A1-20110310-C00285
  • Compound 32.1. Compound 32.1 is prepared according to the procedure for compound 1.11 except for using proparyl alcohol instead of compound 1.10.
  • Compound 32.2. Compound 32.2 is prepared according to the procedure for compound 28.3 except for using compound 32.1 instead of compound 1.12.
  • Compound 32. Compound 32 is prepared according to Example 1 except for using compound 32.2 instead of 1.13.
  • Example 33
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00286
  • which are prepared according to Example 32 except for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00287
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines and their resulting compounds are shown in Table 1.
  • Example 34
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00288
  • which are prepared according to Example 1 for making compound 1.15 except for using compound 32.2 instead of compound 1.13 and for using an amine of the formula H2NZ instead of 3,4-diaminobenzotrifluoride. Illustrative examples of suitable amines and the resulting compounds are shown in Table 2.
  • Example 35
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00289
  • which was prepared according to Scheme N and the protocol below.
  • Figure US20110059976A1-20110310-C00290
  • Compound 35.1. A clear yellow solution of compound 1.11 (2.00 g, 7.00 mmol) in THF (8.4 mL) at room temperature was treated with LiOH (8.4 mL, 8.4 mmol, 1.0 M in H2O) and the reaction progress was monitored by LCMS. After 30 minutes, the reaction mixture was concentrated thoroughly in vacuo to afford compound 35.1 (1.84 g, 100%). LCMS: m/z: 257 (M+1, CO2H).
  • Compound 35.2. A clear, pale yellow solution of compound 35.1 (1.84 g, 7.00 mmol) in DMF (21 mL) at 0° C. was treated slowly and dropwise with oxalyl chloride (1.00 g, 7.70 mmol), and the reaction progress was monitored by LCMS using aliquots quenched with methyl amine (1.0 M in THF). After 2 hours, the reaction mixture had come gradually to room temperature. The solution was recooled to 0° C. and stirred vigorously as ammonia gas was bubbled into the mixture for 5 minutes, at which time a thick yellow precipitate developed. The reaction mixture was next concentrated thoroughly in vacuo, the solid residue was triturated with ethyl acetate (10 mL) and filtered to remove unwanted salts, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (60:40→40:60 hexane/ethyl acetate) to afford compound 35.2 (0.52 g, 29%). LCMS: m/z: 156 (M+1-100).
  • Compound 35.3. A clear, pale yellow solution of compound 35.2 (0.514 g, 2.02 mmol) and pyridine (0.404 g, 5.06 mmol) in dioxane (6.0 mL) at 0° C. was treated slowly and dropwise with TFAA (0.346 g, 2.42 mmol), and the reaction progress was monitored by LCMS. After 30 minutes, the reaction mixture was transferred into saturated aqueous NaHCO3 (20 mL), at which time a precipitate formed. The mixture was treated with ethyl acetate (20 mL), and the solids were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel radial chromatography (4:1→6:4 hexane/ethyl acetate) to afford compound 35.3 (0.45 g, 95%). LCMS: m/z: 238 (M+1).
  • Compound 35.4. A clear, colorless solution of compound 35.3 (0.446 g, 1.88 mmol) in THF (11 mL) at room temperature was treated slowly and dropwise with LHMDS (11.3 mL, 11.3 mmol, 1.0 M THF), and the reaction progress was monitored by LCMS. After 30 minutes, the reaction mixture was treated with 2.0 M HCl (11 mL). After an additional 30 minutes, the reaction mixture was quenched by transferring into saturated NaHCO3 (30 mL), and the resultant mixture was extracted with ethyl acetate (3×). The combined organic extracts were rinsed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel radial chromatography (4:1→3 6:4 hexane/ethyl acetate) to afford compound 35.4 (0.050 g, 10% yield). LCMS: m/z: 255 (M+1).
  • Compound 35.5. A clear, pale amber solution of compound 35.4 (0.050 g, 0.194 mmol) in DMF (5 mL) was treated with 2-bromo-1-(3-trifluoromethylphenyl)-ethanone (0.0674 g, 1.30 mmol), and the reaction progress was monitored by LCMS. After 2 hours, DIPEA (12.6 mg, 0.097 mmol) was added. After an additional 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), extracted with 2:1:1 water/saturated NaHCO3/brine (3×), extracted with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel radial chromatography (4:1→6:4 hexane/ethyl acetate) to afford compound 35.5 (0.040 g, 49%). LCMS: m/z: 422 (M+).
  • Compound 35. Title compound 35 was prepared according to Example 1 for making compound 1.13 except for using compound 35.5 instead of compound 1.11.
  • Example 36
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00291
  • which is prepared according to Example 35 except that compound 13.3 is used instead of compound 1.11.
  • Example 37
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00292
  • which is prepared according to Scheme 0 and the protocol below.
  • Figure US20110059976A1-20110310-C00293
  • Compound 37.1. Compound 37.1 is prepared according to the procedure to prepare compound 33.3 except for using compound 1.11 instead of compound 33.2.
  • Compound 37.2. To compound 37.1 (2.26 g, 8.83 mmol) and triethylamine (1.48 mL, 10.6 mmol) in acetone (35 mL) at 0° C. was added dropwise a solution of ethyl chloroformate (1.44 mL, 15 mmol) in acetone (7 mL). After 30 minutes, NaN3 (1.03 g, 15.9 mmol) in water (4.5 mL) was added. The reaction mixture was stirred for 1 hour and then partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4 and concentrated to afford 37.2 (2.08 g) which was used without additional purification.
  • Compound 37.3. Compound 37.2 (˜2.1 g) was stirred at reflux in dioxane/water (30 mL, 4:1) for 2 hours. The reaction mixture was cooled and then partitioned between dichloromethane and water. The aqueous layer was extracted with CH2Cl2 (2×); the organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography provided compound 37.3 (0.78 g).
  • Compound 37.4. Compound 37.3 (100 mg, 0.44 mmol), 4-isocyanato-1-methyl-2-trifluoromethyl-benzene (88 mg, 0.44 mmol), and THF (2 mL) were added to a sealed tube and stirred at 65° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (eluting with 5% MeOH/CH2Cl2) to provide compound 37.4 as a white solid.
  • Compound 37.5. Compound 37.5 is prepared according to Example 1 for making compound 1.12 except that compound 37.4 is used instead of compound 1.11.
  • Compound 37. Compound 37 is prepared according to Example 1 for making compound 1.13 except for using compound 37.5 instead of compound 1.12.
  • Example 38
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00294
  • where Z is as previously described. These compounds are made according to the procedure of Example 37 except that isocynates of the formula OCN—Z is used instead of 4-isocyanato-1-methyl-2-trifluoromethyl-benzene (in the step to make compound 37.4).
  • Example 39
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00295
  • which is prepared according to Scheme P and the protocol below.
  • Figure US20110059976A1-20110310-C00296
  • Compound 39.1. To compound 37.3 (87 mg, 0.38 mmol) in CH2Cl2 (2 mL) at 0° C. was added 3-methoxy-benzoyl chloride (0.11 mL, 0.77 mmol). The reaction mixture was stirred for 3 hours and then partitioned between CH2Cl2 and 1N HCl. The aqueous layer was extracted with CH2Cl2 (2×) and then concentrated to provide the bis-acylated material. The crude residue was stirred in 1M LiOH/THF (2 mL, 3:1) for 15 minutes. The solution was neutralized with 1N HCl and the mixture was extracted with ethyl acetate (2×). Purification by silica gel chromatography (eluting with ethyl acetate/hexanes, 3:1) provided compound 39.1 (120 mg) as a white powder.
  • Compound 39. Compound 39 is prepared according to Example 37 except for using compound 39.1 instead of compound 37.4.
  • Example 40
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00297
  • where Z is as described previously. These compounds are prepared according to Example 39 except that an acid chloride of the formula Z(C═O)Cl is used instead of 3-methoxy-benzoyl chloride.
  • Example 41
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00298
  • which was prepared according to Scheme Q and the protocol below.
  • Figure US20110059976A1-20110310-C00299
  • Compound 41. Compound 1.4 (99.3 mg, 0.419 mmol, 1 eq.) was dissolved in MeOH (4 mL). DBU (118 mL, 0.839 mmol, 2 eq.) was added and the reaction was microwaved at 105° C. for 15 minutes. The reaction was neutralized by addition of 3N—HCl (300 μL, 0.900 mmol, 1.07 eq.). The same reaction protocol was repeated three more times using 109 mg, 109 mg and 104 mg of compound 1.4. Ethyl acetate and water were added to the combined reaction mixture. The layers were separated and the product was extracted using ethyl acetate (2×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude product was purified using silica gel column chromatography with a gradient of hexanes:ethyl acetate (2:1→1:4→0:100) followed by ethyl acetate:methanol (10:1) to afford compound 41 (157 mg, 0.763 mmol, 43%).
  • Example 42
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00300
  • These compounds are prepared according to Example 1 except for using compound 41 instead of compound 1.6 and for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00301
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines and their resulting compounds are shown in Table 1.
  • Example 43
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00302
  • These compounds are prepared according to Example 1 except for using compound 41 instead of compound 1.6, Boc-glycine aldehyde instead of compound 1.9, compound 10.2 instead of compound 1.11, and diamine of the formula
  • Figure US20110059976A1-20110310-C00303
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 44
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00304
  • where Z is as previously described. These compounds are prepared according to Example 1 for making compound 1.15 except for using compound 41 instead of compound 1.6, compound 13.4 instead of compound 1.12 and 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Example 45
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00305
  • which was prepared according to Scheme R and the protocol below.
  • Figure US20110059976A1-20110310-C00306
  • Compound 45.1. To a cooled (0° C.) solution of 4,6-dichloro-5-amino-pyrimidine (5.04 g, 30.8 mmol) in THF (250 mL) was added sodium hydride (1.48 g, 60% in mineral oil, 36.9 mmol, 1.2 equiv). The reaction mixture was stirred for 2 minutes then the ice bath was removed. Ethyl bromoacetate (4.2 mL, 36.9 mmol, 1.2 equiv) was added, followed by tetrabutylammonium iodide (13.9 g, 36.9 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 3 days, and the resultant orange suspension was filtered. The filtrate was concentrated to a brown oil. The residue was purified by flash column chromatography (10-25% EtOAc/hexanes), and mixed fractions were isolated and repurified (10-12-100% EtOAc/hexanes) to afford compound 45.1 (5.34 g, 69%) as a pale yellow oil.
  • Compound 45.2. A 300 mL pressure vessel was charged with compound 45.1 (2.55 g, 10.2 mmol, 1.0 equiv), ethanol (100 mL), trimethoxybenzylamine•HCl (2.67 g, 11.2 mmol, 1.1 equiv), and triethylamine (3.1 mL, 22.4 mmol, 2.2 equiv). The vessel was sealed tightly and the reaction mixture was heated at 70° C. for 16 hours, then heated at 80° C. for an additional 24 hours. After cooling to room temperature, SiO2 gel was added to the reaction mixture and the resultant suspension was concentrated in vacuo. Purification by flash column chromatography (10-30-50% EtOAc/hexanes) afforded compound 45.2 (2.93 g, 70%) as a yellow oil. LCMS: m/z: 411 (M+1).
  • Compound 45.3. A bomb was charged with bis(acetonitrile)dichloropalladium II (93 mg, 0.36 mmol, 0.05 equiv) and rac-BINAP (0.23 g, 0.36 mmol, 0.05 equiv) followed by a solution of compound 45.2 (2.93 g, 7.13 mmol, 1.0 equiv) in methanol (100 mL). Triethylamine (1.29 mL, 9.27 mmol, 1.3 equiv) was added last. After purging and back-filling the bomb with CO (3×, 50 psi), the bomb was pressurized to 50 psi CO (g). The reaction mixture was stirred at 100° C. for 22 hours, then cooled to rt and the bomb was carefully vented. The reaction mixture contained solid other than palladium by-products so methanol (1 L) and small amounts of DMF were added to attempt to solubilize this solid. The mixture was filtered through celite and concentrated. Purification by flash column chromatography (50-75-100% EtOAc/hexanes) afforded compound 45.3 (1.72 g, 62%) as a yellow solid. LCMS: m/z: 389 (M+1).
  • Compound 45.4. To a suspension of compound 45.3 (0.53 g, 1.36 mmol) in THF (10.2 mL) was added a solution of LiOH (82 mg, 3.41 mmol, 2.5 equiv) in H2O (3.4 mL). The reaction mixture was stirred at rt for 20 hours. When LC-MS indicated complete conversion to product, the reaction mixture was treated dropwise with aqueous 1 N HCl (100 mL). The resultant suspension was filtered, washing solid with ether. The solid was collected, triturated in toluene, concentrated, and dried under high vacuum to provide compound 45.4 (0.281 g, 55%) as a pale yellow solid. LC-MS: m/z: 375 (M+1).
  • Compound 45.5. Compound 45.5 is prepared according to Example 1 except for using compound 45.4 instead of compound 1.7.
  • Compound 45. To a solution of compound 45.5 (160 mg, 0.25 mmol) in dichloromethane (6 mL) was added triethylsilane (0.2 mL, 1.2 mmol, 5 equiv) and trifluoroacetic acid (2 mL). The resultant solution was stirred 3.5 hours, whereupon the reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL). After washing with aqueous saturated NaHCO3 (2×50 mL), the combined aqueous layers were extracted with EtOAc (4×30 mL), the extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The organic layer was adsorbed onto SiO2 gel. Purification by flash column chromatography (80-100% EtOAc/hexanes) afforded compound 45 (80 mg, 69%) as a peach solid. LCMS: m/z: 473 (M+1).
  • Example 46
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00307
  • These compounds are prepared according to Example 45 except for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00308
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 47
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00309
  • These compounds are prepared according to Scheme S and the protocol below.
  • Figure US20110059976A1-20110310-C00310
  • Compound 47.1. Compound 47.1 is prepared according to Example 1 except for using compound 45.4 instead of compound 1.7, Boc-glycine aldehyde instead of compound 1.9, and a diamine of the formula
  • Figure US20110059976A1-20110310-C00311
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Compound 47. Compound 47 is prepared according to Example 45 for making compound 45 except for using compound 47.1 instead of compound 45.5.
  • Example 48
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00312
  • where Z is as previously described. These compounds are prepared according to Scheme T and the protocol below.
  • Figure US20110059976A1-20110310-C00313
  • Compound 48.1. Compound 48.1 is prepared according to Example 1 for making compound 1.15 except for using compound 45.4 instead of compound 1.7, compound 13.4 instead of compound 1.12 and 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Compound 48. Compound 48 is prepared according to Example 45 for making compound 45 except for using compound 48.1 instead of compound 45.5.
  • Example 49
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00314
  • which is prepared according to Scheme U and the protocol below.
  • Figure US20110059976A1-20110310-C00315
  • Compound 49. To a solution of compound 45.3 (388 mg, 1 mmol) in toluene (10 mL) was added DDQ (230 mg, 1 mmol). The reaction mixture was heated to reflux for 7 hours and then cooled to room temperature. The mixture was filtered and the solid was purified by silica gel chromatography to provide compound 49 (205 mg, 53%).
  • Example 50
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00316
  • These compounds are prepared according to Example 1 except for using compound 49 instead of compound 1.7 and for using a diamine of the formula
  • Figure US20110059976A1-20110310-C00317
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Example 51
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00318
  • These compounds are prepared according to Scheme V and the protocol below.
  • Figure US20110059976A1-20110310-C00319
  • Compound 51.1. Compound 51.1 is prepared according to Example 1 except for using compound 49 instead of compound 1.7, Boc-glycine aldehyde instead of compound 1.9, and a diamine of the formula
  • Figure US20110059976A1-20110310-C00320
  • instead of 3,4-diaminobenzotrifluoride (in step for compound 1.15). Illustrative examples of suitable diamines are shown in Table 1.
  • Compound 51. Compound 51 is prepared according to Example 45 for making compound 45 except for using compound 51.1 instead of compound 45.5.
  • Example 52
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00321
  • where Z is as previously described. These compounds are prepared according to Scheme W and the protocol below.
  • Figure US20110059976A1-20110310-C00322
  • Compound 52.1. Compound 53.1 is prepared according to Example 1 for making compound 1.15 except for using compound 49 instead of compound 1.7, compound 13.4 instead of compound 1.12 and 3-methoxy-4-trifluoromethylaniline instead of 3,4-diaminobenzotriflouride (in the step for making compound 1.15).
  • Compound 52. Compound 52 is prepared according to Example 45 for making compound 45 except for using compound 52.1 instead of compound 45.5.
  • Example 53
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00323
  • which is prepared according to Scheme X and the protocol below.
  • Figure US20110059976A1-20110310-C00324
  • Compound 53.1. Compound 1.2 (249 mg, 1.58 mmol, 1 eq.) and 2,4,6-trimethoxybenzylamine (free-based by saturated sodium bicarbonate wash) (313 mg, 1.59 mmol, 1 eq.) were dissolved in dichloromethane (3 mL) at room temperature. Acetic acid (91 μL, 1.58 mmol, 1 eq.) was added and the reaction mixture was heated in a microwave at 100° C. for 5 minutes. Sodium triacetoxyborohydride (410 mg, 1.94 mmol, 1.2 eq.) was added at room temperature and the reaction was stirred overnight. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction mixture and the layers were separated. The product was extracted twice more with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, brine, and then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude product was purified using silica gel column chromatography with a gradient of hexanes/ethyl acetate (1:1→1:2→1:4→0:100) followed by ethyl acetate/methanol (50:1) to afford compound 53.1 (287 mg, 0.846 mmol, 54%).
  • Compound 53.2. Compound 53.1 (109 mg, 0.321 mmol, 1 eq.) was dissolved in THF (3 mL) and triethylamine (224 μL, 1.61 mmol, 5 eq.) was added at room temperature. The reaction mixture was cooled to −78° C. and phosgene (20% solution in toluene, 340 μL, 0.643 mmol, 2 eq.) was added. The reaction was gradually warmed to room temperature. Nitrogen was blown into the reaction mixture to remove any excess phosgene. The reaction was heated in a microwave at 120° C. for 5 minutes. Water and ethyl acetate were added to the reaction mixture and the layers were separated. The product was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified using silica gel column chromatography with a gradient of hexanes/ethyl acetate (1:1→1:2→1:4) to afford compound 53.2 (59.3 mg, 0.163 mmol, 51%).
  • Compound 53.3. Compound 53.3 is prepared according to Example 1 for making compound 1.4 except for using compound 53.2 instead of compound 1.3.
  • Compound 53.4. Compound 53.4 is prepared according to Example 1 except for using compound 53.3 instead of compound 1.6.
  • Compound 53. Compound 53.4 (53.7 mg, 0.0823 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Trifluoroacetic acid (1 mL) was added at room temperature and the reaction was stirred for 0.5 hour. The reaction mixture was azeotroped with toluene. Saturated sodium bicarbonate solution and ethyl acetate were added and the layers were separated. The product was extracted with ethyl acetate (2×). A small amount of methanol was added to ethyl acetate to facilitate extraction. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified using silica gel column chromatography with a gradient of hexanes/ethyl acetate (1:1→1:2→1:4→0:100) followed by ethyl acetate/methanol (25:1) to afford compound 53 (28.3 mg, 0.0600 mmol, 73%).
  • Example 54
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00325
  • which was prepared according to Example 53 except for using compound 13.4 instead of compound 1.12.
  • Example 55
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00326
  • which is prepared according to Scheme Y and the protocol below.
  • Figure US20110059976A1-20110310-C00327
  • Compound 55.1. Compound 55.1 is prepared according to Example 53 for making compound 55.1 except for using methylamine instead of 2,4,6-trimethoxybenzylamine.
  • Compound 55.2. Compound 55.1 (214 mg, 1.24 mmol) was dissolved in THF (2 mL) at room temperature. Pyridine (0.52 mL, 6.43 mmol) and Boc2O (343 mg, 1.56 mmol) was added and the reaction was stirred for 1 hour. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction mixture and the layers were separated. The product was extracted twice more with ethyl acetate. The combined organic layers were washed once with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified using silica gel column chromatography with a gradient of hexanes/ethyl acetate (4:142:1) to afford compound 55.2 (141 mg, 0.516 mmol, 42%).
  • Compound 55.3. Sodium hydride (60% in mineral oil, 30.4 mg, 0.760 mmol, 2 eq.) was rinsed once with hexanes. THF (1.5 mL) was added, followed by compound 55.2 (100 mg, 0.368 mmol, 1 eq.) as a THF (2 mL) solution. After stirring for 5 minutes at room temperature, the reaction was heated at 70° C. for 4 hours. Brine and ethyl acetate were added to the reaction mixture and the layers were separated. The product was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to afford the crude product 55.3 (73.9 mg, ˜100%), which was used without further purification.
  • Compound 55.4. Compound 55.4 is prepared according to Example 1 for making compound 1.4 except for using compound 55.3 instead of compound 1.3.
  • Compound 55. Compound 55 is prepared according to Example 53 except for using compound 55.4 instead of compound 53.3.
  • Example 56
  • This example describes the synthesis of
  • Figure US20110059976A1-20110310-C00328
  • which is prepared according to Example 54 except for using compound 55.4 instead of compound 53.3.
  • Example 57
  • To assess PK and PD response to compound treatment, 2×106 WM-266-4 human melanoma cells (ATCC #CRL-1676; V600D Raf B) were implanted, with matrigel (BD Biosciences), in the right flank of athymic nude female mice (Harlan Sprague Dawley). When tumors reached an average size of 500 mg (approximately three weeks post implantation), test compound suspended in dosing vehicle (1/3/6 DMSO/PEG400/saline) was administered by a single oral gavage. Treated mice were then sacrificed at 1, 3, and 8 hours post dosing and terminal endpoints (plasma drug concentration, tumor drug concentration, and tumor levels of phosphorylated ERK) were collected.
  • Drug concentrations were assessed by LC-MS/MS either from plasma or from freshly excised tumors (a portion of the same tumor sample used for quantifying phosphorylated ERK as described below) following homogenization in PBS (tumor tissue) and extraction with 3× (v/v) 50% acetonitrile. FIG. 1 shows the plasma and tumor concentration of an illustrative compound of the invention.
  • Example 58
  • Tumor levels of phosphorylated ERK were assessed by first grinding freshly harvested tumor samples in liquid nitrogen and then reconstituting the ground tissue in cell extraction buffer (10 mM Tris HCl pH7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 20 mM Na4P2O7, 2 mM Na4VO4, 1% Triton X-100, 10% Glycerol, 0.1% SDS) containing freshly added phosphatase and protease inhibitors (1:100 of 100 mM PMSF, Sigma Phosphatase Inhibitor Cocktail I (Cat #P-2850), and Sigma Phosphatase Inhibitor Cocktail II (Cat #P-5726), and 1:1000 of Sigma Protease Inhibitor Cocktail (Cat #P-2714)). ERK and phospho-ERK levels were assessed by standard Western analyses using antibodies against ERK (Cell Signaling #9102) and phosphorylated ERK (Cell Signaling #9101). FIG. 2 shows the tumor levels of phosphorylated ERK treated with an illustrative compound of the invention.
  • Example 59
  • 2×106 WM-266-4 human melanoma cells were implanted in the right flank of nude mice as described previously. When tumors reached an average size of 260 mg (approximately two weeks post implantation), test compound suspended in dosing vehicle (1/3/6 DMSO/PEG400/saline), was administered by oral gavage either QD×14 or BID×14. Alternatively, a control compound (e.g., 10 mg/kg Camptosar) was administered by IP injection on a QD×10 (M-F) schedule. Body weight and tumor size were recorded two times per week throughout the duration of the study. FIG. 3 shows the tumor growth rate curves for mice treated with an illustrative compound of the invention.
  • While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims (13)

1-57. (canceled)
58. A method of inhibiting RAF kinase activity in:
(a) a patient; or
(b) a biological sample;
which method comprises administering to said patient, or contacting said biological sample with,
a compound of formula (I):
Figure US20110059976A1-20110310-C00329
or pharmaceutically acceptable salt thereof;
wherein A-B together represent:
Figure US20110059976A1-20110310-C00330
Figure US20110059976A1-20110310-P00001
represents a single or double bond as valency permits;
n is an integer from 0-4;
R1 and R2 are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R3 is hydrogen or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
L1 is —O—, —S—, —NRL1A— or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
L2 is a single bond, —O—, —S—, —NRL2A—, a heteroalicyclic or heteroaromatic moiety, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
Y is a cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl moiety; and
Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
or a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
59. The method of claim 58, wherein the method comprises inhibiting RAF kinase activity.
60. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient:
a compound of formula I:
Figure US20110059976A1-20110310-C00331
or pharmaceutically acceptable salt thereof;
wherein A-B together represent:
Figure US20110059976A1-20110310-C00332
Figure US20110059976A1-20110310-P00001
represents a single or double bond as valency permits;
n is an integer from 0-4;
R1 and R2 are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R3 is hydrogen or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
L1 is —O—, —S—, —NRL1A— or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
L2 is a single bond, —O—, —S—, —NRL2A—, a heteroalicyclic or heteroaromatic moiety, or a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO2—, —C(═O)C(═O)—, —C(═O)NRL1A—, —OC(═O)—, —OC(═O)NRL1A—, —NRL1ANRL1B—, —NRL1ANRL1BC(═O)—, —NRL1AC(═O)—, —NRL1ACO2—, —NRL1AC(═O)NRL1B—, —S(═O)—, —SO2—, —NRL1ASO2—, —SO2NRL1A—, —NRL1ASO2NRL1B—, —O—, —S—, or —NRL1A—; wherein each occurrence of RL1A and RL1B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
Y is a cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl moiety; and
Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
or a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
61. The method according to claim 60, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and
said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
62. A method of synthesizing a compound of formula:
Figure US20110059976A1-20110310-C00333
wherein:
Figure US20110059976A1-20110310-P00001
represents a single or double bond; and
Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
the method comprising:
(a) providing a carboxylic acid of formula:
Figure US20110059976A1-20110310-C00334
wherein:
Figure US20110059976A1-20110310-P00001
represents a single or double bond;
and reacting the compound with an amine of formula:
Figure US20110059976A1-20110310-C00335
to form an amide of formula:
Figure US20110059976A1-20110310-C00336
(b) reacting the amide formed in step (a) with a suitable base to form an intermediate of formula:
Figure US20110059976A1-20110310-C00337
and
(c) reacting the intermediate formed in step (b) with H2N—Z to form the compound of formula:
Figure US20110059976A1-20110310-C00338
63. The method of claim 62, wherein the compound is of formula:
Figure US20110059976A1-20110310-C00339
64. The method of claim 62, wherein the compound of formula:
Figure US20110059976A1-20110310-C00340
is selected from the group consisting of:
Figure US20110059976A1-20110310-C00341
Figure US20110059976A1-20110310-C00342
Figure US20110059976A1-20110310-C00343
Figure US20110059976A1-20110310-C00344
Figure US20110059976A1-20110310-C00345
65. The method of claim 62, wherein the suitable base is lithium hydroxide.
66. A method of synthesizing a compound of formula:
Figure US20110059976A1-20110310-C00346
wherein:
Figure US20110059976A1-20110310-P00001
represents a single or double bond;
m is an integer from 0 to 3;
each RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —ORZ2, —SRZ2, —NRZ2RZ3, —SO2NRZ2RZ3, —SO2RZ4, —C(═O)NRZ2RZ3, halogen, —CN, —NO2, —C(═O)ORZ3, —N(RZ2)C(═O)RZ3, wherein each occurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and
RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl;
the method comprising steps of:
(a) providing a carboxylic acid of formula:
Figure US20110059976A1-20110310-C00347
wherein:
Figure US20110059976A1-20110310-P00001
represents a single or double bond;
and reacting the compound with an amine of formula:
Figure US20110059976A1-20110310-C00348
to form an amide of formula:
Figure US20110059976A1-20110310-C00349
(b) reacting the amide formed in step (a) with a suitable base to form an intermediate of formula:
Figure US20110059976A1-20110310-C00350
(c) reacting the intermediate formed in step (b) with a diaminobenzene of formula:
Figure US20110059976A1-20110310-C00351
to form diamide of formula:
Figure US20110059976A1-20110310-C00352
and
(d) treating the diamide formed in step (c) with a suitable acid.
67. The method of claim 66, wherein the compound is of formula:
Figure US20110059976A1-20110310-C00353
68. The method of claim 66, wherein the suitable base is lithium hydroxide.
69. The method of claim 66, wherein the suitable acid is acetic acid.
US12/843,105 2004-12-13 2010-07-26 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors Abandoned US20110059976A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/843,105 US20110059976A1 (en) 2004-12-13 2010-07-26 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63564404P 2004-12-13 2004-12-13
US63674004P 2004-12-16 2004-12-16
US11/301,311 US7767687B2 (en) 2004-12-13 2005-12-12 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors
US12/843,105 US20110059976A1 (en) 2004-12-13 2010-07-26 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US11/301,311 Continuation US7767687B2 (en) 2004-12-13 2005-12-12 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors

Publications (1)

Publication Number Publication Date
US20110059976A1 true US20110059976A1 (en) 2011-03-10

Family

ID=36097240

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/301,311 Expired - Fee Related US7767687B2 (en) 2004-12-13 2005-12-12 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors
US12/843,105 Abandoned US20110059976A1 (en) 2004-12-13 2010-07-26 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/301,311 Expired - Fee Related US7767687B2 (en) 2004-12-13 2005-12-12 Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors

Country Status (6)

Country Link
US (2) US7767687B2 (en)
EP (1) EP1828186A1 (en)
JP (1) JP5111113B2 (en)
AU (1) AU2005316668B2 (en)
CA (1) CA2590294A1 (en)
WO (1) WO2006065703A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080207650A1 (en) * 2007-01-11 2008-08-28 Roger Victor Bonnert Chemical Compounds 636
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases

Families Citing this family (103)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200724142A (en) * 2005-03-25 2007-07-01 Glaxo Group Ltd Novel compounds
CA2621261C (en) 2005-09-22 2014-05-20 Incyte Corporation Azepine inhibitors of janus kinases
EP1940839B1 (en) 2005-10-07 2013-07-31 Exelixis, Inc. PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kalpha
AU2006302148B2 (en) 2005-10-07 2012-12-06 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kalpha
RU2008127486A (en) 2005-12-08 2010-01-20 Милленниум Фармасьютикалз, Инк. (Us) BICYCLIC COMPOUNDS WITH INHIBITOR ACTIVITY AGAINST KINASE
JP4718637B2 (en) 2006-09-15 2011-07-06 ファイザー・プロダクツ・インク Pyrido (2,3-D) pyrimidinone compounds and their use as PI3 inhibitors
RU2478635C2 (en) 2006-10-19 2013-04-10 СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Heteroaryl compounds, compositions containing them and methods of treating with use of such compounds
CN101652365A (en) * 2007-02-01 2010-02-17 阿斯利康(瑞典)有限公司 5,6,7,8-tetrahydropteridine derivatives as HSP90 inhibitors
JP5238172B2 (en) * 2007-03-22 2013-07-17 公益財団法人相模中央化学研究所 Nitrogen-containing six-membered ring compound having perfluoroalkyl group and process for producing the same
JP2010532381A (en) * 2007-06-29 2010-10-07 サネシス ファーマシューティカルズ, インコーポレイテッド Heterocyclic compounds useful as RAF kinase inhibitors
CL2008001933A1 (en) * 2007-06-29 2009-09-25 Millennium Pharm Inc Pyrimidine derived compounds, raph kinase inhibitors; intermediate compounds; preparation procedure; pharmaceutical composition; and its use to treat proliferative, cardiac, neurodegenerative, inflammatory, bone, immunological, viral disease, among others.
EP2330894B8 (en) 2008-09-03 2017-04-19 BioMarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as hdac inhibitors
US8101622B2 (en) 2008-09-30 2012-01-24 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα and mTOR
US8110578B2 (en) 2008-10-27 2012-02-07 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway
EP2379513A1 (en) * 2008-12-30 2011-10-26 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as raf kinase inhibitors
CN102574852B (en) * 2009-10-23 2014-06-25 伊莱利利公司 AKT inhibitors
MX341704B (en) 2009-10-26 2016-08-31 Signal Pharm Llc Methods of synthesis and purification of heteroaryl compounds.
CA2788678C (en) * 2010-02-03 2019-02-26 Signal Pharmaceuticals, Llc Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors
US8901137B2 (en) 2010-02-09 2014-12-02 Exelixis, Inc. Methods of treating cancer using pyridopyrimidinone inhibitors of PI3K and mTOR in combination with autophagy inhibitors
WO2012088266A2 (en) 2010-12-22 2012-06-28 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3
DK2680694T3 (en) 2011-02-28 2019-03-25 Biomarin Pharm Inc HISTONDEACETYLASE INHIBITORS
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
CA2862895A1 (en) * 2011-09-30 2013-04-04 Kineta, Inc. Anti-viral compounds
MY183661A (en) 2011-10-19 2021-03-05 Signal Pharm Llc Treatment of cancer with tor kinase inhibitors
WO2013082344A1 (en) 2011-12-02 2013-06-06 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use
SI2797888T1 (en) 2011-12-31 2017-01-31 BeiGene, Ltd. Mourant Ozannes Corporate Services (Cayman) Limited Fused tricyclic compounds as raf kinase inhibitors
ES2742398T3 (en) 2012-02-24 2020-02-14 Signal Pharm Llc Methods to treat non-small cell lung cancer using a combination therapy of TOR kinase inhibitors
CN107652289B (en) 2012-06-13 2020-07-21 因塞特控股公司 Substituted tricyclic compounds as FGFR inhibitors
WO2014026125A1 (en) 2012-08-10 2014-02-13 Incyte Corporation Pyrazine derivatives as fgfr inhibitors
AU2013203714B2 (en) 2012-10-18 2015-12-03 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
AU2014207641A1 (en) 2013-01-16 2015-08-06 Signal Pharmaceuticals, Llc Substituted Pyrrolopyrimidine Compounds, compositions thereof, and methods of treatment therewith
AU2014228344C1 (en) 2013-03-15 2019-02-07 Biomarin Pharmaceutical Inc. HDAC inhibitors
US9474757B2 (en) 2013-04-17 2016-10-25 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
MX2015014590A (en) 2013-04-17 2016-03-03 Signal Pharm Llc Treatment of cancer with dihydropyrazino-pyrazines.
BR112015026257B1 (en) 2013-04-17 2022-12-20 Signal Pharmaceuticals, Llc USE OF A DIHYDROPYRAZINE-PYRAZINE COMPOUND AND ENZALUTAMIDE, PHARMACEUTICAL COMPOSITION COMPRISING THEM, AND KIT
MX2015014455A (en) 2013-04-17 2016-07-21 Signal Pharm Llc Combination therapy comprising a tor kinase inhibitor and n-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-yl amino)phenyl)acrylamide for treating cancer.
BR112015026238A8 (en) 2013-04-17 2019-12-24 Signal Pharm Llc dihydropyrazino-pyrazine compound, pharmaceutical composition comprising it, use of the compound, methods to inhibit or measure phosphorylation and to inhibit protein kinase activity, as well as a kit
NZ631082A (en) 2013-04-17 2017-06-30 Signal Pharm Llc Methods for treating cancer using tor kinase inhibitor combination therapy
AU2014254050B2 (en) 2013-04-17 2018-10-04 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one
JP6449244B2 (en) 2013-04-19 2019-01-09 インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
AU2014267360B2 (en) 2013-05-14 2018-07-05 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as S100-inhibitors
CA2912627C (en) 2013-05-29 2022-03-15 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use
MX2015017821A (en) 2013-07-02 2016-04-15 Syngenta Participations Ag Pesticidally active bi- or tricyclic heterocycles with sulfur containing substituents.
SI3089971T1 (en) 2014-01-01 2020-11-30 Medivation Technologies Llc Compounds and methods of use
NZ714742A (en) 2014-04-16 2017-04-28 Signal Pharm Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use
WO2015160880A1 (en) 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF
WO2015160882A1 (en) 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc SOLID FORMS COMPRISING 7-(6-(2-HYDROXYPROPAN-2YL) PYRIDIN-3-YL)-1-(TRANS)-4-METHOXYCYCLOHEXYL)-3, 4-DIHYDROPYRAZINO[2,3-b] PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF
ES2823756T3 (en) 2014-04-16 2021-05-10 Signal Pharm Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
JP2017520603A (en) 2014-07-14 2017-07-27 シグナル ファーマシューティカルズ,エルエルシー Method for treating cancer using substituted pyrrolopyrimidine compound and composition thereof
NZ629796A (en) 2014-07-14 2015-12-24 Signal Pharm Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
JP6689821B2 (en) 2014-08-12 2020-04-28 シンジェンタ パーティシペーションズ アーゲー Pesticidally Active Heterocyclic Derivatives Bearing Sulfur-Containing Substituents
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
EP3230284B1 (en) 2014-12-11 2020-04-15 Syngenta Participations AG Pesticidally active tetracyclic derivatives with sulfur containing substituents
UY36547A (en) 2015-02-05 2016-06-01 Bayer Cropscience Ag BICYCLIC CONDENSED HETEROCYCLIC DERIVATIVES REPLACED BY 2- (HET) ARILO AS PESTICIDES
UY36548A (en) 2015-02-05 2016-06-01 Bayer Cropscience Ag BICYCLIC CONDENSED HETEROCYCLIC DERIVATIVES REPLACED BY 2- (HET) ARILO AS PESTICIDES
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
WO2016134320A1 (en) 2015-02-20 2016-08-25 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
CN107810188B (en) 2015-04-08 2020-09-22 拜耳作物科学股份公司 Fused bicyclic heterocyclic derivatives as pest control agents and intermediate products
TWI832668B (en) 2015-04-15 2024-02-11 英屬開曼群島商百濟神州有限公司 Amorphous form, hydrochloride, methanesulfonate, 2-hydroxyethanesulfonate, l-tartrate, and oxalate salts of a b-raf kinase inhibitor and uses therefore
DK3325490T3 (en) 2015-07-23 2020-02-03 Takeda Pharmaceuticals Co 1-SUBSTITUTED 1,2,3,4-TETRAHYDRO-1,7-NAPHTHYRIDINE-8-AMINE DERIVATIVES AND THEIR USE AS EP4 RECEPTOR ANTAGONISTS
KR102580985B1 (en) 2015-08-07 2023-09-20 바이엘 크롭사이언스 악티엔게젤샤프트 2-(Het)aryl-substituted fused heterocycle derivatives as pest control agents
JP6916175B2 (en) 2015-10-26 2021-08-11 バイエル・クロップサイエンス・アクチェンゲゼルシャフト Condensed bicyclic heterocyclic derivative as a pest control agent
EP3380470A1 (en) 2015-11-23 2018-10-03 Syngenta Participations AG Pesticidally active heterocyclic derivatives with sulphur and cyclopropyl containing substituents
WO2017093180A1 (en) 2015-12-01 2017-06-08 Bayer Cropscience Aktiengesellschaft Condensed bicyclic heterocycle derivatives as pest control agents
JP6175519B2 (en) * 2016-01-04 2017-08-09 ベイジーン リミテッド Condensed tricyclic compounds as Raf kinase inhibitors
WO2017144341A1 (en) 2016-02-23 2017-08-31 Bayer Cropscience Aktiengesellschaft Condensed bicyclic heterocycle derivatives as pest control agents
WO2017174414A1 (en) 2016-04-05 2017-10-12 Bayer Cropscience Aktiengesellschaft Naphthaline-derivatives as pest control agents
EP3241830A1 (en) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Condensed bicyclic heterocyclic derivatives as pesticides
CN109475536B (en) 2016-07-05 2022-05-27 百济神州有限公司 Combination of a PD-l antagonist and a RAF inhibitor for the treatment of cancer
PE20190206A1 (en) 2016-07-19 2019-02-07 Bayer Cropscience Ag DERIVATIVES OF BICYCLE HETEROCYCLES CONDENSED AS PESTICIDE
US10660334B2 (en) 2016-08-15 2020-05-26 Bayer Cropscience Aktiengesellschaft Fused bicyclic heterocycle derivatives as pesticides
BR112019003174B1 (en) 2016-08-16 2022-10-25 Bayer Cropscience Aktiengesellschaft PROCESS FOR PREPARING 2-(3,6-DIHALOPYRIDIN-2-IL)-3H-IMIDAZOLE[4,5-C]PYRIDINE DERIVATIVES AND THEIR INTERMEDIATES
MX2019003136A (en) 2016-09-19 2019-07-18 Bayer Cropscience Ag Pyrazolo [1,5-a]pyridine derivatives and their use as pesticides.
KR102477315B1 (en) 2016-10-06 2022-12-13 바이엘 크롭사이언스 악티엔게젤샤프트 2-(het)aryl-substituted fused bicyclic heterocycle derivatives as pest control agents
JP7282031B2 (en) 2016-12-01 2023-05-26 シンジェンタ パーティシペーションズ アーゲー Pesticidal active heterocyclic derivatives with sulfur-containing substituents
CN110291072A (en) 2016-12-16 2019-09-27 巴斯夫欧洲公司 Agricultural chemical compound
WO2018138050A1 (en) 2017-01-26 2018-08-02 Bayer Aktiengesellschaft Condensed bicyclic heterocyclene derivatives as pest control agents
TW201833107A (en) 2017-02-06 2018-09-16 德商拜耳廠股份有限公司 2-(het)aryl-substituted fused heterocycle derivatives as pesticides
ES2923376T3 (en) 2017-04-24 2022-09-27 Bayer Ag Fused bicyclic heterocycle derivatives as pesticides
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
KR20200019229A (en) 2017-06-22 2020-02-21 셀진 코포레이션 Treatment of Hepatocellular Carcinoma Characterized by Hepatitis B Virus Infection
EP3305786A3 (en) 2018-01-22 2018-07-25 Bayer CropScience Aktiengesellschaft Condensed bicyclic heterocycle derivatives as pesticides
BR112020016926B1 (en) 2018-02-21 2022-08-30 Bayer Aktiengesellschaft CONDENSED BICYCLIC HETEROCYCLIC DERIVATIVES, THEIR USE, AGROCHEMICAL FORMULATION, AND METHOD TO CONTROL ANIMAL PESTS
KR20210005081A (en) 2018-04-20 2021-01-13 바이엘 악티엔게젤샤프트 Heterocyclene derivatives as pest control agents
SG11202010882XA (en) 2018-05-04 2020-11-27 Incyte Corp Salts of an fgfr inhibitor
DK3788047T3 (en) 2018-05-04 2024-09-16 Incyte Corp Solid forms of an FGFR inhibitor and methods of making the same
EP3636645A1 (en) 2018-10-11 2020-04-15 Bayer Aktiengesellschaft Process for the preparation of sulfur-substituted pyridine derivatives
ES2980245T3 (en) 2019-02-26 2024-09-30 Bayer Ag Condensed bicyclic heterocycle derivatives as pesticide
CN113710669A (en) 2019-02-26 2021-11-26 拜耳公司 Fused bicyclic heterocyclic derivatives as pesticides
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
AR119140A1 (en) 2019-06-13 2021-11-24 Pi Industries Ltd FUSED HETEROCYCLIC COMPOUNDS AND THEIR USE AS PEST CONTROL AGENTS
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
MX2022004513A (en) 2019-10-14 2022-07-19 Incyte Corp Bicyclic heterocycles as fgfr inhibitors.
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
JP2023505258A (en) 2019-12-04 2023-02-08 インサイト・コーポレイション Tricyclic heterocycles as FGFR inhibitors
BR112022010664A2 (en) 2019-12-04 2022-08-16 Incyte Corp DERIVATIVES OF A FGFR INHIBITOR
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
CN113912608B (en) * 2020-07-10 2023-07-14 江苏恒瑞医药股份有限公司 Pyrimidopyrimidinone derivatives, preparation method thereof and application thereof in medicines
EP4323405A1 (en) 2021-04-12 2024-02-21 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
CA3220274A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6331538B1 (en) * 1997-10-28 2001-12-18 Warner-Lambert Company 7-substituted quinazolin-2,4-diones useful as antibacterial agents
US20030003634A1 (en) * 2001-06-30 2003-01-02 Lowrey Tyler A. Utilizing atomic layer deposition for programmable device
US6534510B2 (en) * 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
US20030114671A1 (en) * 1996-05-23 2003-06-19 Chen Yuhpyng L. Substituted6,6-hetero-bicyclicderivatives
US20040044012A1 (en) * 1998-05-26 2004-03-04 Dobrusin Ellen Myra Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
US20040142945A1 (en) * 2002-11-06 2004-07-22 Joseph Barbosa Fused heterocyclic compounds and use thereof
US20040224958A1 (en) * 2000-01-27 2004-11-11 Booth Richard John Pyridopyrimidinone derivatives for treatment of neurodegenerative disease
US20100209340A1 (en) * 2007-04-11 2010-08-19 Buhr Chris A Pyrido [2, 3-d] pyrimidin-7-one compounds as inhibitors of p13k-alpha for the treatment of cancer

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5716981A (en) 1993-07-19 1998-02-10 Angiogenesis Technologies, Inc. Anti-angiogenic compositions and methods of use
US5525711A (en) * 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
TW477787B (en) 1996-08-27 2002-03-01 Pfizer Pyrido six-membered nitrogen-containing cyclic ring derivatives having corticotropin releasing factor antagonist activity and pharmaceutical composition containing same
WO1998033798A2 (en) * 1997-02-05 1998-08-06 Warner Lambert Company Pyrido[2,3-d]pyrimidines and 4-amino-pyrimidines as inhibitors of cell proliferation
WO1999051613A1 (en) 1998-04-03 1999-10-14 Medivir Ab Prodrugs of phosphorous-containing pharmaceuticals
BR9911590A (en) 1998-05-26 2001-02-13 Warner Lambert Co Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cell proliferation
MXPA02001108A (en) * 1999-09-15 2002-08-20 Warner Lambert Co Pteridinones as kinase inhibitors.
GB2359551A (en) * 2000-02-23 2001-08-29 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
AR030053A1 (en) * 2000-03-02 2003-08-13 Smithkline Beecham Corp 1H-PIRIMIDO [4,5-D] PIRIMIDIN-2-ONAS AND SALTS, PHARMACEUTICAL COMPOSITIONS, USE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND PROCEDURE FOR PRODUCERS
DE10050661A1 (en) 2000-10-13 2002-04-18 Gruenenthal Gmbh New substituted 3,4-dihydro-pyrimido(1,2-a)pyrimidine and 3,4-dihydro-pyrazino(1,2-a)pyrimidine derivatives useful for the treatment of pain, urinary incontinence, pruritis, tinnitus and diarrhea
EP1333833B1 (en) * 2000-10-23 2011-08-24 GlaxoSmithKline LLC Novel trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compound for the treatment of CSBP/p38 kinase mediated diseases
WO2002076954A1 (en) * 2001-03-23 2002-10-03 Smithkline Beecham Corporation Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
EP2198867A1 (en) * 2001-12-07 2010-06-23 Vertex Pharmaceuticals, Inc. Pyrimidine-based compounds useful as GSK-3 inhibitors
RU2004135386A (en) * 2002-05-06 2005-07-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) THIADIAZOLE OR OXADIAZOZOL AND THEIR APPLICATION AS JAK PROTEINKINASE INHIBITORS
US7326788B2 (en) 2003-07-22 2008-02-05 Janssen Pharmaceutica N.V. Quinolinone derivatives as inhibitors of c-fms kinase

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114671A1 (en) * 1996-05-23 2003-06-19 Chen Yuhpyng L. Substituted6,6-hetero-bicyclicderivatives
US6331538B1 (en) * 1997-10-28 2001-12-18 Warner-Lambert Company 7-substituted quinazolin-2,4-diones useful as antibacterial agents
US6825199B2 (en) * 1997-10-28 2004-11-30 Warner-Lambert Company 7-Substituted quinazolin-2,4-diones useful as antibacterial agents
US20040044012A1 (en) * 1998-05-26 2004-03-04 Dobrusin Ellen Myra Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
US20040224958A1 (en) * 2000-01-27 2004-11-11 Booth Richard John Pyridopyrimidinone derivatives for treatment of neurodegenerative disease
US6534510B2 (en) * 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
US20030003634A1 (en) * 2001-06-30 2003-01-02 Lowrey Tyler A. Utilizing atomic layer deposition for programmable device
US20040142945A1 (en) * 2002-11-06 2004-07-22 Joseph Barbosa Fused heterocyclic compounds and use thereof
US20100209340A1 (en) * 2007-04-11 2010-08-19 Buhr Chris A Pyrido [2, 3-d] pyrimidin-7-one compounds as inhibitors of p13k-alpha for the treatment of cancer

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080207650A1 (en) * 2007-01-11 2008-08-28 Roger Victor Bonnert Chemical Compounds 636
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US9695132B2 (en) 2013-03-15 2017-07-04 Celgene Car Llc Heteroaryl compounds and uses thereof
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10189794B2 (en) 2013-03-15 2019-01-29 Celgene Car Llc Heteroaryl compounds and uses thereof
US10618902B2 (en) 2013-03-15 2020-04-14 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10774052B2 (en) 2013-03-15 2020-09-15 Celgene Car Llc Heteroaryl compounds and uses thereof

Also Published As

Publication number Publication date
US20060211702A1 (en) 2006-09-21
EP1828186A1 (en) 2007-09-05
CA2590294A1 (en) 2006-06-22
WO2006065703A1 (en) 2006-06-22
US7767687B2 (en) 2010-08-03
JP5111113B2 (en) 2012-12-26
AU2005316668A1 (en) 2006-06-22
JP2008523099A (en) 2008-07-03
AU2005316668B2 (en) 2012-09-06

Similar Documents

Publication Publication Date Title
US7767687B2 (en) Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors
US7932257B2 (en) Substituted pyrazolo[4,3-d]pyrimidines as aurora kinase inhibitors
US7601725B2 (en) Thienopyrimidines useful as Aurora kinase inhibitors
US10780073B2 (en) N4-phenyl-quinazoline-4-amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases
US10166216B2 (en) Substituted triazoles useful as Axl inhibitors
KR101544624B1 (en) Pyrimidinyl pyridazinone derivatives
US20190071446A1 (en) Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
US7531556B2 (en) Compositions useful as inhibitors of rock and other protein kinases
JP5962622B2 (en) Compounds useful as RAF kinase inhibitors
US20120040951A1 (en) Heteroaryl compounds useful as raf kinase inhibitors
US7855214B2 (en) Fused cyclic systems useful as inhibitors of TEC family protein kinases
JP2024138293A (en) Biomarker-Based Therapeutic Compositions
EA005287B1 (en) Pteridinones as kinase inhibitors
US20220281841A1 (en) Ethynylheterocycles as rho-associated coiled-coil kinase (rock) inhibitors
US20240279224A1 (en) Quinolines and azaquinolines as inhibitors of cd38
KR20110098852A (en) 3-(3-pyrimidine-2-yl-benzyl)-[1,2,4]triazolo[4,3-b]pyridazine derivatives

Legal Events

Date Code Title Description
AS Assignment

Owner name: SUNESIS PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BIOGEN IDEC MA INC.;SUNESIS PHARMACEUTICALS, INC.;REEL/FRAME:026131/0552

Effective date: 20090717

Owner name: BIOGEN IDEC MA INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BIOGEN IDEC MA INC.;SUNESIS PHARMACEUTICALS, INC.;REEL/FRAME:026131/0552

Effective date: 20090717

Owner name: SUNESIS PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OSLOB, JOHAN D.;ZHU, JIANG;BARR, KENNETH;AND OTHERS;SIGNING DATES FROM 20060214 TO 20060414;REEL/FRAME:026129/0224

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION