WO2018127184A1 - 一种间变性淋巴瘤激酶抑制剂及其制备方法和用途 - Google Patents

一种间变性淋巴瘤激酶抑制剂及其制备方法和用途 Download PDF

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WO2018127184A1
WO2018127184A1 PCT/CN2018/071793 CN2018071793W WO2018127184A1 WO 2018127184 A1 WO2018127184 A1 WO 2018127184A1 CN 2018071793 W CN2018071793 W CN 2018071793W WO 2018127184 A1 WO2018127184 A1 WO 2018127184A1
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group
alkyl
pharmaceutically acceptable
compound
acceptable salt
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PCT/CN2018/071793
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English (en)
French (fr)
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刘国成
焦楠
王树龙
闵汪洋
刘希杰
孙莹
张慧
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北京赛林泰医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel pyrrolopyrimidine derivatives having protein kinase inhibitory activity, a process for the preparation thereof, a pharmaceutical composition thereof, and to the use of such compounds and pharmaceutical compositions thereof for the treatment of diseases associated with protein kinases.
  • Anaplastic lymphoma kinase is a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily and is closely related to tumorigenesis.
  • ALK was discovered in the form of an activated fusion oncogene in anaplastic large cell lymphoma, and 21 fusion forms of EML4-ALK have been discovered.
  • ALK can also be fused to genes such as NPM, TFG, KIF5B, KLC1, PTPN3, STRN (Lancet Oncology, 2015, 16(13), e510–e521; OncoTargets and Therapy, 2014, 7, 375–385), including systems.
  • ALK fusion in non-small cell lung cancer is approximately 3% to 7%, and the expression rate in adenocarcinoma patients without EGFR mutation or KRas mutation is approximately 42.8%.
  • the mutation and abnormal activity of ALK in various cancers has become a drug target for the treatment of ALK-positive cancers.
  • Crizotinib has become the first-line treatment for advanced ALK-positive NSCLC.
  • the study confirmed that ALK-positive lung cancer patients treated with crizotinib for 6 weeks, the tumors were significantly reduced, the effective duration was nearly 11 months, the objective response rate of treatment was 74%, and the patient's disease-related symptoms and overall quality of life were significantly improved. Improvements in the confidence of patients to establish follow-up treatment.
  • ALK-positive lung cancer patients benefit significantly, these patients often develop resistance to crizotinib within 1-2 years, and about 70% of NSCLC patients have central nervous system (CNS) during crizotinib treatment.
  • CNS central nervous system
  • Tumor metastasis (Lancet Oncology, 2015, 16(13), e510–e521), its resistance mechanisms are mainly divided into two categories: ALK resistance mutations and activation of other signaling pathways. Mutations in the ALK kinase region (mainly L1196M, G1269A and C1156Y) are common resistance mechanisms for crizotinib.
  • Second-generation ALK protein kinase inhibitors such as ceritinib (Certinib, J. Med. Chem.
  • the compound of the present invention is a novel inhibitor of small molecule ALK protein kinase, which is effective not only for Crizotinib resistant mutations (such as L1196M, etc.), but also for the second-generation ALK inhibitor resistant mutation (G1202R), and can cross blood.
  • the brain barrier is expected to be effective in the treatment of ALK-positive and crizotinib metastatic or advanced non-small cell lung cancer patients.
  • the present invention relates to a compound useful as an ALK inhibitor, or a pharmaceutically acceptable salt thereof, which is useful for the treatment of a disease mediated by ALK.
  • the present invention also relates to a process for the preparation of a compound of the present invention or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and the compound of the present invention or the compound thereof Use of a pharmaceutically acceptable salt or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease mediated by ALK.
  • the invention also discloses a method of treating an ALK-mediated disease using a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described below:
  • A is selected from a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1-3 selected from N, O and S heteroatoms, and A is optionally independently selected from 1 to 3 independently selected from R Substituting a group of 8 ;
  • R 8 is each independently selected from the group consisting of halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, -NR 9 R 10 , 3-8 membered cycloalkyl, and 1-3 selected from N, a 3-8 membered heterocyclic group of O and S heteroatoms, wherein R 9 and R 10 are each independently selected from H and C 1-6 alkyl, said 3-8 membered cycloalkyl and containing 1-3 a 3-8 membered heterocyclyl selected from the group consisting of N, O and S heteroatoms may be optionally substituted by C 1-6 alkyl;
  • R 1 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-8 cycloalkyl;
  • R 2 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl, wherein said C 1-6 An alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group and a C 3-8 cycloalkyl group may be optionally substituted by a halogen;
  • R 3 , R 4 , R 6 and R 7 are each independently selected from H and C 1-6 alkyl;
  • R 5 is C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4.
  • A is selected from the group consisting of a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1-3 selected from the group consisting of N, O, and S heteroatoms, and A is optionally 1-3 Substituents independently selected from R 8 ;
  • R 8 is each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —NR 9 R 10 , 3-8 membered cycloalkyl, and contains 1-3 heteroatoms selected from N, O and S. a 3-8 membered heterocyclic group, wherein R 9 and R 10 are each independently selected from C 1-6 alkyl, the 3-8 membered cycloalkyl group and 1-3 selected from N, O and S
  • the 3-8 membered heterocyclic group of the hetero atom may be optionally substituted by a C 1-6 alkyl group.
  • A is selected from the group consisting of a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1-3 selected from the group consisting of N, O, and S heteroatoms, and A is optionally 1-3 Substituents independently selected from R 8 ;
  • R 8 is each independently selected from -NR 9 R 10 and a 3-8 membered heterocyclic group containing 1-3 selected from N, O and S heteroatoms, wherein R 9 and R 10 are each independently selected from C 1 -6 alkyl, said 3-8 membered heterocyclic group containing 1-3 selected from N, O and S heteroatoms may be optionally substituted by C 1-6 alkyl.
  • A is selected from the group consisting of a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1-3 selected from the group consisting of N, O, and S heteroatoms, and A is optionally selected by 1 Substituted from the group of R 8 ;
  • R 8 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, -NR 9 R 10 , 3-8 membered cycloalkyl and 3- to 3 heteroatoms selected from N, O and S heteroatoms
  • the 3-8 membered heterocyclic group may be optionally substituted by a C 1-6 alkyl group.
  • A is selected from the group consisting of a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1-3 selected from the group consisting of N, O, and S heteroatoms, and A is optionally selected by 1 Substituted from the group of R 8 ;
  • R 8 is selected from -NR 9 R 10 and a 3-8 membered heterocyclic group containing 1-3 selected from N, O and S heteroatoms, wherein R 9 and R 10 are each independently selected from C 1-6 alkane
  • the 3-8 membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S may be optionally substituted by a C 1-6 alkyl group.
  • A is selected from a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group containing 1 or 2 N heteroatoms, and A can be optionally 1 group selected from R 8 Replace
  • R 8 is selected from -NR 9 R 10 and a 3-8 membered heterocyclic group having 1, 2 or 3 N heteroatoms, wherein R 9 and R 10 are each independently selected from C 1-6 alkyl, A 3-8 membered heterocyclic group containing 1, 2 or 3 N heteroatoms may be optionally substituted by a C 1-6 alkyl group.
  • R 1 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl.
  • R 2 is selected from halo, C 1-6 alkyl, and C 1-6 alkoxy, wherein said C 1-6 alkyl and C 1-6 alkoxy are optionally halogen Replace.
  • R 2 is selected from halo, C 1-6 alkyl, and C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with halogen.
  • m is 0, 1, 2 or 3, preferably 1, 2 or 3, more preferably 1 or 2.
  • n is 0, 1, 2 or 3, preferably n is 0, 1 or 2, more preferably n is 0 or 1.
  • R 3 , R 4 , R 6 and R 7 are both H and n is 0.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
  • the invention provides a method of modulating protein kinase activity comprising contacting the protein kinase with a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
  • the protein kinase is selected from the group consisting of ALK.
  • the protein kinase comprises a mutated kinase, wherein the mutant kinase is selected from the group consisting of a mutated ALK kinase.
  • the invention provides both the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of a disease, wherein the disease is associated with a protein kinase (eg ALK)
  • a protein kinase eg ALK
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of a disease mediated by ALK.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of cancer.
  • the ALK-mediated disease or the cancer is selected from the group consisting of non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma , systemic histiocytosis and neuroblastoma, such as ALK-positive non-small cell lung cancer.
  • the present invention provides a method of treating a disease in a mammal (e.g., a human), wherein the disease is associated with protein kinase (e.g., ALK) activity, comprising administering to a human an effective amount of a compound of the present invention or a pharmaceutical thereof An acceptable salt or a pharmaceutical composition of the invention.
  • a mammal e.g., a human
  • ALK protein kinase
  • optionally substituted alkyl means “unsubstituted alkyl” or "substituted alkyl”.
  • the optionally substituted group may be unsubstituted (for example: -CH 2 CH 3 ), fully substituted (for example: -CF 2 CF 3 ), monosubstituted (for example: -CH 2 CH 2 F) or Any level between single and complete substitutions (eg, -CH 2 CHF 2 , -CF 2 CH 3 , -CFHCHF 2 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • Standard chemical terms can be found in references (including Carey and Sundberg, Advanced Organic Chemistry, Fourth Edition, Volume A (2000) and Volume B (2001), Plenum Press, New York). definition. Unless otherwise stated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetic, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods are employed. Unless specifically defined, the terms and experimental procedures and techniques herein for analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients.
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • C 1 - 6 alkyl describes an alkyl group, as defined below, having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms indicated by the abbreviations does not include the carbon atoms on the possible substituents.
  • thick or “fused ring” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spiro” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
  • alkyl refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having from 1 to 12 carbon atoms. , preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, linked to other moieties of the molecule by a single bond, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, n-heptyl, 2-methylhexyl, n-octyl and the like.
  • alkoxy refers to an (alkyl)-O- group, wherein alkyl is as defined in the present invention.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy.
  • alkenyl refers to a straight or branched chain monovalent hydrocarbon radical having only carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 14 carbons.
  • the atom is preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. It is attached to other moieties of the molecule by a single bond, for example, vinyl, 1-propenyl, allyl, 1-butenyl, 1-pentenyl, 1,4-pentadienyl, and the like.
  • alkynyl refers to a straight or branched chain monovalent hydrocarbon radical having only carbon and hydrogen atoms, containing at least one triple bond, and optionally having more It has three or more double bonds and has 2 to 14 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. It is linked to other moieties of the molecule by a single bond, such as ethynyl, 1-propynyl, 1-butynyl and the like.
  • cycloalkyl refers to a stable monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused rings, spiro rings or bridges.
  • a ring system comprising from 3 to 15 ring-forming carbon atoms, preferably from 3 to 10 ring-forming carbon atoms, more preferably from 3 to 8 ring-forming carbon atoms, either saturated or unsaturated, through a single bond to the rest of the molecule Connected.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexanone, cyclooctyl, 1H-indenyl, decahydronaphthyl and the like.
  • heterocyclyl or “heterocycle” as used herein, alone or as part of another ingredient, refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, and 1-6 selected from nitrogen. Heteroatoms of oxygen and sulfur.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring, spiro ring or bridged ring system, and nitrogen, carbon or sulfur on the heterocyclic group may be selective. Oxidized, the nitrogen atom is selectively quaternized, and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be bonded to the remainder of the molecule through a single bond through a carbon atom or a hetero atom on the ring.
  • the heterocyclic group containing a fused ring may contain one or more aromatic or heteroaromatic rings as long as it is attached to the remainder of the molecule to an atom on the non-aromatic ring.
  • the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 member.
  • heterocyclic groups include piperidinyl, piperazinyl, tetrahydropyridyl, morpholinyl, azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuran A group, a dihydroindenyl group, a dioxolyl group, a morpholinyl group, a 2-oxopipyridinyl group, a tetrahydroisoquinolyl group, a trithylalkyl group or the like.
  • halogen means fluoro, chloro, bromo and iodo.
  • the olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
  • the compounds of the invention may contain asymmetric centers. These asymmetric centers can be independently R or S configurations. Some of the compounds of the invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It will be understood that the compounds of the invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods, such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
  • pharmaceutically acceptable salt includes both acid addition salts and base salts.
  • “Pharmaceutically acceptable acid addition” refers to those salts which retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are formed with inorganic or organic acids.
  • “Pharmaceutically acceptable base addition” refers to those salts which retain the biological effectiveness and properties of the free acid of the compound, which are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base.
  • the compound of the present invention or a salt thereof can be administered as an active substance alone, preferably in the form of a pharmaceutical composition thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
  • composition refers to a preparation in which a compound of the present invention is mixed with a medium which is generally accepted in the art for delivering a biologically active compound to a mammal such as a human.
  • This medium contains all pharmaceutically acceptable carriers.
  • the term "acceptable" in connection with a formulation, composition or ingredient means that there is no sustained deleterious effect on the overall health of the subject.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable The biological reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, which can be used in humans and domesticated animals, which have been approved by the relevant government administration. Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compounds with one or more pharmaceutically acceptable carriers via conventional pharmaceutical methods.
  • a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
  • the above carriers need to be compatible with the active compound or other excipients.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral pharmaceutical compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules.
  • the core of the dragee can be coated according to methods well known in the ordinary pharmaceutical practice, such as the use of enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the pharmaceutical composition further comprises at least one other anti-cancer drug.
  • the pharmaceutical composition and at least one other anti-cancer drug are each combined into a combined product in separate dosage forms.
  • These additional drugs can be administered separately from the pharmaceutical compositions containing the compounds of the invention as part of a multi-dose regimen.
  • such a drug may be part of a single dosage form, mixed with a compound of the invention in a single composition.
  • the two active agents can be administered simultaneously, sequentially or at intervals between each other to produce the desired activity of these agents.
  • the invention provides a method of modulating protein kinase activity comprising contacting the protein kinase with a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
  • the protein kinase is selected from the group consisting of ALK.
  • the protein kinase comprises a mutated kinase, wherein the mutant kinase is selected from the group consisting of a mutated ALK kinase.
  • the invention provides both a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for use in the manufacture of a medicament for the treatment of a disease, wherein the disease is associated with a protein kinase (eg ALK)
  • a disease associated with the activity of a mutant thereof such as at least one of the following mutation sites L1196M, F1174L, G1202C, G1269S, R1275Q), such as abnormal cell proliferation, wherein abnormal cell proliferation includes cancer.
  • the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the treatment of a disease mediated by ALK.
  • ALK-mediated diseases include ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, whole body Histiocytosis, neuroblastoma, and the like, preferably include ALK-positive non-small cell lung cancer.
  • ALK positive refers to the fusion of an ALK of a subject with other genes.
  • the present invention provides a method of treating a disease in a mammal (e.g., a human), wherein the disease is with a protein kinase (e.g., ALK or a mutant thereof (e.g., at least one of the following mutation sites L1196M, F1174L, The G1202C, G1269S, R1275Q)) activity is related to the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention to a human.
  • a protein kinase e.g., ALK or a mutant thereof (e.g., at least one of the following mutation sites L1196M, F1174L, The G1202C, G1269S, R1275Q)
  • a protein kinase e.g., ALK or a mutant thereof (e.g., at least one of the following mutation sites L1196M, F1174L, The G1202C, G12
  • the term "therapeutically effective amount” may be one or more physiology that alleviates one or more symptoms of a disease or condition in a subject, causes a disease or condition, or its etiology. Or an amount of biochemical parameter that partially or completely returns to normal, and/or reduces the likelihood of a disease or condition.
  • the compound of the invention is administered at a dose ranging from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In some embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient.
  • dose levels above the upper limit of the above range may be required.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day.
  • the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
  • the compounds of the invention can be prepared according to the route described in Scheme 1.
  • the product obtained by the reaction in Scheme 1 can be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation and the like.
  • the starting materials can be purchased by themselves or purchased from commercial establishments such as, but not limited to, Adrich or Sigma. These materials can be characterized using conventional means such as physical constants and spectral data.
  • the compounds described herein can be synthesized using synthetic methods to obtain a single isomer or a mixture of isomers.
  • Step B Under intermediate nitrogen, intermediate ii (1.0 eq.), R 2 NH 2 (1.05 eq.), Pd 2 (dba) 3 (0.1 eq.), ( ⁇ )-BINAP (0.15 eq.) and cesium carbonate (2.0 eq. Adding to anhydrous toluene, heating at 80-130 ° C for 4-12 h, then removing the solvent under reduced pressure. The residue obtained is dissolved in dichloromethane and water. After washing with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained residue
  • the temperature is Celsius.
  • the reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated.
  • reaction vessel was fitted with a rubber septum to add substrate and reagents via a syringe; glassware was dried and / or heat dry.
  • the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was performed using a thin layer chromatography silica gel prefabricated plate (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ Fleet. (ESI) liquid chromatography-mass spectrometer; optical rotation measurement using SGW-3 automatic polarimeter (Shanghai Shenguang Instrument Co., Ltd.).
  • Nuclear magnetic data (1H NMR) was run at 400 MHz using a Varian device.
  • the solvent used for the nuclear magnetic data was CDCl 3 , DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or based on the residual solvent (CDCl 3 : 7.26 ppm; DMSO-d6: 2.50 ppm).
  • peak shape diversity the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), sept (seven peak), m (multiple peak) ), br (wide peak), dd (double doublet), dt (double triplet). If a coupling constant is given, it is in Hertz (Hz).
  • Xant-phos 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxan
  • Step 1 4-((1-((2-methyl-4-nitro-5-isopropoxyphenyl)piperidin-4-yl)morpholine
  • Step 1 1-(5-Isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 2 4-(4-Amino-5-isopropoxy-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Methyltriphenylphosphonium bromide (835 mg) was added dropwise to a solution of butyllithium (2M, 1.17 ml) in 40 ml of anhydrous tetrahydrofuran at -78 ° C. The temperature was kept constant and stirring was continued for 2 h. A solution of 2-nitro-5-(4-(dimethylamino)piperidin-1-yl)benzaldehyde (500 mg) in 15 ml of dichloromethane was added dropwise, then slowly warmed to room temperature and stirred overnight. The title product (white solid, 430 mg). ESI MS m/z: 276.03 [M+H] + .
  • N,N-Dimethyl-1-(3-vinyl-4-nitrophenyl)piperidin-4-amine 430 mg
  • 10% Pd/C 60 mg
  • the mixture was stirred overnight under aq. EtOAc (methanol).
  • ESI MS m/z: 248.03 [M+H] + .
  • 2-Nitro-5-fluorophenol (1.57 g), sodium difluorochloroacetate (3.05 g) and sodium carbonate (1.03 g) were sequentially added to 30 ml of DMF, and the mixture was heated to 100 ° C for 5 hours, and then cooled to 20 ml of 4 M aqueous HCl solution was added to the reaction mixture at room temperature, stirred at room temperature for 2 h, then quenched, then 20 ml of water was added to the reaction mixture and extracted with ethyl acetate.
  • Step 4 3'-Methoxy-N,N-dimethyl-4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-amine
  • Step 5 3'-Methoxy-N4,N4-dimethyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4,4'-diamine
  • Example 1 N 2 -(4-(4-(Dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N 4 -(2-(isopropylsulfonyl)benzene yl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Step 1 4-Chloro-N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-7-(4-methoxybenzyl)- 6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine
  • Step 2 N 2 -(4-(4-(Dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N 4 -(2-(isopropylsulfonyl)phenyl )-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Step 3 N 2 -(4-(4-(Dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N 4 -(2-(isopropylsulfonyl)phenyl )-6,7 -dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • acetic acid 5 ml
  • Example 7 N 2 -(2-Isopropoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-5-methylphenyl)-N 4 -(2-( Isopropylsulfonyl) phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 8 N 2 -(2-Isopropoxy-4-(piperidin-4-yl)-5-methylphenyl)-N 4 -(2-(isopropylsulfonyl)phenyl) -6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 10 N 2 -(2-Isopropoxy-4-(4-(dimethylamino)piperidin-1-yl)-phenyl)-N 4 -(2-(isopropylsulfonyl) ) phenyl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Example 11 N 2 - (4- ( 4- ( dimethylamino) piperidin-1-yl) -2-ethylphenyl) -N 4 - (2- (isopropylsulfonyl) phenyl )-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 12 N 2 -(2-(Difluoromethoxy)-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-N 4 -(2-(isopropyl) Sulfonyl)phenyl)-6,7-dihydro-5H-pyrrolo[ 2,3- d]pyrimidine-2,4-diamine
  • Example 13 N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(2-methoxy-4-(4-(piperidin-1-yl)piperidin-1-yl ) phenyl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Example 14 N 2 -(2-methoxy-4-(4-(dimethylamino)cyclohex-1-enyl)phenyl)-N 4 -(2-(isopropylsulfonyl) phenyl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Example 15 N 2 -(2-methoxy-4-(4-(dimethylamino)cyclohexyl)phenyl)-N 4 -(2-(isopropylsulfonyl)phenyl)-6 ,7 -Dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 16 N 2 -(4-(4-(Dimethylamino)piperidin-1-yl)-3-fluoro-2-methoxyphenyl)-N 4 -(2-(isopropyl) Sulfonyl) phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 17 N 2 -(2-methoxy-4-(4-(dimethylamino)piperidin-1-yl)-5-fluorophenyl)-N 4 -(2-(isopropyl) Sulfonyl) phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • Example 18 N 2 -(2-methoxy-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-N 4 -(2-(isopropylsulfonyl)- 4-fluoro-phenyl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Example 20 N 4 -(2-(cyclopentylsulfonyl)phenyl)-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxybenzene yl) -6,7-dihydro -5H- pyrrolo [2,3-d] pyrimidine-2,4-diamine
  • Example 21 N 2 -(2-methoxy-3-chloro-4-(4-(dimethylamino)piperidin-1-yl)-phenyl)-N 4 -(2-(isopropyl Sulfonyl) phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
  • ALK(KD) ALK kinase domain
  • HTRF Cisbio's homogeneous phase-resolved fluorescence
  • HTRF is a technique based on fluorescence resonance energy transfer between a donor and a receptor (second fluorescent label) of Eu chelate.
  • the donor is excited by an external source of light, and if it is closer to the receptor, the energy resonance can be transferred to the receptor, causing it to be excited to emit a specific wavelength of emitted light.
  • the Eu-labeled antibody After the phosphorylation of the Biotin-tagged TK substrate by the kinase, it will be recognized by the Eu-labeled antibody.
  • Streptavidin-XL665 interacts with Biotin to make Eu and XL665 close to each other.
  • the specific experimental procedure was as follows: The compounds were serially diluted 3 times with DMSO starting from 100 ⁇ M or 10 ⁇ M, and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM HEPES (pH 7.5), 0.01% BSA, 0.1 mM.
  • the detection reagent establishes a screening method for suspension cell proliferation inhibition.
  • Human blood cancer cell Karpas299 (The Global Bioresource Center) supplemented with 10% fetal bovine serum RPMI-1640
  • the culture medium is cultured at 37 ° C, 95% air and 5% CO 2 , and cultured in a 25 cm 2 or 75 cm 2 plastic tissue culture flask. In the middle, subculture is carried out 2 to 3 times a week.
  • the cells were seeded at a density of 4 ⁇ 10 3 cells/well in a 96-well cell culture plate. Medium, 195 ⁇ l/well, and cultured at 37 ° C, 95% air and 5% CO 2 .
  • the compound is added to a plate inoculated with cells.
  • the final concentration of DMSO in the cell culture medium was 0.1%, and the final concentration of the test compound was 0.3 nM to 10 ⁇ M.
  • the above cells were incubated at 37 ° C for 3 days.
  • the detection reagent establishes a screening method for adherent cell proliferation inhibition.
  • Human non-small cell lung cancer cell NCI-H2228 (The Global Bioresource Center) supplemented with 10% fetal bovine serum RPMI-1640
  • the culture medium is cultured at 37 ° C, 95% air and 5% CO 2 , and cultured in a 25 cm 2 or 75 cm 2 plastic tissue culture flask. In the middle, subculture is carried out 2 to 3 times a week.
  • Cells were seeded at a density of 3 x 10 3 cells/well in 96-well white cell culture plates. Medium, 195 ⁇ l/well, and cultured at 37 ° C, 95% air and 5% CO 2 .
  • the compound is added to a plate inoculated with cells.
  • the final concentration of DMSO in the cell culture medium was 0.1%, and the final concentration of the test compound was 0.3 nM to 10 ⁇ M.
  • the above cells were incubated at 37 ° C for 3 days.
  • the compounds of the present invention are capable of significantly inhibiting the kinase activity of ALK, and the compounds of the present invention have a very strong inhibitory effect on the kinases of the five ALK kinase region mutants, which is superior to the reference compound Crizotinib.
  • the compounds of the examples can be used not only as first-line drugs for patients with ALK fusion tumors, but also for treatment of patients with Crizotinib resistance.
  • the compounds of this invention significantly inhibited cell proliferation ALK fusion, half the effective inhibitor concentration (IC 50) was significantly lower than the reference compound Crizotinib.
  • the animals were orally administered for 8 hours, and whole blood was taken. After centrifugation, the supernatant was taken.
  • the brain was taken, washed and washed with physiological saline, homogenized with methanol at a ratio of 1:4, and the supernatant was taken after centrifugation.
  • the compound was formulated into a 500 ⁇ g/mL compound stock solution in DMSO, and the stock solution was mixed with acetonitrile to prepare a working solution having a concentration of 10, 40, 100, 400, 1000, 4000, and 10000 ng/mL.
  • the compounds of the invention are capable of crossing the blood-brain barrier and are significantly more effective than the reference compound Crizotinib.
  • mice Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups of 3, and the test sample suspension (5 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.
  • Example Example 1 Example 2 Dose (mg/kg) 5 5 T 1/2 (hr) 4.05 9.40 T max (hr) 6.00 6.67 C max (ng/mL) 722 1739 AUC 0-inf (hr*ng/mL) 8523 31983

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Abstract

本发明涉及式(I)化合物及其药物组合物和制备方法，其可用作ALK抑制剂来治疗由ALK介导的疾病。本发明还涉及式(I)化合物及其药物组合物在制备治疗由ALK介导的疾病的药物中的应用。

Description

一种间变性淋巴瘤激酶抑制剂及其制备方法和用途 技术领域
本发明涉及新的具有蛋白激酶抑制活性的吡咯并嘧啶衍生物、其制备方法、其药物组合物，还涉及这类化合物及其药物组合物在治疗与蛋白激酶有关的疾病中的用途。
背景技术
间变性淋巴瘤激酶(ALK)是胰岛素受体超家族的一个受体型蛋白质酪氨酸磷酸激酶，与肿瘤发生发展密切相关。最初，ALK是在间变性大细胞淋巴瘤中以一种激活的融合癌基因的形式被发现的，目前已发现21种EML4-ALK的融合形式。另外，ALK还能与NPM、TFG、KIF5B、KLC1、PTPN3、STRN等基因发生融合(Lancet Oncology,2015,16(13),e510–e521；OncoTargets and Therapy,2014,7,375–385)，其中包括系统性组织异常增生、炎性肌纤维细胞瘤、非小细胞肺癌等(Biochem J,2008,416(2):153-159)。ALK融合在非小细胞型肺癌(NSCLC)中的发生率约为3％～7％，并且在不伴有EGFR突变或KRas突变的腺癌患者中的表达率约为42.8％。ALK在多种癌症中的突变和异常的活性，已经成为一个治疗ALK阳性癌症的药物靶点。
克唑替尼(Crizotinib)已经成为晚期ALK阳性NSCLC的一线治疗药物。研究证实ALK阳性的肺癌患者使用克唑替尼平均治疗6周起效，肿瘤显著缩小，持续有效时间近11个月，治疗的客观缓解率达74％，并且患者的疾病相关症状和整体生活质量得到显著的改善，为患者建立后续治疗的信心。
尽管ALK阳性肺癌患者获益明显，但这部分患者往往在1-2年内出现对克唑替尼耐药，并且约70％的NSCLC患者在克唑替尼治疗期间会出现中枢神经系统(CNS)的肿瘤转移(Lancet Oncology,2015,16(13),e510–e521)，其耐药机制主要分为两大类：ALK耐药突变和其他信号通路的激活。ALK激酶区的突变(主要为L1196M、G1269A和C1156Y)是克唑替尼的常见耐药机制。第二代ALK蛋白激酶抑制剂，如色瑞替尼(Certinib，J.Med.Chem.2013,56,5675-5690)，已被FDA批准用于治疗ALK阳性转移，对克唑替尼进展或不能耐受的NSCLC(Med.Chem.Commun.,2014,5,1266-1279)，第二代ALK抑制剂能够抑制ALK激酶区的继发性耐药突变，从而克服克唑替尼耐药。然而，色瑞替尼等也不可避免的出现了耐药。
发明概述
本发明所述的化合物是新一代ALK蛋白激酶小分子抑制剂，不仅对Crizotinib耐药突变(如L1196M等)有效，对二代ALK抑制剂的耐药突变(G1202R)仍然有效，而且能够跨越血脑屏障，以期能够有效地治疗ALK阳性和克唑替尼转移或进展的非小细胞肺癌患者。
因此，本发明涉及可用作ALK抑制剂的化合物或其药学上可接受的盐，其可用于治疗由ALK介导的疾病。本发明还涉及本发明的化合物或其药学上可接受的盐的制备方法，涉及包含所述本发明的化合物或其药学上可接受的盐的药物组合物，以及所述本发明的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗由ALK介导的疾病的药物中的应用。
本发明还公开了利用本发明的化合物或其药学上可接受的盐或者本发明的药物组合物来治疗由ALK介导的疾病的方法。
本发明提供了如下所述的式(I)化合物，或其药学上可接受的盐：
Figure PCTCN2018071793-appb-000001
其中，
A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1-3个独立地选自R 8的基团取代；
R 8各自独立地选自卤素、-OH、C 1-6烷基、C 1-6烷氧基、-NR 9R 10、3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自H和C 1-6烷基，所述3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代；
R 1选自C 1-6烷基、C 2-6烯基、C 2-6炔基和C 3-8环烷基；
R 2选自卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基和C 3-8环烷基，其中所述C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基和C 3-8环烷基可任选地被卤素取代；
R 3、R 4、R 6和R 7各自独立地选自H和C 1-6烷基；
R 5为C 1-6烷基；
m为0、1、2、3或4；
n为0、1、2、3或4。
在一些实施方式中，A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1-3个独立地选自R 8的基团取代；
R 8各自独立地选自C 1-6烷基、C 1-6烷氧基、-NR 9R 10、3-8元环烷基和含有1-3个选 自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
在一些实施方式中，A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1-3个独立地选自R 8的基团取代；
R 8各自独立地选自-NR 9R 10和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
在一些实施方式中，A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1个选自R 8的基团取代；
R 8选自C 1-6烷基、C 1-6烷氧基、-NR 9R 10、3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
在一些实施方式中，A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1个选自R 8的基团取代；
R 8选自-NR 9R 10和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
在一些实施方式中，A选自3-8元环烷基和含有1或2个N杂原子的3-8元杂环基，并且A可任选地被1个选自R 8的基团取代；
R 8选自-NR 9R 10和含有1、2或3个N杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述含有1、2或3个N杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
在一些实施方式中，R 1选自C 1-6烷基和C 3-8环烷基。
在一些实施方式中，R 2选自卤素、C 1-6烷基和C 1-6烷氧基，其中所述C 1-6烷基和C 1-6烷氧基可任选地被卤素取代。
在一些实施方式中，R 2选自卤素、C 1-6烷基和C 1-6烷氧基，其中所述C 1-6烷氧基可任选地被卤素取代。
在一些实施方式中，m为0、1、2或3，优选为1、2或3，更优选为1或2。
在一些实施方式中，n为0、1、2或3，优选地，n为0、1或2，更优选地，n为0或1。
在一些实施方式中，R 3、R 4、R 6和R 7均为H，且n为0。
另一方面，本发明提供了选自以下化合物的式(I)化合物或其药学上可接受的盐：
Figure PCTCN2018071793-appb-000002
另一方面，本发明提供一种药物组合物，其含有本发明的化合物或其药学上可接受的盐作为活性成份，以及一种或多种药学上可接受的载体。
另一方面，本发明提供一种调节蛋白激酶活性的方法，其中包括将所述蛋白激酶与本发明的化合物或其药学上可接受的盐或本发明的药物组合物接触。优选地，所述蛋白激酶选自ALK。此外，所述蛋白激酶包括突变的激酶，其中突变激酶选自突变的ALK激酶。
再一方面，本发明同时提供本发明的化合物或其药学上可接受的盐或本发明的药物组合物在制备用于治疗疾病的药物中的应用，其中所述疾病是与蛋白激酶(例如ALK) 活性相关的疾病，例如异常细胞增殖，其中异常细胞增殖包括癌症。
本发明还提供本发明的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗由ALK介导的疾病的药物中的应用。本发明还提供本发明的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗癌症的药物中的应用。所述由ALK介导的疾病或所述癌症选自非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤等，如ALK阳性的非小细胞肺癌。
另外，本发明还提供一种治疗哺乳动物(例如人)疾病的方法，其中所述疾病是与蛋白激酶(例如ALK)活性相关的，包括向人给予有效剂量的本发明的化合物或其药学上可接受的盐或者本发明的药物组合物。
发明详述
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述都是示例性的、解释性的，而不是对任何本发明主题的限制。
某些化学术语
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且，任选取代的基团可以是未取代的(例如：-CH 2CH 3)、完全取代的(例如：-CF 2CF 3)、单取代的(例如：-CH 2CH 2F)或者介于单取代和完全取代之间的任意层级(例如：-CH 2CHF 2、-CF 2CH 3、-CFHCHF 2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
可在参考文献(包括Carey和Sundberg，《高等有机化学》第四版，A卷(2000)和B卷(2001)，普莱南出版社(Plenum Press)，纽约)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术 人员选择基团及其取代基以提供稳定的结构部分和化合物。
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如，C 1- 6烷基描述了一个烷基基团，如下定义的那样，具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
本文单独或作为其他组分(比如卤代烷基)的一部分使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃，其具有1-12个碳原子，优选1-8个碳原子，更优选1-6个碳原子，通过单键与分子的其他部分相连，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正庚基、2-甲基己基、正辛基等。
本文单独或组合使用的术语“烷氧基”是指(烷基)-O-基团，其中烷基如本发明中定义。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基。
本文单独或作为其他成分的一部分使用的术语“烯基”是指直链或支链一价碳氢基团，其只有碳原子和氢原子，包含至少一个双键，并具有2-14个碳原子，优选2-10个碳原子，更优选2-6个碳原子。其通过单键与分子的其他部分相连，例如，乙烯基、1-丙烯基、烯丙基、1-丁烯基、1-戊烯基、1,4-戊二烯基等。
本文单独或作为其他成分的一部分使用的术语“炔基”是指直链或支链一价碳氢基团，其只有碳原子和氢原子，包含至少一个三键，有选择性的具有更多三键或更多双键，并具有2-14个碳原子，优选2-10个碳原子，更优选2-6个碳原子。其通过单键与分子的其他部分相连，例如乙炔基、1-丙炔基、1-丁炔基等。
本文单独或作为其他成分的一部分使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团，只包含碳原子和氢原子，可能包括稠环、螺环或桥环系统，包含3-15个成环碳原子，优选包含3-10个成环碳原子，更优选包含3-8个成环碳原子，可饱和也可不饱和，通过单键与分子的其他部分相连。“环烷基”的非限制性实例包括环丙基、环丁基、环戊基、环己基、环己酮基、环辛基、1H-茚基、十氢萘基等。
本文单独或作为其他成分的一部分使用的术语“杂环基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香 单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括哌啶基、哌嗪基、四氢吡啶基、吗啉基、氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、吗啉基、2-氧哌啶基、四氢异喹啉基、三噻烷基等。
本文单独或组合使用的术语“卤素”、“卤代”或“卤化物”是指氟、氯、溴和碘。
除非另有指定，本发明的化合物所含有的烯烃双键包括E和Z异构体。
应理解，本发明的化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本发明的化合物也可显示出顺-反异构现象，这对于本领域技术人员而言是显而易见的。应理解，本发明的化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物，包括外消旋混合物。通过实施或修改已知方法，例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体，或者可以由它们的中间体的合适的异构体分别制备它们。
本文所用术语“药学上可接受的盐”既包括加酸盐，也包括加碱盐。
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其他方面并非不合需要、跟无机酸或有机酸形成的盐。“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性、在生物学上或其他方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。
本发明的化合物或其盐可以作为活性物质单独给药，优选以其药物组合物的形式给药。
因此，另一方面，本发明提供一种药物组合物，其含有本发明的化合物或其药学上可接受的盐作为活性成份，以及一种或多种药学上可接受的载体。
本文所用术语“药物组合物”是指混合有本发明的化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明的化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。
本发明的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
给予本发明的化合物或其药学上可接受的盐或本发明的药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种药学上可接受的载体经由通用的药剂学方法制成。药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。上述载体需要与活性化合物或其他辅料兼容。
本发明的药物组合物可以采用本领域周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其他合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。可以根据通常药物实践中公知的方法对糖衣剂的核心进行包衣，如使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
在其他实施方式中，所述药物组合物还包含至少一种其他的抗癌药物。在另一些实施方式中，所述药物组合物和至少一种其他的抗癌药物分别以独立的剂型组合成组合产品。这些另外的药物可以作为多剂量治疗方案的一部分，与含有本发明的化合物的药物组合物分开给药。或者，这样药物可以是单一剂型的一部分，在单一的组合物中与本发明的化合物混合。当作为多剂量治疗方案的一部分分开给药时，两种活性药剂可以同时、按顺序或者彼此间隔一段时间给药，以产生这些药物的期望活性。
另一方面，本发明提供一种调节蛋白激酶活性的方法，其中包括将所述蛋白激酶与本发明的化合物或其药学上可接受的盐或这本发明的药物组合物接触。优选地，所述蛋白激酶选自ALK。此外，所述蛋白激酶包括突变的激酶，其中突变激酶选自突变的ALK激酶。
再一方面，本发明同时提供本发明的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗疾病的药物中的应用，其中所述疾病是与蛋白激酶(例如ALK或其突变体(如以下至少之一的突变位点L1196M、F1174L、G1202C、G1269S、R1275Q))活性相关的疾病，例如异常细胞增殖，其中异常细胞增殖包括癌症。
另一方面，本发明还提供本发明化合物或其药学上可接受的盐或者本发明的药物组 合物在制备用于治疗由ALK介导的疾病的药物中的应用。所述由ALK介导的疾病包括ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤等，优选地包括ALK阳性的非小细胞肺癌。
本文所用术语“ALK阳性”是指对象的ALK和其它基因融合。
另一方面，本发明还提供一种治疗哺乳动物(例如人)疾病的方法，其中所述疾病是与蛋白激酶(例如ALK或其突变体(如以下至少之一的突变位点L1196M、F1174L、G1202C、G1269S、R1275Q))活性相关的，包括向人给予有效剂量的本发明的化合物或其药学上可接受的盐或者本发明的药物组合物。
在本申请中，术语“治疗有效量”可以是在某种程度上缓解对象中的疾病或病症的一种或多种症状、使与疾病或病症相关或是其病因的一种或多种生理或生物化学参数部分或完全恢复正常、和/或降低疾病或病症的发作可能性的量。
在一些实施方式中，本发明的化合物的施用剂量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。在一些实施方式中，所述化合物的量的范围为约0.5mg/kg体重/天-约50mg/kg体重/天。在一些实施方式中，所述化合物的量为约0.001g/天-约7g/天。在其他实施方式中，所述化合物的量为约0.002g/天-约6g/天。在其他实施方式中，所述化合物的量为约0.005g/天-约5g/天。在其他实施方式中，低于上述范围下限的剂量水平可能已经是足够的。在其他实施方式中，可能需要高于上述范围上限的剂量水平。在一些实施方式中，以单剂量施用所述化合物，每天一次。在其他实施方式中，以多剂量施用所述化合物，每天不只一次。在一些实施方式中，所述药物组合物施用于的个体为哺乳动物。在其他实施方式中，所述哺乳动物是人。
具体的给药方式和剂型取决于化合物本身的理化性质以及所应用疾病的严重程度等。
具体实施方式
以下结合实施例示例性阐述本发明的化合物及其制备方法和用途。
流程1：
Figure PCTCN2018071793-appb-000003
可按照流程1所述路线制备本发明所示化合物。流程1中反应所得的产物可以通过传统分离技术来得到，这种传统技术包括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如，但不限于，Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据。本发明所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。
步骤A：2,4-二氯-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶(中间体i，1.0当量)、R 1NH 2(1.05当量)和三氟乙酸(1.0当量)依次加入到乙二醇单甲醚/三氟乙醇(2/1，v/v)混合溶剂中，加热回流反应12-72h后，减压浓缩除去溶剂，得到的残留物用少量的二氯甲烷和水溶解后，水相分离，经饱和的碳酸氢钠溶液调至pH＝8后，水相用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到的剩余物经硅胶快速层析纯化后得中间体ⅱ；
步骤B：氮气保护下，中间体ii(1.0当量)、R 2NH 2(1.05当量)、Pd 2(dba) 3(0.1当量)、(±)-BINAP(0.15当量)和碳酸铯(2.0当量)依次加入到无水甲苯中，80-130℃加热反应4-12h后，减压浓缩除去溶剂，得到的残留物用少量的二氯甲烷和水溶解后，水相用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到的剩余物经硅胶快速层析分离纯化后得到中间体ⅲ；
步骤C：将中间体iii加入到三氟乙酸溶液(5-20毫升)中，在55℃下搅拌若干小时后，减压浓缩除去溶剂，得到的残留物用二氯甲烷和水溶解后，水相分离，经碳酸钠溶液调至pH＝8后，水相用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到的剩余物经硅胶快速层析分离纯化后得到终产物ⅳ。
除非另有说明，温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司，阿法埃莎(Alfa Aesar)，或北京百灵威科技有限公司等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行；反应瓶上装有橡胶隔膜，以便通过注射器加入底物和试剂；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪；旋光测定使用SGW-3自动旋光仪(上海申光仪器仪表有限公司)。
核磁数据(1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl 3、DMSO-d6等，以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl 3:7.26ppm；DMSO-d6:2.50ppm)。当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、sept(七重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以赫兹(Hz)为单位。
缩略语：
atm：大气压TFA：三氟乙酸
(±)-BINAP：(±)-2,2'-双-(二苯膦基)-1,1'-联萘
DMF：N,N-二甲基甲酰胺
h：小时
M：摩尔每升
Pd/C：钯碳
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
Pd(dppf)Cl 2：[1,1'-双(二苯基磷)二茂铁]二氯化钯
Pd(OAc) 2：醋酸钯
Xant-phos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽
中间体R 1NH 2的制备
中间体A1： 1-(2-甲基-4-氨基-5-异丙氧基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000004
步骤1：1-溴2-甲基-4-硝基-5-异丙氧基苯
Figure PCTCN2018071793-appb-000005
1-溴-2-甲基-4-硝基-5-氟苯(5.2克)和碳酸铯(14.5克)依次加到30毫升的异丙 醇中，升温至60℃反应过夜。反应完毕后，冷却至室温，过滤出去不溶物，滤液减压浓缩后，得到的剩余物经石油醚洗涤后得到产物(棕色固体，5.53克)。 1H-NMR(400MHz,CDCl 3):δ＝7.68(1H,s),7.26(1H,s),4.60(1H,sept,J＝6.1Hz),2.36(3H,s),1.38(6H,d,J＝6.1Hz)。
步骤2：1-(2-甲基-4-硝基-5-异丙氧基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000006
1-溴2-甲基-4-硝基-5-异丙氧基苯(1.0克)、N,N-二甲基哌啶-4-胺(564毫克)、Pd(OAc) 2(83毫克)、Xant-phos(324毫克)和碳酸铯(2.34克)依次加入50mL的1,4-二氧六环中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(二氯甲烷/甲醇，15:1，v/v)分离纯化后得到目标产物(浅黄色固体，459毫克)。 1H-NMR(400MHz,CDCl 3):δ＝7.74(1H,s),6.56(1H,s),4.57(1H,sept,J＝6.8Hz),3.29(2H,d,J＝12Hz),2.67(2H,dt,J 1＝1.7,J 2＝12Hz),2.33(6H,s),2.31-2.26(1H,m),2.23(3H,s),1.95(2H,d,J＝12Hz),1.68(2H,dq,J 1＝3.5,J 2＝12Hz),1.38(6H,d,J＝6.8Hz).ESI MS m/z:322.09[M+H] +。
步骤3：1-(2-甲基-4-氨基-5-异丙氧基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000007
1-(2-甲基-4-硝基-5-异丙氧基苯基)-N,N-二甲基哌啶-4-胺(488毫克)、还原铁粉(425毫克)和氯化铵(423毫克)依次加入到30mL的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，441毫克)。ESI MS m/z:292.07[M+H] +。
中间体A2：4-([1,4'-联哌啶]-1'-基)-2-异丙氧基-5-甲基苯胺
Figure PCTCN2018071793-appb-000008
步骤1：1'-(5-异丙氧基-2-甲基-4-硝基苯基)-1,4'-联哌啶
Figure PCTCN2018071793-appb-000009
1-溴-2-甲基-4-硝基-5-异丙氧基苯(838毫克)、1,4'-联哌啶(514毫克)、Pd(OAc) 2(70毫克)、Xant-phos(261毫克)和碳酸铯(2.0克)依次加入30mL的1,4-二氧六环中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，剩余物经硅胶快速层析(二氯甲烷/甲醇，15:1，v/v)分离纯化后得到目标产物(浅黄色固体，475毫克)。ESI MS m/z:362.11[M+H] +。
步骤2：4-([1,4'-联哌啶]-1'-基)-2-异丙氧基-5-甲基苯胺
Figure PCTCN2018071793-appb-000010
1'-(5-异丙氧基-2-甲基-4-硝基苯基)-1,4'-联哌啶(475毫克)、还原铁粉(368毫克)和氯化铵(352毫克)依次加入到30mL的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，340毫克)。ESI MS m/z:332.12[M+H] +。
中间体A3： 2-异丙氧基-4-((4-吗啉基哌啶-1-基)-5-甲基苯胺
Figure PCTCN2018071793-appb-000011
步骤1：4-((1-((2-甲基-4-硝基-5-异丙氧基苯基)哌啶-4-基)吗啉
Figure PCTCN2018071793-appb-000012
1-溴2-甲基-4-硝基-5-异丙氧基苯(700毫克)、4-(哌啶-4-基)吗啉(571毫克)、Pd(OAc) 2(70毫克)、Xant-phos(265毫克)和碳酸铯(2.5克)依次加入40毫升的1,4-二氧六环中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(二氯甲烷:甲醇，15:1，v/v)分离纯化后得到目标产物(浅黄色固体，410毫克)。ESI MS m/z:363.82[M+H] +。
步骤2：2-异丙氧基-4-(4-吗啉基哌啶-1-基)-5-甲基苯胺
Figure PCTCN2018071793-appb-000013
4-(1-(2-甲基-4-硝基-5-异丙氧基苯基)哌啶-4-基)吗啉(410毫克)、还原铁粉(316毫克)和氯化铵(53.5毫克)依次加入到30毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，376毫克)。ESI MS m/z:333.91[M+H] +。
中间体A4： 4-(4-氨基-5-异丙氧基-2-甲基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
Figure PCTCN2018071793-appb-000014
步骤1：1-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
Figure PCTCN2018071793-appb-000015
1-溴-5-异丙氧基-2-甲基-4-硝基苯(2.0克)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1-(2H)-甲酸叔丁酯(2.5克)、Pd(dppf)Cl 2(540毫克)和碳酸钠(2.0克)依次加入60毫升1,4-二氧六环和水的混合溶剂(10:1，v/v)中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(石油醚:乙酸乙酯，2:1，v/v)分离纯化后得到目标产物(浅黄色固体，2.6克)。 1H-NMR(400MHz,CDCl 3):δ＝7.57(1H,s),6.76(1H,s),5.58(1H,s),4.59(1H,sept,J＝6.1Hz),4.03(2H,br s),3.60(2H,t,J＝5.5Hz),2.30(2H,br s),2.20(3H,s),1.48(9H,s),1.34(6H,d,J＝6.1Hz)。
步骤2： 4-(4-氨基-5-异丙氧基-2-甲基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
1-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(643毫克)、还原铁粉(480毫克)和氯化铵(454毫克)依次加入到40毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，581毫克)。 1H-NMR (400MHz,CDCl 3):δ＝6.54(2H,s),5.50(1H,br s),4.48(1H,sept,J＝6.1Hz),4.01(2H,br s),3.70(2H,br s),3.59(2H,t,J＝5.6Hz),2.31(2H,br s),2.14(3H,s),1.50(9H,s),1.33(6H,d,J＝6.1Hz)。ESI MS m/z:347.23[M+H-56] +。
中间体A5： 4-(2-甲基-4-氨基-5-异丙氧基苯基)哌啶-1-甲酸叔丁酯
Figure PCTCN2018071793-appb-000016
4-(2-甲基-4-硝基-5-异丙氧基苯基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(668毫克)和10％Pd/C(7.5毫克)依次加入到40毫升的甲醇中，在1atm的氢气氛围下搅拌过夜，过滤除去催化剂，浓缩滤液，剩余物经石油醚重结晶后，得到目标产物(棕色油状液体，650毫克)。ESI MS m/z:349.25[M+H] +。
中间体A6： 1-(3-异丙氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000017
步骤1：4-溴-2-异丙氧基-1-硝基苯
Figure PCTCN2018071793-appb-000018
4-溴-2-氟-1-硝基苯(5.0克)和碳酸铯(22.1克)依次加入到50毫升的异丙醇中，60℃反应过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(石油醚:乙酸乙酯，4:1，v/v)分离纯化后得到目标产物(浅黄色固体，4.5克)。 1H-NMR(400MHz,DMSO-d 6):δ＝7.79(1H,d,J＝8.6Hz),7.64(1H,d,J＝1.9Hz),7.29(1H,J 1＝1.9,J 2＝8.6Hz),4.90(1H,sept,J＝6.0Hz),1.27(6H,d,J＝6.0Hz)。
步骤2：1-(3-异丙氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000019
4-溴-2-异丙氧基-1-硝基苯(800毫克)、N,N-二甲基哌啶-4-胺N,N-二甲基哌啶-4-胺(393毫克)、Pd(OAc) 2(67.0毫克)、(±)BINAP(28.0毫克)和碳酸铯(2.0克)依次加入50毫升1,4-二氧六环中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析分离(二氯甲烷:甲醇，12:1，v/v)纯化后得到目标产物(浅黄色固体，515毫克)。ESI MS m/z:308.20[M+H] +。
步骤3：1-(3-异丙氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
1-(3-异丙氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺(515毫克)、还原铁粉(470毫克)和氯化铵(445毫克)依次加入到30毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，337毫克)。ESI MS m/z:278.41[M+H] +。
中间体A7： 1-(3-乙基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000020
步骤1：2-硝基-5-(4-(二甲基氨基)哌啶-1-基)苯甲醛
Figure PCTCN2018071793-appb-000021
2-硝基-5-氯苯甲醛(18.6克)、N,N-二甲基哌啶-4-胺(15.4克)、Pd(OAc) 2(4.58克)、(±)-BINAP(6.23克)和碳酸铯(64克)依次加入200毫升1,4-二氧六环中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(二氯甲烷:甲醇，20:1，v/v)分离纯化后得到目标产物(浅黄色固体，1.52克)。ESI MS m/z:277.97[M+H] +。
步骤2：N,N-二甲基-1-(3-乙烯基-4-硝基苯基)哌啶-4-胺
Figure PCTCN2018071793-appb-000022
-78℃下，甲基三苯基溴化磷(835毫克)滴加到丁基锂(2M，1.17毫升)的40毫升的无水四氢呋喃溶液中，温度保持不变继续搅拌2h后，再缓慢地滴加2-硝基-5-(4-(二甲基氨基)哌啶-1-基)苯甲醛(500毫克)的15毫升的二氯甲烷溶液，然后缓慢升温至室温，搅拌过夜，经硅胶快速层析(二氯甲烷:甲醇，12:1，v/v)分离后得到目标产物(白色固体，430毫克)。ESI MS m/z:276.03[M+H] +。
步骤3：1-(3-乙基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
N,N-二甲基-1-(3-乙烯基-4-硝基苯基)哌啶-4-胺(430毫克)和10％Pd/C(60毫克)依次加入到20毫升甲醇中，在1atm氢气下搅拌过夜，过滤除去催化剂，浓缩滤液，剩余物经石油醚重结晶后，得到产物(棕色油状液体，188毫克)。ESI MS m/z:248.03[M+H] +。
中间体A8： 1-(3-(二氟甲氧基)-4-氨基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000023
步骤1：2-(二氟甲氧基)-4-氟-1-硝基苯
Figure PCTCN2018071793-appb-000024
将2-硝基-5-氟苯酚(1.57克)、二氟氯乙酸钠(3.05克)和碳酸钠(1.03克)依次加到30毫升DMF中，升温至100℃反应5小时后，冷却至室温并向反应液中加入20毫升的4M的HCl水溶液，室温搅拌2h后淬灭，然后将20毫升的水加入到反应混合液中，并用乙酸乙酯萃取，有机相经1N的碳酸氢钠水溶液洗涤、饱和食盐水洗涤和无水硫酸钠干燥及减压浓缩后得到产物(黄色油状液体，2克)。 1H-NMR(400MHz,CDCl 3):δ＝8.05-8.01(1H,m),7.15-7.07(2H,m),6.64(1H,t,J＝72Hz)。
步骤2：1-(3-(二氟甲氧基)-4-硝基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000025
2-(二氟甲氧基)-4-氟硝基苯(2.0克)、N,N-二甲基哌啶-4-胺(1.36克)和碳酸钾(2.7克)依次加入到60毫升DMF中，60℃反应过夜，经硅胶快速层析(二氯甲烷:甲醇，50:1，v/v)分离后得到产物(棕色固体，2.46克)。ESI MS m/z:316.02[M+H] +。
步骤3：1-(3-(二氟甲氧基)-4-氨基苯基)-N,N-二甲基哌啶-4-胺
1-(3-(二氟甲氧基)-4-硝基苯基)-N,N-二甲基哌啶-4-胺(2.46克)，还原铁粉(2.1克)和氯化铵(2.0克)依次加入到40毫升的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色固体，1.9克)。 1H-NMR(400MHz,CDCl 3):δ＝6.71-6.69(3H,m),6.45(1H,t,J＝75Hz),3.57-3.49(4H,m),2.62(2H,dt,J 1＝1.7,J 2＝12Hz),2.32(6H,s),2.27-2.20(1H,m),1.92(2H,d,J＝12Hz),1.65(2H,dq,J 1＝3.8,J 2＝12Hz)。ESI MS m/z:286.03[M+H] +。
中间体A9： 3'-甲氧基-N4,N4-二甲基-2,3,4,5-四氢-[1,1'-联苯基]-4,4'-二胺
Figure PCTCN2018071793-appb-000026
步骤1：2-甲氧基-4-溴-1-硝基苯
Figure PCTCN2018071793-appb-000027
0℃下，金属钠(1.0克)切碎后缓慢地加入到30mL的无水甲醇里，反应1h后，加入2-氟-4-溴-1-硝基苯(10.0克)，室温反应过夜后，经后处理和分离纯化得到目标产 物(白色固体，9.8克)。 1H-NMR(400MHz,CDCl 3):δ＝7.76(1H,d,J＝8.6Hz),7.24(1H,d,J＝1.7Hz),7.18(1H,dd,J 1＝1.8,J 2＝8.6Hz),3.97(3H,s)。
步骤2：8-(3-异丙氧基-4-硝基苯基)-1,4-二氧杂螺[4.5]癸-7-烯
Figure PCTCN2018071793-appb-000028
2-甲氧基-4-溴-1-硝基苯(3.0克)、4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧杂环戊硼烷(3.8克)、Pd(dppf)Cl 2(950毫克)和碳酸钠(3.5克)依次加入1,4-二氧六环和水的混合溶剂中，加热回流过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(石油醚:乙酸乙酯，2:1，v/v)分离纯化后得到目标产物(黄色固体，3.5克)。ESI MS m/z:291.59[M+H-30] +。
步骤3：3'-甲氧基-4'-硝基-2,5-二氢-[1,1'-联苯基]-4(3H)-酮
Figure PCTCN2018071793-appb-000029
8-(3-异丙氧基-4-硝基苯基)-1,4-二氧杂螺[4.5]癸-7-烯(3.5克)加入到20％的三氟乙酸的二氯甲烷混合溶剂(20毫升)中，室温下搅拌过夜，经硅胶快速层析(石油醚:乙酸乙酯，2:1，v/v)分离纯化后得到目标产物(白色固体，2.4克)。ESI MS m/z:247.60[M+H] +。
步骤4：3'-甲氧基-N,N-二甲基-4'-硝基-2,3,4,5-四氢-[1,1'-联苯基]-4-胺
Figure PCTCN2018071793-appb-000030
室温下，3'-甲氧基-4'-硝基-2,5-二氢-[1,1'-联苯基]-4(3H)-酮(2.4克)、二甲胺的四氢呋喃溶液(6.0毫升,2M,12.0毫摩尔)和醋酸(1.0毫升)依次加入到30毫升甲醇中，反应1h后，将氰基硼氢化钠(1.2毫克)加入到上述反应液中，室温搅拌过夜，向反应液中加入20毫升的4M的HCl水溶液，室温搅拌2h后淬灭，然后将100毫升的水加入到反应混合液中，用饱和的碳酸氢钠溶液调至pH＝8后，再用二氯甲烷萃取，有机相经饱和食盐水洗涤和无水硫酸钠干燥及减压浓缩后，剩余物经经硅胶快速层析(二氯甲烷:甲醇，15:1，v/v)分离后得到产物(浅黄色固体，566毫克)。ESI MS m/z:276.95[M+H] +。
步骤5： 3'-甲氧基-N4,N4-二甲基-2,3,4,5-四氢-[1,1'-联苯基]-4,4'-二胺
3'-甲氧基-N,N-二甲基-4'-硝基-2,3,4,5-四氢-[1,1'-联苯基]-4-胺(280毫克)、还原铁粉(280毫克)和氯化铵(267.5毫克)依次加入到30毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓 缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，190毫克)。ESI MS m/z:246.50[M+H] +。
中间体A10： 4-(4-(二甲基氨基)环己基)-2-甲氧基苯胺
Figure PCTCN2018071793-appb-000031
3'-甲氧基-N,N-二甲基-4'-硝基-2,3,4,5-四氢-[1,1'-联苯基]-4-胺(283毫克)和10％Pd/C(38毫克)依次加入到30毫升甲醇中，在1atm氢气下搅拌过夜，过滤除去催化剂，浓缩滤液，剩余物经石油醚重结晶后，分离得到目标产物(棕色油状液体，256毫克)。 1H-NMR(400MHz,CDCl 3):δ＝6.75(1H,d,J＝1.6Hz),6.19(1H,dd,J 1＝1.7,J 2＝7.9Hz),6.65-6.63(2H,m),3.85(3H,s),3.67(2H,br s),3.12-2.91(2H,m),2.62-2.56(1H,m),2.41(6H,s),2.09-2.06(1H,m),1.99-1.92(1H,m),1.65-1.40(4H,m)。ESI MS m/z:249.03[M+H] +。
中间体A11： 1-(2-氟-3-甲氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000032
步骤1：1-(2-氟-3-甲氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000033
1,2-二氟-3-甲氧基-4-硝基苯(2.5克)、N,N-二甲基哌啶-4-胺(2.0克)和碳酸铯(8.5克)依次加入50毫升DMF中，60℃加热过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(二氯甲烷:甲醇，15:1，v/v)分离纯化后得到目标产物(棕色油状液体，1.8克)。ESI MS m/z:297.94[M+H] +。
步骤2：1-(2-氟-3-甲氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
1-(2-氟-3-甲氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺(1.8克)、还原铁粉(1.7克)和氯化铵(1.6毫克)依次加入到40毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，1.52克)。 1H-NMR(400MHz,CDCl 3):δ＝6.56(1H,t,J＝8.6Hz),6.41(1H,dd,J 1＝1.8,J 2＝8.6Hz),3.90(3H,d,J＝1.0Hz),3.67(2H,br s),3.33(2H,d,J＝12Hz),2.64-2.58(2H,m),2.32(6H,s),2.29-2.22(1H,m),1.90-1.87(2H,m),1.78-1.71(2H,m)。ESI MS m/z:267.97[M+H] +。
中间体A12： 1-(2-氟-4-氨基-5-甲氧基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000034
步骤1：1-溴-2-氟-4-硝基-5-甲氧基苯
Figure PCTCN2018071793-appb-000035
0℃下，金属钠(63毫克)切碎后缓慢地加入到30毫升的无水甲醇里，并缓慢升至室温，继续反应1h后，加入1-溴-2,5-二氟-4-硝基苯(5.0克)，室温反应过夜后，经硅胶快速层析(石油醚:乙酸乙酯，4:1，v/v)分离纯化得到目标产物(白色固体，5.2克)。 1H-NMR(400MHz,CDCl 3):δ＝7.72(1H,d,J＝7.6Hz),7.30(1H,d,J＝5.5Hz),3.97(3H,s)。
步骤2：1-(2-氟-4-硝基-5-甲氧基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000036
1-溴-2-氟-4-硝基-5-甲氧基苯(1.0克)、N,N-二甲基哌啶-4-胺(0.6克)和碳酸铯(2.6克)依次加入50毫升的DMF中，60℃加热过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经硅胶快速层析(二氯甲烷:甲醇，15:1，v/v)分离纯化后得到目标产物(棕色油状液体，790毫克)。ESI MS m/z:297.39[M+H] +。
步骤3：1-(2-氟-4-氨基-5-甲氧基苯基)-N,N-二甲基哌啶-4-胺
1-(2-氟-4-硝基-5-甲氧基苯基)-N,N-二甲基哌啶-4-胺(790毫克)、还原铁粉(740毫克)和氯化铵(689毫克)依次加入到50毫升甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，540毫克)。 1H-NMR(400MHz,CDCl 3):δ＝6.51-6.44(2H,m),3.81(3H,s),3.63(2H,br s),3.34(2H,d,J＝12Hz),2.66(2H,t,J＝12Hz),2.23(6H,s),2.29-2.25(1H,m),1.89(2H,d,J＝12Hz),1.78-1.68(2H,m)。ESI MS m/z:267.25[M+H] +。
中间体A13： 1-(2-氯-3-甲氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000037
步骤1：1-氟-2-氯-3-甲氧基-4-硝基苯
Figure PCTCN2018071793-appb-000038
0℃下，金属钠(120毫克)切碎后缓慢地加入到30毫升的无水甲醇里，反应1h后，加入1,3-二氟-2-氯-4-硝基苯(1.0克)，室温反应3h后，经硅胶快速层析(石油醚:乙酸乙酯，4:1，v/v)分离纯化后得到目标产物(白色固体，694毫克)。 1H-NMR(400MHz,CDCl 3):δ＝7.82(1H,dd,J 1＝3.7,J 2＝5.5Hz),7.06(1H,dd,J 1＝1.7,J 2＝9.2Hz),4.06(3H,s)。
步骤2：1-(2-氯-3-甲氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺
Figure PCTCN2018071793-appb-000039
1-氟-2-氯-3-甲氧基-4-硝基苯(400毫克)、N,N-二甲基哌啶-4-胺(255毫克)和碳酸铯(1.27克)依次加入40毫升的DMF中，60℃加热过夜，减压浓缩除去溶剂，得到的残留物用少量的乙酸乙酯和水溶解后，用乙酸乙酯萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和浓缩后，得到的剩余物经经硅胶快速层析(二氯甲烷:甲醇，15:1，v/v)分离纯化后得到目标产物(棕色油状液体，459毫克)。ESI MS m/z:314.02[M+H] +。
步骤3：1-(2-氯-3-甲氧基-4-氨基苯基)-N,N-二甲基哌啶-4-胺
1-(2-氯-3-甲氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺(459毫克)、还原铁粉(409毫克)和氯化铵(387毫克)依次加入到30毫升的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色固体，398毫克)。ESI MS m/z:283.97[M+H] +。
其中，中间体2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺、1-(4-氨基-3-甲氧基苯基)-N、N-二甲基哌啶-4-胺和2-甲氧基-4-吗啉苯胺的制备参考专利CN 102093364 B；中间体4-(4-氨基-3-异丙氧基苯基)哌啶-1-甲酸叔丁酯的制备参考专利申请WO2015/180685；中间体2-甲氧基-4-(4-(哌啶-1-基)哌啶-1-基)苯胺的制备参考专利申请WO2004/080980A1。
中间体R 2NH 2的制备
中间体B1： 2-(异丙基磺酰基)-4-氟苯胺
Figure PCTCN2018071793-appb-000040
步骤1：2-(异丙基磺酰基)-4-氟-1-硝基苯
Figure PCTCN2018071793-appb-000041
2,4-二氟硝基苯(5.0克)、异丙基硫醇(2.86克)和碳酸铯(15.3克)依次加入到80毫升的DMF中，加热至70℃反应过夜。反应液冷却至0℃时，缓慢地加入间氯过氧化苯甲酸(21克)，然后升至室温，反应4h后，向反应液中缓慢地加入50毫升的水淬灭，水相经饱和的碳酸氢钠溶液调至pH＝8后，用乙酸乙酯萃取，有机相用饱和食盐水洗涤后用无水硫酸钠干燥，旋转蒸发去掉溶剂后，得到剩余物经硅胶快速层析(石油醚:乙酸乙酯，4:1，v/v)纯化得到产物(棕色油状液体，4.4克)。ESI MS m/z:248.04[M+H] +。
步骤2：2-(异丙基磺酰基)-4-氟苯胺
用2-(异丙基磺酰基)-4-氟-1-硝基苯(4.4克)、还原铁粉(5.0克)和氯化铵(4.8克)依次加入到80毫升的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却过滤除去沉淀，滤液相经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色固体，3.69克)。 1H-NMR(400MHz,DMSO-d 6):δ＝7.33-7.28(1H,m),7.21(1H,dd,J 1＝3.0,J 2＝8.6Hz),6.91(1H,dd,J 1＝4.5,J 2＝9.1Hz),5.99(2H,br s),3.42(1H,sept,J＝6.8Hz),1.19(6H,d,J＝6.8Hz)。ESI MS m/z:218.06[M+H] +。
中间体B2： 2-(异丁基磺酰基)苯胺
Figure PCTCN2018071793-appb-000042
步骤1：1-(异丁基磺酰基)-2-硝基苯
Figure PCTCN2018071793-appb-000043
1-氟-2-硝基苯(2.4克)、异丁基硫醇(1.4克)和碳酸铯(16.5克)依次加入到60毫升的DMF中，加热至70℃反应过夜。冷却反应至0℃时，向反应液中缓慢地加入间氯过氧化苯甲酸(7.9克)，然后升至室温，反应4h后，向反应液中缓慢地加入40毫升的水淬灭，水相经饱和的碳酸氢钠溶液调至pH>7后，用乙酸乙酯萃取，萃取液用饱和食盐水洗涤后用无水硫酸钠干燥，旋转蒸发去掉溶剂后，得到剩余物经硅胶快速层析(石油醚:乙酸乙酯，4:1，v/v)纯化得到产物(棕色油状液体，0.8克)。ESI MS m/z:244.06[M+H] +。
步骤2：2-(异丁基磺酰基)苯胺
1-(异丁硫基磺酰基)-2-硝基苯(7.04克)、还原铁粉(7.7克)和氯化铵(7.4毫克) 依次加入到60毫升的甲醇和水(1:1，v/v)的混合溶剂中，加热回流1h后，冷却至室温后过滤除去沉淀，滤液经饱和的碳酸氢钠溶液调至pH＝8后，用二氯甲烷萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到剩余物经石油醚重结晶后得到产物(棕色油状液体，5.3克)。 1H-NMR(400MHz,DMSO-d 6):δ＝7.50(1H,d,J＝7.8Hz),7.35(1H,t,J＝7.4Hz),6.88(1H,d,J＝8.1Hz),6.70(1H,t,J＝7.3Hz),6.02(2H,br s),3.09(2H,d,J＝6.2Hz),2.01(1H,sept,J＝6.5Hz),0.95(6H,d,J＝6.6Hz)。ESI MS m/z:214.09[M+H] +。
其中，中间体2-(环戊基磺酰基)苯胺的制备参考专利申请WO 2002/057242。
实施例1： N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-N 4-(2-(异丙基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000044
步骤1：4-氯-N-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-胺
Figure PCTCN2018071793-appb-000045
根据通用的合成方法A，用2,4-二氯-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶(中间体i，680毫克)、1-(4-氨基-3-甲氧基苯基)-N,N-二甲基哌啶-4-胺(603毫克)和三氟乙酸(0.16毫升，250毫克)依次加入到40毫升的乙二醇单甲醚：三氟乙醇(2:1，v/v)混合溶剂中，加热120℃回流24h后，反应液减压浓缩，得到的残留物用少量的二氯甲烷和水溶解后，用饱和的碳酸氢钠溶液调至pH＝8后，二氯甲烷萃取，有机相经饱和食盐水洗涤和无水硫酸钠干燥后，减压浓缩后得到的残留物经硅胶快速层析(二氯甲烷:甲醇，10:1，v/v)分离纯化后得到产物(棕色固体，395毫克)。 1H-NMR(400MHz,CDCl3):δ＝8.35(1H,d,J＝8.5Hz),7.38(1H,br s),7.22(2H,d,J＝8.6Hz),6.86(2H,d,J＝8.6Hz),6.54(1H,s),6.52(1H,dd,J1＝2.5,J2＝8.7Hz),4.53(2H,s),3.85(3H,s),3.79(3H,s),3.61(2H,d,J＝12Hz),3.48-3.44(2H,m),2.93-2.89(2H,m),2.66(2H,dt,J1＝2.0,J2＝12Hz),2.32(6H,s),2.27-2.22(1H,m),1.92(2H,d,J＝12.3Hz),1.68(2H,dq,J1＝3.8, J 2＝12Hz)。ESI MS m/z:523.13[M+H] +。
步骤2：N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-N 4-(2-(异丙基磺酰基)苯基)-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000046
根据通用的合成方法B，用4-氯-N-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-胺(395毫克)、2-(异丙基磺酰基)苯胺(151毫克)、Pd 2(dba) 3(74毫克)、(±)-BINAP(70毫克)和碳酸铯(731毫克)依次加入到无水甲苯中，120℃加热反应12h后，减压浓缩除去溶剂，得到的残留物用少量的二氯甲烷和水溶解后，水相用二氯甲烷萃取，得到的有机相经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，剩余物经硅胶快速层析(二氯甲烷:甲醇，10:1，v/v)分离纯化后得到产物(棕色固体，367毫克)。 1H-NMR(400MHz,CDCl 3):δ＝8.55(1H,d,J＝8.3Hz),8.51(1H,br s),8.31(1H,d,J＝8.8Hz),7.78(1H,dd,J 1＝1.5,J 2＝6.4Hz),7.54(1H,dt,J 1＝1.5,J 2＝8.6Hz),7.25(2H,d,J＝8.6Hz),7.21(1H,s),7.07-7.03(1H,m),6.86(2H,d,J＝8.6Hz),6.56(1H,d,J＝2.5Hz),6.34(1H,dd,J 1＝2.5,J 2＝8.8Hz),4.52(2H,s),3.88(3H,s),3.79(3H,s),3.62(2H,d,J＝12.2Hz),3.45(2H,dt,J 1＝1.9,J 2＝8.3Hz),3.25(1H,sept,J＝6.8Hz),2.83(2H,dt,J 1＝8.2,J 2＝8.7Hz),2.67(2H,dt,J 1＝2.0,J 2＝10Hz),2.32(6H,s),2.29-2.22(1H,m),1.93(2H,d,J＝12Hz),1.70(2H,dq,J 1＝3.8,J 2＝12Hz),1.29(6H,d,J＝6.8Hz)。ESI MS m/z:686.29[M+H] +。
步骤3： N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-N 4-(2-(异丙基磺酰基)苯基)-6,7- 二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
根据通用合成方法C，N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯基)-N 4-(2-(异丙基磺酰基)苯基)-7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺(367毫克)的三氟乙酸(5毫升)溶液在55℃下搅拌过夜，减压浓缩除去溶剂，得到的残留物用二氯甲烷和水溶解后，水相分离，经碳酸钠溶液调至pH＝8后，再用二氯甲烷萃取，萃取液经饱和食盐水洗涤、无水硫酸钠干燥和减压浓缩后，得到的剩余物经乙酸乙酯重结晶后得到产物(白色固体，200毫克)。 1H-NMR(400MHz,CDCl 3):δ＝8.61(1H,br s),8.54(1H,d,J＝8.4Hz),8.18(1H,d,J＝8.7Hz),7.81(1H,dd,J 1＝1.5,J 2＝8.0Hz),7.55(1H,dt,J 1＝1.3,J 2＝8.5Hz),7.12-7.07(2H,m),6.54(1H,d,J＝2.4Hz),6.47(1H,dd,J 1＝2.4,J 2＝8.8Hz),4.51(1H,s),3.86(3H,s),3.70-3.62(4H,m),3.26(1H,sept,J＝6.8Hz),2.95(2H,t, J＝8.4Hz),2.72-2.66(2H,m),2.54-2.47(1H,m),2.43(6H,s),2.04-2.00(2H,m),1.79-1.70(2H,m),1.30(6H,d,J＝6.8Hz)。ESI MS m/z:566.18[M+H] +。
实施例2： N 4-(2-(异丙基磺酰基)苯基)-N 2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000047
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,DMSO-d 6):δ＝8.53-8.50(2H,m),7.70(2H,dt,J 1＝6.8,J 2＝8.3Hz),7.59-7.55(1H,m),7.27(1H,s),7.14(1H,d,J＝7.2Hz),6.77(1H,s),6.60(1H,d,J＝2.4Hz),6.43(1H,dd,J 1＝2.4,J 2＝8.7Hz),3.79(3H,s),3.66(2H,d,J＝11.8Hz),3.53(2H,t,J＝8.5Hz),3.40(1H,sept,J＝6.8Hz),2.80-2.76(2H,m),2.64-2.59(2H,m),2.56-2.51(2H,m),2.39-2.28(5H,m),2.15(3H,s),1.84(2H,d,J＝12Hz),1.51(2H,dq,J 1＝3.2,J 2＝12Hz),1.23(2H,br s),1.17(6H,d,J＝6.8Hz)。ESI MS m/z:621.28[M+H] +。
实施例3： N 4-(2-(异丙基磺酰基)苯基)-N 2-(2-甲氧基-4-吗啉代)-6,7-二氢-5H-吡咯并[2,3-d] 嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000048
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.64(1H,s),8.54(1H,d,J＝8.3Hz),8.19(1H,d,J＝8.8Hz),7.82(1H,dd,J 1＝1.5,J 2＝6.4Hz),7.55(1H,dt,J 1＝1.4,J 2＝8.6Hz),7.18(1H,br s),7.12-7.09(1H,m),6.52(1H,d,J＝2.5Hz),6.41(1H,dd,J 1＝2.4,J 2＝8.8Hz),4.62(1H,br s),3.92-3.84(7H,m),3.70(2H,dt,J 1＝8.3,J 2＝8.6Hz),3.27(1H,sept,J＝6.8Hz),3.11(4H,t,J＝4.7Hz),2.95(2H,dt,J 1＝8.3,J 2＝8.6Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:525.05[M+H] +。
实施例4： N 2-(2-异丙氧基-4-(4-(二甲基氨基)哌啶-1-基)-5-甲基苯基)-N 4-(2-(异丙基磺酰 基)苯基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000049
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.59(1H,s),8.54(1H,d,J＝8.3Hz),8.17(1H,s),7.82(1H,dd,J 1＝1.4,J 2＝8.0Hz),7.58-7.53(1H,m),7.21(1H,br s),7.09(1H,t,J＝7.5Hz),6.61(1H,s),4.53-4.47(2H,m),3.69(2H,dt,J 1＝8.1,J 2＝8.7Hz),3.28(1H,sept,J＝6.8Hz),3.13(2H,d,J＝12Hz),2.97(2H,dt,J 1＝8.3,J 2＝8.6Hz),2.61(2H,dt,J 1＝1.0,J 2＝12Hz),2.43(6H,s),2.25-2.19(1H,m),2.13(3H,s),2.00-1.96(2H,m),1.76-1.72(2H,m),1.36(6H,d,J＝6.1Hz),1.31(6H,d,J＝6.9Hz)。ESI MS m/z:608.24[M+H] +。
实施例5： N 2-(2-异丙氧基-4-(4-(哌啶-1-基)哌啶-1-基)-5-甲基苯基)-N 4-(2-(异丙基磺酰基) 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000050
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.60(1H,s),8.55(1H,d,J＝8.4Hz),8.16(1H,s),7.83(1H,dd,J 1＝1.6,J 2＝8.0Hz),7.57(1H,dt,J 1＝1.6,J 2＝8.4Hz),7.22(1H,s),7.10(1H,t,J＝8.0Hz),6.62(1H,s),4.54-4.48(2H,m),3.70(2H,t,J＝8.4Hz),3.29(1H,sept,J＝6.8Hz),3.14-.311(2H,m),2.98(2H,t,J＝8.4Hz),2.63-2.57(6H,m),2.48-2.35(1H,m),2.14(3H,s),1.95-1.91(2H,m),1.82-1.73(2H,m),1.67-1.59(4H,m),1.53-1.46(2H,m),1.36(6H,d,J＝6.0Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:648.04[M+H] +。
实施例6： N 2-(2-异丙氧基-4-(4-吗啉基哌啶-1-基)-5-甲基苯基)-N 4-(2-(异丙基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000051
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.59(1H,s),8.54(1H,d,J＝8.2Hz),8.16(1H,s),7.82(1H,dd,J 1＝1.5,J 2＝8.0Hz),7.55(1H,dt,J 1＝1.4,J 2＝8.2Hz),7.20(1H,br s),7.09(1H,dt,J 1＝0.8,J 2＝8.0Hz),6.61(1H,s),4.53(1H,br s),4.50(1H,sept,J＝6.1Hz),3.76(4H,t,J＝4.6Hz),3.69(2H,t,J＝8.2Hz),3.28(1H,sept,J＝6.8Hz),3.11(2H,d,J＝12Hz),2.97(2H,dt,J 1＝8.2,J 2＝8.6Hz),2.62-2.60(6H,m),2.30-2.25(1H,m),2.13(3H,s),1.94(2H,d,J＝12Hz),1.72-1.64(2H,m),1.35(6H,d,J＝6.1Hz),1.30(6H,d,J＝6.8Hz)。ESI MS m/z:650.09[M+H] +。
实施例7： N 2-(2-异丙氧基-4-(1,2,3,6-四氢吡啶-4-基)-5-甲基苯基)-N 4-(2-(异丙基磺酰基) 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000052
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.60(1H,s),8.53(1H,d,J＝8.4Hz),8.20(1H,s),7.82(1H,dd,J 1＝1.6,J 2＝8.0Hz),7.56(1H,dt,J 1＝1.2,J 2＝8.4Hz),7.34(1H,s),7.09(1H,t,J＝8.0Hz),6.63(1H,s),5.59(1H,s),4.57-4.51(2H,m),3.70(2H,t,J＝8.4Hz),3.55-3.49(2H,m),3.29(1H,sept,J＝6.8Hz),3.10(2H,t,J＝5.6Hz),2.98(2H,t,J＝8.4Hz),2.31-2.25(2H,m),2.13(3H,s),1.86-1.85(1H,m),1.36(6H,d,J＝6.0Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:563.14[M+H] +。
实施例8：N 2-(2-异丙氧基-4-(哌啶-4-基)-5-甲基苯基)-N 4-(2-(异丙基磺酰基)苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000053
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.59(1H,s),8.54(1H,d,J＝8.4Hz),8.17(1H,s),7.82(1H,d,J＝8.8Hz),7.55(1H,t,J＝8.0Hz),7.29(1H,s),7.09(1H,t,J＝7.2Hz),6.77(1H,s),4.56-4.50(2H,m),3.82-3.73(1H,m),3.70(2H,t,J＝8.4Hz),3.29(1H,hept,J＝6.8Hz),3.23-3.20(2H,m),2.98(2H,t,J＝8.4Hz),2.80-2.75(3H,m,),2.16(3H,s),1.77-1.74(2H,m),1.69-1.59(2H,m),1.35(6H,d,J＝6.1Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:565.17[M+H] +。
实施例9： N 2-(2-异丙氧基-4-(哌啶-4-基)苯基)-N 4-(2-(异丙基磺酰基)苯基)-6,7-二氢-5H- 吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000054
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.61(1H,s),8.53(1H,d,J＝8.4Hz),8.32(1H,d,J＝8.4Hz),7.82(1H,dd,J 1＝1.6,J 2＝7.6Hz),7.57(1H,t,J＝7.2Hz),7.32(1H,s),7.12(1H,t,J＝8.0Hz),6.75(1H,d,J＝1.6Hz),6.71(1H,dd,J 1＝1.6,J 2＝8.0Hz),4.60(1H,sept,J＝6.1Hz),4.54(1H,br s),3.70(2H,t,J＝8.0Hz),3.33-3.24(3H,m),2.97(2H,t,J＝8.0Hz),2.86-2.78(2H,m),2.63-2.55(1H,m),1.90-1.85(3H,m),1.82-1.71(2H,m),1.37(6H,d,J＝6.1Hz),1.30(6H,d,J＝6.8Hz)。ESI MS m/z:551.15[M+H] +。
实施例10： N 2-(2-异丙氧基-4-(4-(二甲基氨基)哌啶-1-基)-苯基)-N 4-(2-(异丙基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000055
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl3):δ＝8.61(1H,s),8.51(1H,d,J＝8.4Hz),8.25(1H,d,J＝8.8Hz),7.82(1H,d,J＝8.0Hz),7.55(1H,t,J＝8.0Hz),7.19(1H,s),7.11(1H,t,J＝8.0Hz),6.53(1H,s),6.45(1H,d,J＝8.4Hz),4.61-4.51(2H,m),3.71-3.63(4H,m),3.27(1H,sept,J＝6.8Hz),3.03-2.91(3H,m),2.75-2.63(8H,m),2.22-2.19(2H,m),1.94-1.85(2H,m),1.37(6H,d,J＝6.0Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:594.23[M+H] +。
实施例11： N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-乙基苯基)-N 4-(2-(异丙基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000056
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl3):δ＝9.29(1H,s),8.73(1H,s),8.08(1H,d,J＝8.4Hz),7.79(1H,dd,J1＝1.6,J2＝7.6Hz),7.36(1H,d,J＝8.4Hz),7.26-7.24(1H,m),7.15(1H,t,J＝8.0Hz),6.92(1H,d,J＝2.4Hz),6.87(2H,dd,J1＝2.4,J2＝8.4Hz),3.90(2H,t,J＝8.8Hz),3.85-3.81(2H,m),3.45-3.37(1H,m),3.24-3.17(1H,m),2.99-2.91(4H,m),2.85(6H,s),2.62(2H,q,J＝7.6Hz),2.24-2.21(2H,m),2.11-2.01(2H,m),1.29(6H,d,J＝6.8Hz),1.17(3H,t,J＝7.6Hz)。ESI MS m/z:564.19[M+H] +。
实施例12：N 2-(2-(二氟甲氧基)-4-(4-(二甲基氨基)哌啶-1-基)苯基)-N 4-(2-(异丙基磺酰基)苯基)-6,7-二氢-5H-吡咯并[ 2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000057
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.66(1H,s),8.46(1H,d,J＝8.4Hz),8.20(1H,d,J＝9.6Hz),7.82(1H,dd,J 1＝1.3,J 2＝8.0Hz),7.52(1H,dt,J 1＝1.3,J 2＝8.4Hz),7.11(1H,t,J＝7.2Hz),6.85(1H,s),6.74-6.72(2H,m),6.49(1H,t,J＝74.0Hz),4.56(1H,s),3.73-3.66(4H,m),3.26(1H,sept,J＝6.8Hz),2.96(2H,t,J＝8.4Hz),2.91-2.81(1H,m),2.74(2H,t,J＝12.0Hz),2.62(6H,s),2.24-2.14(2H,m),1.90-1.79(2H,m),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:602.16[M+H] +。
实施例13： N 4-(2-(异丙基磺酰基)苯基)-N 2-(2-甲氧基-4-(4-(哌啶-1-基)哌啶-1-基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000058
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.65(1H,br s),8.52(1H,d,J＝8.3Hz),8.21(1H,d,J＝8.8Hz),7.83(1H,dd,J 1＝1.6,J 2＝8.0Hz),7.56(1H,dt,J 1＝1.6,J 2＝8.5Hz),7.20(1H,br s),7.13(1H,t,J＝7.1Hz),6.52(1H,d,J＝2.2Hz),6.46(1H,dd,J 1＝2.2,J 2＝8.8Hz),4.66(1H,br s),3.87(1H,s),3.73-3.68(4H,m),3.48-3.45(2H,m),3.29(1H,sept,J＝6.8Hz),3.23-3.18(1H,m),2.97(2H,t,J＝8.6Hz),2.77(2H,t,J＝12Hz),2.39(2H,t,J＝12Hz),2.02-1.74(12H,m),1.32(6H,d,J＝6.8Hz)。ESI MS m/z:606.01[M+H] +。
实施例14： N 2-(2-甲氧基-4-(4-(二甲基氨基)环己-1-烯基)苯基)-N 4-(2-(异丙基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000059
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.64(1H,br s),8.49(1H,d,J＝8.2Hz),8.35(1H,d,J＝8.2Hz),7.83(1H,dd,J 1＝1.6,J 2＝8.0Hz),7.59-7.55(1H,m),7.40(1H,br s),7.12(1H,t,J＝8.0Hz),6.86-6.84(2H,m),5.92(1H,br s),5.34(2H,t,J＝4.5Hz),4.68(2H,d,J＝8.2Hz),3.90(3H,s),3.71(2H,t,J＝8.6Hz),3.43-3.36(1H,m),3.26(1H,sept,J＝6.8Hz),2.97(2H,t,J＝8.6Hz),2.81(6H,s),2.22(3H,t,J＝7.8Hz),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:563.08[M+H] +。
实施例15： N 2-(2-甲氧基-4-(4-(二甲基氨基)环己基)苯基)-N 4-(2-(异丙基磺酰基)苯基)-6,7- 二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000060
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.60(1H,s),8.53(1H,d,J＝8.0Hz),8.25(1H,d,J＝8.4Hz),7.81(1H,dd,J 1＝1.2,J 2＝8.0Hz),7.58(1H,t,J＝8.8Hz),7.30(1H,s),7.11(1H,t,J＝7.6Hz),6.79(2H,d,J＝8.0Hz),4.50(1H,s),3.89(3H,s),3.69(2H,t,J＝8.8Hz),3.26(1H,sept,J＝6.8Hz),2.97(2H,t,J＝8.8Hz),2.68-2.56(1H,m),2.28(6H,s),2.03-1.98(4H,m),1.95-1.81(1H,m),1.68-1.60(4H,m),1.30(6H,d,J＝6.8Hz)。ESI MS m/z:565.16[M+H] +。
实施例16： N 2-(4-(4-(二甲基氨基)哌啶-1-基)-3-氟-2-甲氧基苯基)-N 4-(2-(异丙基磺酰基) 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000061
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.69(1H,s),8.42(1H,d,J＝7.6Hz),8.05(1H,d,J＝8.8Hz),7.84(1H,d,J＝7.6Hz),7.57(1H,t,J＝8.8Hz),7.33(1H,br s),7.15(1H,t,J＝8.0Hz),6.58(1H,t,J＝8.8Hz),4.77(1H,br s),3.97(3H,s),3.73(2H,t,J＝8.4Hz),3.52-3.48(2H,m),3.33-3.16(2H,m),2.97(2H,t,J＝8.4Hz),2.84-2.72(8H,m),2.33-2.30(2H,m),2.08-1.91(2H,m),1.31(6H,d,J＝6.8Hz)。ESI MS m/z:584.02[M+H] +。
实施例17： N 2-(2-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)-5-氟苯基)-N 4-(2-(异丙基磺酰基) 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000062
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz, DMSO-d 6):δ＝8.50(1H,s),8.38(1H,d,J＝8.0Hz),8.01(1H,d,J＝14.8Hz),7.75(1H,dd,J 1＝1.2,J 2＝8.0Hz),7.62(1H,dt,J 1＝1.2,J 2＝8.0Hz),7.32(1H,s),7.21(1H,t,J＝7.6Hz),6.94(1H,s),6.67(1H,d,J＝8.4Hz),3.84(3H,s),3.56(2H,t,J＝8.8Hz),3.44-3.36(3H,m),2.81(2H,t,J＝8.8Hz),2.71-2.65(3H,m),2.55(6H,s),2.01-1.90(2H,m),1.71-1.62(2H,m),1.17(6H,d,J＝6.8Hz)。ESI MS m/z:584.29[M+H] +。
实施例18： N 2-(2-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)苯基)-N 4-(2-(异丙基磺酰基)-4-氟 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000063
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,DMSO-d 6):δ＝8.47(1H,dd,J 1＝4.8,J 2＝9.2Hz),8.34(1H,s),7.67(1H,d,J＝8.8Hz),7.52-7.45(2H,m),7.27(1H,s),6.76(1H,s),6.62(1H,d,J＝2.0Hz),6.44(1H,dd,J 1＝2.4,J 2＝8.8Hz),3.79(3H,s),3.75-3.72(2H,m),3.54-3.44(3H,m),2.96-2.82(1H,m),2.76(2H,t,J＝8.4Hz),2.66-2.58(8H,m),2.00-1.96(2H,m),1.68-1.58(2H,m),1.17(6H,d,J＝6.8Hz)。ESI MS m/z:584.76[M+H] +。
实施例19： N 2-(2-甲氧基-4-(4-(二甲基氨基)哌啶-1-基)-苯基)-N 4-(2-(异丁基磺酰基)苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000064
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,DMSO-d 6):δ＝8.41(1H,d,J＝8.4Hz),8.34(1H,s),7.75(1H,d,J＝8.0Hz),7.70(1H,d,J＝8.8Hz),7.56(1H,t,J＝7.6Hz),7.26(1H,s),7.14(1H,t,J＝8.0Hz),6.76(1H,s),6.61(1H,d,J＝2.0Hz),6.41(1H,dd,J 1＝2.0,J 2＝8.4Hz),3.79(3H,s),3.74-3.69(2H,m),3.52(2H,t,J＝8.8Hz),3.17(2H,d,J＝6.0Hz),2.82-2.71(3H,m),2.66-2.56(8H,m),2.03-1.93(3H,m),1.70-1.57(2H,m),0.92(6H,d,J＝6.4Hz)。ESI MS m/z:580.31[M+H] +。
实施例20： N 4-(2-(环戊基磺酰基)苯基)-N 2-(4-(4-(二甲基氨基)哌啶-1-基)-2-甲氧基苯 基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000065
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.59(1H,s),8.54(1H,d,J＝8.4Hz),8.18(1H,d,J＝8.8Hz),7.83(1H,dd,J 1＝1.2,J 2＝8.0Hz),7.54(1H,dt,J 1＝1.2,J 2＝8.0Hz),7.12(1H,s),7.09(1H,t,J＝7.6Hz),6.55(1H,d,J＝2.4Hz),6.48(1H,dd,J 1＝2.4,J 2＝8.4Hz),4.51(1H,s),3.86(3H,s),3.69(2H,t,J＝8.4Hz),3.64-3.54(3H,m),2.95(2H,t,J＝8.4Hz),2.69(2H,t,J＝12Hz),2.36(6H,s),2.09-1.94(5H,m),1.87-1.58(8H,m)。ESI MS m/z:591.97[M+H] +。
实施例21： N 2-(2-甲氧基-3-氯-4-(4-(二甲基氨基)哌啶-1-基)-苯基)-N 4-(2-(异丙基磺酰基) 苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺
Figure PCTCN2018071793-appb-000066
用与实施例1相同的步骤使用不同的反应物得到目标化合物。 1H-NMR(400MHz,CDCl 3):δ＝8.69(1H,br s),8.20(1H,d,J＝8.6Hz),7.84(1H,dd,J 1＝1.6,J 2＝8.0Hz),7.57-7.52(2H,m),7.14(1H,t,J＝7.4Hz),6.73(1H,d,J＝8.6Hz),5.35(1H,t,J＝4.4Hz),4.69(1H,s),3.89(3H,s),3.73(2H,t,J＝8.6Hz),3.46(2H,t,J＝12Hz),3.26(1H,sept,J＝6.8Hz),3.23-3.20(1H,m),2.97(2H,t,J＝8.6Hz),2.80(6H,s),2.73(2H,t,J＝12Hz),2.33-2.29(2H,m),2.03-1.96(2H,m),1.32(6H,d,J＝6.8Hz)。ESI MS m/z:600.14[M+H] +。
生物活性实验
1.化合物的体外酶学活性测定：
采取Cisbio公司的匀相时间分辨荧光(HTRF)方法建立了ALK激酶结构域(ALK(KD))及其突变体的激酶活性检测平台，进行化合物活性的测定。
HTRF是基于Eu螯和物的供体与受体(第二荧光标记物)之间的荧光共振能量转移的一项技术。供体被外来光源激发，如果它与受体比较接近，可以将能量共振转移到受体上，使其受到激发，发出特定波长的发射光。本实验中，Biotin标记的TK底物被激酶磷酸化以后，将会被Eu标记的抗体所识别，此时Streptavidin-XL665通过与Biotin的相互作用使得Eu与XL665相互靠近，当Eu被激发后(320nM)，其能量会共振转移 到XL665上并使后者激发产生特定波长)的激发光(665nM)。当小分子抑制剂对酶活产生抑制作用时，磷酸化产物减少，最终导致665nM处荧光信号的减弱。
具体实验操作如下：将化合物分别从100μM或10μM开始用DMSO进行3倍的梯度稀释，每个浓度取4μL加入到96μL的反应缓冲液中(50mM HEPES(pH7.5),0.01％BSA,0.1mM NaVO 3,0.001％TWEEN-20,5mM MnCl 2,50nM SEB，1mM DTT)，取2.5μL加入到384孔板(OptiPlate-384,PerkinElmer)，然后加入5μL的激酶(4nM(WT,L1196M,R1275Q，F1174L,G1269S)；实验室制备)，离心混匀，再加入5μL的ATP(0.8μM(WT,L1196M,R1275Q)；0.2μΜ(F1174L,G1269S)；Sigma)和TK Substrate-biotin(4μM；Cisbo)启动反应。将384孔板放于孵育箱中23℃反应1小时后，加入5μL的50倍稀释的Eu3+-Cryptate标记的TK-Antibody(Cisbo)，5μL的streptavidin-XL665(500nM；Cisbo)进行检测。在23℃反应1小时后，在Envision(PerkinElmer)上读取荧光值。化合物的IC 50值使用GraphPad Prism 5.0软件计算得到。
2.化合物的细胞增殖活性测定：
(1)采用Promega公司的
Figure PCTCN2018071793-appb-000067
检测试剂建立了悬浮细胞增殖抑制筛选方法。
人血癌细胞Karpas299(The Global Bioresource Center)用补充有10％胎牛血清
Figure PCTCN2018071793-appb-000068
的RPMI-1640
Figure PCTCN2018071793-appb-000069
培养基进行培养，培养条件是37℃，95％空气和5％的CO 2，培养于25cm 2或75cm 2塑料组织培养瓶
Figure PCTCN2018071793-appb-000070
中，一周传代培养2～3次。
将细胞以4×10 3细胞/孔的密度接种在96-孔细胞培养板
Figure PCTCN2018071793-appb-000071
中，195μl/孔，并在37℃，95％空气和5％的CO 2中进行培养。24小时后加入待测化合物：将化合物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释，每个浓度取4μl加入到96μl的无血清培养基中，最后取5μl培养基稀释后的化合物加入到接种有细胞的培养板中。细胞培养液中DMSO的终浓度为0.1％，所试化合物的终浓度是0.3nM～10μM。将上述细胞37℃温育3天。
3天后，通过CellTiter-Blue试剂盒(Promega公司)进行细胞活力测定，最后通过Prism程序计算化合物对细胞增殖的半抑制浓度，即IC 50值。
(2)采用Promega公司的
Figure PCTCN2018071793-appb-000072
检测试剂建立了贴壁细胞增殖抑制筛选方法。
人非小细胞肺癌细胞NCI-H2228(The Global Bioresource Center)用补充有10％胎牛血清
Figure PCTCN2018071793-appb-000073
的RPMI-1640
Figure PCTCN2018071793-appb-000074
培养基进行培养，培养条件是37℃，95％空气和5％的CO 2，培养于25cm 2或75cm 2塑料组织培养瓶
Figure PCTCN2018071793-appb-000075
中，一周传代培养2～3次。
将细胞以3×10 3细胞/孔的密度接种在96-孔白色细胞培养板
Figure PCTCN2018071793-appb-000076
中，195μl/孔，并在37℃，95％空气和5％的CO 2中进行培养。24小时后加入待测化合物：将化合 物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释，每个浓度取4μl加入到96μl的无血清培养基中，最后取5μl培养基稀释后的化合物加入到接种有细胞的培养板中。细胞培养液中DMSO的终浓度为0.1％，所试化合物的终浓度是0.3nM～10μM。将上述细胞37℃温育3天。
3天后，通过CellTiter-Glo试剂盒(Promega公司)进行细胞活力测定，最后通过Prism程序计算化合物对细胞增殖的半抑制浓度，即IC 50值。
表1.化合物对ALK及其突变体的活性抑制作用
Figure PCTCN2018071793-appb-000077
注：表中的“/”表示未测试。
本发明的化合物能够显著抑制ALK的激酶活性，并且本发明的化合物对五种ALK激酶区突变体的激酶都具有非常强的抑制作用，优于参照化合物Crizotinib。这意味着实施例中的化合物不仅可以作为ALK融合肿瘤病人的一线用药，还可用于治疗Crizotinib耐药的病人的治疗。
表2.细胞增殖实验数据
Figure PCTCN2018071793-appb-000078
注：表中的“/”表示未测试。
本发明的化合物能够显著抑制ALK融合细胞的增殖，其有效半抑制剂浓度(IC 50) 显著低于参照化合物Crizotinib。
(3)化合物的血脑屏障通透性检测
动物实验：
动物口服给药8h后取全血，离心后取上清液。取脑，用生理盐水清洗干净称重，与甲醇以1:4的比例进行匀浆，离心后取上清液。
分析脑及血浆：B/P
将化合物用DMSO配制成500μg/mL的化合物储存液，再用此储存液与乙腈配制成浓度为10、40、100、400、1000、4000、10000ng/mL的工作液。
取一定体积的空白血浆，依次加入配好的工作液，并加入内标液，配成已知浓度的标曲(1、4、10、40、100、400、1000ng/mL)，离心后取上清液加入96孔板(康宁万佳生物科技有限公司)。未知血浆样品操作相同，工作液以同体积的乙腈代替。
取一定体积的空白脑匀浆上清液，依次加入配好的工作液，并加入内标液，配成已知浓度的标曲(10、40、100、400、1000、4000、10000ng/mL)，离心后取上清液加入96孔板(康宁万佳生物科技有限公司)。未知脑组织样品操作相同，工作液以同体积的乙腈代替。
表3.化合物的血脑屏障通透性检测
Figure PCTCN2018071793-appb-000079
本发明的化合物能够跨越血脑屏障，其效果明显优于参照化合物Crizotinib。
3.药代动力学测定
雄性SD大鼠来源于北京维通利华实验动物技术有限公司，将大鼠分组，每组3只，分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。
表4.药代动力学数据
实施例 实施例1 实施例2
剂量(mg/kg) 5 5
T 1/2(hr) 4.05 9.40
T max(hr) 6.00 6.67
C max(ng/mL) 722 1739
AUC 0-inf(hr*ng/mL) 8523 31983

Claims (11)

  1. 式(I)所示化合物或其药学上可接受的盐
    Figure PCTCN2018071793-appb-100001
    其中，
    A选自3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，并且A可任选地被1-3个独立地选自R 8的基团取代；
    R 8各自独立地选自卤素、OH、C 1-6烷基、C 1-6烷氧基、NR 9R 10、3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自H和C 1-6烷基，所述3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代；
    R 1选自C 1-6烷基、C 2-6烯基、C 2-6炔基和C 3-8环烷基；
    R 2选自卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基和C 3-8环烷基，其中所述C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基和C 3-8环烷基可任选地被卤素取代；
    R 3、R 4、R 6和R 7各自独立地选自H和C 1-6烷基；
    R 5为C 1-6烷基；
    m为0、1、2、3或4；
    n为0、1、2、3或4。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 8各自独立地选自C 1-6烷基、C 1-6烷氧基、-NR 9R 10、3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基，其中，R 9和R 10各自独立地选自C 1-6烷基，所述3-8元环烷基和含有1-3个选自N、O和S杂原子的3-8元杂环基可任选地被C 1-6烷基取代。
  3. 根据权利要求1-2任一项所述的化合物或其药学上可接受的盐，其中R 1选自C 1-6烷基和C 3-8环烷基。
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中R 2选自 卤素、C 1-6烷基和C 1-6烷氧基，其中所述C 1-6烷基和C 1-6烷氧基可任选地被卤素取代。
  5. 根据权利要求1-4任一项所述的化合物或其药学上可接受的盐，其中m为1、2或3，n为0或1。
  6. 根据权利要求1-5任一项所述的化合物或其药学上可接受的盐，其中R 3、R 4、R 6和R 7均为H，且n为0。
  7. 以下化合物或其药学上可接受的盐：
    Figure PCTCN2018071793-appb-100002
  8. 一种药物组合物，其含有权利要求1-7任一项所述的化合物或其药学上可接 受的盐作为活性成份，以及一种或多种药学上可接受的载体。
  9. 权利要求1-7任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备用于治疗由ALK介导的疾病的药物中的用途。
  10. 权利要求9所述的用途，其中所述的ALK介导的疾病选自癌症。
  11. 根据权利要求10所述的用途，其中所述癌症选自非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤。
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