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WO2005009384A2 - Inhibiteurs de la tyrosine kinase egfr - Google Patents

Inhibiteurs de la tyrosine kinase egfr Download PDF

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Publication number
WO2005009384A2
WO2005009384A2 PCT/US2004/023662 US2004023662W WO2005009384A2 WO 2005009384 A2 WO2005009384 A2 WO 2005009384A2 US 2004023662 W US2004023662 W US 2004023662W WO 2005009384 A2 WO2005009384 A2 WO 2005009384A2
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Prior art keywords
oxa
triaza
dibenzo
cyclohepten
amine
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WO2005009384A3 (fr
Inventor
Yaron Hadari
Leon M. Ii Smith
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ImClone LLC
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ImClone Systems Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention encompasses compounds that inhibit, modulate, or regulate kinases, compositions that contain such compounds, methods of making the compounds, and methods of treating kinase-dependent diseases and conditions in subjects in need of such treatment using the compounds.
  • EGFR epidermal growth factor receptor
  • ErbBl EGFR
  • HER2/neu ErbB2
  • HER3 ErbB3
  • HER4 ErbB4
  • EGFR is overexpressed in tumors of epithelial origin, including cancers of the lung, breast, head and neck, colon, and bladder. Patients expressing high levels of EGFR usually have poor prognosis. See, Bradenber et al, Clin. Cancer Res., 7, 1850-1855 (2001). Physiological regulation of EGFR is necessary to understand the mechanisms causing oncogenic activation.
  • EGFR activation is mediated by the binding to a number of growth factors such as epidermal growth factor (EGF), transforming growth factor alpha (TGF ⁇ ), and neuregulin.
  • EGF epidermal growth factor
  • TGF ⁇ transforming growth factor alpha
  • neuregulin neuregulin
  • tyrosine residues activates the tyrosine kinase catalytic domain and generates phosphorylated tyrosine residues that serve as preferred docking sites for cytoplasmatic signaling proteins containing Src homology-2 (SH2) and protein tyrosine- binding (PTB) domains.
  • SH2 Src homology-2
  • PTB protein tyrosine- binding domains.
  • EGFR mediates activation of a number of intracellular signal transduction pathways.
  • One of the intracellular signal transduction pathways is the Ras/MAPK cascade, which is mediated by the interaction of the SH2 domain of the adaptor protein Grb2 with tyrosine phosphorylated residue on EGFR.
  • EGFR mediates the activation of the phosphatidylinositol-3 ⁇ -kinase pathway by the interaction of the SH2 domain of p85 with tyrosine phosphorylated residue.
  • Other pathways that are activated by EGFR include phospholipase C ⁇ , protem kinase B/Akt, Src family kinases, and STATs. See, Y. Yarden, Eur. J. Cancer, 37, 3-8 (2001). Studies have implicated EGFR in the development of several human tumors, thus establishing EGFR as a target for cancer therapy. See, Blume- Jensen, Nature, 411, 355- 365.
  • One therapeutic approach is to inhibit the kinase activity of EGFR by using ATP-competitive small molecules inhibitors of the kinase domain.
  • the small molecules interact with the ATP binding pocket of EGFR and prevent ATP binding and kinase activation.
  • a therapeutic drug comprising the small molecules competing for the ATP binding pocket should be selective toward EGFR and other ErbB family members and have a good toxicity/safety profile.
  • the present invention addresses the ongoing need to develop kinase inhibitors which have higher activity and efficacy while demonstrating good toxicity and safety profiles such that they can be used, ter alia, in cancer therapy.
  • One embodiment of the invention encompasses methods of inhibiting, modulating, or regulating kinase activity.
  • the invention encompasses methods of treating kinase-dependent diseases and conditions in mammals using compounds of the Formula I, II, III, or a combination thereof.
  • One embodiment of the invention encompasses compounds of Formula II: Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherein X is O or S; Y is O, S, or R 7 ; R 1 is independently 1) C C 6 alkyl; 2) C 3 -C 6 cycloalkyl; 3) C 3 -C 8 heterocyclyl; 4) C 4 -C 8 cycloalkylalkyl; 5) C 3 -C 8 heterocyclylalkyl; 6) C 5 -C 10 aryl; 7) C 6 -C 10 aralkyl; 8) C 3 -C 10 heteroaryl; or 9) C 5 -C 10 heteroaralkyl; R 2 is absent when seven membered ring has a carbon-nitrogen double bond, or is hydrogen or C Cs alkyl when seven membered ring has a carbon-nitrogen single bond; R 3 , Rj, R 5 , or Re each independently is: 1) hydrogen,
  • R is substituted with at least one R 8 wherein R 8 is halo, hydroxyl, C C 6 alkyl, C . -C ⁇ alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 8 heterocyclyl, C5-C 10 aryl, C 3 -C 10 heteroaryl, C 5 - Cio aryloxy, -COR 9 , -CO 2 R 9 , -SR 9 , -SO R 9 , -NH 2 , -NHR 9 , -NR 9 R 9 , or -NHCONR 9 R 9 , wherein R 9 is independently H, C .
  • Yet another embodiment of the invention encompasses compounds of Formula II, wherein at least one of R 3 , R 4 , R 5 , or R 6 is substituted with at least one R 10 wherein R 10 is halo, hydroxyl, d-C 6 alkyl, C .
  • Another embodiment of the invention encompasses compounds of Formula II, wherem R 3 and t , R t and R 5 , or R 5 and R 6 are taken together to form a C 5 -C 8 cycloalkyl, or C 4 -C 10 heterocyclyl.
  • Another embodiment of the invention encompasses methods of inhibiting kinase activity comprising administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, to a subject in need of such inhibition wherein the compound of Formula II has the formula:
  • X is O or S; Y is O, S, orNR 7 ;
  • R is independently 1) Ci-C ⁇ alkyl; 2) C 3 -C 6 cycloalkyl; 3) C 3 -C 8 heterocyclyl; 4) C -C 8 cycloalkylalkyl; 5) C 3 -C 8 heterocyclylalkyl; 6) C 5 -C 10 aryl; 7) C 6 -C 10 aralkyl; 8) C 3 -C 10 heteroaryl; or 9) C 5 -C 10 heteroaralkyl;
  • R 2 is absent when seven membered ring has a carbon-nitrogen double bond, or is hydrogen or d-C 8 alkyl when seven membered ring has a carbon-nitrogen single bond;
  • R 3 , t , R 5 , or R ⁇ each independently is: 1) hydrogen, halo, cyano, nitro, or amino; 2) Ci-C ⁇ alkyl; 3) C 2 -C 6
  • Another embodiment of the invention encompasses methods of inhibiting kinase activity comprising administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherein R] is substituted with at least one R 8 wherein R 8 is halo, hydroxyl, d-C 6 alkyl, d-C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 8 heterocyclyl, C 5 -C 10 aryl, C 3 -C 10 heteroaryl, -COR 9 , -CO 2 R 9 , -SR 9 , -SO 2 R 9 , -NH 2 , -NHR 9 , -NR 9 R 9 , or -NHCONR 9 R 9 , wherein R 9 is independently H, d-C 6 alkyl, C5-Q 0 aryl, C 6 -C 10 aralkyl, or C 3 -C 10 hetero
  • Yet another embodiment of the invention encompasses methods of inhibiting kinase activity comprising admimstering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherein at least one of R 3 , t, R 5 , or Re is substituted with at least one R 10 wherein R 10 is halo, hydroxyl, d-d alkyl, d-C 8 alkoxy, C 3 -C 8 cycloalkyl, C 4 -C 10 heterocyclyl, C 5 -C 10 aryl, C 3 -C 10 heteroaryl, NH 2 , NH(d-C 6 alkyl), or N(d-C 6 alkyl) 2 .
  • Yet another embodiment of the invention encompasses methods of inhibiting kinase activity comprising administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherein R 3 and t , Rt and R 5 , or R 5 and R 6 are taken together to form a C 5 -C 8 cycloalkyl, or C -C 10 heterocyclyl.
  • Another embodiment of the invention encompasses methods of inhibiting kinase activity comprising administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, to treat conditions or diseases in which angiogenesis is implicated, cancer, tumor growth, atherosclerosis, age related macular degeneration, retinal vascularization, inflammatory diseases, or cell prohferative disorders.
  • the present invention encompasses compounds of capable of inhibiting, modulating, or regulating the activity of tyrosine kinases.
  • the invention encompasses compounds of Formula I:
  • alkyl refers to a saturated hydrocarbon radical having 1 to 8 carbon atoms.
  • the alkyl group may be straight, branched, substituted or unsubstituted.
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, or pentyl.
  • alkenyl refers to a non-aromatic hydrocarbon radical, which may be straight chain or branched, substituted or unsubstituted, having from 2 to 8 carbon atoms and at least one carbon to carbon double bond.
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, or 2-methylbutenyl.
  • alkynyl refers to a hydrocarbon radical, wliich may be straight chained or branched, substituted or unsubstituted, having 2 to 8 carbon atoms and at least one carbon to carbon triple bond.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl, or butynyl.
  • alkoxy refers to a substituted or unsubstituted an
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, or vinyloxy.
  • cycloalkyl refers to a cyclic hydrocarbon radical having 3 to 8 carbon atoms, which may be substituted or unsubstituted.
  • the cycloalkyl group may have at least one carbon to carbon double bond.
  • Cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, or cyclohexyl.
  • heterocyclyl or “heterocycle” refers to cycloalkyl rings that include within the ring at least one nitrogen, oxygen, or sulfur atom.
  • the heterocyclyl may include one or two double bonds.
  • heterocyclyl also refers to dihydro and tetrahydro analogs of heteroaryls.
  • the heterocyclyl ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
  • the heterocycle ring may be substituted or unsubstituted including, but not limited to, aziridinyl, homopiperazmyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholino, oxadiazolyl, oxazolidinyl, oxazolinyl, 4-piperidonyl, piperazinyl, pyranyl, pyradazinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tertrahydrofuranyl, tetrahydrothienyl, tetrahydrothiophenyl, thiazolidinyl, thiazolinyl, thiomorpholino, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, or thiophenyl.
  • aryl refers to carbocyclic aromatic groups including, but not limited to, phenyl, biphenyl, naphthyl, or anthracyl.
  • aryl also refers to any bicyclic group in which a cycloalkyl or heterocyclyl ring is fused to a benzene ring, examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, benzopyranyl, benzothiazolyl, benzothienyl, benzotriazole, benzoxazolyl, indolinyl, indolizinyl, indolyl, isoindolyl, isoquinolinyl, or quinolinyl.
  • aryl ring may be unsubstituted or substituted with at least one suitable substituent.
  • heteroaryl refers to a monocyclic or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and at least one heteroatom, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, or sulfLir.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heteroaryl includes, but is not limited to, azepinyl, benzimidazoyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, isoimidazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazoyl, thiazolyl, thienyl, triazinyl, 1,2,3 -triazolyl, or 1,2,4-triazolyl.
  • a heteroaryl group can be unsubstituted or substituted.
  • aralkyl refers to a straight-chain alkyl, alkenyl, or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with an aryl moiety.
  • Typical aralkyl groups include, but are not limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl, naphthenobenzyl, and the like.
  • aryloxy group refers to an -O-aryl or -O-heteroaryl, wherein aryl or heteroaryl is as defined above.
  • An aryloxy group can be unsubstituted or substituted with one or two suitable substituents.
  • the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryloxy.”
  • carbonyl refers to a divalent group of the formula -CO-, which also may be referred to as oxo.
  • alkylcarbonyl refers a monovalent group of the formula -CO-alkyl.
  • the hydrocarbon chain of an alkylcarbonyl group is d-C 8 atoms in length, referred to herein as a "lower alkylcarbonyl” group.
  • arylcarbonyl refers to a monovalent group of the formula -CO-aryl or -CO-heteroaryl, wherein the aryl is optionally substituted with a suitable substituent.
  • alkoxycarbonyl refers to a monovalent group of the formula -CO-alkoxy.
  • the hydrocarbon chain of an alkoxycarbonyl group is d-C 8 atoms in length, referred to herein as a "lower alkoxycarbonyl” group.
  • carbamoyl refers to a radical -CON(R)- or -(R)NCO-, wherein R is further defined herein.
  • urea or “urealyl” refers to a radical -RNHCONR-, wherein R may be the same or different is further defined herein.
  • the term “carbamic acid” or “carbamyl” refers to a radical -RNHCOO-, wherein R is further defined herein.
  • a "suitable substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
  • suitable substituents include, but are not limited to: d-C 8 alkyl; C 2 -C 8 alkenyl; C 2 -C 8 alkynyl; C 6 aryl; C 3 -C 5 heteroaryl; C 3 -C 7 cycloalkyl; d-C 8 alkoxy; C 6 aryloxy; -CN; -OH; oxo; halo; -CO 2 H; -NH 2 ; -NH(d-C 8 alkyl); -N(d-C 8 alkyl) 2 ; -NH(C 6 aryl); -N(C 6 aryl) 2 ; -CHO; -CO(d-C 8 alkyl); -CO(C 6 aryl); -CO 2 (d-C 8 alkyl); and
  • halo or halogen includes fluorine, chlorine, bromine, or iodine, including fluoro, chloro, bromo, and iodo.
  • chiral centers are present in the compounds of the present invention, the individual isomers, i.e., enantiomers, diastereomers, etc. and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. Also included are individual polymorphs of each compound of the present invention.
  • the terms “pharmaceutically acceptable salts” and “hydrates” refer to those salts and hydrated forms of the compound that would be apparent to those in the art, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism, and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, and flowability of the resulting bulk drug. Pharmaceutically acceptable salts may be prepared by the addition of an appropriate acid. Thus, the compound can be used in the form of salts derived from inorganic or organic acids.
  • Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, pamoate, / pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, or undecanoate.
  • the term “subject” refers to a mammal, preferably a human, but can also be an animal in need of veterinary treatment.
  • the term “modulation” or “modulating” refers to a reduction in the level and/or activity of target gene product relative to the level and/or activity of the target gene product in the absence of the modulatory treatment.
  • the term, as used herein refers to a reduction in the number and/or proliferation rate of the transformed cancer cells as compared to the proliferation rate of the transformed cancer cells in the absence of the modulatory treatment.
  • treating refers to an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • successful treatment may include a reduction in the proliferation of cancer cells or diseased tissue, a halting in capillary proliferation, or a halting in the progression of a disease such as cancer or in the growth of cancerous cells.
  • treating includes, but is not limited to, preventing the disease from occurring in a subject which may be predisposed to the disease but does not yet experience or display symptoms of the disease, inhibiting the disease, i.e., arresting the development of the disease, or relieving symptoms of the disease, i.e., causing regression of the disease.
  • the term "therapeutically effective amount” refers to the amount of kinase inhibitor, or a pharmaceutically acceptable salt thereof, which, alone or in combination with other drags, provides a therapeutic benefit in the prevention, treatment, or management of conditions or diseases in which neoangiogenesis is implicated, cancer, tumor growth, atherosclerosis, age related macular degeneration, retinal vascularization, inflammatory diseases, neoplasia, cell prohferative disorders, or one or more symptoms associated with such disorders.
  • the amount of the compound will depend upon on the subject being treated. The subject's weight, severity of illness, manner of administration, and judgment of the prescribing physician should be taken into account in deciding the proper amount.
  • One embodiment of the invention encompasses compounds wherein two six membered rings are fused to a seven membered ring having a nitrogen atom and an oxygen or sulfur atom, wherein at least one of the six membered rings is pyrimidine.
  • the compounds inhibit, modulate, or regulate kinases and consequently, are useful in treating or preventing kinase dependent diseases or conditions in a subject.
  • the compounds of the invention encompass substituted or unsubstituted oxa-triaza- dibenzocycloheptene or thia-triaza-dibenzocycloheptene compounds.
  • the compounds of the invention are represented in Formula (I):
  • X is O or S; Y is O, S, orNR 7 ;
  • Ri is independently 1) alkyl, optionally substituted R 8 ; 2) alkenyl, optionally substituted with at least one R 8 ; 3) alkynyl, optionally substituted with at least one R 8 ; 4) cycloalkyl, optionally substituted with at least one R 8 ; 5) heterocyclyl, optionally substituted with at least one R 8 ; 6) cycloalkylalkyl, optionally substituted with at least one R 8 ; 7) heterocyclylalkyl, optionally substituted with at least one R 8 ; 8) aryl, optionally substituted with at least one R 8 ; 9) heteroaryl, optionally substituted with at least one R 8 ; 10) aralkyl, optionally substituted with at least one R 8 ; or 11) heteroaralkyl, optionally substituted
  • Another embodiment of the invention encompasses compounds of Formula II: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherem X is O or S; Y is O, S, orNR 7 ; R is independently 1) d-C 6 alkyl, optionally substituted R 8 ; 2) C 3 -C 6 cycloalkyl, optionally substituted with at least one R 8 ; 3) C 3 -C 8 heterocyclyl, optionally substituted with at least one R 8 ; 4) C 4 -C 9 cycloalkylalkyl, optionally substituted with at least one R 8 ; 5) C 3 -C 8 heterocyclylalkyl, optionally substituted with at least one R 8 ; 6) d- o aryl, optionally substituted with at least one R 8 ; 7) C ⁇ -C ⁇ o aralkyl, optionally substituted with at least one R 8 ; 8) C 3 -C 10 heteroaryl, optionally
  • R 3 and Rt, and R 5 , or R 5 and R 6 are taken together to form a C 5 -C 8 cycloalkyl, C 4 -C 10 heterocyclyl, C 5 -do aryl, or C 3 -C 10 heteroaryl; and R 7 is hydrogen or d-C 8 alkyl, wherein if Y together with R ⁇ is benzylamine, anilinyl, piperidine, morpholine, or n-BuNH, then R 4 is not H, Cl, or Br.
  • a prefened embodiment of the invention includes compounds having Formula TTT:
  • X is O or S; Y is O, S, orNR 7 ;
  • R ! is independently 1) C 5 -C 10 aryl, optionally substituted with R 8 ; 2) C 3 -C 10 heteroaryl, optionally substituted with R 8 ; 3) C 6 -C 10 aralkyl, optionally substituted with at least one R 8 ; or 4) C -do heteroaralkyl, optionally substituted with at least one R 8 , wherein R 8 is F, Cl, Br, hydroxyl, d-C 6 alkyl, C 5 -C 8 cycloalkyl, C 4 -C 6 heterocyclyl, Cs-C 10 aryl, C 6 -do heteroaryl, -NH 2 , -NHR 9 , or -NR 9 R 9 , wherein R 9 is independently H, d-C 6 alkyl, C 5 -do
  • Formula IV or a pharmaceutically acceptable salt, stereoisomer, hydrate, or pro-drug thereof, wherein, X is O or S; Ri is independently 1) d-do aryl, optionally substituted with R 8 ; or 2) C 3 -C 10 heteroaryl, optionally substituted with R 8 , wherein R 8 is F, Cl, Br, d-C 6 alkyl, or C ⁇ -C 6 alkynyl; R 2 is absent when the seven membered ring has a carbon-nitrogen double bond, or is hydrogen or C ⁇ -C 6 alkyl when the seven membered ring has a carbon-nitrogen single bond; R t and R 5 each independently is: 1) d-Cs alkoxy, optionally substituted with at least one R 10 ; 2) C 3 -C 8 cycloalkyl, optionally substituted with at least one R 10 ; 3) C 4 -C 10 heterocyclyl, optionally substituted with at least one R 10 ; 4) C 4 -C 10
  • NH 2 NH(d-C 6 alkyl), or N(C ⁇ -C 6 alkyl) 2 .
  • Even more prefened compounds of Formula I include: 3-(8-Methoxy-10,ll-dihydro-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l- ylamino)-b enzonitrile; Benzyl-(5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl)amine; (4-Chlorophenyl)-(5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten-l -yl)amine; (8-Bromo-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl)-(3-chloro-4-fluoro- phenyl)-amine; (8-Bromo
  • Another embodiment of the invention encompasses methods of preparing compounds of the Formula I, Formula II, or Formula III or pharmaceutically acceptable salts, stereoisomers, hydrates or pro-drugs thereof, which is described in further detail.
  • the compounds of the invention are synthesized using a variety of schemes, such as those illustrated below and exemplified in the Example section.
  • reaction conditions may vary slightly due to specific reactants, when necessary the compounds may use protecting groups, or that more than one substituent may be included in the reaction.
  • one method comprises selecting a starting material with more than one substituent, i.e., the aromatic ring may contain R 3 , R , R 5 , and/or R 6 .
  • additional substituents may be added by the functionalization of existing groups, as illustrated below in Scheme 2.
  • the reactions may be carried out with intervening isolation and/or purification steps or the products may be carried forth in the reaction sequence without isolation and/or purification.
  • Starting materials useful for the preparing the compounds of the invention and intermediates therefor are commercially available or can be prepared by well known synthetic methods.
  • the oxazepine and dihydro oxazepine compounds of the invention are synthesized by various steps, as illustrated in Scheme 1.
  • the functionalized pyrimidine is allowed to react with a functionalized aniline in aqueous ethanol and in the presence of HCI with heating to yield the mono-halide Compound A.
  • An alternative reaction includes, but is not limited to, dissolving the pyrimidine compound in an organic solvent such as dimethylforamide (DMF) and heating the mixture at a temperature of about 80 ° C. Thereafter, Compound A is allowed to react under basic conditions with a substituted or unsubstituted ⁇ -hydroxybenzaldehyde to yield the oxazepine Compound B. See, Levkovskaya et al, Khim. Geterotsikl.
  • bases for the reaction include, but are not limited to, hydrides such as LiH, NaH, or KH, and suitable reaction temperatures include about 100°C to 110°C.
  • suitable reaction temperatures include about 100°C to 110°C.
  • Compound B may undergo reduction to yield the dihydro-oxazepine.
  • Typical reduction methods include hydrogenation, or borohydride reduction. See, Nagarajan et al, Indian J. of Chem., 24B, 840-844 (1985).
  • the suitable reducing agents include, but are not limited to, LiBE , NaBH 4 , or iAlH 4 .
  • Scheme 2 illustrates one method of using protecting groups in the functionalization of R 3 , t , R 5 , or
  • R 5 The Example section further illustrates functionalization of R 3 , R t , R 5 , or R ⁇
  • R 5 represents as -ORa
  • the adjacent oxygen is protected with tert-butylsilane (TBS) to yield Compound D.
  • TBS tert-butylsilane
  • deprotection using a halide source followed by a second alkylation yields the oxazepine Compound E.
  • the oxazepine may be reduced to yield the dihydro- oxazepine Compound F.
  • Compound E Compound F Scheme 2
  • the thiazepine compounds of Formula I i.e., compounds of Formula I wherein X is sulfur, were synthesized as illustrated in Scheme 3.
  • the synthetic method comprises reacting a dihaloaminopyrimidme compound with a benzenethiol compound to obtain a thiol ether compound; reacting the thiol ether compound with paraformaldehyde to obtain a thiazepine compound; and reacting the thiazepine compound with a substituted aniline, phenol, or thiophenol to obtain a compound of Formula I.
  • the synthetic sequence will be fttrther explained with reference to Scheme 3. Although illustrated with aniline, the skilled artisan readily recognizes that phenol or thiophenol also may be used.
  • a dihaloaminopyrimidme compound is allowed to react with a substituted or unsubstituted benzenethiol in the presence of a base and heated to yield the thiol ether Compound G.
  • the reaction is carried out at a suitable temperature and using a suitable solvent.
  • a suitable reaction temperature is about the reflux temperature of an organic solvent used in the reaction.
  • the temperature is about 70 °C to about 80 °C and more preferably, the reaction temperature is about 75 °C.
  • the organic solvent may be any organic solvent that does not react with the reactants including, but not limited to, alcohols, ethers, or heterocyclics.
  • the solvents include, but are not limited to, ethanol, isopropanol, tetrahydrofuran, dioxane, or N,N-dimethylforamide.
  • the reaction temperature is about 30°C to about 50°C, and preferably, the reaction temperature is about 40 °C.
  • Any acid may be used, for example an organic acid, inorganic acid, or a combination thereof.
  • Inorganic acids include, but are not limited to, at least one of HCI, HI, H 2 SO 4 , H 2 CO 3 , H 3 PO , or NaH 2 PO 4 .
  • Organic acids include, but are not limited to, at least one of acetic acid, formic acid, or trifluoroacetic acid.
  • the amount of acid present in the reaction is from about 0.5 to about 1.5 molar equivalents, preferably, the acid is present in an amount of about 1 equivalent to the thiol ether Compound H.
  • the reaction may further comprise reacting Compound H with a substituted aniline or phenol in the presence of a catalytic amount of HCI while heating to yield the thiazepine Compound I.
  • a catalytic amount refers to an amount of about 1% to about 10% percent (mol equivalents) based upon the amount of Compound G present in the reaction. Typically, the catalytic amount is from about 5%.
  • the reaction temperature is from about 90 °C to about 140°C, and preferably the reaction temperature is from about 110°C to about 130°C.
  • nucleophilic substitutions may be facilitated in the presence of an organic or inorganic base depending upon the nature of the nucleophile. See e.g., U.S. patent No. 5,849,910, herein inco ⁇ orated by reference.
  • the bases for the reaction include, but are not limited to, K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 , Et 3 N, or DIPEA.
  • the products of the above-described synthesis may be purified using techniques commonly known to one skilled in the art such as preparatory chromatography, thin-layer chromatography, HPLC, or crystallization.
  • compositions which include at least one compound of Formula I, II, III, or a pharmaceutically acceptable salt, hydrate or pro-drug thereof, in combination with a pharmaceutically acceptable carrier.
  • Compositions of the invention are suitable for oral, mucosal (e.g., nasal, vaginal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), sublingual, transdermal, or buccal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated.
  • the compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in pharmacy.
  • Dosage forms include tablets, caplets, troches, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft elastic gelatin capsules, patches, and the like. Prefened dosage forms are those suitable for oral administration.
  • the compositions of the present invention may be employed in solid or liquid form including for example, powder or crystalline form, in solution or in suspension.
  • the choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • the carrier employed may be, for example, either a solid or liquid.
  • One method of administering a solid dosage form is to form solid compositions for rectal administration, which include suppositories formulated in accordance with known methods and containing at least one compound of the present invention.
  • solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged abso ⁇ tion of the injectable compositions can be brought about by use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • Solutions of the active compound or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
  • aqueous solutions also including solutions of the salts in pure distilled water, may be used for intravenous admimstration with the proviso that their pH is suitably adjusted, that the solutions are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, inadiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions.
  • Sterile injectable solutions are prepared by inco ⁇ orating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by inco ⁇ orating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation may include vacuum drying and a freeze-dry technique that yields a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • injectable solids include powders that are reconstituted, dissolved, or suspended in a liquid prior to injection.
  • the carrier typically includes sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • sterile water e.g., saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • various buffering agents, preservatives and the like can be included within the compositions of the present invention.
  • the active compound may be administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be inco ⁇ orated directly with the food of the diet, or may be inco ⁇ orated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • oral solid dosage forms include tablets, capsules, troches, lozenges and the like.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • Carriers for oral use may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • time delay materials such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • lactose and liquid carrier such as high molecular weight polyethylene glycols.
  • Topical administration in the form of gels (water or alcohol based), creams or ointments, for example, containing compounds of the invention may be used.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Topical formulations can be used for example, to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • Compounds of the invention may be also inco ⁇ orated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
  • compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • compositions according to the invention may also be formulated in a manner that resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the viral particles at the desired site of action.
  • a periadventitial depot comprising a compound according to the invention may be used for sustained release.
  • One such useful depot for administering a compound according to the invention may be a copolymer matrix, such as ethylene- vinyl acetate, or a polyvinyl alcohol gel sunounded by a Silastic shell.
  • a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
  • microparticles may be included a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (J. Am.
  • a composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • a biocompatible or non-cytotoxic (homo or hetero) polymer such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • Such polymers have been described, for example, in application WO93/08845. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available.
  • Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons.
  • perfusion balloons which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action.
  • a channeled balloon catheter such as "channeled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Co ⁇ ., Watertown, Mass.
  • This catheter includes a conventional balloon covered with a layer of 24 perforated channels that are perfused via an independent lumen through an additional infusion orifice.
  • a pharmaceutical composition including a compound according to the invention and poloxamer, such as Poloxamer 407, which is a non-toxic, biocompatible polyol, commercially available (e.g., from BASF, Parsippany, N.J.).
  • poloxamer such as Poloxamer 407, which is a non-toxic, biocompatible polyol, commercially available (e.g., from BASF, Parsippany, N.J.).
  • a poloxamer impregnated with a compound according to the invention may be deposited for example, directly on the surface of the tissue to be treated, for example during a surgical intervention.
  • Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.
  • the use of a channel balloon catheter with a poloxamer impregnated with a compound according to the invention may be advantageous in that it may keep the balloon inflated for a longer period of time, while retaining the properties of facilitated sliding, and of site-specificity of the poloxamer.
  • the composition may also be administered to a patient via a stent device.
  • the composition is a polymeric material in which the compound of the invention is inco ⁇ orated, which composition is applied to at least one surface of the stent device.
  • Polymeric materials suitable for inco ⁇ orating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly(ethylene-co- vinyl acetate) or poly(vinyl acetate or silicone gum rubber and polymers having similar relatively low processing temperatures.
  • compositions of the present invention optionally contain one or more excipients that are conventional in the art.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, troches, pills, capsules and the like.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used.
  • the active compound may be inco ⁇ orated into sustained-release preparations and formulations. The percentage of active ingredient in the compositions of the invention may be varied. Several unit dosage forms may be administered at about the same time. A suitable dose employed may be determined by a physician or qualified medical professional, and depends upon various factors including the desired therapeutic effect, the nature of the illness being treated, the route of administration, the duration of the treatment, and the condition of the patient, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
  • doses are generally from about 0.001 to about 100 mg/kg body weight and preferably, about 0.01 to about 100 mg/kg body weight per day.
  • the compounds and compositions according to the invention may be administered as frequently as necessary as determined by a skilled practitioner in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. For other patients, it may be necessary to prescribe not more than one or two doses per day.
  • the compounds of the present invention may also be formulated for use in conjunction with other therapeutically active compounds or in connection with the application of therapeutic techniques to address pharmacological conditions, which may be ameliorated through the application of a compound according to the present invention.
  • One embodiment of the invention encompasses method of treating cancer using the compounds of the invention.
  • the disclosed compounds can be used to treat subjects with cancer, including multi-drug resistant cancers.
  • a cancer is resistant to a drug when it resumes a normal rate of tumor growth while undergoing treatment with the drug after the tumor had initially responded to the drug.
  • multi-drug resistant cancer refers to cancer that is resistant to two or more drugs, typically five or more.
  • the disclosed compounds can be co-administered with other anticancer agents such as Taxol, Vincristine, Adriamycin, Etoposide, Doxorubicin, Dactinomycin, Mitomycin C, Bleomycin, Vinblastine, Cisplatin, Erbitux, Avastin, Irressa, and the like. Additionally, the disclosed compounds can be co-administered with bioactive anticancer agents such as kinase inhibitors, kinase receptors, antigenesis inhibitors, cell cycle inhibitors, cytotoxic targeting agents, signal transduction pathway inhibitors, and the like. The method can also be canied in combination with other cancer treatments such as surgery, radiation, and the like.
  • the compounds of Formula I may be used for in vivo and in vitro investigative, diagnostic, or prophylactic methods, which are well known in the art.
  • the methods of the present invention encompass administration of a therapeutically effective amount of at least one compound of Formula I to a subject in need of such treatment.
  • administering means delivering the compounds of the present invention to a subject by any method that may achieve the result sought.
  • the method may be, for example, orally, parenterally (intravenously or intramuscularly), topically, transdermally, or by inhalation.
  • subject as used herein is intended to include, but is not limited to, humans, laboratory animals, domestic pets and farm animals.
  • therapeutically effective amount as used herein with respect to the treatment or prevention of cancer encompasses an amount of compound of the present invention that inhibits, modulates, or regulates kinases as compared to the rate in the absence of a compound of the invention, preferably the rate is about 20% to , about 100%.
  • Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art.
  • amounts sufficient to treat or prevent such disorders, but insufficient to cause adverse effects associated with compounds of Formula I are also encompassed by dosage amounts and dose frequency schedules.
  • One embodiment of the invention encompasses methods of inhibiting, modulating or regulating kinases by administering to a subject a therapeutically effective amount of one or more of the compounds set forth herein.
  • the diseases and conditions that may treated or prevented by the present methods include, for example, cancer, conditions or diseases in which neoangiogenesis is implicated, tumor growth, atherosclerosis, age related macular degeneration, retinal vascularization, inflammatory diseases, or cell prohferative disorders, in mammals, which conditions or diseases may overlap with one another.
  • Tyrosine kinase inhibition can be determined using methods known to the skilled artisan.
  • the compounds of the present invention generally involve inhibition or regulation of phosphorylation events.
  • phosphorylation assays are useful in determining antagonists useful in the context of the present invention.
  • Tyrosine kinase inhibition maybe determined by measuring the autophosphorylation level of recombinant kinase receptor, and/or phosphorylation of natural or synthetic substrates.
  • Some assays for tyrosine kinase activity are described in Panek et al, J. Pharmacol. Exp. Thera., 283: 1433-44 (1997) and Batley et al, Life Sci., 62: 143-50 (1998).
  • compounds maybe screened using, for example, using an ELISA, PAGE, HTRF assay, or western blot.
  • Yet another embodiment of the invention encompasses treating or preventing cancer in a mammal in need of such treatment, which includes administering to the mammal a therapeutically effective amount of at least one of the compounds of Formula I, III, or III.
  • Cancers that may be treated by the methods of the present invention include cancers such as cancers of the brain, genitourinary tract, lymphatic system, stomach, renal, colon, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma, fibrosarcoma, mammary carcinoma, ovarian, gioblastomas and small cell lung cancers.
  • Additional examples include cancers in wliich overexpression or activation of Raf- activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic, melanoma, and breast cancer.
  • Another embodiment of the invention encompasses methods of treating or preventing inflammatory diseases by administering to a mammal in need of such treatment a therapeutically effective amount of at least one of the compounds of Formula I, II, or III.
  • inflammatory diseases that may be treated by the methods of the present invention include, but are not limited to, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • the anti-proliferative activity of the compounds of Formula I were tested in a variety of zn vitro and in vivo assays.
  • the experimental section discusses the assays in detail.
  • the in vitro assays include: a) EGFR TK enzymatic assays (which determines the ability of a test compound to inhibit the kinase enzyme of the EGF receptor). This test employed one of two detection methods: 1) ELISA or 2) HTRF. b) EGFR cell-based phosphorylation assays: (which determines the ability of a test compound to prevent phosphorylation of EGFR TK in cells). This test employed one of test cell lines: 1) A431 or 2) DiFi.
  • EGFR cell-based proliferation assay (which determines the ability of a test compound to inhibit the EGF-stimulated growth of DiFi cells).
  • the in vivo assay determines the ability of test compound (administered orally as a suspension in phosal) to inhibit the growth of human vuval epidermoid carcinoma cell line (A431) xenografts using a group of nude mice.
  • Tables 1-3 summarize the assay results for compounds of Formula I, II, or III.
  • ingredients and method steps should be understood as examples that are intended to be illustrative only.
  • the invention is not intended to be limited to the methods, protocols, conditions and the like specifically recited herein, insofar as those skilled in the art would be able to substitute other conditions, methods, amounts, materials, etc. based on the present disclosure to arrive at compounds within the scope of the invention.
  • the present invention is described with respect to particular examples and prefened embodiments, the present invention is not limited to these examples and embodiments.
  • the compounds of the present invention are not limited to the exemplary species' recited herein.
  • the methods of the present invention are not limited to treating only the exemplified diseases and conditions, but rather any disease or condition that may be treated by regulation of kinases. Additionally, the methods of synthesis of the present invention are not limited to the methods exemplified in the examples. The methods of the present invention include methods of making any of the compounds set forth in the present invention that those skilled would be able to make in view of the present disclosure, and are not limited to the exemplified method. For example, methods encompassed by the present invention may involve the use of a different starting material depending on the desired final compound, different amounts of various ingredients, or substitution of different ingredients such as other reactants or catalysts that would be suitable depending on the starting material and result to be achieved. Using the synthetic pathway illustrated in Scheme 4, compounds 1-60 were synthesized.
  • Example 1 Compound 1 Preparation of 3-(8-Methoxy-10,l l-dihydro-5-oxa-2,4,l l-triaza-dibenzo[a,d]cyclo- hepten- 1 -ylamino)-benzonitrile:
  • LiBH 4 (9.52 mg, 0.44 mmol) was added to a solution of 3-(8-methoxy-5-oxa-2,4,ll- triazadiben__o[a,d]cyclo-hepten-l-ylamino)-benzonitrile la (150 mg, 0.44 mmol) in THF under an argon atmosphere. The mixture was stined at room temperature for 18 h.
  • Example 2-60 Following the procedure of Example 1 and using the appropriate starting materials the following compounds were prepared.
  • Example 13 Compound 13 (3-Bromo-phenyl)-(8-trifluoromethoxy- 10, 11 -dihydro-5-oxa-2,4, 11 -triaza- dibenzo[a,d]cyclohepten-l-yl)-amine: 'HNMR (DMSO-d 6 ) ⁇ (ppm) 8.78 (s, IH), 8.05- 8.11 (m, 2H), 7.79-7.82 (m, IH), 7.60-7.61 (m, IH), 7.49-7.51 (m, 2H), 7.32-7.39 (m IH), 7.24-7.28 (m, IH), 5.50-5.53 (m, IH), 4.61 (d, 2H). MS m/z: 453 (M+l).
  • the starting material, (3-Chloro-4-fluoro-phenyl)-[8-(3-chloro-propoxy)-7-methoxy-5- oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 62a was prepared by adding crude 1 -(3-chloro-4-fluoro-phenylamino)-7-methoxy-5-oxa-2,4, 11- triazadibenzo[a,d]cyclohe ⁇ ten-8-ol 62b (1.00 g, 0.26 mmol) and K 2 CO 3 (1.07 g, 0.77 mmol) to DMF (25 ml) at room temperature under an argon atmosphere.
  • the starting material, l-(3-chloro-4-fluoro- ⁇ henylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]cycloheptene-7,8-diol 62c was obtained by adding 2,4,5- trihydroxybenzaldehyde (1.68 g, 1.10 mmol) to a solution of 4-(4-fluoro-3-chloroanilino)- 5-amino-6-chloropyrimidine (3.0 g, 1.10 mmol) in DMF (6.5 ml) under argon atmosphere. The mixture was stined at 100°C for 3 hours. Afterwards, the mixture was cooled to room temperature and water (60 ml) added.
  • the 6-chloro-N4-(3-chloro-4-fluoro-phenyl)-pyrimidine-4,5-diamine 62d used as starting material was prepared by combining 5-amino-4,6-dichloropyrimidine (3 g, 18.3 mmol) and 4-fluoro-3-chloroaniline (2.42 g, 16.6 mmol) in DMF (4.5 ml) at 25°C with under an argon atmosphere. The mixture was stirred at 80°C for 18 hours before cooling to room temperature. The crude material was poured into 5% NaHCO 3 (aq) (30 ml), stined for 10 minutes, and extracted with EtOAc (2 x 50 ml).
  • Example 63 Compound 63 Preparation of 3-Chloro-4-fluoro-phenyl)-[8-(3-dimethylamino-propoxy)-7-methoxy- 10,11 -dihydro-5-oxa-2,4, 1 l-triaza-dibenzo[a,d]cyclohepten- 1 -yl]-amine:
  • Example 65 Compound 65 Preparation of (3-Chloro-4-fluoro-phenyl)-[7-methoxy-8-(3-morpholin-4-yl-propoxy)-5- oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 66 Compound 66 Preparation of [7,8-Bis-(3-methoxy-propoxy)-10,l l-dihydro-5-oxa-2,4,l 1-triaza- dibenzo [a,d] -cyclohepten- 1 -yl]-(3 -chloro-4-fluoro-phenyl)-amine dihydrochloride :
  • the free base was converted directly into the dihydrochloride salt by dissolution in MeOH (1.0 ml) and treatment with 2.0 M HCI ethereal (0.15 ml, 0.3 mmol). After stirring at room temperature for 2 hours, the resulting precipitate was filtered, washed with diethyl ether, and dried in vacuo to leave the HCI salt as an off-white solid (35 mg, 43%).
  • Example 68 Compound 68
  • the starting material, l-(3-Chloro-4-fluoro-phenylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]-cyclohepten-7-ol 68a was prepared in the following manner: 6-Chloro-N4-(3-chloro-4-fluoro-phenyl)-pyrimidine-4,5-diamine 62d (1.0 g, 3.66 mmol) was dissolved in dry DMF (4.5 ml) at room temperature under argon with stirring. 2,4- dihydroxybenzaldehyde (506 mg, 3.66 mmol) was added and the mixture stined at 110°C for 1.5 hrs at which time a precipitate formed.
  • Example 69 Compound 69 (3-Chloro-4-fluoro-phenyl)-[7-(3-dimethylamino-propoxy)-5-oxa-2,4,l l-triaza- dibenzo[a,d]cyclohepten-l-yl]-amine:
  • 3-dimethylaminopropyl-p-toluene sulfonate 69a was prepared in the following manner: p-Toluenesulfonyl chloride (2.22 g, 11.6 mmol) was dissolved in anhydrous pyridine (2.5 ml) at -5°C with stirring. A solution of 3-dimethylaminopropanol (1.0 g, 9.7 mmol) in anhydrous pyridine (10 ml) was added dropwise over a 15 minute period. The resultant solution continued to stir for 3 hours at -5°C. Then, the mixture was diluted with H 2 O (5 ml) and extracted with DCM (3 x 10 ml).
  • Example 71 Compound 71 (3-chloro-4-fluoro-phenyl)-[7-(3-mo ⁇ holin-4-yl-propoxy)-5-oxa-2,4, 11 -triaza- dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 73 Compound 73 Preparation of (3-Chloro-4-fluoro-phenyl)-[7-methoxy-8-(2-[l,2,3]triazol-l-yl-ethoxy)- 10,l l-dihydro-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • the starting material (3-chloro-4-fluoro-phenyl)-[7-methoxy-8-(2-[l,2,3]triazol-l-yl- ethoxy)-5-oxa-2,4,l l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 73a was prepared as follows: 1 -(3-Chloro-4-fluoro-phenylamino)-7-methoxy-5-oxa-2,4, 11 -triaza- dibenzo[a,d]cyclohepten-8-ol 62b (150 mg, 0.39 mmol) and triphenylphosphine (polymer supported) (516 mg, 1.50 mmol) were combined in THF (10 ml) under a blanket of argon.
  • 1 -(3 -chloro-4-fluoro-phenylamino)-7-methoxy-5-oxa-2,4, 11 -triaza- dibenzo[a,d]cyclohepten-8-ol 62b was prepared as follows: 6-Chloro-N 4 -(3-chloro-4-fluoro-phenyl)-pyrimidine-4,5-diamine 62d (0.86 g, 3.15 mmol), 2,5-dihydroxy-4-methoxy-benzaldehyde 73b (0.53 g, 3.15 mmol), MgSO 4 (0.76 g, 6.3 mmol), and DMF (6 ml) were combined in a oven-dried sealed tube and stined for 2 hours at 65°C.
  • reaction temperature was increased to 95°C for 2 hours and then reduced to room temperature for 16 hours. Afterwards, the mixture was treated with water followed by NH 3 (2 M in MeOH, 3 ml) with stirring. After 15 minutes lapsed, the resulting solids were collected by filtration and washed with Et 2 O (0.99 g, 81.77%).
  • Example 74 Compound 74 Preparation of (3-Chloro-4-fluoro-phenyl)-[7-methoxy-8-(2-mo ⁇ holin-4-yl-ethoxy)- 10,ll-dihydro-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 76 Compound 76
  • the imine intermediate 77a (40 mg, 0.1 mmol) dissolved in EtOH/THF (1 : 1, 10 ml) was treated with NaBH 4 (11 mg, 0.3 mmol) at room temperature. The mixture was stined at 65°C for 3 hours. Upon completion, the mixture was cooled to room temperature and HCI (3.5 eq., 4.0 M solution in dioxane) was added. The organics were removed in vacuo and the resulting solids isolated by filtration. The product 77 was washed with H 2 O (2 ml), EtOAc (2 ml), and Et 2 O (5 ml) to yield an off-white solid (30 mg, 64%).
  • Example 78 Compound 78
  • the starting material, l-(3-Bromo-phenylamino)-7-methoxy-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclohepten-8-ol 79a was prepared in the following manner: l-(3-Bromo-phenylamino)-5-oxa-2,4,ll-triaza-dibenzo[a,d]cycloheptene-7,8-diol 79b (4.78 g, 12.0 mmol) was dissolved in dry DMF (60 ml) under argon. The temperature was reduced to -5°C with a salt ice bath.
  • N -(3-Bromo-phenyl)-6-chloro-pyrimidine-4,5-diamine 79c was prepared in following manner:
  • Example 80 Compound 80 (3-Bromo-phenyl)-[7-(2-dimethylamino-ethoxy)-10,l l-dihydro-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cyclohepten-l-yl]-amine:
  • NaBH 4 (O.Olg, 0.22 mmol) was added to a solution of the 3-Bromo-phenyl)-[7-(2- dimethylamino-ethoxy)-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 80a (0.07 g, 147 mmol) in THF (0.5 ml) and EtOH (0.5 ml). The mixture was stined at 65 °C temperature overnight. Afterwards, the solvent was evaporated and water (10 ml) added. The resulting suspension was stined for 10 minutes.
  • the starting material, l-(3-Bromo-phenylamino)-5-oxa-2,4,l l-triaza- dibenzo[a,d]cyclohepten-7-ol 80b was prepared by combining 2,4- dihydroxybenzaldehyde (1.38 g, 0.01 mol) and N4-(3-Bromo-phenyl)-6-chloro- pyrimidine-4,5-diamine (3.0 g, 0.01 mol) in DMF (3.0 ml) under a blanket of argon and heating at 110° C for 1 hour.
  • Example 81 Compound 81 Preparation of (3-Bromophenyl)-[7-(3-mo ⁇ holin-4-yl-propoxy)-10,l l-dihydro-5-oxa- 2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 84 Compound 84
  • NaBH 4 (0.02 g, 0.59 mmol) was added to a solution of the (3-Bromo-phenyl)-[8-(3- mo ⁇ holin-4-yl-propoxy)-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten- 1 -yl]-amine 84a (0.2 g, 0.39 mmol) in THF/EtOH (3:2, 5 ml). The mixture was stined at 65 °C temperature 1 hour. Afterwards, the solvent was evaporated and water (5 ml) added. The resulting suspension was stined for 10 minutes before adjusting pH to 2 with 5% HCI and then to pH 9 with saturated NaHCO 3 (aq.).
  • the starting material, l-(3-Bromo-phenylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclohepten-8-ol 84b was prepared by combining N4-(3-Bromo-phenyl)-6- chloro-pyrimidine-4,5-diamine 79c (2.9g, 9.80 mmol) and 2,5-dihydroxybenzaldehyde (1.35 g, 9.80 mmol) in DMF (5 ml) under a blanket of argon and stirring at 100°C for 3 hours. After cooling the mixture to room temperature, water ( ⁇ 60 ml) was added, and the resulting precipitate filtered.
  • [a,d]cycloheptene-7,9-diol 87a was prepared as follows: N ⁇ -(3-Bromo-phenyl)-6-chloro-pyrimidine-4,5-diamine 79c (1.3 g, 0.0043 mol) and
  • Example 88 Compound 88 Preparation of [7,8-Bis-(2-methoxy-ethoxy)-10,l l-dihydro-5-oxa-2,4,l 1 -triaza- dibenzo [a,d] -cyclohepten- 1 -yl] -(3 -bromo-phenyl)-amine dihydrochloride :
  • the starting material, (3-bromo-phenyl)-[7-ethoxy-8-(3-mo ⁇ holin-4-yl-propoxy)-5-oxa- 2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 91b was prepared in the following manner: A suspension of mo ⁇ holino propyl chloride (977 mg, 6.0 mmol), Nal (30 mg, 0.2 mmol), l-(3-Bromo-phenylamino)-7-ethoxy-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten-8-ol 91c (1.7 g, 4.0 mmol), and K 2 CO 3 (1.66 g, 12.0 mmol) in anhydrous DMF (20 ml) was prepared.
  • the starting material, l-(3-bromo-phenylamino)-7-ethoxy-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclohepten-8-ol 91c was obtain the following manner: To a stirring solution of (3-Bromo-phenyl)-[8-(tert-butyl-dimethyl-silanyloxy)-7-ethoxy- 5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 91d (2.1g, 3.9 mmol) in anhydrous THF (15 ml), was added TBAF (7.8 ml, IM solution in THF) at room , temperature while stirring under an argon atmosphere.
  • the starting material, (3-bromo-phenyl)-[8-(tert-butyl-dimethyl-silanyloxy)-7-ethoxy-5- oxa-2,4, 11 -triaza-dibenzo [a,d] cyclohepten- 1 -yl] -amine 91 d was obtained as follows : 1 -(3-Bromo-phenylamino)-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cycloheptene-7,8-diol 79b (4.5 g, 11.3 mmol) was dissolved in anhydrous DMF (50 ml) under an argon atmosphere.
  • the resultant salt was freebased by suspending in saturated aqueous NaHCO 3 (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with saturated aqueous NaHCO 3 (100 ml) followed by brine (100 ml), dried over MgSO 4 , and evaporated. The resulting crude product was purified by column chromatography (5 % MeOH/ DCM) to yield an off white solid (20 mg, 6%).
  • the starting material, (3-bromo-phenyl)-[7-isopropoxy-8-(3-mo ⁇ holin-4-yl-propoxy)-5- oxa-2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 93a was prepared in the following manner: A suspension of mo ⁇ holinopropyl chloride (1.3 g, 7.7 mmol), Nal (1.3 g, 8.6 mmol), 1 -(3-bromo-phenylamino)-7-isopropoxy-5-oxa-2,4, 11 -triaza- dibenzo[a,d]cyclohepten-8-ol 93b (1.7 g, 3.9 mmol), and K 2 CO 3 (1.6 g, 11.7 mmol) in anh.
  • the starting material, (3-bromo-phenyl)-[8-(tert-butyl-dimethyl-silanyloxy)-7- isopropoxy-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 93c was obtained as follows: To a solution of 1 -(3 -bromo-phenylamino)-5 -oxa-2,4, 11 -triaza-dibenzo [a,d]cyclo- he ⁇ tene-7,8-diol 79b (4.5 g, 11.3 mmol) dissolved in anhydrous DMF (50 ml) under argon atmosphere, NaH (496 mg, 12.4 mmol, 60% dispersion in oil) was added. After one hour, isopropyl iodide (1.24 ml, 12.4 mmol) was added and reaction heated at 65°C.
  • Example 96 Compound 96
  • HOOCCHCHCOOH (3-Bromo-phenyl)-[7-methoxy-8-(l-methyl-pynolidin-3-yloxy)-10,ll-dihydro-5-oxa- 2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 97 (0.1 mmol. 50 mg) was dissolved in ethanol (3 ml). Fumaric acid (0.1 mmol, 11.6 mg) was added with stirring at RT. After 1 hour, the solvent was removed under vacuum and the residue was triturated in ether (10 ml), filtered, and washed with EtOAc (10 ml).
  • the starting material, l-(3-Ethynyl-phenylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclohepten-7-ol 98b was prepared by combining 6-chloro-N -(3-ethynyl- phenyl)-pyrimidine-4,5-diamine 98c (0.30 g, 1.23 mmol) and 2,4-dihydroxybenzaldehyde
  • Mo ⁇ holinopropyl chloride (1.23 g, 0.0075 mol) was added to a stirring suspension of l-(3-ethynyl-phenylamino)-7-methoxy-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cyclohepten-8-ol (0.896 g, 0.0025 mol), K 2 CO 3 (1.38 g, 0.01 mol), and Nal (1.12 g, 0.0075) in dry DMF (20 ml) under a blanket of argon at RT. After stirring at 100°C for 15 hours, the mixture was cool to RT, filtered, and filtrate concentrated in vacuo.
  • the starting material, l-(3-ethynyl-phenylamino)-7-methoxy-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclohepten-8-ol 102a was prepared in the following manner:
  • Example 103 Compound 103 Preparation of 3-[7-(2-Methoxy-ethoxy)-10,l l-dihydro-5-o ⁇ a-2,4,l l-triaza-dibenzo[a,d]- cyclohepten- 1 -ylamino] -benzonitrile :
  • Example 104 Compound 104 Preparation of 3-[8-Methoxy-7-(2-[l,2,3]triazol-l-yl-ethoxy)-10,l l-dihydro-5-oxa- 2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-ylamino]-benzonitrile:
  • Example 105 Compound 105
  • the starting material, 2,4-dihydroxy-5-methoxy-benzaldehyde 105b was prepared in the following manner (according to Demyttenaere, et al, Tetrahedron, 58, 2163-2166 (2002): To a suspension of aluminum trichloride (21.2 g) in dichloromethane (100 ml), was added a solution of 2,4,5-trimethoxy-benzaldehyde (8.01 g, 40.9 mmol) in dichloromethane (40 ml) drop wise with stirring at ambient temperature. After it was stined for 2 hrs, another portion of aluminum trichloride (20.7 g) suspension in dichloromethane (110 ml) was added slowly and stirring continued over the weekend.
  • Example 106 Compound 106
  • Example 108 Compound 108
  • Example 111 Compound 111
  • Example 113 Compound 113 Preparation of 3-[7-Methoxy-8-(2-[l,2,3]triazol-l-yl-ethoxy)-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cyclohepten-l-ylamino]-benzonitrile:
  • Example 114 Compound 114 Preparation of 3-(8-Hydroxy-7-methoxy-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l- ylamino)-benzonitrile:
  • Example 115 Compound 115 Preparation of 3-[7-Methoxy-8-(l -methyl-piperidin-4-yloxy)- 10, 11 -dihydro-5-oxa- 2,4, 11 -triaza-dibenzo[a,d]cyclohepten-l -ylamino] -benzonitrile:
  • Example 112 Following the same procedure used for the synthesis of Example 112, the product 115 was obtained by reaction of 3-[7-methoxy-8-(l-methyl-piperidin-4-yloxy)-5-oxa-2,4,l 1- triaza-dibenzo[a,d]cyclohepten-l-ylamino]-benzonitrile 115a with sodium borohydride (0.036 g, 52.4%).
  • Trifluoroacetic acid (1 ml) was added to a solution of 4-[l-(4-bromo-2-fluoro- phenylamino)-8-methoxy-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-7-yloxymethyl]- piperidine-1 -carboxylic acid tert-butyl ester 120a (100 mg, 0.19 mmol) in dichloromethane (5 ml). After the solution was stined for 1 hour at room temperature, the volatiles were removed under vacuum. The residue was triturated with a mixture of water and dichloromethane. The organic layer was separated, and the aqueous layer was washed again with dichloromethane.
  • methyl iodide (76 mg, 0.54 mmol, 1.5 equiv.) was added and the reaction was allowed to warm up to room temperature. Stirring continued for 5 hours until no more starting material was observed by TLC (30 % ethyl acetate/hexane). The solvent was removed using high vacuum and the residue was purified by column chromatography using 3% methanol/dichloromethane mixture as an eluent. The product showed some instability on silica gel column. The desired product 120a (100 mg, 44%) was obtained as a yellow solid.
  • the starting material, l-(4-Bromo-2-fluoro-phenylamino)-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cycloheptene-7,8-diol 120c was prepared in the following manner: A solution that contained N -(4-Bromo-2-fluoro-phenyl)-6-chloro-pyrimidine-
  • 4,5-diamine 120d (1.10 g, 3.86 mmol, 1 equiv.) and 2,4,5-trihydroxybenzaldehyde (536 mg, 3.48 mmol, 1 equiv.) in anhydrous ⁇ , ⁇ -dimethylformamide (3 ml) was stined for 1 hour under argon atmosphere at 100°C. The mixture formed a solid that was rinsed with methanol to afford 960 mg (60%) of desired product 115c as a bright yellow solid. 1H
  • N ⁇ -(4-Bromo-2-fluoro-phenyl)-6-chloro-pyrimidine-4,5-diamine 120d was prepared in the following manner:
  • Example 121 Compound 121
  • Example 123 Compound 123
  • Example 125 Compound 125
  • Example 126 Compound 126
  • Example 127 Compound 127
  • Example 128 Compound 128 Preparation of l-(3-Bromo-4-methyl-phenylamino)-7-methoxy-5-oxa-2,4,l 1 -triaza- dibenzo [a,d] cyclohepten-8-ol:
  • N4-(3-Bromo-4-memyl-phenyl)-6-chloro-pyrimidine-4,5-diamine 128a was prepared in the following manner: To a 200 ml round bottom flask, were placed 3-bromo-4-methyl-phenylamine (3.7 g, 19.9 mmol), 4,6-dichloro- ⁇ yrimidin-5-ylamine (3.26 g, 20 mmol), EtOH (10 ml), water (50 ml), cone. HCI (1.0 ml). The mixture was stined at 100°C overnight and then was cooled to ambient temperature.
  • Example 129 Compound 129
  • Example 130 Compound 130 Preparation of (4-Bromo-3-methyl-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)- 10,ll-dihydro-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 135 Compound 135 3-(8-Hydroxy-7-methoxy- 10, 11 -dihydro-5 -oxa-2,4, 11 -triaza-dibenzo [a,d] cyclohepten- 1 - ylamino)-benzonitrile:
  • Example 136 Compound 136 Preparation of (3-Chloro-2-fluoro-phenyl)-[7-methoxy-8-(tetrahydro-furan-3-yloxy)- 10,ll-dihydro-5-oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 138 Compound 138
  • 5-Ammo-4,6-dichloropyrimidine (4.0 g, 24.6 mmol) was added to a solution containing water (60 ml), ethanol (10 ml), concentrated hydrochloric acid (1 ml), and 2-fluoro-3- chloroaniline (3.2 g, 22.1 mmol).
  • the solution was refluxed overnight at 100°C, cooled down, and filtered.
  • the material was washed with water and diethyl ether and further stined with a solution of EtOAc and saturated NaHCO 3 (1:1, 200 ml) for 1 hour.
  • Example 139 Compound 139 Preparation of (4-bromo-2-fluoro-phenyl)-[8-(4-ethyl-piperazin-l -ylmethyl)-l 0, 11- dihydro-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten-l -yl]-amine:
  • N-(4-Bromo-2-fluoro-phenyl)-6-chloro-pyrim (1 mmol, 0.316 g) and 4- hydroxy-benzene-l,3-dicarboxaldehyde (1 mmol, 0.150 g) were stined in DMF (5 ml) for 20 h at 110°C. Then, the reaction was cooled down to RT and ether was added. The resultant solid was filtered and washed with ether (2x10 ml). The organic layer was diluted with water resulting in the formation of additional solid which was filtered and washed with methanol and ether, respectively, to leave the product 139b as a red-solid (0.214 g, yield: 52%).
  • Example 141 Compound 141
  • Example 145 Compound 145 Preparation of (4-Bromo-2-fluoro-phenyl)- ⁇ 8-methoxy-7-[2-(4-methyl-piperazin-l-yl)- ethoxy]-10,l 1 -dihydro-5 -oxa-2,4, 1 l-triaza-dibenzo[a,d]cyclohepten-l-yl ⁇ -amine:
  • the starting material, l-(2-fluoro-3-chloro-phenylamino)-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cycloheptene-7,8-diol 148a was prepared as follows: 2,4,5-trihydroxybenzaldehyde (5.36 g, 34.8 mmol) was added to a solution of 6-chloro- N4-(3-chloro-2-fluoro-phenyl)-pyrimidine-4,5-diamine 148b (9.5 g, 34.8 mmol) in DMF (15 ml) under an argon atmosphere and heated at 100°C for 3 hours.
  • 6-chloro-N 4 -(3-chloro-2-fluoro-phenyl)-pyrimidine-4,5 -diamine ' 148b was prepared in the following manner: 5-Amino-4,6-dichloropyrimidine (4.0 g, 24.6 mmol) was added to a solution containing water (60 ml), ethanol (10 ml), concentrated hydrochloric acid (1 ml), and 2- fluoro-3-chloroaniline (3.2 g, 22.1 mmol) and heated at 100°C for 16 hours. After cooling the reaction to room temperature, the resultant solids were collected by filtration.
  • Example 150 Compound 150 Preparation of (3-Bromo-4-fluoro-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)-5- oxa-2,4, 11 -triaza-dibenzo [a,d] cyclohepten- 1 -yl] -amine :
  • the starting material, l-(3-bromo-4-fluoro-phenylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]cyclo-heptene-7,8-diol 150a was prepared in analogous manner as described in the preparation of 148a by the reaction of N 4 -(3-bromo-4-fluoro-phenyl)-6-chloro- pyrimidine-4,5-diamine 150b and 2,4,5-trihydroxybenzaldehyde.
  • Example 151 Compound 151
  • the starting material, (3,4-difluoro-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)-5- oxa-2,4,ll-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine 151a was prepared using an analogous procedure described in Example 148 by reacting l-(3,4-difluoro- phenylamino)-5-oxa-2,4,l l-triaza-dibenzo[a,d]cycloheptene-7,8-diol 151b with the appropriate reagents.
  • the starting material, l-(3,4-difluoro-phenylamino)-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cycloheptene-7,8-diol 151b was prepared in analogous manner described in the preparation of 148a with the reaction of 6-chloro-N 4 -(3,4-difluoro-phenyl)- pyrimidine-4,5-diamine 151c and 2,4,5-trihydroxybenzaldehyde.
  • Example 152 Compound 152
  • the title compound 152b was prepared in analogous manner described in the preparation of 148a with the reaction of N 4 -(4-bromophenyl)-6-chloro-pyrimidine-4,5- diamine 152c and 2,4,5-trihydroxybenzaldehyde.
  • 1 HNMR 300 MHz, DMSO
  • Example 153 Compound 153 (4-Bromo-phenyl)-(7,8-dimethoxy-10,l l-dihydro-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cyclohepten-l -yl)-amine:
  • Example 154 Compound 154
  • the title compound 155b was prepared in analogous manner described in the preparation of 148a with the reaction of 6-chloro-Nr-(4-fluoro-phenyl)-pyrimidine-4,5-diamine 155c and 2,4,5-trihydroxybenzaldehyde.
  • 1 HNMR 300 MHz, DMSO
  • Example 156 Compound 156
  • the starting material, l-(3-trifluoromethyl-phenylamino)-10,ll-dihydro-5-oxa-2,4,ll- triaza-dibenzo[a,d]cyclo-heptene-7,8-diol 156b was prepared in analogous manner described in the preparation of Example 148a with the reaction of 6-chloro-N4-(3- trifluoromethylphenyl)-pyrimidine-4,5-diamine 156c and 2,4,5-trihydroxybenzaldehyde. The product was used directly in subsequent reaction step.
  • the starting material, l-(3-chloro-phenylamino)-7-methoxy-5-oxa-2,4,l 1-triaza- dibenzo[a,d]cyclohepten-8-ol 157b was prepared as follows: l-(3-Chloro-phenylamino)-5-oxa-2,4,ll-triaza-dibenzo[a,d]cycloheptene-7,8-diol 157c (0.90 g, 0.0025 mol) dissolved in DMF (10 ml) under a blanket of argon was treated with NaH (0.10 g, 0.0025 mol, 60% oil dispersion) at 0°C.
  • the starting material, l-(3-Chloro-phenylamino)-5-oxa-2,4,ll-triaza- dibenzo[a,d]cycloheptene-7,8-diol 157c was prepared as follows: 6-Chloro-N4-(3-chloro-phenyl)-pyrimidine-4,5-diamine (1.8 g, 0.0071 mol) and 2,4,5- trihydroxybenzaldehyde (1.09 g, 0.0071 mol) were added to DMF (3.0 ml) heated to 110°C under argon atmosphere. After stirring for 2 hours, the reaction was cooled to RT and the resultant precipitate collected by filtration. Subsequently, the crude material was washed with MeOH to leave the desired product 157c (0.904 g) sufficiently pure for the next reaction step. MS m/z: 355 (M+l).
  • Example 158 Compound 158 Preparation of (4-Chloro-2-fluoro-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)- 10,l l-dihydro-5-o ⁇ a-2,4,l l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine:
  • Example 159 Compound 159
  • the title compound 161 was isolated as side-product during the purification of the imine precursor in the synthesis of (2-chloro-4-fluoro- ⁇ henyl)-[7-methoxy-8-(3- mo ⁇ holin-4-yl-propoxy)- 10, 11 -dihydro-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten-l - yl]-amine 159.
  • Example 164 Compound 164 (3 -Bromo-phenyl)- [7-methoxy-8 -(1 -methyl-piperidin-3 -ylmethoxy)- 10,11 -dihydro-5 - oxa-2,4, 11 -triaza-dibenzo [a,d] cyclohepten- 1 -yl] -amine :
  • Diisobutylalumium hydride (10 mmol, 10 ml, 1 M in THF) was dropwise added to a solution of (3-Bromo-phenyl)-[7-methoxy-8-(l -methyl-piperidin-3-ylmethoxy)-5-oxa- 2,4,1 l-triaza-dibenzo[a,d]cyclohepten-l-yl]-amine (0.5 mmol) in DME (8 ml) at 0°C. The mixture was stined at 0°C for 30 min then 1.5 h at RT.
  • Example 165 Compound 165
  • Example 166 Compound 166
  • Example 167 Compound 167 Preparation of (3-Chloro-4-methoxy-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)- 10, 11 -dihydro-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten- 1 -yl] -amine:
  • Example 168 Compound 168
  • Example 169 Compound 169 Preparation of (3-Chloro-2-methoxy-phenyl)-[7-methoxy-8-(3-mo ⁇ holin-4-yl-propoxy)- 10, 11 -dihydro-5-oxa-2,4, 11 -triaza-dibenzo[a,d]cyclohepten- 1 -yl] -amine: To an acetone (1.0 ml) solution of 169b ( 31 mg, 0.08 mmol) was added K 2 CO 3 (40 mg), Nal ( 10 mg) and 4-(3-chloro- ⁇ ropyl)-mo ⁇ holine (30 mg). The mixture was then stined at 60 °C overnight.

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Abstract

L'invention porte sur des composés qui inhibent, modulent ou régulent des kinases, des compositions qui contiennent des composés inhibant des kinases, et sur des procédés de traitement de maladies et de conditions qui dépendent de la kinase chez des sujets qui ont besoin d'un tel traitement. L'invention porte aussi sur des procédés de fabrication de ces composés qui inhibent, modulent ou régulent les kinases.
PCT/US2004/023662 2003-07-21 2004-07-21 Inhibiteurs de la tyrosine kinase egfr Ceased WO2005009384A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006089298A3 (fr) * 2005-02-18 2007-01-25 Attenuon Llc Derives de diazepine fusionnes pyrimidine et pteridines fusionnees indole
WO2010040527A1 (fr) * 2008-10-10 2010-04-15 Priaxon Ag Nouveaux composés qui modulent l'activité kinase
JP2010523619A (ja) * 2007-04-11 2010-07-15 ナームローゼ・フエンノートチヤツプ・オルガノン 鏡像異性的に純粋なベンゾアゼピンの調製方法
CN102690278A (zh) * 2011-03-21 2012-09-26 长春吉大天元化学技术股份有限公司 新颖嘧啶并环化合物作为细胞因子抑制剂
CN103509024A (zh) * 2012-06-28 2014-01-15 辰欣药业股份有限公司 嘧啶并苯并氮杂卓类化合物及其作为抗肿瘤药物的应用

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SU671271A1 (ru) * 1977-04-27 1982-10-07 Всесоюзный научно-исследовательский химико-фармацевтический институт им.Серго Орджоникидзе Производные пиримидо-[4,5- @ ] [1,4]-бензоксазепина и способ их получени

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006089298A3 (fr) * 2005-02-18 2007-01-25 Attenuon Llc Derives de diazepine fusionnes pyrimidine et pteridines fusionnees indole
JP2010523619A (ja) * 2007-04-11 2010-07-15 ナームローゼ・フエンノートチヤツプ・オルガノン 鏡像異性的に純粋なベンゾアゼピンの調製方法
WO2010040527A1 (fr) * 2008-10-10 2010-04-15 Priaxon Ag Nouveaux composés qui modulent l'activité kinase
CN102690278A (zh) * 2011-03-21 2012-09-26 长春吉大天元化学技术股份有限公司 新颖嘧啶并环化合物作为细胞因子抑制剂
CN102690278B (zh) * 2011-03-21 2015-07-15 长春吉大天元化学技术股份有限公司 新颖嘧啶并环化合物作为细胞因子抑制剂
CN103509024A (zh) * 2012-06-28 2014-01-15 辰欣药业股份有限公司 嘧啶并苯并氮杂卓类化合物及其作为抗肿瘤药物的应用
CN103509024B (zh) * 2012-06-28 2015-10-28 上海医药工业研究院 嘧啶并苯并氮杂卓类化合物及其作为抗肿瘤药物的应用

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