• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    COMPOUND AS C-MET KINASE INHIBITORS AND THEIR USES. The present invention concerns compounds, processes for their preparation, pharmaceutical compositions containing them as active ingredient, method for the treatment of pathological conditions associated with the inhibition of protein tyrosine kinase activity of growth factor receptors such as, by eg c-Met, thus making them useful as anticancer agents, for their use as medicines for use in the production of inhibiting tyrosine kinases, reducing the effects in warm blooded animals such as humans .
    公开号:BR112013005523B1
    申请号:R112013005523-5
    申请日:2011-09-09
    公开日:2021-06-08
    发明作者:Paul Chen Guoqing
    申请人:Advenchen Laboratories, Llc；
    IPC主号:
    专利说明:

    [001] This patent application claims the benefit of US Provisional Patent Application Number 61/381995 filed September 12, 2010. FIELD OF THE INVENTION
    [002] The present invention deals with compounds, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of pathological conditions associated with the inhibition of protein tyrosine kinase activity of growth factor receptors , such as, for example, c-Met, thus making them useful as anticancer agents, for their use as medicines for use in the production of inhibition of tyrosine kinases, reducing the effects in warm-blooded animals, as, for example, human beings. FUNDAMENTALS OF THE INVENTION:
    [003] Receptor tyrosine kinases are large enzymes that cross the cell membrane and have an extracellular binding domain for growth factors, a transmembrane domain and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and, therefore, influence cell proliferation. Tyrosine kinases can be classified as growth factor receptors (eg EGFR, PDGFR, FGFR and erbB2) or non-receptor kinases (eg c-src and bcr-abl). Such kinases may be aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon cancer, rectal cancer or stomach cancer, leukemia, ovarian cancer, breast cancer. bronchi or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, gastric cancer, and colon cancer.
    [004] The kinase, c-Met, is the prototype element of a subfamily of heterodimeric receptor tyrosine kinases (RTKs), which include Met, Ron and Sea. The antiproliferative and antiangiogenic activity of c-Met makes an attractive target. The endogenous ligand for c-Met is hepatocyte growth factor (HGF), also known as healing factor (SF), due to its ability to interrupt colony formation in vitro. HGF is a derivative cytokine known to induce receptor activation through autophosphorylation, resulting in increased receptor-dependent signaling in normal and neoplastic cells (Sonnenberg et al., J. Cell Biol 123:223-235, 1993 ; Matsumato et al., Crit. Rev. Oncog 3:27-54,1992; and Stoker et al., Nature 327:239-242, 1987). Anti-HGF antibodies or HGF antagonists also demonstrated inhibition of tumor metastasis.
    [005] Normal angiogenesis plays an important role in a variety of processes, including embryonic development, wound healing, and various components of female reproductive function. Unwanted or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability is mainly regulated by vascular endothelial growth factor (VEGF) (tumor-derived), which acts through at least two different receptors: VEGF-R1 (Flt-1) and VEGF-R2 (KDR, Flk-1). The VEGF KDR receptor is highly specific for vascular endothelial cells (Endocr. Rev. 1992, 13, 18; FASEB J. 1999, 13, 9).
    [006] The present invention is based on the discovery of compounds that surprisingly inhibit the effects of c-Met and VEGF, as well as other signal transduction of kinases, a property of value in the treatment of disease states associated with cell proliferation, angiogenesis and/ or other signal transduction pathways, such as, for example, cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scarring and adhesions , lymphoedema, endometriosis, dysfunctional uterine bleeding and eye diseases with retinal vessel proliferation.
    [007] It has now been found that the compounds of Formula I described below are a new class of compounds that have advantageous pharmacological properties and inhibit the activity of protein tyrosine kinases such as, for example, c-Met, VEGFr, EGFr, c- kit, PDGF, FGF, SRC, Ron, Tie2, etc. They can also be irreversible inhibitors of protein tyrosine kinases.
    [008] Examples of compounds that are similar in structure to the compounds of the present invention are described in the following literatures: WO2005117867, WO2006108059, WO2007035428, WO2007054831, WO2008041053, WO2008112408 and WO2010045095. SUMMARY OF THE INVENTION
    [009] The present invention relates to the compounds of Formula I:

    [010] Where: - X and Y are independently selected from O, S; - W and Z are independently selected from O, S, NR or CH-R; - G is selected from CR, C-(CN) or N ;- R is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, amino, alkylamino, alkoxyamino, cycloalkyl, cycloalkenyl, aryl, lower alkylaryl, heterocyclyl or alkyl- lower heterocyclyl; - R1, R2, R3 and R8 are independently selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl or lower alkynyl; - R4 and R5 are independently selected from H, halogen, halogenated lower alkyl, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, aryl, lower alkylaryl, heterocyclic lila, lower alkyl-heterocyclyl, lower alkyl-OC(=O)-, aryl-OC(=O)-, lower alkylaryl-OC(=O)-, heterocyclyl-OC(=O)-, lower alkyl-heterocyclyl- OC(=O)-,lower alkylenylaryl-OC(=O)-, lower alkyl-C(=O)-, aryl-C(=O)-,lower alkylenylaryl-C(=O)-, lower alkyl-SO2 -, aryl-SO2-, lower alkylenylaryl-SO2-, lower alkyl-N(R)C(=O)-, aryl-N(R)C(=O)-, or lower alkylenylaryl-N(R)C( =O)-; R4 and R5 connect to each other to form a 38-element saturated or unsaturated ring, with its nitrogen attached; - R6, R7 and R9 are selected from H, halogenated lower alkyl and lower alkyl; - R10 is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxy, lower alkenyl, lower alkynyl, amino, alkylamino, alkoxyamino, cycloalkyl, cycloalkenyl, aryl, lower alkylaryl, heterocyclyl or lower alkyl-heterocyclyl; - a and c are independently selected from 0, 1, 2, 3 or 4; - b and b are independently selected from 1, 2, 3, 4 or 5; - the Q ring is a monocyclic, bicyclic or tricyclic moiety of 5-13 elements, wherein said moiety may be saturated or unsaturated, aromatic or non-aromatic and may optionally contain 1-3 heteroatoms independently selected from O, N and S;- or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION
    [011] It is the present invention of new compounds that can inhibit protein tyrosine kinase, such as, for example, c-Met and VEGF, and the use of these compounds for the inhibition of c-Met or angiogenesis in the treatment of angiogenic diseases or chronic inflammatory or neoplastic or proliferative ones that are caused by excessive or inappropriate angiogenesis in a mammal in need thereof.
    [012] In the compounds of Formula (I):- X and Y are independently selected from O, S; preferably, X and Y are O;- W and Z are independently selected from O, S, N-R or CH-R; preferably, W and Z are selected from O or N-R; - G is selected from CR, -C(CN) or N; preferably, they are chosen from CR or N; - R is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, amino, alkylamino, alkoxyamino, cycloalkyl, cycloalkenyl, aryl, lower alkylaryl, heterocyclyl or lower alkylheterocyclyl; are preferably selected from H, halogen, halogenated lower alkyl or lower alkyl;- R1, R2, R3 and R8 are independently selected from H, halogen, halogen lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl or alkynyl bottom; preferably they are selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy; - R4 and R5 are independently selected from H, halogen, halogenated lower alkyl, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, aryl, lower alkylaryl, heterocyclyl, lower alkyl-heterocyclyl, lower alkyl-OC(=O)-, aryl-OC(=O)-, lower alkylaryl- OC(=O)-, heterocyclyl-OC(=O)-, lower alkyl heterocyclyl-OC(=O)-, lower alkylenylaryl-OC(=O)-, lower alkyl-C(=O)-, aryl- C(=O)-, lower alkylenylaryl-C(=O)-, lower alkyl-SO2-, ari-SO2-, lower alkylenylaryl-SO2-, lower alkyl-N(R)C(=O)-, aryl- N(R)C(=O)-, or lower alkylenylaryl-N(R)C(=O)-; preferably selected from H, halogenated lower alkyl, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy, lower alkyl-OC(=O)-, aryl-OC(=O)-, lower alkylaryl-OC(=O) -, heterocyclyl-OC(=O)-, lower alkylheterocyclyl-OC(=O)-, lower alkylenylaryl-OC(=O)-; R4 and R5 connect together to form a ring of 3-8 saturated or unsaturated elements, with their nitrogen attached; preferably, R4 and R5 are connected together to form a cycloalkyl or heterocyclyl group;- R6, R7 and R9 are selected from H, halogenated lower alkyl and lower alkyl; preferably, H1 -R10 is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxy, lower alkenyl, lower alkynyl, amino, alkylamino, alkoxyamino, cycloalkyl, cycloalkenyl, aryl, lower alkylaryl, heterocyclyl or lower alkyl heterocyclyl; preferably it is an aryl and preferably is selected from phenyl, substituted phenyl or heterocyclyl; a and c are independently selected from 0, 1, 2, 3 or 4; preferably, are selected from 0, 1 or 2;- b and d are independently selected from 1, 2, 3, 4 or 5; preferably, they are chosen from 1, 2 or 3;
    [013] The Q ring is a monocyclic, bicyclic or tricyclic portion of 5-13 elements, said portion may be saturated or unsaturated, aromatic or non-aromatic and may optionally contain 1-3 heteroatoms independently selected from O, N and S; preferably, ring Q is aryl and preferably is selected from a phenyl or a substituted phenyl; or the Q ring is a 5-6 element heteroaromatic moiety containing 1-3 heteroatoms independently selected from O, N and S; preferably it is a pyridine; or a pharmaceutically acceptable salt thereof.
    [014] The term "halogen", as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, such as, for example, fluorine and chlorine.
    [015] The term "halogenated lower alkyl", as used herein, unless otherwise indicated, includes 1-6-alkyl substituted by halogen, such as, for example, trifluoromethyl.
    [016] The term "lower alkyl", as used herein, unless otherwise indicated, includes 1-6 monovalent saturated hydrocarbon radicals having straight or branched moieties, including but not limited to methyl, ethyl, n-propyl , iso-propyl, n-butyl, sec-butyl, tert-butyl and the like.
    [017] The term "lower alkenyl", as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon double bond, such as, for example, -CH2-CH= CH2.
    [018] The term "lower alkynyl", as used herein, unless otherwise indicated, includes lower alkyl groups as defined above having at least one carbon-carbon triple bond, such as, for example, -CH2- ^ = CH.
    [019] The term "lower alkoxy", as used herein, unless otherwise indicated, includes -O-lower alkyl groups, lower alkyl being as defined above, such as, for example, methoxy and ethoxy.
    [020] The term "lower alkoxyalkoxy", as used herein, unless otherwise indicated, includes -O-lower alkyl-O-lower alkyl groups, the lower alkyl being as defined above, such as, for example, - OCH2CH2OCH3.
    [021] The term "lower alkylenyl", as used herein, unless otherwise indicated, includes 1-6 saturated radicals -CH2-.
    [022] The term "amino", as used herein, unless otherwise indicated, includes -NH2 group, -NH- lower alkyl group or -N(lower alkyl)2 group, with lower alkyl as defined above , such as, for example, methylamino and dimethylamino.
    [023] The term "alkyamino", as used herein, unless otherwise indicated, includes lower alkyl group-NH2, lower alkyl group-NH-lower alkyl or lower alkyl group-N(lower alkyl)2, wherein alkyl lower is as defined above, such as -CH2CH2NHCH3.
    [024] The term "alkoxyamino", as used herein, unless otherwise indicated, includes -O-lower alkyl-NH2 group, -O-lower alkyl-NH-lower alkyl group or -O-lower alkyl-N group (lower alkyl)2 wherein lower alkyl is as defined above, such as, for example, -OCH2CH2NHCH3.
    [025] The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as, for example, phenyl or naphthyl, preferably phenyl, and is unsubstituted or substituted by one or two substituents selected from halogen, halogenated lower alkyl, lower alkenyl, lower alkyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxy, carboxyalkyl, amino, carbamoyl, carbamate, ureido, mercapto , sulfo, lower alkylsulfinyl, lower alkanesulfonyl, sulfonamide; aryl includes an aromatic ring fused to an aliphatic ring, such as, for example, a saturated or partially saturated ring, such as, for example, tetrahydronaphthyl.
    [026] The term "heterocyclic", as used herein, unless otherwise indicated, includes simple and fused non-aromatic saturated or partially saturated rings, suitably containing up to four heteroatoms in each ring, each independently selected from O , N and S, and said rings may be independently substituted or unsubstituted by, for example, up to three substituents. Each heterocyclic ring suitably has 4-7, preferably 5 or 6 ring atoms. A fused heterocyclic ring system can include carbocyclic rings and need only include one heterocyclic ring which can be saturated or partially saturated. Heterocyclyl includes monocyclic, bicyclic and tricyclic heteroaromatic ring systems comprising up to four, preferably 1 or 2 heteroatoms, each selected from O, N and S. Each ring may have from 4 to 7, preferably 5 or 6 atoms in the ring. A bicyclic or tricyclic ring system can include a carbocyclic ring. The carbocyclic ring includes a cycloalkyl, cycloalkenyl or aryl ring. Examples of heterocyclic groups include, but are not limited to: azetidine, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazol, indazol, trizol, benzotriazole, imidazole, benzoimdazole, thiophene, benzothiophene, thiozole, benzothiazole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine, pyrimidine, trizine, quinoline, isoquinoline, quinazoline, indoline, tetralinone, benzote hydroisoquinoline, methylene-dioxyphenyl. Heterocyclic and heterocyclyl rings may be optionally substituted and the substituents selected from the group defined above as substituents for aryl.
    [027] The term "cycloalkyl", as used herein, unless otherwise indicated, includes cyclic radicals having from three to eight ring carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups may optionally be substituted one or more times, the substituents being selected from the group defined above as substituents for aryl, preferably halogen, lower alkyl.
    [028] The term "cycloalkyl lower alkyl", as used herein, unless otherwise indicated, includes a cycloalkyl-lower alkyl group, with lower cycloalkyl and cycloalkyl being as defined above.
    [029] The term "cycloalkenyl", as used herein, unless otherwise indicated, includes cycloalkyl groups, as defined above, having at least one carbon-carbon double bond.
    [030] The term "lower alkylaryl", as used herein, unless otherwise indicated, includes an aryl-lower alkyl group, lower alkyl and aryl being as defined above.
    [031] The term "lower alkyl-heterocyclyl", as used herein, unless otherwise indicated, includes a heterocyclyl-lower alkyl group, heterocyclyl and lower alkyl being as defined above.
    [032] The term "lower alkylenylaryl", as used herein, unless otherwise indicated, includes an aryl-lower alkynyl group, wherein aryl and lower alkylenyl are as defined above.
    [033] Most tyrosine kinase inhibition activities in vitro can be tested with Millipore Ltd, in their kinase screening panel.
    [034] The compounds listed in the examples had the following inhibition activities for c-Met and some tumor cell lines.


    [035] Tests of antitumor activity in animals can be performed by various cancer xenograft models.
    [036] A compound of Formula I can be administered alone or in combination with one or more other therapeutic agents, including, but not limited to, 17α-ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, acetate Megestrol, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone Acetate, Leuprolide, Flutamide, Toremifene, Zoladex, Appropriate inhibitors of metalloproteinaceous matrix receptors, EGFR , Erlotinib and Cetuximab. Pan-HER inhibitors include canertinib, EKB-569 and GW-572016. VEGF inhibitors such as, for example, Avastin, ZD6474 and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632 and CEP-7055. Also included are Src inhibitors as well as Casodex™ (bicalutamide, Astra Zeneca), Tamoxifen, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 inhibitors and PDGF inhibitors such as, for example, imatinib. Also included are inhibitors of IGF1R, inhibitors of receptor and non-receptor tyrosine kinases, and inhibitors of integrin signaling. Also included are antiangiogenic and antivascular agents that, by interrupting the flow of blood to solid tumors, make cancer cells quiescent by deprivation of nutrition. Other cytotoxic agents include melphalan, hexamethylmelamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. Other anticancer agents include microtubule stabilizing agents such as, for example, paclitaxel, docetaxel, 09/712,352, filed November 14, 2000), C-4 paclitaxelmethylcarbonate, epothilone A, epothilone B, epothilone C, epothilone D, deoxyepothilone A , deoxyepothilone and microtubule disturbing agents. Also suitable are CDK inhibitors, an antiproliferative cell cycle inhibitor, epidophyllotoxin; an antineoplastic enzyme, a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers, growth inhibitors; anti-hormonal therapeutic agents; leucovorin; tegafur and hematopoietic growth factors. Castration, which also renders androgen-dependent carcinomas non-proliferative, can also be used. Possible combination therapy takes the form of fixed combinations, or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents .
    [037] A compound of Formula I may, furthermore, be administered especially for tumor therapy in combination with chemotherapy, radiation therapy, surgical intervention, or a combination thereof. Long-term therapy is also possible as it is an adjunct therapy in the context of other treatment strategies as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example, in patients at risk. A compound of Formula I is useful in the treatment of a variety of cancers, including, but not limited to: (a) carcinoma, including breast, bladder, colon, kidney, liver, lung, including small cell lung cancer, esophagus. , gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; (b) hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; (c) myeloid lineage hematopoietic tumors, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; (d) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas, and; (f) other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, follicular carcinoma and Kaposi's sarcoma.
    [038] A compound, according to the present invention, is not only for the care of humans, but also for the treatment of other warm-blooded animals, such as, for example, commercially useful animals. Such a compound can also be used as a reference standard in the test systems described above, to allow a comparison with other compounds.
    Salts are, especially, the pharmaceutically acceptable salts of the compounds of Formula I. Pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as, for example, acid addition salts formed with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and organic acids , for example, succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. Other salts may be used, for example, in isolating or purifying compounds of Formula (I) and are included within the scope of the present invention.
    [040] The compounds of the present invention may be in crystalline or non-crystalline form, and, if they are in crystalline form, they may optionally be hydrated or solvated. The present invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
    [041] The present invention extends to all isomeric forms, including stereoisomers and geometric isomers of the compounds of Formula (I), including enantiomers and mixtures thereof, such as, for example, racemates. The different isomeric forms can be separated or disaggregated from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
    Those skilled in the art will recognize various synthetic methodologies that can be used to prepare pharmaceutically acceptable non-toxic prodrugs from the compounds encompassed by General Formula I. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic solvents that can be used to prepare solvates of the compounds of the present invention, such as, for example, water, ethanol, mineral oil, vegetable oil and dimethylsulfoxide.
    [043] The compounds of general Formula I can be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable adjuvants and carriers. Oral administration in the form of a tablet, capsule, elixir, syrup, tablet, lozenge or the like is particularly preferred. The term "parenteral" as used herein includes injections via subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal, or similar injection or infusion techniques. Furthermore, a pharmaceutical formulation comprising a compound of the general Formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and, if desired, other active ingredients. Pharmaceutical compositions containing compounds of the general Formula I may be in a form suitable for oral use, such as, for example, in the form of tablets, lozenges, tablets, aqueous or oily suspensions, granules or dispersible powders, emulsions, soft or hard capsules, or syrups or elixirs.
    [044] Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, so as to provide pharmaceutically pleasing and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as, for example, corn starch, or alginic acid, binding agents, such as, for example, starch, gelatin or acacia, and lubricating agents, such as, for example, magnesium stearate, stearic acid or talc . The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and therefore provide a prolonged action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used.
    [045] Formulations for oral use can also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft capsules gelatine, the active ingredient being mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.
    [046] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents can be a naturally occurring phosphatide, such as, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as, for example, polyoxyethylene-sorbitol monooleate, or oxide condensation products. ethylene with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as, for example, sucrose or saccharin.
    [047] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set out above, and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant agent such as ascorbic acid.
    [048] Dispersible granules and powders suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, such as sweeteners, flavors and colorings, may also be present.
    [049] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water type emulsions. The oily phase can be a vegetable oil, such as, for example, olive oil or peanut oil, or a mineral oil, such as, for example, liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums such as, for example, acacia gum or gum tragacanth, naturally occurring phosphatides, such as, for example, soy, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, such as , for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents.
    [050] Syrups and elixirs can be formulated with sweetening agents, such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent agent, a preserving agent, a flavoring agent and a coloring agent.
    [051] The compounds can also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
    [052] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art, through the use of suitable dispersants or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, such as, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally employed as a suspending medium or solvent. For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
    [053] The compounds of the present invention may also be administered transdermally, through the use of methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp and others in International Patent Application WO 94/04157, filed March 3, 1994.).
    [054] The compounds of General Formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as, for example, local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
    [055] For administration to non-human animals, the composition can also be added to animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal ingests an appropriate amount of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to animal feed or drinking water.
    [056] For all regimens of use described herein for compounds of Formula I, the daily oral dosage regimen will preferably be between 0.01 and 200 mg/kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily dosage regimen via the vaginal route will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably range from 0.01 to 200 mg administered between one to four times a day. The transdermal concentration will preferably be that necessary to maintain a daily dose of 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
    [057] It should be noted, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, the diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs and the severity of the particular illness undergoing therapy.
    [058] Preferred compounds of the present invention will have certain pharmacological properties. These properties include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding, and desirable in vitro and in vivo half-lives. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes can be used to predict compound toxicity. Serum protein binding can be predicted using albumin binding assays. The half-life of the compound is inversely proportional to the frequency of dosing a compound. The in vitro half-lives of compounds can be predicted from microsomal half-life assays.
    [059] Representative examples of the preparation of the present invention are shown in Scheme I - Scheme II. Those skilled in the art will recognize that the starting materials can be varied and additional steps employed to produce compounds encompassed by the present invention.


    [060] The following examples of the general Formula II, but not limited thereto, can be similarly prepared according to the methods described in Scheme I - Scheme II. Formula II

    [061] Wherein:- W and Z are independently selected from O or NR; - G is selected from CR or N; - R is H; - R1, R2, R3 and R8 are independently selected from H, halogen, lower alkyl halogenated, lower alkyl, hydroxy, lower alkoxy; - R4 and R5 are independently selected from H, halogen, halogenated lower alkyl, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy, aryl, lower alkylaryl, heterocyclyl, lower alkyl heterocyclyl, t-butyl-OC(=O)-, benzyl-OC(=O)-, 4-methoxybenzyl-OC(=O)-;- R6, R7 and R9 are H;- R10 is selected from phenyl, substituted phenyl or heterocyclyl;- and b and are selected from 1, 2 or 3;- ring Q is selected from phenyl, substituted phenyl or pyridine;- or a pharmaceutically acceptable salt thereof.
    [062] The following examples of general Formula III, but not limited thereto, can be similarly prepared according to the methods described in Scheme I - Scheme II.Formula III

    [063] Wherein:- W is selected from O or NR; - G is selected from CR or N; - R is H; - R1 and R2 are independently selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy;- R4 and R5 are independently selected from H, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy, aryl, lower alkylaryl, heterocyclyl, lower alkylheterocyclyl, t-butyl-OC(=O)-, benzyl- OC(=O)-, 4-methoxybenzyl-OC(=O)-;- R10 is selected from phenyl, substituted phenyl or heterocyclyl;- or a pharmaceutically acceptable salt thereof.
    [064] The following examples of the general Formula IV, but not limited thereto, can be similarly prepared according to the methods described in Scheme I - Scheme II.

    [065] Wherein:- R1 is selected from 2-F or 3-F;- R5 is selected from H, halogenated lower alkyl, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, aryl, lower alkylaryl, heterocyclyl, lower alkylheterocyclyl , t-butyl-OC(=O)-, benzyl-OC(=O)-, 4-methoxybenzyl-OC(=O)-;- R10 is selected from phenyl, substituted phenyl or pyridine;- or a pharmaceutically acceptable salt of the same.
    [066] The following examples, but not limited thereto, can be similarly prepared according to the methods described in Scheme I - Scheme II.



    or a pharmaceutically acceptable salt thereof.
    [067] In some cases, protection of certain reactive functionality may be necessary to achieve some of the above transformations. In general, the need to have such protecting groups will be apparent to those skilled in the art of organic synthesis, as will the conditions necessary to link and remove such groups. Those skilled in the art will recognize that, in certain cases, it will be necessary to use different solvents or reagents to achieve some of the above transformations.
    [068] The descriptions made in this patent application of all articles and references, including patents, are hereby incorporated by reference in their entirety.
    [069] The present invention will also be illustrated by the examples below, which should not be interpreted as limiting the invention, both in terms of scope and scope of the specific procedures described in this report.
    [070] Different starting materials and intermediates can be obtained from commercial sources, prepared from commercially available organic compounds or prepared by using well-known synthetic methods.
    [071] Representative methods for preparing intermediates of the present invention are described below in the examples.
    [072] The following abbreviations have been used and others are standard representation of chemical formula: EtOH: ethanol; MeOH: methanol; RT: room temperature, DIPEA: diisopropylethylamine; DCM: dichloromethane; DMF: N,N-dimethylformamide; EtOAc: ethyl acetate; HOBt: 1-hydroxybenzotriazole hydrate; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; MsCl: methanesulfonyl chloride; eq: equivalent; g: grass; mg: milligram; ml: milliliter, Example 14-methoxybenzyl-1-((4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate
    [073] A mixture of methyl-1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)-cyclopropanecarboxylate (29.2 g, US12,036.244) and 2-fluoro-4-nitrophenol (20.5 mg) in pyridine (50 ml) was heated at 110°C for 4 hours and cooled. The reaction was evaporated, water (300 ml) was added and this was sonicated for a further 20 minutes. The solid was filtered and washed with water and then with acetone to obtain the product as methyl-1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (32g). This product (3.9 g) was mixed with LiOH (0.82 g) in THF/H 2 O (40 ml/20 ml), and the mixture was refluxed for 4 hours. The solution was evaporated and acidified with AcOH, the precipitate was filtered and washed with water and then with acetone to obtain the product in the form of 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin) acid -7-yloxy)-methyl)propanecarboxylic. This acid (1 g) was mixed with DIPEA (0.53 ml) in acetone (50 ml) and cooled to 0°C. To the reaction mixture isobutylchloroformate was slowly added and stirred for a further 1 hour at 0°C. To the reaction, NaN3 (1.52 g) in water (2 ml) was added and stirred for a further 2 hours at 0°C. EtOAc (100 ml) was added to the reaction mixture and washed with brine, dried over Na2SO4. The solution was evaporated to approximately 10 ml and toluene (70 ml) was added, followed by the addition of 4-methoxybenzyl alcohol. The solution was refluxed for 4 hours and cooled, EtOAc (50 ml) and water (50 ml) were added and then extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified on a silica gel column to obtain 4-methoxybenzyl-1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)-cyclopropylcarbamate (850 mg) which was mixed with Fe powder (1 g) and NH 4 Cl (100 mg) in EtOH/H 2 O (20 ml, 16 ml/4 ml). The solution was refluxed for two hours and filtered through Celite and washed with MeOH. The filtrate was evaporated and partitioned with water and DCM, the aqueous layer was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to obtain 4-methoxybenzyl-1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (650 mg) for the next step, without purification. additional.
    [074] To a mixture of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4.2 g) and 4-fluoroaniline (3.3 g) in DCM (40 ml) was added EDC (7.4 g) and HOBt (4 g ), the reaction mixture was stirred at room temperature for 4 hours and washed with 1N HCl, NaHCO3 solution, water, brine and dried with Na2SO4. The solution was evaporated and the residue was mixed with NaOH (3.2g) and MeOH/H2O (60ml/6ml). The mixture was refluxed for 30 minutes and then evaporated. The residue was acidified with 4N HCl and the precipitate was filtered. The filter cake was washed with water followed by cold EtOH to obtain the product as 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid (2.8 g). This product (1.8 g) was mixed with DCM (30 ml) and two drops of DMF. Oxalyl chloride (1.2 ml) was added to the solution and the reaction mixture was refluxed for one hour. The solvent was removed, followed by the addition of DCM (20 ml) and DIPEA (1.3 ml). To the above solution, 4-methoxy-benzyl-1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropylcarbamate (1.5 g) was added to the mixture. The reaction was stirred at room temperature for 4 hours. Saturated NaHCO3 (30 ml) and DCM (80 ml) were added to the reaction, the solution was also extracted twice with DCM. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified on a silica gel column to obtain 2.1 g of the title compound. Mass: (M+1), 739.Example 2N-(4-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane -1,1-dicarboxamide
    [075] The product from Example 1 (2.1 g) was mixed with 10% TFA/DCM (50 ml) and stirred at 0°C for 2 hours. Saturated NaHCO3 (80 ml) was added to the solution at 0°C and the solution was also extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to obtain the title compound for the next step without further purification. Mass: (M+1), 575Example 3N-(3-fluoro-4-(6-methoxy-7-((1-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)methoxy)quinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
    [076] The product from Example 2 (200 mg) was mixed with tetrahydro-4H-pyran-4-one (45 mg), NaHB (OAc)3 (96 mg) and HOAc (42 mg) in DCM (5 ml) . The reaction mixture was stirred at 30°C overnight. Saturated NaHCO3 (20 ml) was added to the reaction and the solution was also extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified by preparative TLC plate to obtain the title compound. Mass: (M+1), 659.Example 4N-(4-(7-((1-(cyclohexylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluoro-phenyl)-N-( 4-fluorophenyl)cyclopropane-1,1-dicarboxamide
    [077] The title compound was prepared by the similar method to Example 3, using cyclohexanone in place of tetrahydro-4H-pyran-4-one. Mass: (M+1), 657.Example 5N-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide
    [078] The title compound was prepared in the similar manner to Example 3, using cyclopropanecarbaldehyde in place of tetrahydro-4H-pyran-4-one. Mass: (M+1), 629.Example 6N-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluoro-phenyl)-N-( 4-fluorophenyl)cyclopropane-1,1-dicarboxamide
    [079] The title compound was prepared by the similar method to Example 3, using cyclopentanone in place of tetrahydro-4H-pyran-4-one. Mass: (M+1), 643.Example 74-methoxybenzyl-1-((4-(4-(1-(3,4-difluorophenylcarbamoyl) cyclopropanecarboxamido)-3-fluoro-phenoxy)-6-methoxyquinolin-7- yloxy)methyl)cyclopropylcarbamate
    [080] The title compound was prepared in the similar manner to Example 1, using 1-(3,4-difluorophenylcarbamoyl)cyclopropanecarboxylic acid in place of 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid. 3-Fluoro-4-nitrophenol was used in place of 2-fluoro-4-nitrophenol. Mass: (M+1), 757.Example 8N-(4-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(3,4-difluorophenyl )cyclopropane-1,1-dicarboxamide
    [081] The title compound was prepared by the similar method to Example 2, using the product of Example 7 instead of the product of Example 1. Mass: (M+1), 593.Example 9N-(3,4-difluorophenyl) -N-(2-fluoro-4-(6-methoxy-7-((1-(tetrahydro-2H-pyran-4-ylamino)-cyclopropyl)methoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1 -dicarboxamide
    [082] The title compound was prepared by the similar method to Example 3, using the product of Example 8 instead of the product of Example 2. Mass: (M+1), 677.Example 10N-(4-(7-( (1-(cyclohexylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide
    [083] The title compound was prepared by the similar method to Example 4, using the product of Example 8 instead of the product of Example 2. Mass: (M+1), 675.Example 11N-(4-(7-( (1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide
    [084] The title compound was prepared by the similar method to Example 5, using the product of Example 8 in place of the product of Example 2. Mass: (M+1), 647.Example 12N-(4-(7-( (1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide
    [085] The title compound was prepared by the similar method to Example 6, using the product of Example 8 instead of the product of Example 2. Mass: (M+1), 661.Example 134-methoxybenzyl-1-((4 -(4-(1-(phenylcarbamoyl)cyclopropanecarboxamido)-2-fluoro-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate
    [086] The title compound was prepared in the similar manner to Example 1, using 1-(phenylcarbamoyl)cyclopropanecarboxylic acid in place of 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid. Mass: (M+1), 721.Example 14N-(4-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(phenyl)cyclopropane-1 ,1-dicarboxamide
    [087] The title compound was prepared by the similar method to Example 2, using the product of Example 13 instead of the product of Example 1. Mass: (M+1), 557.Example 15N-(phenyl)-N-( 2-fluoro-4-(6-methoxy-7-((1-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)-methoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide
    [088] The title compound was prepared by the similar method to Example 3, using the product of Example 14 in place of the product of Example 2. Mass: (M+1), 641.Example 16N-(4-(7-( (1-(cyclohexylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamide
    [089] The title compound was prepared by the similar method to Example 4, using the product of Example 14 in place of the product of Example 2. Mass: (M+1), 639.Example 17N-(4-(7-( (1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamide
    [090] The title compound was prepared by the similar method to Example 5, using the product of Example 14 in place of the product of Example 2. Mass: (M+1), 611.Example 18N-(4-(7-( (1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamide
    [091] The title compound was prepared in the similar manner to Example 6, using the product of Example 14 in place of the product of Example 2. Mass: (M+1), 625.Examples of salt formation
    [092] A compound from Example 1-18 (100 mg) was dissolved in EtOAc (1 ml) and to the solution was added 2N ether/HCl solution (0.5 ml). The solution was evaporated to obtain an off-white solid as its HCl salt.
    [093] A compound from Example 1-18 (100 mg) was mixed with EtOH (1 ml) and to the mixture was added tartaric acid (80 mg). The reaction was refluxed for 30 minutes and cooled to room temperature. The precipitate was filtered to obtain the tartaric acid salt.
    [094] The other pharmaceutically acceptable salts, such as, for example, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or succinic, maleic, acetic, fumaric, citric, benzoic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic acid salt can be prepared in a similar manner. It can be made at higher temperatures with EtOH, MeOH or isopropanol as well as other acceptable pharmaceutical solvents. Formulation Examples
    [095] The following examples are merely illustrative examples of formulations and should in no way be interpreted as restrictive.

    权利要求:
    Claims (7)
    [0001]
    1. COMPOUND AS KINASE C-MET INHIBITOR, represented by General Formula IV:
    [0002]
    2. COMPOUND according to claim 1, characterized in that it is selected from the group consisting of:
    [0003]
    3. COMPOUND according to claim 1, characterized in that it is selected from the group consisting of: 4-methoxybenzyl-1-((4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl))cyclopropanecarboxamido)-phenoxy )-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamateN-(4-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamideN-(3-fluoro-4-(6-methoxy-7-((1-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)methoxy)quinolin-4-yloxy)phenyl)- N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclohexylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluoro-phenyl)-N -(4-fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4 -fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-3-fluoro-phenyl)-N-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide4-methoxybenzyl-1-((4-(4-(1-(3,4-diflu) orophenylcarbamoyl)cyclopropanecarboxamido)-3-fluoro-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamateN-(4-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2- fluorophenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamideN-(3,4-difluorophenyl)-N-(2-fluoro-4-(6-methoxy-7-((1-(tetrahydro)) -2H-pyran-4-ylamino)-cyclopropyl)methoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclohexylamino)cyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide N-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)methoxy)- 6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6 - methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide4-methoxybenzyl-1-((4-(4-(1-(phenylcarbamoyl))cyclopropanecarboxamido )-2-fluoro-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamateN-(4-(7-((1-aminocycle) propyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamideN-(phenyl)-N-(2-fluoro-4-(6-methoxy-) 7-((1-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)-methoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclohexylamino) )cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)) methoxy)-6-methoxyquinolin-4-yloxy)-2-fluorophenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-2-fluoro-phenyl)-N-(phenyl)cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.
    [0004]
    4. COMPOUND according to claim 1, characterized in that it is selected from the group consisting of: N-(3-fluoro-4-(6-methoxy-7-((1-(tetrahydro-2H-pyran-4-) ylamino)cyclopropyl)methoxy)quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4 -yloxy)-3-fluoro-phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopropylmethylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4- yloxy)-2-fluorophenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamideN-(4-(7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy )-2-fluoro-phenyl)-N-(3,4-difluorophenyl)cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.
    [0005]
    5. COMPOUND according to any one of claims 1 to 4, characterized in that the pharmaceutically acceptable salt is hydrochloric acid salt (HCl) or tartaric acid salt.
    [0006]
    6. COMPOUND according to any one of claims 1 to 5, characterized in that it is for use in the treatment of a neoplastic or proliferative or inflammatory disease, or a disease related to transplantation.
    [0007]
    7. COMPOUND according to any one of claims 1 to 5, for use according to claim 6, characterized in that the transplant-related disease is caused by excessive or inappropriate tyrosine kinase.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112013005523B1|2021-06-08|compound as c-met kinase inhibitor
    ES2643619T3|2017-11-23|Compounds substituted by spiro as angiogenesis inhibitors
    ES2416711T3|2013-08-02|Siro compounds substituted as angiogenesis inhibitors
    CN1867331B|2010-05-26|Thalidomide analogs as TNF-alpha modulators
    ES2714100T3|2019-05-27|Fused quinoline compounds as mTor inhibitors, pi3k
    ES2617678T3|2017-06-19|Compounds that act as kinase inhibitors
    CN105121443B|2017-04-12|Certain protein kinase inhibitors
    ES2782113T3|2020-09-10|Quinoline compounds fused as PI3K / mTor inhibitors
    CN108707139A|2018-10-26|Amino-metadiazine compound and its preparation method and application
    同族专利:
    公开号 | 公开日
    CN103328447B|2015-09-16|
    KR20140021509A|2014-02-20|
    EP2621904A4|2014-03-26|
    CN103328447A|2013-09-25|
    JP2013537197A|2013-09-30|
    KR20180021901A|2018-03-05|
    US20120123126A1|2012-05-17|
    EP2621904B1|2020-04-22|
    CN105153028A|2015-12-16|
    EP2621904A2|2013-08-07|
    WO2012034055A3|2012-07-19|
    NZ609283A|2015-02-27|
    CA2810528C|2020-01-14|
    WO2012034055A2|2012-03-15|
    HK1218758A1|2017-03-10|
    AU2011299082A1|2013-05-02|
    KR101934243B1|2018-12-31|
    CN105153028B|2019-03-26|
    CA2810528A1|2012-03-15|
    AU2011299082B2|2016-09-29|
    JP5939254B2|2016-06-22|
    US8664244B2|2014-03-04|
    BR112013005523A2|2016-05-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CH514879A|1968-10-25|1971-06-15|Suisse Horlogerie|Frequency multiplier for time device|
    WO1994004573A1|1992-08-14|1994-03-03|The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon Health Sciences University|cDNA CLONE ENCODING AN EXPRESSIBLE GABA TRANSPORTER|
    PT2213661E|2003-09-26|2011-12-15|Exelixis Inc|C-met modulators and methods of use|
    US7459562B2|2004-04-23|2008-12-02|Bristol-Myers Squibb Company|Monocyclic heterocycles as kinase inhibitors|
    AU2006231646A1|2005-04-06|2006-10-12|Exelixis, Inc.|C-Met modulators and methods of use|
    MX2007014617A|2005-05-20|2008-02-11|Methylgene Inc|Inhibitors of vegf receptor and hgf receptor signaling.|
    BRPI0610322B8|2005-05-20|2021-05-25|Methylgene Inc|vegf receptor and hgf receptor signaling inhibitors and pharmaceutical composition|
    US7880004B2|2005-09-15|2011-02-01|Bristol-Myers Squibb Company|Met kinase inhibitors|
    US8148532B2|2007-03-14|2012-04-03|Guoqing Paul Chen|Spiro substituted compounds as angiogenesis inhibitors|
    US8163923B2|2007-03-14|2012-04-24|Advenchen Laboratories, Llc|Spiro substituted compounds as angiogenesis inhibitors|
    MX2011004018A|2008-10-14|2011-06-24|Ning Xi|Compounds and methods of use.|
    CA2752421C|2009-03-21|2013-08-06|Ning Xi|Amino ester derivatives, salts thereof and methods of use|
    US8664244B2|2010-09-12|2014-03-04|Advenchen Pharmaceuticals, LLC|Compounds as c-Met kinase inhibitors|JP5933544B2|2010-07-26|2016-06-08|バイオマトリカ， インコーポレーテッド|Compositions for stabilizing blood DNA, RNA and proteins and other biological samples shipped and stored at ambient temperature|
    CA2806734A1|2010-07-26|2012-02-09|Biomatrica, Inc.|Compositions for stabilizing dna, rna and proteins in saliva and other biological samples during shipping and storage at ambient temperatures|
    US8664244B2|2010-09-12|2014-03-04|Advenchen Pharmaceuticals, LLC|Compounds as c-Met kinase inhibitors|
    US20150182622A1|2012-06-14|2015-07-02|The Schepens Eye Research Institute|Treatment and prevention of retinal injury and scarring|
    EP2934572A4|2012-12-20|2016-11-23|Biomatrica Inc|Formulations and methods for stabilizing pcr reagents|
    US9783498B2|2013-01-18|2017-10-10|Advenchen Pharmaceuticals, LLC|Process for preparing the anti-tumor agent 6-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and its crystalline|
    WO2015002729A2|2013-06-13|2015-01-08|Biomatrica, Inc.|Cell stabilization|
    CN104135504B|2014-02-11|2015-12-30|腾讯科技（深圳）有限公司|A kind of service providing method, Apparatus and system based on application|
    EP3942931A1|2014-06-10|2022-01-26|Biomatrica, INC.|Stabilization of thrombocytes at ambient temperatures|
    EP3387411A4|2015-12-08|2019-07-31|Biomatrica, INC.|Reduction of erythrocyte sedimentation rate|
    CN106008339B|2016-06-08|2018-09-07|上海准视生物科技有限公司|A kind of radioactivity C-MET targets affine micromolecular compound and its application|
    CN110437145A|2016-09-13|2019-11-12|上海翔锦生物科技有限公司|Tyrosine kinase inhibitor and its application|
    WO2018072614A1|2016-10-18|2018-04-26|北京康辰药业股份有限公司|Quinolinyl-substituted carboxylic acid compound or pharmaceutically acceptable salt thereof, pharmaceutical composition thereof, and use thereof|
    CN108503650B|2017-02-27|2021-02-12|北京赛特明强医药科技有限公司|Dioxane and quinazoline compound or medicinal salt or hydrate thereof and application of dioxane and quinazoline compound or medicinal salt or hydrate thereof as tyrosine kinase inhibitor|
    KR20200118146A|2018-02-11|2020-10-14|베이징 사이텍-엠큐 파마슈티컬즈 리미티드|Dioxynoquinoline compound, preparation method and use thereof|
    SG11202006921PA|2018-01-26|2020-08-28|Exelixis Inc|Compounds for the treatment of kinase-dependent disorders|
    CN112312909A|2018-01-26|2021-02-02|埃克塞里艾克西斯公司|Compounds for the treatment of kinase-dependent disorders|
    EP3766870A4|2018-03-02|2021-12-22|Chia Tai Tianqing Pharmaceutical Group Co., Ltd.|Crystal of compound as c-met kinase inhibitor and preparation method therefor and use thereof|
    WO2020027723A1|2018-08-01|2020-02-06|Agency For Science, Technology And Research|Bicyclic compounds as kinase modulators, methods and uses thereof|
    WO2020154610A1|2019-01-25|2020-07-30|Exelixis, Inc.|Compounds for the treatment of kinase-dependent disorders|
    EP3942045A1|2019-03-21|2022-01-26|Onxeo|A dbait molecule in combination with kinase inhibitor for the treatment of cancer|
    WO2021089791A1|2019-11-08|2021-05-14|INSERM |Methods for the treatment of cancers that have acquired resistance to kinase inhibitors|
    WO2021148581A1|2020-01-22|2021-07-29|Onxeo|Novel dbait molecule and its use|
    WO2021163192A1|2020-02-10|2021-08-19|Stemsynergy Therapeutics, Inc.|Myc inhibitors and uses thereof|
    WO2021185234A1|2020-03-16|2021-09-23|正大天晴药业集团股份有限公司|Combined pharmaceutical composition of compound as c-met kinase inhibitor and use thereof|
    WO2021244551A1|2020-06-02|2021-12-09|正大天晴药业集团股份有限公司|Combined pharmaceutical composition of c-met kinase inhibitor and anti-pd-l1 antibody|
    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-03-10| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-03-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US38199510P| true| 2010-09-12|2010-09-12|
    US61/381,995|2010-09-12|
    US13/227,866|2011-09-08|
    US13/227,866|US8664244B2|2010-09-12|2011-09-08|Compounds as c-Met kinase inhibitors|
    PCT/US2011/051061|WO2012034055A2|2010-09-12|2011-09-09|Compounds as c-met kinase inhibitors|
    [返回顶部]