WO2016184434A1 - 一种吡啶并氮杂环化合物及其制备方法和用途 - Google Patents

一种吡啶并氮杂环化合物及其制备方法和用途 Download PDF

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WO2016184434A1
WO2016184434A1 PCT/CN2016/083011 CN2016083011W WO2016184434A1 WO 2016184434 A1 WO2016184434 A1 WO 2016184434A1 CN 2016083011 W CN2016083011 W CN 2016083011W WO 2016184434 A1 WO2016184434 A1 WO 2016184434A1
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compound
unsubstituted
substituted
alkyl
hydrogen
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French (fr)
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龙亚秋
耿美玉
许忠良
艾菁
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中国科学院上海药物研究所
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Priority to US15/575,903 priority Critical patent/US10710996B2/en
Priority to CN201680031083.8A priority patent/CN107709320B/zh
Priority to JP2017560796A priority patent/JP6621486B2/ja
Priority to EP16795921.2A priority patent/EP3299369B1/en
Publication of WO2016184434A1 publication Critical patent/WO2016184434A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50Pyridazines; Hydrogenated pyridazines
    • A61K31/501Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a pyrido nitrogen heterocyclic compound, an isomer thereof, and a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, a process for producing the same, and a composition comprising the same .
  • the present invention also relates to the use of the compound, an isomer thereof, and a pharmaceutically acceptable salt thereof and a pharmaceutical composition as a multi-target protein kinase inhibitor for the preparation of a disease associated with a protein kinase, particularly c-Met, for treating a tumor disease or the like. Use of the drug.
  • c-Met is an important member of the receptor tyrosine kinase family, which is highly expressed in most cancers and some sarcomas and closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, Gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, etc.
  • c-Met induces cell proliferation, invasion, migration, inhibition of apoptosis, and promotes angiogenesis by interacting with its ligand HGF/SF or by other means to activate intracellular tyrosine kinase, in the process of tumor development. Play an important role.
  • c-Met acts as a key node in the tumor signaling network pathway and interacts with other tumor-associated molecules on the cell surface, thereby cross-linking activation to amplify tumor-associated effects, greatly promoting tumorigenesis, development and metastasis.
  • Met gene amplification is closely related to 20% of epidermal growth factor inhibitor (EGFR-TKIs) acquired resistance; the combination of Met inhibitor and EGFR inhibitor can delay the acquisition of acquired resistance of EGFR-TKIs, Extend its clinical lifespan. Therefore, targeting the c-Met/HGF pathway has become a new and attractive strategy for tumor therapy.
  • EGFR-TKIs epidermal growth factor inhibitor
  • kinase inhibitors show excellent targeted therapeutic effects in the clinic, the occurrence of tumor resistance mutations greatly reduces the effectiveness of long-term treatment of these drugs. Sex. The similarity in chemical structure also makes the problem of cross-resistance of kinase inhibitors increasingly serious.
  • the selectivity of kinases is closely related to off-target effects. Therefore, the discovery of lead compounds in new structures and mechanisms is the focus of current anti-tumor drug development targeting c-Met kinase.
  • a pyrido nitrogen heterocyclic compound an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutical composition comprising the same Things.
  • Another object of the present invention is to provide a process for the preparation of the above compounds.
  • the present invention provides a pyrido nitrogen heterocyclic compound, an isomer thereof, and a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate having the structure represented by the following Formula I:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen and halogen; preferably, R 1 and R 2 are each independently selected from the group consisting of hydrogen, F, Cl and Br; more preferably, R 1 is selected from the group consisting of hydrogen, Cl and Br; 2 is selected from the group consisting of hydrogen, F and Cl; further preferably, R 1 is hydrogen, Cl or Br; R 2 is hydrogen or F;
  • X is absent (as a direct bond), or X and Y are each independently selected from C, N, O and S; preferably, X is absent, or X and Y are each independently selected from C, N and O;
  • n 0, 1, 2 or 3; preferably, n is 0, 1 or 2; m is 0 or 1;
  • R 3 is absent or is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted, containing 1-2 selected from N, O, A five- or six-membered saturated or unsaturated heterocyclic group of a hetero atom in S, a substituted or unsubstituted five- or six-membered saturated or unsubstituted heteroatom selected from N, O, and S Saturated heterocyclic carbonyl, Or a substituted or unsubstituted five- or six-membered heteroaryl ring group containing 1-2 hetero atoms selected from N, O, S, wherein the substituents may be 1 or 2 and independently Is selected from the group consisting of halogen, -CN, -CF 3 , -NO 2 , hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted amine, C 1
  • R 6 is absent or is selected from hydrogen and C 1 -C 6 alkyl; preferably absent or selected from hydrogen and C 1 -C 4 alkyl; more preferably absent or selected from hydrogen and C 1 -C 2 Alkyl; most preferably absent or hydrogen or methyl;
  • R 7 is absent or is selected from hydrogen and C 1 -C 6 alkyl; preferably absent or is hydrogen, methyl, ethyl or propyl; most preferably absent or methyl;
  • Z is an amino group, a phenylacetamide group or any of the following structures:
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl and C 5 -C 10 aryl or heteroaryl; preferably, R 4 is selected from hydrogen and C 1 -C 6 alkyl; more preferably, R 4 is selected from hydrogen and C 1 -C 3 alkyl; most preferably, R 4 is hydrogen or methyl; R 5 and R 5 ' are each independently selected from hydrogen, halogen And a C 1 -C 6 alkoxy group; preferably, R 5 and R 5 ' are each independently selected from the group consisting of hydrogen, F, Cl, Br and C 1 -C 4 alkoxy; more preferably, R 5 and R 5 ' each independently selected from the group consisting of hydrogen, F and C 1 -C 2 alkoxy;
  • Z is an amino group, a phenylacetamide group or any of the following structures:
  • Ring B is a five- or six-membered saturated or unsaturated heterocyclic group or a heteroaromatic group containing 1 or 2 hetero atoms selected from N, O, S; preferably, ring B contains 1 or 2 a five- or six-membered saturated or unsaturated heterocyclic group or heteroaromatic group selected from hetero atoms in N or O; more preferably, ring B is a five- or six-membered saturated one or two N atoms Or an unsaturated heterocyclic group or a heteroaromatic group; most preferably, ring B and pyridine or together with X form a structure having one of the following formulas:
  • halogen includes F, Cl, Br, I;
  • the compound is selected from one of the following compounds:
  • a process for producing a pyrido nitrogen heterocyclic compound represented by the above formula I, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof such as One of the following reaction options:
  • R 8 is R 9 is The definitions of Y, R 2 , R 3 , R 7 , Z, m and n are the same as defined in the above formula I;
  • Compound 5 is obtained by chlorination of compound 4, and the chlorinating reagent is thionyl chloride (SOCl 2 )/N, N-dimethylformate (DMF), phosphorus oxychloride (POCl 3 )/DMF. Or POCl 3 /N,N-diisopropylethylamine (DIEA) / acetonitrile (MeCN), etc., preferably POCl 3 /DMF.
  • SOCl 2 thionyl chloride
  • DMF N-dimethylformate
  • POCl 3 phosphorus oxychloride
  • POCl 3 /N,N-diisopropylethylamine (DIEA) / acetonitrile (MeCN), etc. preferably POCl 3 /DMF.
  • the deprotecting reagent is: boron tribromide (BBr 3 ) / dichloromethane (DCM), 40% aqueous solution of hydrogen bromide (HBr), pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid - aluminum chloride, aluminum chloride - Ethyl mercaptan, trimethylchlorosilane (TMSCl) / sodium iodide (NaI), trifluoromethanesulfonic acid. Trifluoromethanesulfonic acid is preferred.
  • TIPA Trigger/PPh 3 .
  • ADDP 1,1'-(azodicarboxylic acid) dipiperidine
  • TMAD ammonium tetramethylazodicarboxylate
  • DHTD 4,7-di Methyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazepinein-3,8-dione
  • CMBP cyanomethylene three n-Butylphosphine
  • CMMP cyanomethylenetrimethylphosphine It is preferably DEAD/PPh 3 .
  • the selected reagent is a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, triethylamine (TEA), DIEA, potassium t-butoxide, hydrogenation.
  • TEA triethylamine
  • DIEA potassium t-butoxide
  • hydrogenation sodium, sodium methoxide, sodium ethoxide; preferably anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide.
  • Compound 8 is debrominated to give compound 9, preferably under the conditions of palladium carbon Pd/C-formic acid ammonium chloride, Pd/C-acetamide, Pd/C-hydrogen; preferably Pd/C-ammonium formate.
  • R 8 is R 9 is The definitions of Y, R 2 , R 3 , R 7 , Z, m and n are the same as defined in the above formula I;
  • Compound 11 is obtained by deprotection of compound 10.
  • the deprotecting reagent is: BBr 3 /DCM, 40% aqueous solution of HBr, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminum chloride, aluminum chloride-ethanethiol, TMSCl/NaI, trifluoromethanesulfonic acid. Trifluoromethanesulfonic acid is preferred.
  • Compound 12 is subjected to nucleophilic substitution reaction to give compound 9, and the selected reagent is a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, Sodium ethoxide; preferably anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide.
  • a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide.
  • R 10 is R 9 is X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as defined in claims 1-5;
  • X' is Cl or Br;
  • chlorinating reagent is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN, etc., preferably POCl 3 /DIEA/MeCN;
  • Compound 17 is subjected to nucleophilic substitution reaction to give compound 18, and the selected reagent is a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, Sodium ethoxide; preferably anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide;
  • R 10 is R 9 is X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as defined in claims 1-5;
  • X' is Cl or Br;
  • Compound 15 is subjected to chlorination to give compound 15I, and the chlorinating reagent is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN, etc., preferably POCl 3 /DIEA/MeCN;
  • Compound 15I is subjected to nucleophilic substitution reaction to give compound 15II.
  • the selected reagent is a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, Sodium ethoxide; preferably anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide;
  • R 10 is R 9 is The definitions of X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as in claims 1-5, respectively;
  • the selected reagent is a common organic base or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide;
  • the chlorination reagent is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN, etc., preferably POCl 3 /DIEA/MeCN;
  • the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; preferably no Potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide.
  • a common organic or inorganic base such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; preferably no Potassium carbonate, cesium carbonate, TEA, DIEA, potassium t-butoxide.
  • Another aspect of the invention also provides a combination comprising a therapeutically effective amount selected from the group consisting of one or more compounds of formula I, isomers thereof, pharmaceutically acceptable salts or pharmaceutically acceptable solvates Things.
  • the present invention provides a compound of the formula I, an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, and a combination thereof for the preparation of a medicament as a multi-target protein kinase inhibitor Application in preparation For the prevention of tyrosine kinase c-Met activity in the preparation of a cell for the prevention or treatment of hepatocyte growth factor receptor (c-Met) associated with abnormal cell proliferation, morphological changes and hyperkinesia Use in related diseases and drugs for diseases associated with angiogenesis or tumor metastasis, especially in the preparation of a medicament for preventing or treating tumor growth and metastasis.
  • c-Met hepatocyte growth factor receptor
  • the kinases include c-Met, Flt-1, PDGFR- ⁇ , PDGFR- ⁇ , RET, c-Src, EPH-A2, FGFR, Abl, Lck, KDR, IGF-1 ⁇ , and ALK.
  • the medicament is for the treatment and/or prevention of diseases associated with protein kinases, in particular c-Met, such as tumors.
  • the tumor is lung cancer, medullary thyroid tumor, glioblastoma, gastric cancer, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer or colorectal cancer.
  • the inventors found that the compound represented by the above formula I has a high inhibitory activity against c-Met kinase at 10 nM; it is highly efficient at 100 nM for tumor cells highly expressed by c-Met kinase. Inhibition activity.
  • the small molecule inhibitor animal has good curative effect: oral administration once a day, continuous administration for 21 days in the 100 mg/kg group, and the relative tumor growth rate T/C of human lung cancer EBC-1 nude mice is 9.5%.
  • the tumor volume growth inhibition rate GI was 96.5%
  • the tumor weight inhibition rate was 86.9%
  • the effective dose was safe and non-toxic. Therefore, the compound represented by the general formula I can effectively target the c-Met-mediated signaling pathway and can be used for the treatment of diseases associated with tumors and the like caused by overexpression of c-Met kinase.
  • the pharmaceutically acceptable pharmaceutical composition containing the compound represented by the general formula I can also effectively target the c-Met-mediated signaling pathway and can be used for diseases associated with tumors caused by overexpression of c-Met kinase. treatment.
  • Figure 1 shows the experimental therapeutic effect of compound 7S on human lung cancer EBC-1 nude mice xenografts.
  • reagents and methods employed in the present invention are reagents and methods well known in the art unless otherwise specified.
  • Dimethyl cyclopropanedicarboxylate (10.12 g, 63.99 mmol) was dissolved in 100 mL (1:1 V:V) CH 3 OH/H 2 O, stirred at room temperature, and weighed (2.68 g, 63.99 mmol) Lithium is dissolved in 20 ml of H 2 O, and slowly added to the above solution in three portions at room temperature. After the addition, the reaction is stirred for 1 h. After the reaction is completed, the pH is adjusted to 3 with dilute hydrochloric acid, extracted with DCM, dried over anhydrous sodium sulfate, The next reaction is continued by purification.
  • Compound 27 was prepared as the compound 26, the starting material was p-fluoro-N-methylaniline; 1 H NMR (DMSO, 300 MHz): ⁇ 9.56 (s, 1H), 9.42 (s, 1H), 7.35-7.23 (m) , 2H), 7.19-7.03 (m, 2H), 6.97-6.87 (m, 1H), 6.85-6.75 (m, 1H), 3.22 (s, 3H), 1.38-1.10 (m, 4H).
  • Compound 32 was prepared in the same manner as Compound 31, and the starting material was p-1,4-phenylenediamine in a two-step yield of 56%.
  • Treatment of zinc Weigh a certain amount of zinc powder into dilute hydrochloric acid, add the amount of dilute hydrochloric acid to make the zinc powder slowly bubble out, stir at room temperature for 30min to remove the oxide layer on the zinc surface, then pour off the water, and then use Wash twice with water, wash twice with acetone, wash twice with ether, and drain under reduced pressure.
  • the compound obtained above was suspended in 10 ml/g of diphenyl ether, and the temperature was raised to 220 ° C. After stirring for 1 hour, a large amount of solid was precipitated, cooled to room temperature, washed with a large amount of petroleum ether, and filtered to give the product compound 58 in a yield of 96%.
  • the synthesis route is the same as compound 38S, and the starting materials are compound 1S and 1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-pyrazole.
  • the compound 39S was dissolved in tetrahydrofuran, and 2 eq of DIEA was added thereto with stirring at room temperature. Then, 1.1 eq of methylsulfonyl chloride was slowly added dropwise, and the reaction was stirred at room temperature for 30 min, followed by TLC. After the reaction was completed, EA was diluted and saturated. The solution was washed with a Na 2 CO 3 solution, washed with saturated NaCI, dried over anhydrous Na?
  • compound 96 is the same as compound 38S, and the starting materials are compound 1S and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). -1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester.
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/ml, 125 ⁇ L/well coated ELISA plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 ⁇ L/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM dithiothreitol (DTT) to each well.
  • ATP adenosine triphosphate
  • the compound was diluted with dimethyl sulfoxide (DMSO) to a suitable concentration, 1 ⁇ L/well or containing the corresponding concentration of DMSO (negative control well), and then added to the c-Met kinase domain recombinant protein diluted with 49 ⁇ L of reaction buffer to initiate the reaction.
  • DMSO dimethyl sulfoxide
  • Each experiment requires two wells without ATP control wells.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm).
  • the plate was washed three times with T-PBS.
  • One anti-PY99 dilution was added to 100 ⁇ L/well, and the reaction was shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • OPD o-phenylenediamine
  • the inhibition rate of the sample is obtained by the following formula:
  • the compound having the activity of inhibiting c-Met kinase (the inhibition rate of the compound at 10 -5 M to the receptor tyrosine kinase c-Met >50%) obtained by the above screening was subjected to a gradient concentration, and IC 50 evaluation was performed.
  • the IC 50 values of the protein level inhibitory protein tyrosine kinases of each compound were calculated by a four-parameter method, and the results were classified into the following Table 1 according to their concentration ranges:
  • a test compound inhibits c-Met kinase activity.
  • RESULTS Several compounds of the present invention were found to have different degrees of inhibitory activity against c-Met kinase. Some compounds have a strong inhibitory effect on c-Met kinase at a concentration of 10 nM, and the semi-inhibitory concentration is 1 nM ⁇ IC 50 ⁇ 10 nM. . It is suggested that the compound of the present invention has a high potency against c-Met kinase and is a novel structural c-Met kinase inhibitor.
  • EBC-1 cells MET extension-expressing cell line, Met-dependent tumor cell line
  • SRB sulforhodamine B staining.
  • a certain number of EBC-1 cells in logarithmic growth phase were inoculated in a 96-well culture plate at 90 ⁇ L per well. After incubation overnight, 10 ⁇ L of different concentrations of compound or solvent control were added, respectively, at a concentration of 3 replicate wells.
  • the adherent cells were removed from the culture medium, and 10% (w/v) trichloroacetic acid (100 ⁇ L/well) was added and fixed at 4 ° C for 1 hr, followed by rinsing with distilled water five times, at room temperature. After drying, add 100 ⁇ L of SRB solution (4 mg/mL, dissolved in 1% glacial acetic acid) to each well, incubate for 15 min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, and dry at room temperature.
  • SRB solution 4 mg/mL, dissolved in 1% glacial acetic acid
  • inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%. The experiment was repeated twice. The IC 50 data is derived from the test results of the initial screening concentration.
  • the experimental method was the same as Experimental Example 1, and the experimental results are shown in Table 2.
  • the compound 7S of the present invention exhibits an inhibitory activity against various kinases such as c-Met, Flt-1, PDGFR- ⁇ , PDGFR- ⁇ , RET, c-Src, and EPH-A2, and is a New structure of multiple kinase inhibitors.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of the compound in rat plasma was determined by LC/MS/MS.
  • the pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix 1.3 software (Pharsight, USA).
  • the peak concentration C max and the peak time T max are measured values
  • AUC 0- ⁇ AUC 0-t + C t / ke
  • Ct the blood concentration of the last measurable time point
  • k e the elimination rate constant
  • Average residence time MRT AUMC / AUC.
  • Absolute bioavailability F (AUC gavage ⁇ D vein) / (AUC vein ⁇ D gavage) ⁇ 100%
  • EBC-1 cells were subcutaneously inoculated into the right axilla of nude mice at 5 ⁇ 10 6 / each, and the transplanted tumors were formed and then used in nude mice for three generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 under aseptic conditions, and inoculated into the right axilla of the nude mice.
  • the diameter of the transplanted tumor was measured with a vernier caliper.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous transplanted tumor.
  • the animals were randomly divided into tumors with an average tumor volume of about 120-130 mm 3 .
  • the 7S, 100 mg/kg and 10 mg/kg groups were orally administered once a day for 21 days (qd/21, po).
  • the positive control drug PF2341066 50 mg/kg was orally administered once a day for 21 days.
  • the solvent control gave an equal amount of solvent.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 ), and V t is the tumor volume at each measurement.
  • the compound 7S 100 mg/kg group was orally administered once a day for 21 days, which significantly inhibited the growth of subcutaneous xenografts of human lung cancer EBC-1 nude mice.
  • the effect, the percentage of T/C obtained on the 21st day was 9.58%.
  • the compound 7S 10 mg/kg group was orally administered once a day for 21 days, which inhibited the growth of subcutaneous xenografts of human lung cancer EBC-1 nude mice.
  • the percentage of T/C obtained on the 21st day was 46.24. %.
  • the positive control drug PF2341066 50mg/kg group was administered orally once a day for 21 days.
  • mice in each of the administration groups were in good condition during the administration, and no mice died.

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Abstract

本发明公开了一种如下通式I所示的吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其制备方法以及包含所述化合物的组合物,以及作为多靶点蛋白激酶抑制剂在制备用于治疗肿瘤疾病等与蛋白激酶特别是c-Met有关的疾病的药物中的用途。通式I表示的化合物对c-Met激酶高表达的肿瘤细胞有高效的抑制活性,能够有效的靶向c-Met介导的信号通路,能够用于与c-Met激酶过度表达引起的肿瘤等相关疾病的治疗。

Description

一种吡啶并氮杂环化合物及其制备方法和用途 技术领域
本发明涉及药物化学领域,具体涉及一种吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其制备方法以及包含所述化合物的组合物。本发明还涉及所述化合物、其异构体及药学上可接受的盐及药物组合物作为多靶点蛋白激酶抑制剂在制备用于治疗肿瘤疾病等与蛋白激酶特别是c-Met有关的疾病的药物中的用途。
背景技术
世界卫生组织(WHO)在《全球癌症报告2014》称,2012年全球癌症患者为1400万人,预计到2025年递增至1900万人,到2035年将达到2400万人。2012年,中国新增307万癌症患者并造成约220万人死亡,分别占全球总量的21.9%和26.8%。在中国,每五个死亡者中就有一个死于癌症。癌症成为仅次于心血管疾病的第二大杀手,严重威胁着人类的健康。近年随着人们对肿瘤生物学的深入研究,受体酪氨酸激酶由于在肿瘤发生、发展、耐药中发挥重要的作用,已成为一种抗肿瘤药物研发的靶点。
c-Met是受体酪氨酸激酶家族的重要成员,在绝大部分的癌及部分肉瘤中具有高表达且和预后差紧密相关,如肺癌、乳腺癌、结肠癌、前列腺癌、胰癌、胃癌、肝癌、卵巢癌、肾癌、神经胶质瘤、黑色素瘤等。c-Met通过与其配体HGF/SF相互作用或者通过其他途径激活胞内段的酪氨酸激酶,诱导细胞增殖、侵袭、迁移,抑制细胞凋亡,促进血管生成,在肿瘤的发生发展过程中发挥重要的作用。不同于其他激酶,c-Met作为肿瘤信号网络通路中的关键节点,可以与细胞表面其他肿瘤相关分子相互作用,从而交联激活放大肿瘤相关效应,极大地促进了肿瘤的发生、发展和转移。研究表明,Met基因扩增与20%的表皮生长因子抑制剂(EGFR-TKIs)获得性耐药密切相关;Met抑制剂与EGFR抑制剂的联合用药能够延缓EGFR-TKIs获得性耐药的产生,延长其临床使用寿命。因此,靶向c-Met/HGF通路成为引人注目的肿瘤治疗新策略,基于c-Met信号通路的化学阻断特别是小分子c-Met激酶抑制剂的抗癌药物研究成为目前癌症治疗领域的研究热点。到目前为止,已有17个小分子c-Met抑制剂进入或正在进行临床试验,其中PF-2341066(Crizotinib)作为高度选择性的ALK/c-Met双重激酶抑制剂,于2011年被美国FDA批准用于ALK融合基因阳性的非小细胞肺癌的治疗;XL184/BMS907351作为Met、VEGFR-2和RET等多重激酶抑制剂,于2012年底获准用于甲状腺髓样癌的治疗。虽然激酶抑制剂在临床上表现出优良的靶向治疗效果,但肿瘤耐药性变异的发生大大降低了这类药物长期治疗的有效 性。化学结构的相似也使得激酶抑制剂的交叉耐药性问题日益严重。另一方面,虽然没有直接证据证明特异性激酶抑制剂优于多重激酶抑制剂,但激酶的选择性与脱靶效应密切相关。因此,新结构新机制先导化合物的发现是目前靶向c-Met激酶的抗肿瘤药物研发的重点方向。
发明内容
为了解决上述技术问题,本发明的一个目的是提供一种吡啶并氮杂环化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物,以及包含该化合物的药物组合物。
本发明另一方面的目的是提供上述化合物的制备方法。
本发明又一方面的目的是提供上述化合物在制备用于抑制酪氨酸激酶c-Met活性的药物中的应用,在制备用于预防或治疗与生物体内的肝细胞生长因子及其受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或癌转移相关的疾病的药物中的应用,尤其是用于制备预防或治疗肿瘤生长与转移的药物中的应用。
为了实现上述发明目的,本发明采用如下的技术方案:
本发明一方面提供一种吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其具有如下通式I所示的结构:
Figure PCTCN2016083011-appb-000001
其中,
Figure PCTCN2016083011-appb-000002
表示单键或双键;
R1和R2各自独立地选自氢和卤素;优选地,R1和R2各自独立地选自氢、F、Cl和Br;更优选地,R1选自氢、Cl和Br;R2选自氢、F和Cl;进一步优选地,R1为氢、Cl或Br;R2为氢或F;
X不存在(为直键),或者X和Y各自独立地为选自C、N、O和S;优选地,X不存在,或者X和Y各自独立地选自C、N和O;
n为0、1、2或3;优选地,n为0、1或2;m为0或1;
R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
Figure PCTCN2016083011-appb-000003
或者取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地为选自卤素、-CN、-CF3、-NO2、羟基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷氧基、苄基、卤素取代的C1-C6烷氧基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基或杂芳环基;更优选地,R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
Figure PCTCN2016083011-appb-000004
或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-CN、苄基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;进一步优选地,R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
Figure PCTCN2016083011-appb-000005
或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、苄基、C1-C4烷基、C1-C4烷基取代的胺基、C1-C4烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;最优选地,R3不存在或者为C1-C3的烷基、取代或未取代的吡啶基、取代或未取代的吗啉基、取代或未取代的吗啉基羰基、
Figure PCTCN2016083011-appb-000006
代或未取代的哌啶基、取代或未取代的咪唑基、取代或未取代的哌嗪基、取代或未取代的恶唑基、取代或未取代的异恶唑基、取代或未取代的嘧啶基、取代或未取代的噻唑基、取代或未取代的异噻唑基、 取代或未取代的苯基、或者取代或未取代的吡唑基,其中,所述取代基可以为1或2个并各自独立地选自F、Cl、Br、-NO2、C1-C3烷基、苄基、C1-C3烷基磺酰基、C1-C3烷基取代的胺基、未取代的或C1-C6烷基取代的哌啶基和吗啉基;
R6不存在或者选自氢和C1-C6的烷基;优选不存在或者选自氢和C1-C4的烷基;更优选不存在或者选自氢和C1-C2的烷基;最优选不存在或者为氢或甲基;
R7不存在或者选自氢和C1-C6的烷基;优选不存在或者为氢、甲基、乙基或丙基;最优选不存在或者为甲基;
Z为氨基、苯基乙酰胺基或以下任一结构:
Figure PCTCN2016083011-appb-000007
在上述通式II、III、IV、V中,R4选自氢、C1-C6烷基和C5-C10芳基或者杂芳基;优选地,R4选自氢和C1-C6烷基;更优选地,R4选自氢和C1-C3烷基;最优选地,R4为氢或甲基;R5和R5’各自独立地选自氢、卤素和C1-C6烷氧基;优选地,R5和R5’各自独立地选自氢、F、Cl、Br和C1-C4烷氧基;更优选地,R5和R5’各自独立地选自氢、F和C1-C2烷氧基;
最优选地,Z为氨基、苯基乙酰胺基或以下任一结构:
Figure PCTCN2016083011-appb-000008
环B为含有1或2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;优选地,环B为含有1或2个选自N或O中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;更优选地,环B为含有1或2个N原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;最优选地,环B与吡啶或者连同X形成具有如下简式之一所示的结构:
Figure PCTCN2016083011-appb-000009
其中,卤素包括F、Cl、Br、I;
最优选地,所述化合物选自下述化合物中的一种化合物:
Figure PCTCN2016083011-appb-000010
Figure PCTCN2016083011-appb-000011
Figure PCTCN2016083011-appb-000012
Figure PCTCN2016083011-appb-000013
Figure PCTCN2016083011-appb-000014
Figure PCTCN2016083011-appb-000015
Figure PCTCN2016083011-appb-000016
Figure PCTCN2016083011-appb-000017
Figure PCTCN2016083011-appb-000018
Figure PCTCN2016083011-appb-000019
Figure PCTCN2016083011-appb-000020
Figure PCTCN2016083011-appb-000021
Figure PCTCN2016083011-appb-000022
Figure PCTCN2016083011-appb-000023
Figure PCTCN2016083011-appb-000024
本发明另一方面提供一种上述通式I所示吡啶并氮杂环化合物、其异构体、其药学上可接受的盐或其药学上可接受的溶剂合物的制备方法,该方法如以下反应方案之一所示:
反应方案一:
Figure PCTCN2016083011-appb-000025
其中,R8
Figure PCTCN2016083011-appb-000026
R9
Figure PCTCN2016083011-appb-000027
Y、R2、R3、R7、Z、m和n的定义与上述通式I中的定义相同;
(1)化合物5由化合物4经氯代反应得到,氯代试剂为氯化亚砜(SOCl2)/N,N-二甲基甲酸铵(DMF)、三氯氧磷(POCl3)/DMF或POCl3/N,N-二异丙基乙胺(DIEA)/乙腈(MeCN)等,优选为POCl3/DMF。
(2)化合物6由化合物5去保护得到。去保护试剂为:三溴化硼(BBr3)/二氯甲烷(DCM)、40%溴化氢(HBr)水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、三甲基氯硅烷(TMSCl)/碘化钠(NaI)、三氟甲磺酸。优选为三氟甲磺酸。(3)化合物6经Mitsunobu反应生成化合物7,所选试剂为偶氮二甲酸二乙酯(DEAD)/三苯基膦(PPh3)、N′,N′-四异丙基偶氮二羧酰胺(TIPA)-三丁膦TBP、1,1′-(偶氮二羧酸)二哌啶(ADDP)-TBP、四甲基偶氮二甲酸铵(TMAD)-TBP、4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD)-TBP、氰基亚甲基三正丁基膦(CMBP)或氰基亚甲基三甲基膦(CMMP)。优选为DEAD/PPh3
(4)化合物7经亲核取代反应生成化合物8,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、三乙胺(TEA)、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
(5)化合物8经脱溴得到化合物9,优选反应条件为:钯碳Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵。
反应方案二:
Figure PCTCN2016083011-appb-000028
其中,R8
Figure PCTCN2016083011-appb-000029
R9
Figure PCTCN2016083011-appb-000030
Y、R2、R3、R7、Z、m和n的定义与上述通式I中的定义相同;
(1)化合物5脱溴得到化合物10,优选反应条件为:Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵。
(2)化合物11由化合物10去保护得到。去保护试剂为:BBr3/DCM、40%HBr水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、TMSCl/NaI、三氟甲磺酸。优选为三氟甲磺酸。
(3)化合物11经Mitsunobu反应生成化合物12,所选试剂为DEAD/PPh3、TIPA-TBP、ADDP-TBP、TMAD-TBP、DHTD-TBP、CMBP或CMMP。优选为DEAD/PPh3
(4)化合物12经亲核取代反应生成化合物9,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
反应方案三:
Figure PCTCN2016083011-appb-000031
其中,R10
Figure PCTCN2016083011-appb-000032
R9
Figure PCTCN2016083011-appb-000033
X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
(1)化合物14经脱氯得到化合物15,反应试剂为锌(Zn)/醋酸(MeCOOH);
(2)化合物16经氯代反应得到化合物17,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(3)化合物17经亲核取代反应生成化合物18,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
反应方案四:
Figure PCTCN2016083011-appb-000034
其中,R10
Figure PCTCN2016083011-appb-000035
R9
Figure PCTCN2016083011-appb-000036
X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
(1)化合物15经氯代反应得到化合物15I,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(2)化合物15I经亲核取代反应生成化合物15II,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
(3)化合物15II经Suzuki偶联反应生成化合物18,所用的碱为醋酸钾、磷酸钾或碳酸钾;所用溶剂为二甲基亚砜,DMF,二氧六环或者甲苯,加入适量的水;所用的催化剂为四三苯基膦钯,1,1′-双二苯基膦二茂铁二氯化钯PdCl2(dppf);
反应方案五:
Figure PCTCN2016083011-appb-000037
其中,R10
Figure PCTCN2016083011-appb-000038
R9
Figure PCTCN2016083011-appb-000039
X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;
(1)取代反应生成化合物19,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
(2)化合物19经还原得到化合物20,所用的还原试剂为氯化镍(NiCl2)/硼氢化钠(NaBH4)、Zn/AcOH、Pd/C-H2、Fe/氯化氢(HCl)、硫化钠(Na2S)/乙醇(EtOH)、硫氢化铵(NH4HS)、氢化铝锂(LiAlH4);优选为NiCl2/NaBH4、Pd/C-H2
(3)化合物20经环合得到化合物21及22,环合条件为醛基乙酸乙酯,溶剂为各种常规溶剂,例如甲醇(MeOH)、EtOH、乙腈(MeCN)、二氧六环等;
(4)氯代反应,其氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(5)亲核取代反应,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
本发明另一方面还提供一种包含治疗有效量的选自一种或多种通式I所示化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物的组合物。
本发明另一方面还提供通式I所示化合物、其异构体、药学上可接受的盐、药学上可接受的溶剂合物及其组合物在制备作为多靶点蛋白激酶抑制剂的药物中的应用,在制备用 于抑制酪氨酸激酶c-Met活性的药物中的应用,在制备用于预防或治疗与生物体内的肝细胞生长因子受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或肿瘤转移相关的疾病的药物中的应用,尤其是在制备预防或治疗肿瘤生长与转移的药物中的应用。
所述激酶包括c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2、FGFR、Abl、Lck、KDR、IGF-1α和ALK。
所述药物用于治疗和/或预防与蛋白激酶特别是c-Met有关的疾病,如肿瘤。
在本发明中,所述肿瘤为肺癌、甲状腺髓样瘤、恶性胶质瘤、胃癌、肾细胞癌、乳腺癌、卵巢癌、前列腺癌或结直肠癌。
本发明有如下有益效果:
通过对c-Met激酶活性筛选,发明人发现:上述通式I表示的化合物在10nM下对c-Met激酶有高效的抑制活性;在100nM下对c-Met激酶高表达的肿瘤细胞有高效的抑制活性。代表性化合物7S表现出良好的药代性质:生物利用度F=51.8%,平均滞留时间MRT=2.6h,半衰期t1/2=1.66h,药时面积AUC=16652h*ng/ml。而且,该小分子抑制剂动物体内疗效良好:每天口服给药一次,100mg/kg组连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤相对肿瘤增殖率T/C为9.5%,肿瘤体积增长抑制率GI为96.5%,瘤重抑制率为86.9%,有效剂量内安全无毒。因此,通式I表示的化合物能够有效的靶向c-Met介导的信号通路,能够用于与c-Met激酶过度表达引起的肿瘤等相关疾病的治疗。制剂学上允许的含有通式I表示的化合物的药物组合物同样能起到有效的靶向c-Met介导的信号通路,能够用于与c-Met激酶过度表达引起的肿瘤等相关疾病的治疗。
附图说明
图1显示了化合物7S对人肺癌EBC-1裸小鼠移植瘤的实验治疗作用。
具体实施方式
实施例:
下面结合实施例对本发明作进一步描述,但不限制本发明的保护范围。
化合物的1H-NMR光谱数据测量使用Varian Mercury-300MHz或Varian Mercury-400MHz核磁共振,质谱EI-MS用Finnigan MAT 95质谱仪,ESI-MS使用Finnigan LCQ Deca质谱仪测定。快速柱层析在硅胶H(10-40μM)上进行。试剂纯化参照Purification of laboratory Chemicals;D.D.Perrin;W.L.F.Armarego and D.R.Perrin Eds., Pergamon Press:Oxiford,1980。
如未作特别说明,本发明所采用的试剂和方法等为本领域熟知的试剂和方法。
实施例1片段II系列的合成
本片段合成参考WO 2011/137342 A1
Figure PCTCN2016083011-appb-000040
1-(甲氧基羰基)环丙烷单羧酸(23)
将环丙烷二羧酸二甲酯(10.12g,63.99mmol)溶解在100mL(1∶1V∶V)CH3OH/H2O中,室温下搅拌,称取(2.68g,63.99mmol)氢氧化锂溶于20ml H2O中,室温下分三次慢慢加入上述溶液中,加完后继续搅拌反应1h,反应完成后用稀盐酸调节pH值到3,DCM萃取,无水硫酸钠干燥,不经纯化继续下一步反应。
1-((4-氟苯基)氨基甲酰)环丙烷单羧酸(25)
将(9.21g,63.99mmol)化合物23、(12.15ml,127.98mmol)对氟苯胺溶于150ml DCM中,室温下加入(12.97g,95.98mmol)HOBt(羟基苯并三唑)、(14.90g,95.98mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC),室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物24粗品。将得到的粗品直接溶于100mL(1∶1V∶V)MeOH/H2O中,室温下搅拌,后加入(3.06g,127.98mmol)氢氧化锂,加完后继续搅拌反应1h,TLC跟踪反应,反应完成后用稀盐酸调节pH值到3,即析出大量固体,过滤,干燥得灰白色固体10.56g,两步产率74.1%。1H NMR(CDCl3,300MHz):δ7.57-7.53(m,2H),7.05-7.00(m,2H),1.46-1.43(m,2H),1.40-1.37(m,2H)。
N-(3-氟-4-羟基苯基)-N-(4-氟苯基)环丙烷-1,1-二酰胺(26)
将(2.00g,8.97mmol)化合物25、(1.14g,8.97mmol)4-氨基-2-氟苯酚溶于10ml DCM中,室温下加入(1.21g,13.46mmol)HOBt,(1.77g,13.46mmol)EDC,室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水 洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,甲醇结晶得黄褐色固体63%。1H NMR(DMSO,400MHz):δ10.51(s,1H),10.32(s,1H),10.00(s,1H),7.77(d,J=12.9Hz,1H),7.66-7.61(m,2H),7.41(d,J=8.7Hz,1H),7.30(t,J=8.8Hz,1H),7.15(d,J=9.0Hz,2H),1.61(m,2H),1.44(m,2H).
N-(3-氟-4-羟基苯基)-N-(4-氟苯基)-N-甲基环丙烷-1,1-二酰胺(27)
Figure PCTCN2016083011-appb-000041
化合物27的制备同化合物26,初始原料为对氟-N-甲基苯胺;1H NMR(DMSO,300MHz):δ9.56(s,1H),9.42(s,1H),7.35-7.23(m,2H),7.19-7.03(m,2H),6.97-6.87(m,1H),6.85-6.75(m,1H),3.22(s,3H),1.38-1.10(m,4H).
N-(3,4-二氟苯基)-N-(3-氟-4-羟基苯基)环丙烷-1,1-二酰胺(28)
Figure PCTCN2016083011-appb-000042
化合物28的制备同化合物26,初始原料为3,4-二氟苯胺;1H NMR(CDCl3,300MHz):δ10.64(s,1H),7.72-7.58(m,1H),7.13-7.00(m,2H),6.83(t,J=8.5Hz,1H),6.52-6.34(m,2H),1.97(m,2H).
N-(4-氟-3-甲氧基)-N-(3-氟-4-羟基苯基)环丙烷-1,1-二酰胺(29)
Figure PCTCN2016083011-appb-000043
化合物29的制备同化合物26,初始原料为4-氟-3-甲氧基苯胺;1H NMR(DMSO,400MHz):δ10.08(s,1H),9.87(s,1H),9.62(s,1H),7.57-7.48(m,2H),7.21-7.11(m,3H),6.87(t,J=9.2Hz,1H),3.80(s,3H),1.50-1.37(m,4H)
N-(4-氟苯基)-N-(4-羟基苯基)环丙烷-1,1-二酰胺(31)
Figure PCTCN2016083011-appb-000044
将(0.50g,2.24mmol)化合物25加入圆底烧瓶中,加入2ml SOCl2,80℃反应2h,后浓缩得化合物30粗品,将浓缩物用5ml DCM稀释;称取(366mg,3.36mmol)对羟基苯胺溶入30ml DCM中,加入(386mg,3.36mmol)DIEA,冰浴下将化合物30慢慢滴加到反应液中,滴加完毕后移至室温继续搅拌反应1h,反应完成后加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得土黄色固体化合物31,两步产率63%。1H NMR(DMSO,300MHz):δ10.18(s,1H),9.74(s,1H),9.25(s,1H),7.63(dd,J=8.1,5.2Hz,2H),7.36(d,J=8.2Hz,2H),7.15(t,J=8.4Hz,2H),6.70(d,J=7.9Hz,2H),1.47-1.41(m,2H),1.14-1.06(m,2H).
N-(4-氨基苯基)-N-(4-羟基苯基)环丙烷-1,1-二酰胺(32)
Figure PCTCN2016083011-appb-000045
化合物32的制备同化合物31,初始原料为对1,4-苯二胺,两步产率56%。1H NMR(DMSO,300MHz):δ10.25(s,1H),9.57(s,1H),7.68-7.60(m,2H),7.30-7.10(m,4H),6.51(d,J=8.6Hz,2H),4.96(s,2H),1.53-1.37(m,4H).
实施例2片段III的合成
Figure PCTCN2016083011-appb-000046
1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酸(34)
将(300mg,1.95mmol)2-氧代-2H-吡喃-3-甲酸甲酯、(0.19ml,1.96mmol)对氟苯胺溶于5ml DMF中,室温下搅拌反应6h后,后向反应液中加入(0.49g,2.54mmol)EDC、(60mg,0.49mmol)DMAP(二甲基氨基吡啶),室温下搅拌反应过夜,反应完成后,加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品。将得到的粗品直接溶于20mL 2N的NaOH的THF/H2O(1∶1V∶V)中,65℃搅拌反应2h,反应完成后用稀盐酸调节pH值到1,即析出大量固体,过滤,干燥得土黄色固体化合物34。1H NMR (DMSO,300MHz):δ8.47(dd,J=7.1,2.2Hz,1H),8.19(dd,J=6.6,2.2Hz,1H),7.59-7.63(m,2H),7.39-7.44(m,2H),6.78(dd,J=6.6,7.1Hz,1H).
N-(3-氟-4-羟基苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(36)
将(0.52g,2.24mmol)化合物34加入圆底烧瓶中,加入2ml SOCl2,80℃反应2h,后浓缩得化合物35,将浓缩物用5ml DCM稀释;称取(427mg,3.36mmol)对羟基-3氟-苯胺溶入30ml DCM中,加入(386mg,3.36mmol)DIEA,冰浴下将化合物35慢慢滴加到反应液中,滴加完毕后移至室温继续搅拌反应1h,反应完成后加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得土黄色固体化合物36,两步产率52%。1H NMR(DMSO,300MHz):δ11.79(s,1H),9.72(s,1H),8.55(d,J=7.2Hz,1H),8.11(dd,J=13.6,6.3Hz,1H),7.74(d,J=13.5Hz,1H),7.59(dt,J=13.0,6.5Hz,2H),7.41(dd,J=16.3,7.6Hz,2H),7.20-7.09(m,1H),6.92(t,J=9.2Hz,1H),6.72(dd,J=14.6,7.3Hz,1H).
实施例3片段IV的合成
Figure PCTCN2016083011-appb-000047
4-(苄氧基)-3-氟苯胺(37)
将对羟基-3-氟苯胺(1.0g,7.87mmol)溶解在10mL无水DMF中,冷却到0℃,加入(0.88g,7.87mmol)叔丁醇钾,搅拌10min后,加入(1.35g,7.87mmol)苄溴,TLC跟踪,反应完成后加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物37粗品,柱层析得无色液体,产率52%。1H NMR(CDCl3,300MHz):δ7.41-7.28(m,5H),6.91(dd,1H),6.46(dd,1H),6.32(m,1H),4.97(s,2H),4.98(s,2H).
1-(4-(苄基氧基)-3-氟苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(41)
化合物41的合成同36,初始原料为4-(苄氧基)-3-氟苯胺(37)。1H NMR(DMSO,300MHz):δ11.93(s,1H),8.56(dd,J=7.2,1.9Hz,1H),8.10(dd,J=6.6,1.9Hz,1H),7.79-7.70(m,2H),7.65-7.37(m,7H),7.37-7.27(m,1H),7.20(t,J=8.8Hz,2H),6.70(t,J=7.0 Hz,1H),5.30(s,2H).
1-(3-氟-4-羟基苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(42)
将上述(432mg,1mmol)化合物41溶入3ml三氟乙酸中,后滴入100μl三氟甲磺酸,搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用2N的NaOH调节pH=6,EA萃取,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物42粗品,柱层析得淡黄色固体,产率87%。1H NMR(DMSO,300MHz):δ11.96(s,1H),10.40(s,1H),8.55(dd,J=7.3,2.1Hz,1H),8.08(dd,J=6.6,2.1Hz,1H),7.73(dd,J=8.9,5.0Hz,2H),7.47(dd,J=11.8,2.3Hz,1H),7.26-7.03(m,4H),6.69(t,J=6.9Hz,1H).
实施例4 片段V的合成
本片段合成参考J Med Chem,2008,51,5330-5341
Figure PCTCN2016083011-appb-000048
3-氧代-4-苯丁酸乙酯(44)
称取(2g,13.9mmol)丙二酸环(亚)异丙酯溶于40ml二氯甲烷中,加入(1.65g,20.9mmol)吡啶,冷却到0℃,后慢慢滴加(2.14g,13.9mmol)苯乙酰氯,0℃下继续搅拌反应3h,完成后加入100mlDCM冲稀,加入50ml 1N的HCl,搅拌,分离有机相,无水Na2SO4干燥,浓缩得到粗品。将粗品直接加入50ml EtOH中,回流过夜,浓缩后柱层析得浅黄色油状物,两步反应产率44%。1H NMR(CDCl3,300MHz):δ7.42-7.14(m,5H),4.15(q,J=7.1Hz,2H),3.81(s,2H),3.43(s,2H),1.24(t,J=7.2Hz,3H).
4-(二甲氨基)-2-((二甲氨基)亚甲基)-3-氧代-4-苯丁酸乙酯(45)
将上述液体加入DMF-DMA中,110℃下搅拌反应3h,反应完成后浓缩,加入EA搅拌得白色固体,产率81%。1H NMR(DMSO,300MHz):δ7.37-7.14(m,5H),7.06(s,1H),7.04(s,1H),4.07-3.87(m,2H),2.92(s,6H),2.65(s,6H),1.13(t,J=7.1Hz,3H).
4-氧代-5-苯基-1,4-二氢吡啶-3-甲酸乙酯(46)
将上述固体溶于EtOH中,加入3eq的NH4Cl,回流2h,后冷却到室温,过滤干燥得淡黄色固体,产率76%。1H NMR(DMSO,300MHz):δ8.22(s,1H),7.86(s,1H),7.64-7.56(m,2H),7.47-7.25(m,3H),4.21(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).
4-氧代-5-苯基-1,4-二氢吡啶-3-甲酸(47)
将上述固体溶于乙醇中,加入2N的NaOH,70℃搅拌反应2h,完成后冷却,加入1.5N的HCl,得固体,过滤干燥,产率90%。1H NMR(DMSO,300MHz):δ13.21(s,1H),8.62(s,1H),8.25(s,1H),7.75-7.62(m,2H),7.53-7.36(m,3H).
5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸(48)
Figure PCTCN2016083011-appb-000049
化合物48的合成同47,初始原料为对氟苯乙酰氯。1H NMR(DMSO,300MHz):δ13.21(s,1H),8.63(s,1H),8.27(s,1H),7.73(dd,J=8.7,5.7Hz,2H),7.29(t,J=8.9Hz,2H).
实施例5 N-(4-((7-氯-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(1S)的合成
Figure PCTCN2016083011-appb-000050
5-(甲氧基亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(49)
将10g米氏酸加入40ml原碳酸三甲酯中,100℃搅拌反应3h,反应完成后冷却,加入石油醚超声得大量沉淀,过滤,PE冲洗得产物,无需纯化直接用于下一步。
5,7-二氯-1,6-萘啶-4(1H)-酮(51)
将1g,6.13mmol的2,6-二氯-4-氨基吡啶溶于异丙醇中,后加入2eq化合物49,后升 温至110℃搅拌反应1h后析出大量固体,继续搅拌反应2h,后冷却到室温,用异丙醇洗,乙醚洗得产物,产率96%;
将上述得到的化合物悬浮于二苯醚中10ml/g,升温至220℃搅拌反应1h后析出大量固体,冷却到室温,加入大量PE洗涤,过滤得产物,产率94%。1H NMR(300MHz,DMSO)δ12.11(s,1H),7.93(dd,J=7.7,5.5Hz,1H),7.48(s,1H),6.17(d,J=7.5Hz,1H).
7-氯-1,6-萘啶-4(1H)-酮(52)
锌的处理:称取一定量的锌粉加入稀盐酸,加入稀盐酸的量为使锌粉缓慢冒出气泡,室温下搅拌30min,以除去锌表面的氧化层,后将水倒掉,再用水洗两次,丙酮洗两次,乙醚洗两次,减压抽干备用。
将1eq的化合物51溶于干燥的MeOH溶液中,后加入4eq的锌粉,室温下搅拌加入10eq的醋酸,后迅速升温至70℃,TLC跟踪,反应完成后过滤,浓缩后加入水超声的固体,过滤,1∶1的EtOH/Et2O洗涤得目标化合物,产率74%;1H NMR(300MHz,DMSO)δ8.99(s,1H),8.00(d,J=7.6Hz,1H),7.49(s,1H),6.17(d,J=7.6Hz,1H).
4,7-二氯-1,6-萘啶(53)
将(340mg,1.89mmol)的化合物52溶于1,2-二氯乙烷中,加入(653μl,3.95mmol)DIEA,搅拌下滴入(345μl,3.78mmol)三氯氧磷,70℃搅拌反应30min,冷却到室温,后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率94%;1H NMR(300MHz,DMSO)δ9.47(d,J=0.6Hz,1H),9.10(d,J=4.7Hz,1H),8.18(s,1H),7.94(d,J=4.8Hz,1H).
N-(4-((7-氯-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(1S)
将(0.2g,1mmol)的化合物53溶于无水DMF中,加入1.1eq的酚,后加入1.1eq叔丁醇钾,用N2置换三次,110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率76%;1H NMR(300MHz,DMSO)δ10.77(s,1H),9.92(s,1H),9.57(d,J=0.7Hz,1H),8.95(d,J=5.3Hz,1H),8.23-8.04(m,2H),7.62(dd,J=9.2,5.1Hz,2H),7.51(dd,J=11.2,2.6Hz,1H),7.36-7.13(m,3H),6.82(d,J=5.3Hz,1H),1.68-1.52(m,4H).
实施例6 N-(4-((7-二甲氨基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(2S)的合成
Figure PCTCN2016083011-appb-000051
7-(二甲氨基)-1,6-萘啶-4(1H)-酮(54)
将1eq的化合物52溶于干燥的DMF溶液中,后加入2eq的叔丁醇钾(t-BuOK),升温至110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;1H NMR(400MHz,DMSO)δ11.28(s,1H),8.80(s,1H),7.70(dd,J=7.5,5.8Hz,1H),6.22(s,1H),5.82(d,J=7.6Hz,1H),3.08(s,6H).
4-氯-1,6-萘啶-7-二甲胺(55)
将1eq的化合物54溶于1,2-二氯乙烷溶液中,后加入3eq的DIEA,2eq的三氯氧磷,升温至70℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;1H NMR(300MHz,CDCl3)δ9.23(s,1H),8.63(d,J=4.7Hz,1H),7.07(d,J=4.7Hz,1H),6.80(s,1H),3.20(d,J=0.9Hz,6H).
N-(4-((7-二甲氨基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(2S)
将(0.2g,0.97mmol)的化合物55溶于无水DMF中,加入1.1eq的酚,后加入1.1eq叔丁醇钾,用N2置换三次,110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率81%。1H NMR(300MHz,CDCl3)δ7.74-7.61(m,1H),7.43-7.29(m,2H),7.14-7.05(m,1H),7.05-6.95(m,1H),6.95-6.82(m,2H),6.72-6.64(m,1H),6.63-6.53(m,1H),6.38(d,J=2.4Hz,1H),6.20(d,J=2.3Hz,1H),3.25(s,6H),1.49(m,4H);EI MS m/z 503[M]+.
实施例7 N-(4-((7-甲氧基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(3S)的合成
Figure PCTCN2016083011-appb-000052
3-溴-2-甲氧基-4-氨基吡啶(56)
将(5g,40.3mmol)的2-甲氧基-4-氨基吡啶溶于MeCN中,0℃下分批加入(7.18g,40.3mmol)的NBS,后慢慢回到室温搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,保险粉洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率77%。1H NMR(300MHz,CDCl3)δ7.57(d,1H),6.36(d,1H),6.20(s,2H),3.7(s,3H).
7-甲氧基-1,6-萘啶-4(1H)-酮(59)
将1eq的3-溴-2-甲氧基-4-氨基吡啶溶于异丙醇中,后加入2eq化合物49,后升温至110℃搅拌反应1h后析出大量固体,2h后冷却到室温,用异丙醇洗,乙醚洗得产物化合物57,产率92%;
将上述得到的化合物悬浮于二苯醚中10ml/g,升温至220℃搅拌反应1h后析出大量固体,冷却到室温,加入大量石油醚洗涤,过滤得产物化合物58,产率96%。
将上述固体溶于甲醇中,加入2eq的甲酸铵,后加入10%重量的10%Pd/C,60℃下搅拌反应,TLC跟踪,反应完成后,冷却过滤,滤液浓缩,后用EA萃取,饱和和NaCl洗涤,无水Na2SO4干燥,减压浓缩得化合物59。1H NMR(400MHz,DMSO)δ8.89(s,1H),8.46(s,1H),7.87(d,J=7.6Hz,1H),6.75(s,1H),5.97(d,J=7.6Hz,1H),3.91(s,3H).
4-氯-7-甲氧基-1,6-萘啶(60)
将(332mg,1.89mmol)的化合物59溶于20ml乙腈中,加入(653μl,3.95mmol)DIEA,搅拌下滴入(345μl,3.78mmol)三氯氧磷,70℃搅拌反应30min,冷却到室温,后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率92%;1H NMR(300MHz,CD3OD)δ9.33(s,1H),8.85(d,J=4.8Hz,1H),7.55(d,J=4.8Hz,1H),7.23(s,1H), 4.10(s,3H).
N-(4-((7-甲氧基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(3S)
合成路线同2S,初始原料为化合物60。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.48(s,1H),8.79(d,J=5.2Hz,1H),7.94(d,J=13.3Hz,1H),7.66(dd,J=9.2,5.1Hz,2H),7.58-7.46(m,2H),7.26(s,1H),7.17(t,J=8.9Hz,2H),6.49(d,J=5.1Hz,1H),4.04(s,3H),1.55-1.36(m,4H).
实施例8 4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯胺(4S)的合成
Figure PCTCN2016083011-appb-000053
8-溴-4-氯-7-甲氧基-1,6-萘啶(61)
将(482mg,1.89mmol)的化合物58溶于10ml DMF中,搅拌下滴入(345μl,3.78mmol)三氯氧磷,室温搅拌反应30min,TLC跟踪,反应完成后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率83%;1H NMR(300MHz,CDCl3)δ9.25(s,1H),8.94(d,J=4.7Hz,1H),7.39(d,J=4.7Hz,1H),4.18(s,3H).
8-溴-4-氯-7-羟基-1,6-萘啶(62)
取3ml三氟甲磺酸于圆底烧瓶中,冰浴下分批加入(516mg,1.89mmol)的化合物61,搅拌溶解后移入180℃油浴搅拌反应10min,TLC跟踪,反应完成后冷却到室温,加入少量EA冲稀,加入大量的DCM,静置得到大量固体,过滤。滤饼用MeCN溶解,用2N的NaOH调节pH到8,得到大量黄色固体。过滤,滤饼干燥后快速柱得目标化合物,黄色固体,产率84%;1H NMR(300MHz,DMSO)δ8.86(s,1H),8.55(d,J=4.6Hz,1H),7.00 (d,J=4.8Hz,1H).
7-(4-吗啡啉乙氧基)-8-溴-4-氯-1,6-萘啶(63)
将(1.5g,5.79mmol)的化合物62溶于40ml THF中,搅拌下加入(1.14g,8.69mmol)4-羟乙基吗啉,(1.58g,8.69mmol)无水硫酸镁,室温搅拌10min,后加入(2.28g,8.69mmol)三苯基膦,慢慢滴加(1.7ml,8.69mmol)DEAD,室温搅拌6h,TLC跟踪,反应完成后EA萃取,饱和NaHCO3洗涤两次取有机相,有机相用pH等于3的稀HCl洗涤两次,取无机相,用2N的NaOH调节pH等于8,EA萃取,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率73%;1H NMR(300MHz,CDCl3)δ9.23(s,1H),8.95(d,J=4.7Hz,1H),7.62(d,J=4.6Hz,1H),4.72(t,J=5.7Hz,2H),3.77-3.62(m,4H),2.89(t,J=5.8Hz,2H),2.70-2.56(m,4H).
4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯胺(4S)
合成路线同2S,初始原料为63和对羟基-3-氟苯胺。1H NMR(DMSO,300MHz):δ9.40(s,1H),8.87(d,J=5.3Hz,1H),7.15(t,J=9.0Hz,1H),6.63-6.53(m,2H),6.50(d,J=8.6Hz,1H),5.58(s,2H),4.67(t,J=5.7Hz,2H),3.63-3.52(m,4H),2.89-2.75(m,2H),2.63-2.53(m,4H).
实施例9 2-氟-N1-(7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)苯基-1,4-二胺(5S)的合成
Figure PCTCN2016083011-appb-000054
将(0.93g,2mmol)的化合物4S溶于40ml甲醇中,加入(0.18g,4mmol)的甲酸铵,后加入20mg的10%Pd/C,60℃下反应30min,TLC跟踪,反应完成后,冷却过滤,滤液浓缩,后用EA萃取,饱和和NaCl洗涤,无水Na2SO4干燥,减压浓缩柱层析得产物。1H NMR(400MHz,DMSO)δ11.15(s,1H),9.38(s,1H),8.84(d,J=5.1Hz,1H),7.83(d,J=12.3Hz,1H),7.38-7.30(m,1H),7.29-7.17(m,1H),6.44(d,J=5.3Hz,1H),4.74(t,J=5.7Hz,2H),3.74(d,J=5.2Hz,4H),2.91(t,J=9.8Hz,2H),2.76-2.62(m,4H)。
实施例10 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(6S)的合成
Figure PCTCN2016083011-appb-000055
合成路线同2S,初始原料为化合物63和化合物26。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.45(s,1H),8.77(d,J=5.4Hz,1H),7.93(d,J=13.0Hz,1H),7.68-7.59(m,2H),7.57-7.47(m,2H),7.22(s,1H),7.18-7.12(m,1H),6.47(d,J=5.1Hz,1H),4.49(t,J=5.8Hz,2H),2.75(t,J=5.4Hz,2H),2.57-2.51(m,4H),2.41-2.26(m,4H),2.15(s,3H),1.55-1.43(m,4H).
实施例11 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(7S)的合成
Figure PCTCN2016083011-appb-000056
合成路线同5S,初始原料为6S。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.45(s,1H),8.78(d,J=5.2Hz,1H),7.93(d,J=13.9Hz,1H),7.65(dd,J=8.7,5.1Hz,2H),7.60-7.45(m,2H),7.24(s,1H),7.17(t,J=8.8Hz,2H),6.48(d,J=5.2Hz,1H),4.52(t,J=5.6Hz,2H),3.65-3.53(m,4H),2.77(t,J=5.6Hz,2H),2.56-2.50(m,4H),1.54-1.40(m,4H).
实施例12 N-(3-氟-4-((7-(2-吗啡啉丙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(8S)的合成
Figure PCTCN2016083011-appb-000057
4-氯-7-羟基-1,6-萘啶(64)
取3ml三氟甲磺酸于圆底烧瓶中,冰浴下分批加入(367mg,1.89mmol)的60,搅拌溶解后移入150℃油浴搅拌反应2h,TLC跟踪,反应完成后冷却到室温,后倒入冰中,用2N的NaOH调节pH到8,EA多次萃取,浓缩。快速柱得目标化合物,黄色固体,由于化合物不稳定,产率不稳定,产率41%;1H NMR(300MHz,DMSO)δ11.57(s,1H),9.16(s,1H),8.83(d,J=4.7Hz,1H),7.52(d,J=4.7Hz,1H),7.01(s,1H).
4-(3-((4-氯-1,6-萘啶-7-烷基)氧基)丙基)吗啉(65)
合成路线同化合物63,初始原料为N-(3-羟丙基)吗啉。1H NMR(CDCl3,300MHz):δ9.31(s,1H),8.80(d,J=4.7Hz,1H),7.32(d,J=4.6Hz,1H),7.25(s,1H),4.45(t,J=6.3Hz,2H),3.73-3.65(m,4H),2.60-2.53(m,2H),2.52-2.43(m,4H),2.05(t,J=7.0Hz,2H).
N-(3-氟-4-((7-(2-吗啡啉丙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(8S)
合成路线同化合物2S,初始原料为化合物65和化合物26。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.45(s,1H),8.77(d,J=5.2Hz,1H),7.94(d,J=12.3Hz,1H),7.73-7.61(m,2H),7.60-7.44(m,2H),7.27-7.11(m,3H),6.48(d,J=5.1Hz,1H),4.43(t,J=6.3Hz,2H),3.72-3.54(m,4H),2.49-2.21(m,5H),2.04-1.90(m,2H),1.55-1.36(m,4H).
实施例13 N-(3-氟-4-((7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(9S)的合成
Figure PCTCN2016083011-appb-000058
4-氯-7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-萘啶(66)
化合物66的合成同化合物63,初始原料为4-哌啶甲醇,产率63%。1H NMR(300MHz,CDCl3)δ9.27(s,1H),8.77(d,J=4.7Hz,1H),7.28(d,J=4.7Hz,1H),7.20(s,1H),4.21(d,J=6.2Hz,2H),2.87(d,J=11.4Hz,2H),2.33-2.21(s,3H),1.95-1.82(m,4H),1.54-1.34(m,2H),1.33-1.16(m,1H).
N-(3-氟-4-((7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(9S)
合成路线同化合物2S,初始原料为化合物66和化合物26。1H NMR(DMSO,300MHz): δ10.48(s,1H),10.05(s,1H),9.46(s,1H),8.78(d,J=5.3Hz,1H),7.95(d,J=13.1Hz,1H),7.72-7.61(m,2H),7.61-7.43(m,2H),7.25(s,1H),7.16(t,J=7.9Hz,2H),6.49(d,J=5.2Hz,1H),4.32(d,J=6.1Hz,2H),3.01-2.79(m,2H),2.69(s,3H),2.19-1.87(m,3H),1.77-1.57(m,2H),1.56-1.32(m,4H).
实施例14 N-(4-((8-溴-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(10S)的合成
Figure PCTCN2016083011-appb-000059
8-溴-4-氯-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-萘啶(67)
合成路线同63,初始原料为化合物62和1-(2-羟乙基)-4-甲基哌嗪。1H NMR(CDCl3,300MHz):δ9.20(s,1H),8.92(d,J=4.7Hz,1H),7.37(d,J=4.7Hz,1H),4.69(t,J=5.9Hz,2H),2.89(t,J=5.9Hz,2H),2.79-2.61(m,4H),2.54-2.34(m,4H),2.26(s,3H).
N-(4-((8-溴-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(10S)
合成路线同化合物2S,初始原料为化合物67和化合物26。1H NMR(DMSO,300MHz):δ10.47(s,1H),10.02(s,1H),9.43(s,1H),8.89(d,J=5.3Hz,1H),7.95(d,J=12.4Hz,1H),7.77-7.44(m,3H),7.17(t,J=8.2Hz,2H),6.62(d,J=5.4Hz,1H),4.66(t,J=5.1Hz,2H),3.41-3.24(m,4H),2.85(t,J=5.4Hz,2H),2.78-2.57(m,4H),2.39(s,3H),1.56-1.32(m,4H).
实施例15 N-(3-氟-4-((7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(11S)的合成
Figure PCTCN2016083011-appb-000060
合成路线同化合物5S,初始原料为化合物10S。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.45(s,1H),8.77(d,J=5.4Hz,1H),7.93(d,J=13.0Hz,1H),7.68-7.59(m,2H),7.57-7.47(m,2H),7.22(s,1H),7.18-7.12(m,1H),6.47(d,J=5.1Hz,1H), 4.49(t,J=5.8Hz,2H),2.75(t,J=5.4Hz,2H),2.57-2.51(m,4H),2.41-2.26(m,4H),2.15(s,3H),1.55-1.43(m,4H).
实施例16 N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(12S)的合成
Figure PCTCN2016083011-appb-000061
4-(2-((4-氯-1,6-萘啶-7-烷基)氧基)乙基)吗啉(68)
合成路线同化合物63,初始原料为化合物64和4-羟乙基吗啉。1H NMR(DMSO,300MHz):δ9.27(s,1H),8.77(d,J=4.7Hz,1H),7.29(d,J=4.7Hz,1H),7.24(s,1H),4.54(t,J=5.8Hz,2H),3.72-3.66(m,4H),2.83(t,J=5.8Hz,2H),2.61-2.53(m,4H).
N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(12S)
合成路线同化合物2S,初始原料为化合物68和化合物31。1H NMR(DMSO,300MHz):δ10.24(s,1H),10.06(s,1H),9.42(s,1H),8.75(d,J=5.2Hz,1H),7.80(d,J=9.1Hz,2H),7.71-7.57(m,2H),7.31(d,J=9.0Hz,2H),7.23-7.10(m,3H),6.43(d,J=5.2Hz,1H),4.52(t,J=7.2Hz,2H),3.58(d,J=4.9Hz,4H),2.77(t,J=7.1Hz,2H),2.52(m,4H),1.63-1.38(m,2H).
实施例17 N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氨基)苯基)环丙基-1,1-二酰胺(13S)的合成
Figure PCTCN2016083011-appb-000062
将1eq的化合物68溶于干燥的DMF溶液中,后加入1.2eq的68,升温至130℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;产率72%。1H NMR(DMSO,300MHz):δ10.16(s,1H),10.07(s,1H),9.47(s,1H),8.42(s,1H),7.84-7.59(m,5H),7.33(d,J=8.6Hz,2H),7.17(t,J=8.8Hz,2H),6.98(s,1H),6.61(d,J=5.6Hz,1H),4.47(t,J= 5.9Hz,2H),3.66-3.55(m,4H),2.76(t,J=5.7Hz,2H),2.51-2.48(m,4H),1.55-1.39(m,4H).
实施例18 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)-N-甲基环丙基-1,1-二酰胺(14S)的合成
Figure PCTCN2016083011-appb-000063
合成路线同化合物2S,初始原料为化合物68和化合物27。1H NMR(DMSO,300MHz):δ10.00(s,1H),9.45(s,1H),8.79(d,J=5.0Hz,1H),7.60-7.39(m,3H),7.37-7.27(m,2H),7.24(s,1H),7.21-7.05(m,2H),6.46(d,J=5.1Hz,1H),4.52(t,J=6.3Hz,2H),3.66-3.51(m,4H),3.25(s,3H),2.77(t,J=6.0Hz,2H),2.56-2.49(m,4H),1.51-1.38(m,2H),1.30-1.20(m,2H).
实施例22 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(15S)的合成
Figure PCTCN2016083011-appb-000064
合成路线同化合物2S,初始原料为化合物68和化合物36。1H NMR(DMSO,300MHz):δ12.18(s,1H),9.52(s,1H),8.83(d,J=5.3Hz,1H),8.61(d,J=7.2Hz,1H),8.22-8.06(m,2H),7.71-7.47(m,4H),7.53-7.23(m,3H),6.76(t,J=7.5Hz,1H),6.61(d,J=5.1Hz,1H),4.90-4.75(m,2H),4.02-3.76(m,4H),3.69-3.60(m,2H),2.53-2.43(m,4H).
实施例23 1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(16S)的合成
Figure PCTCN2016083011-appb-000065
合成路线同化合物2S,初始原料为化合物68和化合物42。1H NMR(DMSO,300MHz):δ11.65(s,1H),9.46(s,1H),8.74(s,2H),7.74-7.60(m,3H),7.56-7.40(m,2H),7.38-7.30(m,1H),7.28(s,1H),7.02(t,J=8.7Hz,2H),6.65(t,J=7.1Hz,1H),6.48(d,J=5.3Hz,1H),4.58(t,J=5.3Hz,2H),3.82-3.66(m,4H),2.88(t,J=5.6Hz,2H),2.71-2.54(m,4H).
实施例24 1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(17S)的合成
Figure PCTCN2016083011-appb-000066
1-(3-氟-4-羟基苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(69)的合成
将(400mg,1.13mmol)25溶液3ml的TFA中,加入3%的三氟甲磺酸,室温搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。1H NMR(DMSO,300MHz):δ10.31(s,1H),8.11(d,J=7.1Hz,1H),7.93(d,J=4.6Hz,1H),7.34(d,J=11.5Hz,1H),7.05(s,2H),6.39(t,J=6.3Hz,1H),3.76(s,3H).
1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(17S)的合成
合成路线同化合物2S,初始原料为化合物68和化合物69。1H NMR(CDCl3,300MHz):δ9.45(s,1H),8.72(d,J=5.2Hz,1H),8.27(d,J=4.9Hz,1H),7.61(d,J=4.7Hz,2H),7.49-7.37(m,2H),7.29(d,J=9.2Hz,1H),6.47-6.32(m,2H),4.57(t,J=5.8Hz,2H),3.91(s,3H),3.79-3.65(m,4H),2.88(t,J=5.7Hz,2H),2.71-2.56(m,4H).
实施例25 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-2-苯乙酰胺(18S)的合成
Figure PCTCN2016083011-appb-000067
将(100mg,0.22mmol)4S溶于10ml THF中,加入3eq的DIEA,冷却到0℃。将1.5eq苯乙酰氯慢慢加入,继续保持温度搅拌反应1h。反应完全后,加入EA冲稀,用 饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。产率86%。1H NMR(CDCl3,300MHz):δ10.58(s,1H),9.43(s,1H),8.87(d,J=5.3Hz,1H),7.92(d,J=13.3Hz,1H),7.64-7.20(m,6H),6.64(d,J=5.2Hz,1H),4.67(t,J=5.7Hz,2H),3.70(s,2H),3.63-3.49(m,4H),2.82(t,J=6.0Hz,2H),2.60-2.50(m,4H).
实施例26 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-4-氧代-5-苯基-1,4-二氢吡啶-3-碳酰胺(19S)的合成
Figure PCTCN2016083011-appb-000068
将(100mg,0.22mmol)化合物4S、(71mg,0.33mmol)化合物47溶于10ml DCM中,室温下加入(130mg,0.66mmol)HOBt、(89mg,0.66mmol)EDC,室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得目标化合物。产率63%。1H NMR(DMSO,300MHz):δ13.60(s,1H),9.44(s,1H),8.89(s,1H),8.65(s,1H),8.26-8.04(m,2H),7.74-7.63(m,2H),7.63-7.30(m,5H),6.69(d,J=5.4Hz,1H),4.68(t,J=5.7Hz,2H),3.64-3.53(m,4H),2.81(t,J=5.8Hz,2H),2.60-2.52(m,4H).
实施例27 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-4-氧代-5-苯基-1,4-二氢吡啶-3-碳酰胺(20S)的合成
Figure PCTCN2016083011-appb-000069
合成路线同化合物5S,初始原料为化合物19S。1H NMR(DMSO,300MHz):δ13.31(s,1H),9.47(s,1H),8.78(d,J=5.2Hz,1H),8.65(s,1H),8.17-8.04(m,2H),7.67(d,J=6.8Hz,2H),7.61-7.53(m,2H),7.50-7.32(m,4H),7.25(s,1H),6.56(d,J=5.2Hz,1H),4.54(t,J=5.7Hz,2H),3.65-3.54(m,4H),2.81(t,J=6.8Hz,2H),2.58-2.52(m,4H).
实施例28 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(21S)的合成
Figure PCTCN2016083011-appb-000070
合成路线同化合物19S,初始原料为化合物4S和化合物48。1H NMR(DMSO,300MHz):δ13.39(s,1H),9.44(s,1H),8.89(d,J=5.3Hz,1H),8.65(s,1H),8.18-8.03(m,2H),7.81-7.65(m,2H),7.55(s,2H),7.34-7.20(m,2H),6.68(d,J=4.3Hz,1H),4.68(t,J=5.6Hz,2H),3.61-3.54(m,4H),2.81(t,J=5.7Hz,2H),2.61-2.53(m,4H).
实施例29 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(22S)的合成
Figure PCTCN2016083011-appb-000071
合成路线同化合物5S,初始原料为化合物21S。1H NMR(DMSO,300MHz):δ13.26(s,1H),9.46(s,1H),8.78(d,J=5.3Hz,1H),8.64(s,1H),8.16-8.07(m,2H),7.76-7.67(m,3H),7.55-7.48(m,2H),7.30-7.24(m,3H),6.55(d,J=5.4Hz,1H),4.54(t,J=5.6Hz,2H),3.63-3.57(m,4H),2.82(t,J=7.3Hz,2H),2.61-2.52(m,4H).
实施例30 N-(3,4-二氟苯基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(23S)的合成
Figure PCTCN2016083011-appb-000072
N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(3,4-二氟苯基)环丙基-1,1-二酰胺(70)
合成路线同化合物2S,初始原料为化合物63和化合物28。1H NMR(DMSO,300MHz):δ10.40(s,1H),10.21(s,1H),9.43(s,1H),8.89(d,J=5.4Hz,1H),7.94(d,J=13.6Hz,1H),7.89-7.75(m,1H),7.64-7.48(m,2H),7.46-7.32(m,2H),6.62(d,J=5.3Hz,1H), 4.68(t,J=5.7Hz,2H),3.67-3.52(m,4H),2.83(t,J=6.0Hz,2H),2.68-2.54(m,4H),1.57-1.41(m,4H).
N-(3,4-二氟苯基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(23S)
合成路线同化合物5S,初始原料为化合物70。1H NMR(CD3OD,300MHz):δ9.48(d,J=0.6Hz,1H),8.71(d,J=5.4Hz,1H),7.86(d,J=12.7Hz,1H),7.71(dd,J=11.7,6.3Hz,1H),7.46-7.36(m,2H),7.28-7.15(m,3H),6.52(d,J=5.4Hz,1H),4.70-4.64(m,2H),3.80-3.71(m,4H),3.08-3.01(m,2H),2.85-2.75(m,4H),1.64(m,4H).
实施例31 N-(4-氟-3-甲氧基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(24S)的合成
Figure PCTCN2016083011-appb-000073
N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(3-甲氧基-4-氟苯基)环丙基-1,1-二酰胺(71)
合成路线同化合物2S,初始原料为化合物63和化合物29。1H NMR(DMSO,300MHz):δ10.40(s,1H),10.00(s,1H),9.43(s,1H),8.88(d,J=7.4Hz,1H),7.94(d,J=12.9Hz,1H),7.64-7.50(m,3H),7.25-7.14(m,2H),6.60(d,J=8.2Hz,1H),4.66(t,J=6.1Hz,2H),3.81(s,3H),3.64-3.55(m,4H),2.80(t,J=8.4Hz,2H),2.65-2.55(m,4H),1.54-1.44(m,4H).
N-(4-氟-3-甲氧基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(24S)
合成路线同化合物5S,初始原料为化合物71。1H NMR(DMSO,300MHz):δ9.97(s,1H),9.44(s,1H),9.32(s,1H),8.68(d,J=5.1Hz,1H),8.30(s,1H),7.80(t,J=12.8Hz,1H),7.45-7.29(m,2H),7.23-7.19(m,1H),7.06-6.83(m,2H),6.32(t,J=4.9Hz,1H),4.56(t,J=5.7Hz,2H),3.89(s,3H),3.79-3.69(m,4H),2.88(t,J=5.8Hz,2H),2.68-2.57(m,4H),1.83-1.75(m,2H),1.68-1.57(m,2H).
实施例32 N-(3-氟-4-((7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(25S)的合成
Figure PCTCN2016083011-appb-000074
8-溴-4-氯-7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘(72)
合成路线同化合物63,初始原料为化合物62和1-(2-羟乙基)吡啶。1H NMR(CDCl3,300MHz):δ9.21(s,1H),8.94(d,J=4.7Hz,1H),8.52(d,J=5.9Hz,2H),7.40(d,J=4.7Hz,1H),7.30(d,J=5.9Hz,2H),4.77(t,J=6.5Hz,2H),3.18(t,J=6.5Hz,2H).
N-(4-((8-溴-7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(73)
合成路线同化合物2S,初始原料为化合物72和化合物26。1H NMR(DMSO,300MHz):δ10.44(s,1H),10.01(s,1H),9.44(s,1H),8.89(d,J=5.3Hz,1H),8.51(d,J=7.6Hz,2H),7.94(d,J=13.9Hz,1H),7.69-7.62(m,2H),7.58-7.48(m,2H),7.49-7.37(m,2H),7.17(t,J=8.9Hz,2H),6.62(d,J=6.2Hz,1H),4.80(t,J=7.2Hz,2H),3.16(t,J=7.2Hz,2H),1.54-1.43(m,4H).
N-(3-氟-4-((7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(25S)
合成路线同化合物5S,初始原料为化合物73。1H NMR(CDCl3,300MHz):δ10.19(s,1H),9.44(s,1H),8.68(d,J=5.2Hz,1H),8.52(d,J=6.0Hz,2H),8.10(s,1H),7.78(dd,J=12.1,2.3Hz,1H),7.48-7.38(m,2H),7.29-7.25(m,3H),7.21(m,2H),7.10-6.99(m,2H),6.33(d,J=5.4Hz,1H),4.67(t,J=6.7Hz,2H),3.17(t,J=6.6Hz,2H),1.86-1.76(m,2H),1.61-1.57(m,2H).
实施例33 N-(3-氟-4-((7-((1-吗啡啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(26S)的合成
Figure PCTCN2016083011-appb-000075
4-(2-((8-溴-4-氯-1,6-二氮杂萘-7-烷基)氧代)丙基)吗啡啉(74)
合成路线同化合物63,初始原料为化合物62和N-(2-羟丙基)吗啉。1H NMR(CDCl3,300MHz):δ9.21(s,1H),8.93(d,J=4.7Hz,1H),7.38(d,J=4.7Hz,1H),5.68-5.57(m,1H),3.57(t,J=4.6Hz,4H),2.65-2.50(m,4H),1.81-1.66(m,2H),1.43(d,J=6.2Hz,3H).
N-(4-((8-溴-7-((1-吗啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(75)
合成路线同化合物2S,初始原料为化合物74和化合物26。1H NMR(CDCl3,300MHz):δ110.20(s,1H),9.35(s,1H),8.81(d,J=5.3Hz,1H),8.00(s,1H),7.78(d,J=12.4Hz,1H),7.48-7.38(m,2H),7.28-7.25(m),7.06(t,J=8.6Hz,2H),6.40(d,J=5.4Hz,1H),5.72-5.59(m,1H),3.60(t,J=4.4Hz,4H),2.63-2.53(m,4H),1.86-1.78(m,2H),1.63-1.58(m,4H),1.45(d,J=6.3Hz,3H).
N-(3-氟-4-((7-((1-吗啡啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(26S)
合成路线同化合物5S,初始原料为化合物75。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.44(s,1H),8.75(d,J=5.2Hz,1H),7.93(dd,J=13.1,2.3Hz,1H),7.64(dd,J=9.1,5.0Hz,2H),7.59-7.45(m,2H),7.22-7.10(m,3H),6.46(d,J=5.2Hz,1H),5.58-5.46(m,1H),3.55-3.48(m,4H),2.78-2.56(m,2H),2.50-2.43(m,4H),1.52-1.44(m,4H),1.34(d,J=6.2Hz,3H).
实施例34 N-(3-氟-4-((7-吗啡啉-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(27S)的合成
Figure PCTCN2016083011-appb-000076
7-吗啡啉-1,6-二氮杂萘-4(1H)-酮(76)
将(340mg,1.89mmol)的化合物52溶于吗啡啉中,190℃下反应1h,TLC跟踪,反应完成后冷却到室温,加入乙醚沉淀,过滤,乙醚洗得粗品。1H NMR(DMSO,400MHz):δ8.83(s,1H),7.74(d,J=7.6Hz,1H),6.45(s,1H),5.87(d,J=7.6Hz,1H),3.75-3.65(m,4H),3.54-3.45(m,4H).
N-(3-氟-4-((7-吗啡啉-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(27S)
合成路线同化合物2S,初始原料为化合物76。1H NMR(DMSO,400MHz):δ10.54(s,1H),10.02(s,1H),9.55(s,1H),8.84(d,J=6.0Hz,1H),7.99(d,J=12.8Hz,1H),7.72-7.62(m,2H),7.62-7.51(m,2H),7.17(t,J=8.5Hz,2H),7.03(s,1H),6.63(d,J=7.1Hz,1H),3.84-3.76(m,4H),3.75-3.69(m,4H),1.57-1.43(m,4H).
实施例35 N-(3-氟-4-((7-(4-吗啡啉哌啶-1-基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(28S)的合成
Figure PCTCN2016083011-appb-000077
合成路线同化合物27S,初始原料为4-(4-哌啶基)吗啉。1H NMR(CDCl3,300MHz):δ10.05(s,1H),9.39(s,1H),8.55(d,J=5.3Hz,1H),8.15(s,1H),7.75(d,J=12.5Hz,1H),7.43(dd,J=9.3,4.4Hz,2H),7.23-7.16(m,1H),7.05(t,J=8.8Hz,2H),6.96(s,1H),6.17(d,J=4.7Hz,1H),4.50(d,J=12.3Hz,2H),3.84-3.63(m,4H),3.04-2.85(m,2H),2.67-2.54(m,4H),2.52-2.41(m,1H),2.04-1.92(m,2H),1.87-1.75(m,2H),1.69-1.54(m,4H).
实施例36(S)-N-(3-氟-4-((7-(2-(3-甲基吗啡啉)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(29S)的合成
Figure PCTCN2016083011-appb-000078
合成路线同化合物26S,初始原料为化合物62和(S)-2-(3-甲基吗啉)乙醇。1H NMR(CDCl3,300MHz):δ10.17(s,1H),9.45(s,1H),8.68(d,J=5.2Hz,1H),8.10(s,1H),7.77(d,J=12.3Hz,1H),7.43(dd,J=9.0,4.8Hz,2H),7.30-7.22(m,3H),7.05(t,J=8.6Hz,2H),6.32(d,J=4.9Hz,1H),4.53(t,J=6.0Hz,2H),3.80(d,J=11.5Hz,1H),3.72-3.60(m,2H), 3.31-3.15(m,2H),2.95-2.74(m,2H),2.65-2.51(m,2H),1.85-1.77(m,2H),1.63-1.56(m,2H),1.04(d,J=6.3Hz,3H).
实施例37(R)-N-(3-氟-4-((7-(2-(3-甲基吗啡啉)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(30S)的合成
Figure PCTCN2016083011-appb-000079
合成路线同化合物26S,初始原料为化合物62和(R)-2-(3-甲基吗啉)乙醇。1H NMR(CDCl3,300MHz):δ10.19(s,1H),9.45(s,1H),8.68(d,J=5.2Hz,1H),8.13(s,1H),7.77(d,J=12.5Hz,1H),7.55-7.35(m,2H),7.27-7.19(m,2H),7.05(t,J=8.6Hz,2H),6.33(d,J=5.2Hz,1H),4.55(t,J=4.5Hz,2H),3.86-3.74(m,1H),3.75-3.60(m,2H),3.37-3.14(m,2H),3.01-2.76(m,2H),2.70-2.51(m,2H),1.87-1.74(m,2H),1.68-1.53(m,2H),1.05(d,J=6.1Hz,3H).
实施例38 N-(4-((7-(2-(1H-咪唑-1-基)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(31S)的合成
Figure PCTCN2016083011-appb-000080
合成路线同化合物26S,初始原料为化合物62和2-(1H-咪唑-1-烷基)乙醇。1H NMR(CDCl3,300MHz):δ10.40(s,1H),9.41(s,1H),8.68(d,J=5.3Hz,1H),8.55(s,1H),7.78(d,J=12.1Hz,1H),7.65(s,1H),7.43(dd,J=9.0,4.7Hz,2H),7.33-7.26(m,1H),7.24-7.15 (m,2H),7.11-6.97(m,4H),6.34(d,J=5.2Hz,1H),4.72(t,J=5.3Hz,2H),4.41(t,J=5.2Hz,2H),1.86-1.75(m,2H),1.67-1.55(m,2H).
实施例39 N-(4-((7-(4-苄基哌嗪基-1-基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(32S)的合成
Figure PCTCN2016083011-appb-000081
合成路线同化合物27S,初始原料为4-苄基吗啉。1H NMR(CDCl3,300MHz):δ10.03(s,1H),9.39(s,1H),8.55(d,J=5.3Hz,1H),8.18(s,1H),7.74(d,J=12.1Hz,1H),7.49-7.39(m,2H),7.39-7.26(m,5H),7.23-7.15(m,1H),7.05(t,J=8.5Hz,2H),6.92(s,1H),6.18(d,J=5.1Hz,1H),3.74-3.63(m,4H),3.57(s,2H),2.69-2.54(m,4H),1.84-1.75(m,2H),1.61-1.54(m,2H).
实施例40 N-(3-氟-4-((3-氧代-3,4-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(33S)的合成
N-(3-氟-4-((2-氧代-1,2-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(34S)的合成
Figure PCTCN2016083011-appb-000082
N-(4-((2-氨基-3-硝基吡啶-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(88)
将(1g,5.8mmol)的2-氨基-3-硝基-4-氯吡啶溶于无水DMF中,加入1.1eq的26,后加入1.1eq叔丁醇钾,用N2置换三次,80℃搅拌反应1h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,81%。1H NMR(300MHz,DMSO)δ10.64(s,1H),9.94(s,1H),8.05(d,J=5.7Hz,1H),7.97(t,J=8.6Hz,1H),7.62(dd,J=9.0,5.0Hz,2H),7.32(d,J=11.2Hz,1H),7.25(s,2H),7.18(t,J=8.9Hz,2H),7.06(d,J=8.4Hz,1H),6.06(d,J=5.6Hz,1H),1.58(t,J=10.6Hz,4H).
N-(4-((2,3-二氨基吡啶-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(89)
将1eq的化合物88溶于20ml THF/MeOH(V∶V=1∶1)溶液中,后加入4eq的NiCl2·6H2O,0℃下搅拌下分批加入2eq的NaBH4,继续搅拌反应10min,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。1H NMR(300MHz,CD3OD)δ8.02(d,J=5.7Hz,1H),7.87(dd,J=13.2,2.3Hz,1H),7.68-7.58(m,2H),7.48(d,J=9.0Hz,1H),7.36(t,J=9.0Hz,1H),7.24(s,1H),7.20-7.07(m,2H),5.97(d,J=5.7Hz,1H),1.52-1.40(m,4H).
N-(3-氟-4-((3-氧代-3,4-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(33S)的合成
N-(3-氟-4-((2-氧代-1,2-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(34S)的合成
将(100mg,0.23mmol)化合物89溶于乙醇中,60℃搅拌下,加入2eq的醛基乙酸乙酯的甲苯溶液,继续搅拌反应3h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。产率: 33S:31%,34S:48%。33S:1H NMR(DMSO,300MHz):δ12.96(s,1H),10.40(s,1H),10.01(s,1H),8.37(d,J=5.7Hz,1H),8.20(s,1H),7.91(d,J=13.3Hz,1H),7.65(dd,J=9.1,5.1Hz,2H),7.51(d,J=8.0Hz,1H),7.39(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.56(d,J=5.6Hz,1H),1.58-1.36(m,4H).34S:1H NMR(DMSO,300MHz):δ12.67(s,1H),10.41(s,1H),10.00(s,1H),8.43(s,1H),8.35(d,J=5.4Hz,1H),7.89(d,J=13.7Hz,1H),7.64(dd,J=8.7,5.0Hz,2H),7.50(d,J=9.2Hz,1H),7.40(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),6.81(d,J=5.5Hz,1H),1.49-1.44(m,4H).
实施例41 N-(4-((7-((1-乙基-3-氟哌啶-4-基)氨基)-1,6-萘啶-4-基)氧基)-3-氟苯基)-2-(4-氟苯基)-3-氧-2,3-二氢哒嗪-4-碳酰胺(35S)的合成
Figure PCTCN2016083011-appb-000083
合成路线同27S,初始原料为N-乙基-4-氨基-3-氟哌啶。1H NMR(DMSO,300MHz):δ9.06(d,J=15.0Hz,1H),8.93(s,1H),8.82(d,J=12.5Hz,1H),8.59(d,J=12.3Hz,1H),7.55(dd,J=16.0,3.0Hz,1H),7.50-7.41(m,2H),7.41-7.31(m,2H),7.25(d,J=14.8Hz,1H),7.16(s,1H),7.12(dd,J=14.9,3.0Hz,1H),6.83(dd,J=14.9,10.0Hz,1H),5.23-4.91(m,1H),4.06-3.80(m,1H),3.23-2.98(m,1H),2.83-2.69(m,1H),2.57-2.28(m,4H),2.19-2.02(m,1H),1.86-1.68(m,1H),1.09(t,J=12.6Hz,3H).
实施例42 N-(3-氟-4-((7-(2-吗啡啉-2-乙酰氧基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(36S)的合成
Figure PCTCN2016083011-appb-000084
合成路线同化合物26S,初始原料为化合物62和2-羟基-1-吗啡啉乙酰胺。1H NMR(CDCl3,300MHz):δ10.07(s,1H),9.37(s,1H),8.72(s,1H),8.65(d,J=5.3Hz,1H),7.62(d,J=12.0Hz,1H),7.50-7.41(m,2H),7.31(s,1H),7.21-7.14(m,1H),7.13-7.07(m,1H),7.07-7.00(m,2H),6.24(d,J=5.9Hz,1H),5.18(s,2H),3.79-3.68(m,4H),3.68-3.56(m,4H),1.80-1.72(m,2H),1.62-1.57(m,2H).
实施例43 N-(3-氟-4-((7-(2-(3-氧代吗啡啉)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(37S)的合成
Figure PCTCN2016083011-appb-000085
合成路线同化合物26S,初始原料为化合物62和2-羟基乙基-2-吗啡啉酮。1H NMR(CDCl3,300MHz):δ10.23(s,1H),9.43(s,1H),8.68(d,J=5.3Hz,1H),8.26(s,1H),7.78(d,J=12.0Hz,1H),7.43(dd,J=8.9,4.7Hz,2H),7.29(d,J=8.8Hz,1H),7.24-7.17(m,2H),7.05(t,J=8.5Hz,2H),6.34(d,J=5.2Hz,1H),4.63(t,J=4.9Hz,2H),4.17(s,2H),3.93-3.81(m,4H),3.67-3.55(m,2H),1.86-1.75(m,2H),1.65-1.54(m,2H).
实施例44 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(38S)的合成
Figure PCTCN2016083011-appb-000086
将(50mg,0.10mmol)化合物1S溶于的二氧六环水中(v∶v=3∶2)中,后加入2eq的磷酸钾,2eq的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑,N2保护下130℃下搅拌反应3h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率81%。1H NMR(CDCl3,300MHz):δ10.20(s,1H),9.70(s,1H),8.73(d,J=5.4Hz,1H),8.23(s,1H),8.06(d,J=8.3Hz,2H),7.96(s,1H),7.78(d,J=12.0Hz,1H),7.50-7.35(m,2H),7.30-7.26(m,1H),7.04(t,J=8.6Hz,2H),6.46(d,J=5.3Hz,1H),3.98(s,3H),1.84-1.78(m,2H),1.63-1.57(m,2H).
实施例45 N-(4-((7-(1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(39S)的合成
Figure PCTCN2016083011-appb-000087
合成路线同化合物38S,初始原料为化合物1S和1-叔丁氧基甲酰-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(CDCl3,300MHz):δ9.61(s,1H),8.64(d,J=5.3Hz,1H),8.14(s,1H),7.93(s,1H),7.69(d,J=12.0Hz,1H),7.41-7.31(m,2H),7.31-7.20(m,2H),7.20-7.06(m,1H),6.91(t,J=8.5Hz,2H),6.46(d,J=5.3Hz,1H),1.69-1.49(m,4H).
实施例46 N-(3-氟-4-((7-(1-(甲磺酰基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(40S)的合成
Figure PCTCN2016083011-appb-000088
将化合物39S溶于四氢呋喃中,室温搅拌下加入2eq的DIEA,后慢慢滴加1.1eq的甲基磺酰氯,继续室温下搅拌反应30min,TLC跟踪,反应完成后加入EA冲稀,用饱和的Na2CO3溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率68%。1H NMR(CDCl3,300MHz):δ10.25(s,1H),9.77(s,1H),8.93-8.86(m,1H),8.80(d,J=6.0Hz,1H),8.69(s,1H),8.43(s,1H),8.07(s,1H),7.99(s,1H),7.80(d,J=11.7Hz,1H),7.45-7.41(m,2H),7.32-7.28(m,1H),7.09-7.00(m,2H),6.55(d,J=5.5Hz,1H),3.41(s,3H),1.85-1.80(m,2H),1.59-1.57(m,2H).
实施例47 N-(3-氟-4-((7-(1-(异丙基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(41S)的合成
Figure PCTCN2016083011-appb-000089
合成路线同化合物38S,初始原料为化合物1S和1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(CDCl3,300MHz):δ10.22(s,1H),9.75(d,J=0.8Hz,1H),8.78(d,J=5.3Hz,1H),8.18(s,2H),8.13(s,1H),8.02(d,J=0.8Hz,1H),7.83(dd,J=12.1,2.2Hz,1H),7.50-7.43(m,2H),7.33-7.31(m,1H),7.30-7.29(m,1H),7.14-7.05(m,2H),6.50(dd,J=5.3,1.2Hz,1H),4.61(dt,J=13.4,6.7Hz,1H),1.85(dd,J=7.9,4.8Hz,2H),1.65-1.60(m,8H).
实施例48 N-(3-氟-4-((7-(1-(哌啶-4烷基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(42S)的合成
Figure PCTCN2016083011-appb-000090
化合物96的合成同化合物38S,初始原料为化合物1S和4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯。1H NMR(CDCl3,300MHz):δ10.21(s,1H),9.70(s,1H),8.74(d,J=5.3Hz,1H),8.27-8.07(m,3H),7.97(s,1H),7.79(d,J=12.0Hz,1H),7.43(dd,J=9.0,4.8Hz,2H),7.35-7.26(m,2H),7.05(t,J=8.5Hz,1H),6.46(d,J=5.2Hz,1H),4.46-4.18(m,3H),3.03-2.82(m,2H),2.30-2.12(m,2H),2.07-1.89(m,2H),1.88-1.76(m,2H),1.66-1.55(m,2H),1.47(s,9H).
将化合物96溶于DCM中,加入5%的TFA,室温下搅拌反应30min,TLC跟踪反应,反应完成后浓缩,柱层析得产物42S。1H NMR(DMSO,300MHz):δ9.72(s,1H),8.82(d,J=5.5Hz,1H),8.45(s,1H),8.25(s,1H),8.08(s,1H),7.88(d,J=12.5Hz,1H),7.56(dd,J=9.1,4.8Hz,2H),7.51-7.35(m,2H),7.07(t,J=8.8Hz,2H),6.69(d,J=5.4Hz,1H),4.73-4.60(m,1H),3.68-3.50(m,2H),3.27-3.18(m,2H),2.48-2.22(m,4H),1.69-1.54(m,4H).
实施例48 N-(3-氟-4-((7-(1-(1-异丙基哌啶-4烷基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(43S)的合成
Figure PCTCN2016083011-appb-000091
将化合物42S溶于乙腈中,室温搅拌下加入2eq的碳酸铯,后滴加2eq的2-碘代丙烷,升温至85℃下搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的Na2CO3溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率 67%。1H NMR(CD3OD,300MHz):δ9.64(s,1H),8.64(d,J=5.4Hz,1H),8.44(s,1H),8.23(s,1H),8.04(s,1H),7.44-7.36(m,2H),7.18(t,J=8.7Hz,2H),7.03-6.96(m,1H),6.89-6.81(m,2H),6.25(d,J=5.2Hz,1H),5.29-5.19(m,1H),4.73-4.59(m,1H),3.67-3.56(m,4H),2.46-2.41(m,4H),1.49(m,2H),1.42-1.39(m,8H).
实施例49 N-(4-((7-(3,5-二甲基异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(45S)的合成
Figure PCTCN2016083011-appb-000092
7-溴-4-氯-1,6-二氮杂萘(97)
化合物97的合成同53,起始原料为2,6-二溴-4-氨基吡啶。1H NMR(300MHz,CDCl3)δ9.40(s,1H),8.93(d,J=4.7Hz,1H),8.16(s,1H),7.57(d,J=4.7Hz,1H).
4-(4-氯-1,6-二氮杂萘-7-烷基)-3,5-二甲基异恶唑(98)
化合物97的合成同38S,起始原料为3,5-二甲基异恶唑-4-硼酸频哪醇酯,反应温度为50℃。1H NMR(400MHz,DMSO)δ9.68(s,1H),9.09(d,J=4.8Hz,1H),8.11(s,1H),7.92(d,J=4.7Hz,1H),2.67(s,3H),2.47(s,3H).
N-(4-((7-(3,5-二甲基异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(45S)
化合物45S的合成同1S,起始原料为98和26。1H NMR(300MHz,CDCl3)δ10.28(s,1H),9.83(s,1H),8.81(d,J=5.3Hz,1H),7.99(s,1H),7.88(s,1H),7.81(d,J=12.4Hz,1H),7.53-7.37(m,2H),7.28(m,2H),7.06(t,J=8.6Hz,2H),6.56(d,J=5.2Hz,1H),2.67(s,3H),2.52(s,3H),1.83(m,2H),1.60(m,2H).
实施例50 N-(3-氟-4-((7-(吡啶-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(46S)的合成
Figure PCTCN2016083011-appb-000093
化合物46S的合成同化合物38S,初始原料为化合物1S和4-吡啶硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.39(s,1H),9.92(s,1H),8.89(d,J=5.3Hz,1H),8.82(s,2H),8.44(s,1H),8.14(d,J=4.5Hz,2H),7.86(dd,J=12.1,2.2Hz,1H),7.54-7.43(m,2H),7.39-7.30(m,2H),7.17-7.04(m,2H),6.65(d,J=5.2Hz,1H),1.93-1.87(m,2H),1.70-1.60(m,2H).
实施例51 N-(3-氟-4-((7-(嘧啶-5-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(47S)的合成
Figure PCTCN2016083011-appb-000094
化合物47S的合成同化合物38S,初始原料为化合物1S和嘧啶-5-硼酸嚬哪醇酯。1H NMR(400MHz,DMSO):δ10.46(s,1H),10.03(s,1H),9.88(s,1H),9.67(s,2H),9.32(s,1H),8.97(d,J=5.3Hz,1H),8.75(s,1H),7.96(d,J=13.5Hz,1H),7.65(dd,J=9.1,5.1Hz,2H),7.61-7.51(m,2H),7.17(t,J=8.9Hz,2H),6.79(d,J=5.4Hz,1H),1.53-1.44(m,4H).
实施例52 N-(3-氟-4-((7-(4-硝基苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(48S)的合成
Figure PCTCN2016083011-appb-000095
化合物48S的合成同化合物38S,初始原料为化合物1S和4-硝基苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.47(s,1H),10.03(s,1H),9.88(s,1H),8.97(d,J=5.3Hz,1H),8.69(s,1H),8.62(s,1H),8.60(s,1H),8.41(s,1H),8.39(s,1H),7.97(d,J=12.7Hz,1H), 7.65(dd,J=9.1,5.1Hz,2H),7.59-7.54(m,2H),7.17(t,J=8.9Hz,2H),6.79(d,J=4.8Hz,1H),1.53-1.44(m,4H).
实施例52 N-(3-氟-4-((7-(3,4-二氟苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(49S)的合成
Figure PCTCN2016083011-appb-000096
化合物49S的合成同化合物38S,初始原料为化合物1S和3,4-二氟苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.46(s,1H),10.03(s,1H),9.81(s,1H),8.93(d,J=6.4Hz,1H),8.58(s,1H),8.44-8.34(m,1H),8.23(s,1H),7.96(d,J=13.4Hz,1H),7.73-7.60(m,5H),7.60-7.48(m,3H),7.17(t,J=8.7Hz,2H),6.74(d,J=6.9Hz,1H),1.55-1.41(m,4H).
实施例53 N-(3-氟-4-((7-(4-吗啡啉苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(50S)的合成
Figure PCTCN2016083011-appb-000097
化合物50S的合成同化合物38S,初始原料为化合物1S和4-吗啡啉苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.45(s,1H),10.03(s,1H),9.74(s,1H),8.86(d,J=5.0Hz,1H),8.31(s,1H),8.20(d,J=8.5Hz,2H),7.95(d,J=12.9Hz,1H),7.65(dd,J=9.0,5.0Hz,2H),7.58-7.50(m,2H),7.16(t,J=8.9Hz,2H),7.10(d,J=8.5Hz,2H),6.64(d,J=4.7Hz,1H),3.86-3.72(m,4H),3.31-3.19(m,4H),1.54-1.42(m,4H).
实施例54 N-(4-((7-(异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(51S)的合成
Figure PCTCN2016083011-appb-000098
N-(4-((7-溴-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(99)
化合物99的合成同1S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(CDCl3,300MHz):δ10.32(s,1H),9.56(s,1H),8.81(d,J=5.2Hz,1H),8.14(s,1H),8.01(s,1H),7.82(d,J=11.6Hz,1H),7.54-7.39(m,2H),7.35-7.27(m,1H),7.07(t,J=8.4Hz,2H),6.58(d,J=5.1Hz,1H),1.91-1.79(m,2H),1.35-1.17(m,2H).
N-(4-((7-(异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(51S)
化合物51S的合成同化合物38S,初始原料为化合物99和4-异恶唑硼酸频哪醇酯。1H NMR(DMSO,300MHz):δ10.43(s,1H),9.99(s,1H),9.74(s,2H),9.42(s,1H),8.89(d,J=5.3Hz,1H),8.40(s,1H),7.93(d,J=12.1Hz,1H),7.65-7.59(m,2H),7.58-7.49(m,2H),7.14(t,J=8.9Hz,2H),6.69(d,J=5.4Hz,1H),1.50-1.41(m,4H).
实施例55 N-(4-((7-(异噻唑-3-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(52S)的合成
Figure PCTCN2016083011-appb-000099
化合物52S的合成同化合物38S,初始原料为化合物99和3-异噻唑硼酸频哪醇酯。1H NMR(DMSO,300MHz):δ10.46(s,1H),10.03(s,1H),9.77(s,1H),8.95(d,J=5.3Hz,1H),8.72(d,J=1.7Hz,1H),8.66(s,1H),8.32(d,J=1.7Hz,1H),7.96(d,J=13.7Hz,1H), 7.66-7.62(m,2H),7.58-7.52(m,2H),7.17(t,J=8.9Hz,2H),6.77(d,J=5.0Hz,1H),1.48(d,J=3.9Hz,4H).
实施例56 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺(53S)的合成
Figure PCTCN2016083011-appb-000100
化合物53S的合成同45S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(300MHz,CDCl3)δ9.64(s,1H),9.10(d,J=15.0Hz,1H),8.38(d,J=21.8Hz,1H),8.30(s,1H),8.22(s,1H),7.96(d,J=3.1Hz,1H),7.77(d,J=3.1Hz,1H),7.61-7.57(m,1H),7.58-7.55(m,1H),7.56-7.52(m,1H),7.45-7.36(m,2H),7.25(d,J=15.0Hz,1H),7.15(dd,J=15.0,3.0Hz,1H),6.86(dd,J=15.0,10.1Hz,1H),5.95(d,J=21.8Hz,1H),3.94(s,3H).
实施57 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-基)氧基)苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(54S)的合成
Figure PCTCN2016083011-appb-000101
化合物53S的合成同45S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(300MHz,CDCl3)δ9.64(s,1H),9.49(s,1H),9.10(d,J=15.0Hz,1H),8.30(s,1H),7.96(d,J=3.1Hz,1H),7.93(s,1H),7.71(d,J=2.9Hz,1H),7.58(dd,J=16.0,3.0Hz,1H),7.32-7.24(m,3H),7.23(s,2H),7.15(dd,J=15.0,3.0Hz,1H),6.86(dd,J=15.0,10.1Hz,1H),3.94(s,3H).
实施例58 N-(4-((3-氯吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(55S)的合成
Figure PCTCN2016083011-appb-000102
将200mg的33S溶于乙腈中,加入2eq的DIEA,室温下滴入三氯氧磷0.5ml,搅拌反应,TLC跟踪,反应完成后用乙酸乙酯萃取,依次用碳酸氢钠,饱和食盐水洗,无水硫酸钠干燥,浓缩上柱最终得到产物55S,产率80%。1H NMR(400MHz,DMSO):δ10.43(s,1H),10.01(s,1H),9.14(s,1H),8.96(d,J=5.1Hz,1H),7.93(d,J=13.0Hz,1H),7.64(dd,J=8.8,5.1Hz,2H),7.54(d,J=9.1Hz,1H),7.45(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),7.03(d,J=5.2Hz,1H),1.58-1.40(m,4H);
实施59 N-(4-((2-氯吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(56S)的合成
Figure PCTCN2016083011-appb-000103
反应操作同55S,原料为34S,产率83%。1H NMR(400MHz,DMSO):δ10.44(s,1H),10.01(s,1H),9.24(s,1H),8.96(d,J=5.3Hz,1H),7.94(dd,J=13.3,2.2Hz,1H),7.64(dd,J=9.1,5.1Hz,2H),7.54(d,J=8.9Hz,1H),7.46(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),7.03(d,J=5.2Hz,1H),1.51-1.45(m,4H);
实施60 N-(4-((3-吗啡啉基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(57S)的合成
Figure PCTCN2016083011-appb-000104
室温下将20mg的55S溶于四氢呋喃中,加入吗啉0.5mL,室温下搅拌反应,TLC跟踪,反应完成后,乙酸乙酯萃取,碳酸氢钠,饱和食盐水洗,无水硫酸钠干燥,浓缩过柱得目标化合物。微黄色固体产物,产率68%。1H NMR(400MHz,DMSO):δ10.38(s,1H),10.01(s,1H),8.86(s,1H),8.60(d,J=5.4Hz,1H),7.88(d,J=13.1Hz,1H),7.64(dd,J=9.0, 5.0Hz,2H),7.49(d,J=10.2Hz,1H),7.37(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.55(d,J=5.4Hz,1H),3.84(d,J=4.5Hz,4H),3.77(d,J=4.6Hz,4H),1.47(m,J=3.4Hz,4H);
实施61 N-(4-((2-吗啡啉基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(58S)的合成
Figure PCTCN2016083011-appb-000105
反应操作同57S,原料为56S,产率74%。1H NMR(400MHz,DMSO):δ10.34(s,1H),10.02(s,1H),9.00(s,1H),8.51(d,J=5.1Hz,1H),7.86(dd,J=13.3,2.2Hz,1H),7.64(dd,J=9.1,5.0Hz,2H),7.46(d,J=8.7Hz,1H),7.32(t,J=9.0Hz,1H),7.22-7.11(m,2H),6.86(d,J=5.1Hz,1H),3.8-3.63(m,8H),1.52-1.42(m,4H);
实施62 N-(3-氟-4-((3-(4-甲基哌嗪-1-烷基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(59S)的合成
Figure PCTCN2016083011-appb-000106
反应操作同57S,原料为55S及N-甲基哌嗪,产率44%。1H NMR(400MHz,DMSO):δ10.39(s,1H),10.02(s,1H),8.87(s,1H),8.58(d,J=5.3Hz,1H),7.89(d,J=14.8Hz,1H),7.73-7.57(m,2H),7.49(d,J=10.1Hz,1H),7.36(t,J=9.0Hz,1H),7.16(t,J=8.8Hz,2H),6.53(d,J=5.3Hz,1H),3.90-3.83(m,4H),2.50-2.43(m,4H),2.26(s,3H),1.51-1.44(m,4H);
实施63 N-(3-氟-4-((3-(2-吗啡啉乙氧基基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(60S)的合成
Figure PCTCN2016083011-appb-000107
室温下将4eq的2-吗啉乙醇加入到四氢呋喃溶液,后加入1.5二氢的叔丁醇钾,搅拌反应10min后,加入1eq的55S,继续搅拌反应,TLC跟踪,反应完成后,EA萃取,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,柱层析得产物。微黄色固体,产率62%。1H NMR(400MHz,DMSO):δ10.41(s,1H),10.01(s,1H),8.76(d,J=5.5Hz,1H),8.71(s,1H),7.91(d,J=11.9Hz,1H),7.64(dd,J=8.8,5.0Hz,2H),7.51(d,J=8.6Hz,1H),7.42(t,J=9.0Hz,1H),7.16(t,J=9.0Hz,2H),6.79(d,J=5.2Hz,1H),4.63(t,J=5.6Hz,2H),3.68-3.49(m,4H),2.81(t,J=7.3Hz,2H),2.56-2.51(m,4H),1.56-1.39(m,4H);
实施64 N-(3-氟-4-((3-(3-吗啡啉丙氧基基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(61S)的合成
Figure PCTCN2016083011-appb-000108
反应操作同57S,原料为55S及3-吗啉丙醇,产率42%。1H NMR(DMSO,400MHz):δ10.42(s,1H),10.02(s,1H),8.75(d,J=5.4Hz,1H),7.93(d,J=13.4Hz,1H),7.69-7.61(m,2H),7.54(d,J=8.9Hz,1H),7.45(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),6.77(d,J=5.3Hz,1H),4.58(t,J=6.4Hz,2H),3.66-3.57(m,4H),2.70-2.53(m,4H),2.49-2.42(m,2H),2.11-1.97(m,2H),1.54-1.41(m,4H).
实施65 N-(3-氟-4-((3-((3-吗啡啉丙基)氨基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(62S)的合成
Figure PCTCN2016083011-appb-000109
将20mg的55S和N-(3-氨丙基)吗啉100μL溶于四氢呋喃溶液,油浴60℃下搅拌反应,TLC跟踪,反应完成后,EA萃取,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,柱层析得产物。白色固体,产率62%。1H NMR(400MHz,DMSO):δ10.37(s,1H),10.01(s,1H),8.50(d,J=5.4Hz,1H),8.33(s,1H),8.11(t,J=6.2Hz,1H),7.88(d,J=13.1Hz,1H),7.64(dd,J=9.0,5.0Hz,2H),7.48(d,J=8.8Hz,1H),7.35(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.46(d,J=5.2Hz,1H),3.68-3.54(m,4H),3.47-3.42(m,2H),2.44-2.30(m,6H),1.84-1.72(m,2H),1.52-1.39(m,4H);
实施66 N-(3-氟-4-((2-((3-吗啡啉丙基)氨基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(63S)的合成
Figure PCTCN2016083011-appb-000110
反应操作同62S,原料为56S及N-(3-氨丙基)吗啉,产率66%。1H NMR(DMSO,400MHz):δ10.34(s,1H),10.01(s,1H),8.46(s,1H),8.40(d,J=5.3Hz,1H),7.98(t,J=5.5Hz,1H),7.86(d,J=13.8Hz,1H),7.68-7.58(m,2H),7.44(d,J=8.1Hz,1H),7.28(t,J=9.1Hz,1H),7.16(t,J=8.9Hz,2H),6.81(d,J=5.0Hz,1H),3.55-3.47(m,6H),2.44-2.25(m,6H),1.76-1.63(m,2H),1.54-1.42(m,4H);
实施67 N-(4-((2-哌嗪基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(64S)的合成
Figure PCTCN2016083011-appb-000111
反应操作同62S,原料为56S及哌嗪,产率45%。1H NMR(400MHz,CDCl3):δ8.61(s,1H),8.57(d,J=5.6Hz,1H),7.75(d,J=12.3Hz,1H),7.49-7.43(m,2H),7.27-7.21(m,2H),7.05-7.00(m,2H),6.46(d,J=3.4Hz,2H),3.95-3.89(m,4H),3.11-2.95(m,4H),1.71-1.62(m,4H);
实施68 N-(4-((2-哌嗪基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(65S)的合成
Figure PCTCN2016083011-appb-000112
反应操作同62S,原料为56S及哌嗪,产率48%。1H NMR(400MHz,DMSO):δ10.33(s,1H),10.01(s,1H),8.97(s,1H),8.48(d,J=5.1Hz,1H),7.85(d,J=13.2Hz,1H),7.64(dd,J=9.1,5.1Hz,2H),7.45(d,J=8.5Hz,1H),7.30(t,J=9.1Hz,1H),7.15(t,J=8.9Hz,2H),6.85(d,J=5.1Hz,1H),3.73-3.63(m,4H),2.86-2.77(m,4H),1.50-1.44(m,4H);
实施69 N-(3-氟-4-((2-(2-(4-甲基哌嗪-1-烷基)乙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(66S)的合成
Figure PCTCN2016083011-appb-000113
反应操作同57S,原料为56S及1-羟乙基-4-甲基哌嗪,产率63%。1H NMR(400MHz,DMSO):δ10.73(s,1H),10.35(s,1H),9.15(s,1H),9.06(d,J=5.2Hz,1H),8.23(d,J=12.9Hz,1H),8.03-7.92(m,2H),7.87-7.79(m,1H),7.69(t,J=9.0Hz,1H),7.49(t,J=8.7Hz,2H),7.33(d,J=5.2Hz,1H),4.84(t,J=5.4Hz,2H),3.67(s,4H),3.05(t,J=5.7Hz,2H),2.90-2.76(m,7H),1.90-1.72(m,4H).
实施70 N-(3-氟-4-((2-(2-吗啡啉乙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(67S)的合成
Figure PCTCN2016083011-appb-000114
反应操作同57S,原料为56S及2-吗啉乙醇,产率68%。1H NMR(400MHz,DMSO):δ10.40(s,1H),10.02(s,1H),8.84(s,1H),8.75(d,J=5.0Hz,1H),7.91(d,J=12.6Hz,1H),7.73-7.60(m,2H),7.50(d,J=9.5Hz,1H),7.37(t,J=9.8Hz,1H),7.17(t,J=9.5Hz,2H),7.01(d,J=4.3Hz,1H),4.64-4.46(m,2H),3.68-3.46(m,4H),2.84-2.66(m,2H),2.60-2.33 (m,4H),1.60-1.41(m,4H);
实施71 N-(3-氟-4-((2-(3-吗啡啉丙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(68S)的合成
Figure PCTCN2016083011-appb-000115
反应操作同57S,原料为56S及3-吗啉丙醇,产率64%。1H NMR(400MHz,DMSO):δ10.40(s,1H),10.02(s,1H),8.81(s,1H),8.76-8.64(m,1H),7.91(d,J=13.0Hz,1H),7.72-7.56(m,2H),7.51(d,J=8.7Hz,1H),7.39(t,J=9.1Hz,1H),7.17(t,J=7.6Hz,2H),6.97(d,J=4.7Hz,1H),4.48(t,J=7.1Hz,2H),3.64-3.46(m,4H),2.50-2.26(m,6H),1.98(t,J=9.1Hz,2H),1.59-1.40(m,4H).
实验实施例
实验实施例1:吡啶并氮杂环化合物对c-Met激酶的抑制作用
受体酪氨酸激酶c-Met分子水平酶活抑制初步评价实验
1、试验方法
将酶反应底物Poly(Glu,Tyr)4∶1用无钾离子的PBS(10mM磷酸钠缓冲液,150mM NaCl,pH7.2-7.4)稀释成20μg/ml,125μL/孔包被酶标板,置37℃反应12-16小时。弃去孔中液体后洗板,用200μL/孔的T-PBS(含0.1%Tween-20的PBS)洗板三次,每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM 4-羟乙基哌嗪乙磺酸(HEPES)pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM二硫苏糖醇(DTT))稀释的三磷酸腺苷(ATP)溶液50μL,终浓度5μM。化合物用二甲基亚砜(DMSO)稀释成合适的浓度,1μL/孔或者或含相应浓度的DMSO(阴性对照孔),再加入用49μL反应缓冲液稀释的c-Met激酶域重组蛋白启动反应,每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的邻苯二胺(OPD)显色液100μL/孔(用含有0.03%H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH=5.4)稀释),25℃避光反应1-10分钟。(OPD溶解时需用超声,显色液需现配现用)。加入2M H2SO4 50μL/孔中止反应,用可调 波长式微孔板酶标仪SPECTRA MAX 190读数,波长为490nm。
样品的抑制率通过下列公式求得:
Figure PCTCN2016083011-appb-000116
将上述筛选得到的具有有效抑制c-Met激酶活性的化合物(化合物在10-5M对受体酪氨酸激酶c-Met的抑制率>50%)配成梯度浓度,进行IC50评价。用四参数法计算各化合物分子水平抑制蛋白酪氨酸激酶的IC50值,按照其浓度范围将所得结果分类列入下表1中:
表1 本发明的化合物对c-Met激酶的抑制活性及其对c-Met介导的EBC-1细胞增殖的抑制活性
Figure PCTCN2016083011-appb-000117
Figure PCTCN2016083011-appb-000118
Figure PCTCN2016083011-appb-000119
a被测化合物抑制c-Met激酶活性。A:1nM<IC50<10nM;B:10nM<IC50<100nM;C:100nM<IC50<1μM;D:1μM<IC50<10μM;ND:未测试。
结果:研究发现多个本发明化合物对c-Met激酶有不同程度的抑制活性,部分化合物在10nM浓度下对c-Met激酶具有非常强的抑制作用,其半抑制浓度为1nM<IC50<10nM。提示本发明的化合物具有高效作用于c-Met激酶,是结构新颖的c-Met激酶抑制剂。
实验实施例2:本发明化合物对c-Met介导的细胞株增殖能力的影响
化合物对非小细胞癌细胞EBC-1细胞(MET基因扩增导致Met持续活化细胞株,为Met依赖性肿瘤细胞株)的生长抑制检测采用磺酰罗单明B(sulforhodamine B,SRB)染色法。接种一定数量处于对数生长期的EBC-1细胞于96孔培养板中,每孔90μL,培养过夜后分别加入10μL不同浓度的化合物或者溶剂对照,每个浓度3复孔。化合物作用72小时后,作用结束后,贴壁细胞去培养液,加入10%(w/v)三氯乙酸(100μL/孔)于4℃固定1hr,随后用蒸馏水冲洗五次,待在室温下干燥后,每孔加入SRB溶液(4mg/mL,溶于1%冰乙酸)100μL,室温下孵育染色15min后,用1%冰乙酸冲洗五次洗去未结合的SRB,室温下干燥后,每孔加入10mM Tris溶液100μL,VERSMax酶标仪测定515nm波长下的光密度(OD值)。按以下列公式计算化合物对肿瘤细胞生长的抑制率:抑制率(%)=(OD对照孔-OD给药孔)/OD对照孔×100%。实验重复两次。IC50数据根据初筛设置浓度的测试结果推算出范围。
结果:本发明的多个化合物对c-Met激酶高表达的EBC-1细胞增殖有明显的抑制作 用,表明该化合物能够抑制由c-Met活化介导的细胞增殖活性。具体数据见上表1,表中ND表示未进行相关测试,无相关数据。
实验实施例3:化合物7S对多个蛋白激酶的抑制作用
实验方法同实验实施例1,实验结果如表2所示。
表2.化合物7S对酪氨酸激酶活性的抑制率(%)
Figure PCTCN2016083011-appb-000120
由上表可以看出,本发明的化合物7S表现出对c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2等多种激酶的抑制活性,是一个新结构的多重激酶抑制剂。
实验实施例4:化合物7S和8S对大鼠药代药动学试验
1.给药方案
SD大鼠14只,雄性,体重200-220g,随机分成4组,每组4/3只,分别灌胃和静脉给予7S和8S,化合物溶于5%的DMSO的生理盐水中,加入5%的tween-80(吐温80)助溶,最终样品浓度为1mg/ml。具体安排见下表3:
表3 化合物7S和8S大鼠药代药动学试验给药方案
Figure PCTCN2016083011-appb-000121
试验前禁食12h,自由饮水。给药后2h统一进食。
2.采血时间点及样品处理:
灌胃给药:给药后0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0和24h;
静脉给药:给药后5min、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h;
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml,置肝素化试管中,11000rpm离心5min,分离血浆,于-20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。
采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
达峰浓度Cmax和达峰时间Tmax为实测值;
药时曲线下面积AUC0-t值:采用梯形法计算;AUC0-∞=AUC0-t+Ct/ke,Ct为最后一个可测得时间点的血药浓度,ke为消除速率常数;
消除半衰期t1/2=0.693/ke;
平均滞留时间MRT=AUMC/AUC。
清除率CL=D/AUC0-∞
稳态分布容积Vss=CL×MRT
绝对生物利用度F=(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100%
实验数据详见表4和表5。
表4、大鼠静脉注射5mg/kg化合物7S和8S的药动学参数
Figure PCTCN2016083011-appb-000122
表5、大鼠灌胃10mg/kg化合物7S和8S的药动学参数
Figure PCTCN2016083011-appb-000123
结果显示,化合物7S表现出良好的药代性质:生物利用度F=51.8%,平均滞留时间MRT=2.6h,半衰期t1/2=1.66h,药时面积AUC=16652h*ng/ml。
实验实施例5:化合物7S对人肺癌EBC-1裸小鼠皮下移植瘤的生长抑制作用
实验方法
EBC-1细胞按5×106/只分别皮下接种于裸小鼠右侧腋窝,形成移植瘤后再在裸小鼠体内传三代后使用。取生长旺盛期的肿瘤组织,无菌条件下剪切成1.5mm3左右,接种于裸小鼠右侧腋窝皮下。用游标卡尺测定移植瘤直径,裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径,待肿瘤平均体积生长至120-130mm3左右将动物随机分组。7S,100mg/kg和10mg/kg组,每天口服给药一次,连续给药21天(qd/21,po)。阳性对照药物PF2341066 50mg/kg,每天口服给药一次,连续给药21天。溶剂对照给等量溶剂。整个实验过程中,每周2次测量移植瘤直径,同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(%),计算公式如下:T/C(%)=(TRTV/CRTV)×100%,TRTV:治疗组RTV;CRTV:阴性对照组RTV;2)肿瘤体积增长抑制率GI%,计算公式如下:GI%=[1-(TVt-TV0)/(CVt-CV0)]×100%,TVt为治疗组每次测量的瘤体积;TV0为治疗组分笼给药时所得瘤体积;CVt为对照组每次测量的瘤体积;CV0为对照组分笼给药时所得瘤体积;3)瘤重抑制率,计算公式如下:瘤重抑制率%=(Wc-WT)/Wc×100%,Wc:对照组瘤重,WT:治疗组瘤重。
实验结果:如图1和表6所示,化合物7S 100mg/kg组,每天口服给药一次,连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤的生长有极其显著的抑制作用,在第21天所得T/C百分数为9.58%。化合物7S 10mg/kg组,每天口服给药一次,连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤的生长有一定的抑制作用,在第21天所得T/C百分数为46.24%。阳性对照药物PF2341066 50mg/kg组,每天口服给药一次,连续给药21天,对EBC-1裸小鼠皮下移植瘤有极其显著的抑制作用,第21天所有小鼠肿瘤均完全消退,所得T/C百分数为0.00%。给药期间各给药组小鼠状态均良好,无小鼠死亡。
表6. 7S对人肺癌EBC-1裸小鼠皮下移植瘤的实验治疗作用
Figure PCTCN2016083011-appb-000124
p<0.001,“()”内为肿瘤消退小鼠数

Claims (9)

  1. 一种具有如下通式I所示的结构的吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,
    Figure PCTCN2016083011-appb-100001
    其中,
    Figure PCTCN2016083011-appb-100002
    表示单键或双键;
    R1和R2各自独立地选自氢和卤素;
    X不存在,或者X和Y各自独立地为选自C、N、O和S;
    n为0、1、2或3;m为0或1;
    R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
    Figure PCTCN2016083011-appb-100003
    或者取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地为选自卤素、-CN、-CF3、-NO2、羟基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷氧基、苄基、卤素取代的C1-C6烷氧基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基或杂芳环基;
    R6不存在或者选自氢和C1-C6的烷基;
    R7不存在或者选自氢和C1-C6的烷基;
    Z为氨基、苯基乙酰胺基或以下任一结构:
    Figure PCTCN2016083011-appb-100004
    在上述通式II、III、IV、V中,R4选自氢、C1-C6烷基和C5-C10芳基或者杂芳基;R5和R5′各自独立地选自氢、卤素和C1-C6烷氧基;
    环B为含有1或2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
  2. 根据权利要求1所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,
    R1和R2各自独立地选自氢、F、Cl和Br;
    X不存在,或者X和Y各自独立地选自C、N和O;
    n为0、1或2;m为0或1;
    R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
    Figure PCTCN2016083011-appb-100005
    或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-CN、苄基、-NO2、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;
    R6不存在或者选自氢和C1-C4的烷基;
    R7不存在或者选自氢、甲基、乙基和丙基;
    R4选自氢和C1-C6烷基;R5和R5′各自独立地选自氢、F、Cl、Br和C1-C4烷氧基;
    环B为含有1或2个选自N或O中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
  3. 根据权利要求1或2所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,
    R1选自氢、Cl和Br;R2选自氢、F和Cl;
    X不存在,或者X和Y各自独立地选自C、N和O;
    n为0、1或2;m为0或1;
    R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、
    Figure PCTCN2016083011-appb-100006
    或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-NO2、苄基、C1-C4烷基、C1-C4烷基取代的胺基、C1-C4烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;
    R6不存在或者选自氢和C1-C2的烷基;
    R7不存在或者为甲基;
    R4选自氢和C1-C3烷基;优选地,R4为氢或甲基;
    R5和R5′各自独立地选自氢、F和C1-C2烷氧基;;
    环B为含有1或2个N原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
  4. 根据权利要求1-3所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,
    R1为氢、Cl或Br;R2为氢或F;
    X不存在,或者X和Y各自独立地选自C、N和O;
    n为0、1或2;m为0或1;
    R3不存在或者为C1-C3的烷基、取代或未取代的吡啶基、取代或未取代的吗啉基、取代或未取代的吗啉基羰基、
    Figure PCTCN2016083011-appb-100007
    取代或未取代的哌啶基、取代或未取代的咪唑基、取代或未取代的哌嗪基、取代或未取代的恶唑基、取代或未取代的异恶唑基、取代或未取代的嘧啶基、取代或未取代的噻唑基、取代或未取代的异噻唑基、取代或未取代的苯基、或者取代或未取代的吡唑基,其中,所述取代基可以为1或2个并各自独立地选自F、Cl、Br、-NO2、苄基、C1-C3烷基、C1-C3烷基取代的胺基、C1-C3烷基磺酰基、未取代的或 C1-C6烷基取代的哌啶基和吗啉基;
    R6不存在或者为氢或甲基;
    R7不存在或者为甲基;
    Z为氨基、苯基乙酰胺基或以下任一结构:
    Figure PCTCN2016083011-appb-100008
    环B与吡啶或者连同X形成具有如下简式之一所示的结构:
    Figure PCTCN2016083011-appb-100009
  5. 根据权利要求1-4中任一项所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,所述化合物选自下述化合物中的一种化合物:
    Figure PCTCN2016083011-appb-100010
    Figure PCTCN2016083011-appb-100011
    Figure PCTCN2016083011-appb-100012
    Figure PCTCN2016083011-appb-100013
    Figure PCTCN2016083011-appb-100014
    Figure PCTCN2016083011-appb-100015
    Figure PCTCN2016083011-appb-100016
    Figure PCTCN2016083011-appb-100017
    Figure PCTCN2016083011-appb-100018
    Figure PCTCN2016083011-appb-100019
    Figure PCTCN2016083011-appb-100020
    Figure PCTCN2016083011-appb-100021
    Figure PCTCN2016083011-appb-100022
    Figure PCTCN2016083011-appb-100023
  6. 根据权利要求1-5任一项所述的化合物、其异构体、其药学上可接受的盐或其药学上可接受的溶剂合物的制备方法,该方法如以下反应方案之一所示:
    反应方案一:
    Figure PCTCN2016083011-appb-100024
    其中,R8
    Figure PCTCN2016083011-appb-100025
    R9
    Figure PCTCN2016083011-appb-100026
    Y、R2、R3、R7、Z、m和n的定义与权利要求1-5中相同;
    (1)化合物5由化合物4经氯代反应得到,氯代试剂为氯化亚砜(SOCl2)/N,N-二甲基甲酸铵(DMF)、三氯氧磷(POCl3)/DMF或POCl3/N,N-二异丙基乙胺(DIEA)/乙腈(MeCN)等,优选为POCl3/DMF;
    (2)化合物6由化合物5去保护得到,去保护试剂为:三溴化硼(BBr3)/二氯甲烷(DCM)、40%溴化氢(HBr)水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、三甲基氯硅烷(TMSCl)/碘化钠(NaI)、三氟甲磺酸,优选为三氟甲磺酸;
    (3)化合物6经Mitsunobu反应生成化合物7,所选试剂为偶氮二甲酸二乙酯(DEAD)/三苯基膦(PPh3)、N′,N′-四异丙基偶氮二羧酰胺(TIPA)-三丁膦TBP、1,1′-(偶氮二羧酸)二哌啶(ADDP)-TBP、四甲基偶氮二甲酸铵(TMAD)-TBP、4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD)-TBP、氰基亚甲基三正丁基膦(CMBP)或氰基亚甲 基三甲基膦(CMMP),优选为DEAD/PPh3
    (4)化合物7经亲核取代反应生成化合物8,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、三乙胺(TEA)、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
    (5)化合物8经脱溴得到化合物9,优选反应条件为:钯碳(Pd/C)-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵;
    反应方案二:
    Figure PCTCN2016083011-appb-100027
    其中,R8
    Figure PCTCN2016083011-appb-100028
    R9
    Figure PCTCN2016083011-appb-100029
    Y、R2、R3、R7、Z、m和n的定义分别与权利要求1-5相同;
    (1)化合物5脱溴得到化合物10,优选反应条件为:Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵;
    (2)化合物11由化合物10去保护得到;去保护试剂为:BBr3/DCM、40%HBr水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、TMSCl/NaI、三氟甲磺酸,优选为三氟甲磺酸;
    (3)化合物11经Mitsunobu反应生成化合物12,所选试剂为DEAD/PPh3、TIPA-TBP、ADDP-TBP、TMAD-TBP、DHTD-TBP、CMBP或CMMP;优选为DEAD/PPh3
    (4)化合物12经亲核取代反应生成化合物9,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
    反应方案三:
    Figure PCTCN2016083011-appb-100030
    其中,R10
    Figure PCTCN2016083011-appb-100031
    R9
    Figure PCTCN2016083011-appb-100032
    X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
    (1)化合物14经脱氯得到化合物15,反应试剂为锌(Zn)/醋酸(MeCOOH);
    (2)化合物16经氯代反应得到化合物17,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
    (3)化合物17经亲核取代反应生成化合物18,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
    反应方案四:
    Figure PCTCN2016083011-appb-100033
    其中,R10
    Figure PCTCN2016083011-appb-100034
    R9
    Figure PCTCN2016083011-appb-100035
    X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
    (1)化合物15经氯代反应得到化合物15I,氯代试剂为SOCl2/DMF、POCl3/DMF、 POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
    (2)化合物15I经亲核取代反应生成化合物15II,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
    (3)化合物15II经Suzuki偶联反应生成化合物18,所用的碱为醋酸钾、磷酸钾或碳酸钾;所用溶剂为二甲基亚砜,DMF,二氧六环或者甲苯,加入适量的水;所用的催化剂为四三苯基膦钯,1,1′-双二苯基膦二茂铁二氯化钯PdCl2(dppf);
    反应方案五:
    Figure PCTCN2016083011-appb-100036
    其中,R10
    Figure PCTCN2016083011-appb-100037
    R9
    Figure PCTCN2016083011-appb-100038
    X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;
    (1)取代反应生成化合物19,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
    (2)化合物19经还原得到化合物20,所用的还原试剂为氯化镍(NiCl2)/硼氢化钠(NaBH4)、Zn/AcOH、Pd/C-H2、Fe/氯化氢(HCl)、硫化钠(Na2S)/乙醇(EtOH)、硫氢化铵(NH4HS)、氢化铝锂(LiAlH4);优选为NiCl2/NaBH4、Pd/C-H2
    (3)化合物20经环合得到化合物21及22,环合条件为醛基乙酸乙酯,溶剂为各种常规溶剂,例如甲醇(MeOH)、EtOH、乙腈(MeCN)、二氧六环等;
    (4)氯代反应,其氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等, 优选为POCl3/DIEA/MeCN;
    (5)亲核取代反应,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
  7. 包含治疗有效量的选自权利要求1-5中任一项所述化合物中的一种或多种化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物的组合物。
  8. 权利要求1-5中任一项所述化合物、其异构体、药学上可接受的盐、药学上可接受的溶剂合物及其权利要求7所述组合物在制备作为多靶点蛋白激酶抑制剂的药物中的应用;在制备用于抑制酪氨酸激酶c-Met活性的药物中的应用;在制备用于预防或治疗与生物体内的肝细胞生长因子受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或肿瘤转移相关的疾病的药物中的应用;在制备预防或治疗肿瘤生长与转移的药物中的应用;
    其中,所述激酶包括c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2、FGFR、Abl、Lck、KDR、IGF-1α和ALK。
  9. 根据权利要求8所述的应用,其中,所述肿瘤为肺癌、甲状腺髓样瘤、恶性胶质瘤、胃癌、肾细胞癌、乳腺癌、卵巢癌、前列腺癌或结直肠癌。
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