WO2018077227A1 - 作为c-MET抑制剂的吡啶酮类化合物 - Google Patents

作为c-MET抑制剂的吡啶酮类化合物 Download PDF

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Publication number
WO2018077227A1
WO2018077227A1 PCT/CN2017/107964 CN2017107964W WO2018077227A1 WO 2018077227 A1 WO2018077227 A1 WO 2018077227A1 CN 2017107964 W CN2017107964 W CN 2017107964W WO 2018077227 A1 WO2018077227 A1 WO 2018077227A1
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Prior art keywords
acid
pharmaceutically acceptable
group
acceptable salt
compound according
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PCT/CN2017/107964
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English (en)
French (fr)
Inventor
徐雄彬
李刚
丁照中
胡利红
胡国平
黎健
陈曙辉
池志刚
王坤
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Medshine Discovery Inc
Fujian Cosunter Pharmaceutical Co Ltd
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Medshine Discovery Inc
Fujian Cosunter Pharmaceutical Co Ltd
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Priority to RS20201448A priority Critical patent/RS61126B1/sr
Priority to JP2019540379A priority patent/JP6719679B2/ja
Priority to CN201780036464.XA priority patent/CN109311812B/zh
Priority to LTEP17864813.5T priority patent/LT3533787T/lt
Priority to HRP20201985TT priority patent/HRP20201985T1/hr
Priority to MYPI2019002142A priority patent/MY189557A/en
Priority to ES17864813T priority patent/ES2835301T3/es
Priority to US16/343,387 priority patent/US10501443B2/en
Priority to PE2019000855A priority patent/PE20190912A1/es
Priority to PL17864813T priority patent/PL3533787T3/pl
Priority to SG11201903801YA priority patent/SG11201903801YA/en
Priority to CA3041164A priority patent/CA3041164C/en
Priority to MX2019004626A priority patent/MX374439B/es
Application filed by Medshine Discovery Inc, Fujian Cosunter Pharmaceutical Co Ltd filed Critical Medshine Discovery Inc
Priority to SI201730558T priority patent/SI3533787T1/sl
Priority to EA201990952A priority patent/EA038108B1/ru
Priority to KR1020197014236A priority patent/KR102070748B1/ko
Priority to AU2017348810A priority patent/AU2017348810B2/en
Priority to PH1/2019/500875A priority patent/PH12019500875B1/en
Priority to DK17864813.5T priority patent/DK3533787T3/da
Priority to BR112019008415-0A priority patent/BR112019008415B1/pt
Priority to UAA201904417A priority patent/UA122737C2/uk
Priority to EP17864813.5A priority patent/EP3533787B1/en
Priority to NZ753020A priority patent/NZ753020B2/en
Publication of WO2018077227A1 publication Critical patent/WO2018077227A1/zh
Priority to IL266126A priority patent/IL266126B/en
Anticipated expiration legal-status Critical
Priority to ZA2019/03074A priority patent/ZA201903074B/en
Priority to CONC2019/0005165A priority patent/CO2019005165A2/es
Ceased legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic 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
    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a class of pyridone compounds as c-MET inhibitors, and specifically discloses a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the proto-oncogene Met-encoded c-Met is a highly binding receptor tyrosine kinase belonging to the RON subfamily and the only known receptor for scattering factors or hepatocyte growth factor (HGF).
  • the c-Met protein is a heterodimer linked by a disulfide bond of a 50 kD alpha subunit and a 145 kD beta subunit, and is divided into an extracellular domain and an intracellular domain.
  • the extracellular domain contains three functionally distinct domains: an N-terminal ligand binding domain (SEMA region) covering the entire alpha chain and a portion of the beta chain, a cystine enrichment region with four conserved disulfide bonds, and immunity. Globulin-like domain.
  • SEMA region N-terminal ligand binding domain
  • the intracellular domain is also composed of three regulatory regions: the juxtamembrane domain with Tyr1003 phosphorylation site, the tyrosine kinase catalytic domain with Tyr1234 and Tyr1235 phosphorylation sites, and Tyr1349 and Tyr1356 binding tyrosine C-terminal multifunctional bonding area
  • Binding of HGF to the extracellular domain of c-Met induces phosphorylation of c-Met and recruits a variety of interstitial factors such as GAB1 (growth factor receptor binding protein-1) and GAB2 (growth factor) in the C-terminal multifunctional region.
  • Receptor binding protein-2 etc., further attracts SHP2, PI3K and other molecules to bind thereto, thereby activating RAS/MAPK, PI3K/AKT, JAK/STAT pathway, etc., thereby regulating cell growth, migration, proliferation and survival.
  • Abnormal c-Met pathway induces tumorigenesis and metastasis, and abnormally high levels of c-Met are found in various human malignancies such as bladder cancer, gastric cancer, lung cancer, and breast cancer.
  • c-Met is also associated with tumor resistance to multiple kinase inhibitors.
  • c-Met there is a crosstalk between c-Met and various membrane receptors, which constitutes a complex network system.
  • the interaction between c-Met and the adhesion receptor CD44 amplifies the response of the signal peptide; interaction with the brain protein receptor from the protein activates the non-dependent ligand HGF c-Met, enhancing the invasion;
  • the interaction between the pro-apoptotic receptor FAS accelerates apoptosis; interaction with various receptor tyrosine kinases such as EGFR, VEGFR, etc., causes activation between each other to be regulated, and the angiogenesis process is affected.
  • the interaction between c-Met and these membrane receptors promotes tumorigenesis and metastasis, and induces drug resistance.
  • the transcription factor HIF-1 ⁇ is a major regulator of tumor cell adaptation to hypoxic stress.
  • VEGFR inhibitors cause tumor hypoxia in the early stage of treatment.
  • HIF-1 ⁇ up-regulates c-Met levels, and the increase of c-Met concentration promotes tumor cell metastasis, causing regional expansion or metastasis of tumors, resulting in tumor escaping oxygen deficiency. Environment, building a more invasive and growing cloning system.
  • the cause of tumor resistance to EGFR inhibitors may be related to up-regulation of ligand HGF levels. Amplification of c-Met was detected in 4% to 20% of patients with non-small cell lung cancer resistant to gefitinib and erlotinib.
  • HGF regulates PI3K/AKT and ERK pathways via GAB1 directly to EGFR kinase inhibitors Produce resistance.
  • BRAF-mutated melanoma cell line the researchers found that up-regulation of HGF is resistant to the action of the BRAF inhibitor ramurafenib.
  • the interaction between c-Met and membrane receptors induces resistance to kinase target therapy.
  • anti-tumor drugs such as alkylating agents, anti-metabolites, anti-tumor antibiotics, immunomodulators, etc., but most of them are due to toxicity and patient intolerance.
  • alkylating agents such as alkylating agents, anti-metabolites, anti-tumor antibiotics, immunomodulators, etc.
  • Molecular targeted therapy for a variety of malignant tumors has received extensive attention and high attention.
  • Molecular targeted drugs are highly selective, broad-spectrum effective, and their safety is superior to cytotoxic chemotherapy drugs, which is a new direction in the field of cancer therapy.
  • c-Met small molecule inhibitors that have been studied or have entered clinical research include PF-2341066, EMD-1214063, XL-184 or ARQ-197.
  • Tepotinib (EMD1214063), despite its high selectivity, still has the disadvantages of low metabolic stability and large in vivo clearance. Therefore, the clinical need for metabolically stable c-Met inhibitors to make up for this deficiency.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of H and F;
  • R 2 is selected from H, CH 3 ;
  • R 2 is not H, the carbon atom attached to R 2 is in the R configuration or the S configuration;
  • A is selected from the group consisting of 1, 2 or 3 R 3 substituted: phenyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl or thiazolyl;
  • R' is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F.
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R 1 is selected from H.
  • R 1 is selected from F.
  • R 2 is selected from H.
  • R 2 is selected from CH 3 .
  • the carbon atom attached to R 2 is in the R configuration.
  • the carbon atom attached to R 2 is in the S configuration.
  • the above A is selected from the group consisting of, optionally substituted by 1, 2 or 3 R 3 :
  • the above A is selected from the group consisting of:
  • the above A is selected from the group consisting of:
  • the above A is selected from the group consisting of:
  • the above compound is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating a tumor.
  • the invention focuses on the precise structural modification of the metabolite site, so that the metabolic stability of the target compound is greatly improved.
  • a novel pyridone core structure was designed and synthesized, which significantly enhanced the binding ability of the target compound to c-METase, and thus obtained a more excellent activity for inhibiting tumor growth.
  • in vivo pharmacodynamic results showed that the tumor growth rate of the compound of the present invention was significantly lower than that of Tepotinib (EMD1214063) at the same dose, further demonstrating that the compound of the present invention has better tumor suppressing activity.
  • the compound of the present invention has an increased half-life, an extended action time for the target, enhanced metabolic stability, and more excellent inhibitory activity.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • the acid addition salt is obtained in a suitable inert solvent by contacting a sufficient amount of the acid with the neutral form of such compound.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.)
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers and mixtures thereof are included in the present invention Within the scope of the Ming.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof.
  • Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Example 1-1 The preparation method of Example 1-1 gave Example 1-2 (100.6 mg, 23.91% yield) from Intermediate 1G-2. .
  • Step B Intermediate 2B-1 and intermediate 2B-2 are prepared as in the intermediate 1G-1.
  • Step C The same procedure as in Example 1 was carried out to obtain Examples 2-1 and 2-2.
  • Intermediate 3E was prepared as in the method of Intermediate 1F.
  • Examples 3-1 and 3-2 were prepared as in Example 1.
  • Example 4 was prepared as in Example 1.
  • Example 5 was prepared as in Example 1.
  • Example 6 was prepared as in Example 1.
  • Trifluoroacetic acid (4.62 g, 40.52 mmol, 3.00 mL) was added dropwise to a solution of Intermediate 7G (50.00 mg, 83.80 ⁇ RTIgt; The reaction was stirred at 25 ° C for 1 hour. The reaction was concentrated to dryness to give crystalljjjjjjjjjjj LCMS (ESI) m/z: 497.2 (M+1).
  • the examples 8-1 and 8-2 were prepared as in the method of Example 1.
  • Examples 9-1, 9-2 were prepared as described in Example 1.
  • intermediate 11B (283.69 mg, 1.26 mmol), intermediate 4A (500.00 mg, 900.15 micromoles), 1,1-di(tert-butylphosphonium)ferrocene palladium chloride (58.67 mg, 90.02) Micromolar) and potassium phosphate trihydrate (479.44 mg, 1.80 mmol) in a mixed solution of tetrahydrofuran (5.00 ml) and water (1.00 ml) were stirred at 65 ° C for 12 hours. The reaction mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated. , filtered, concentrated.
  • This experiment utilizes the LanthaScreenTM Eu Kinase Binding Assay, as shown in Figure 1, to detect Alexa Fluor conjugate or kinase "tracer" binding by the addition of Eu-labeled antibodies.
  • the binding of the tracer and antibody to the kinase results in a high degree of FRET, whereas the use of a kinase inhibitory compound in place of the tracer results in FRET loss.
  • test compound preparation 10 mM test compound and reference compound were diluted to 0.667 mM with 100% DMSO, using a fully automated microplate pretreatment system ECHO for 3-fold dilution, 8 concentration gradients, double double wells, 75 nL per well .
  • the compound of the present invention has strong inhibitory activity against c-METase.
  • Test compound c-MET IC 50 (nM) Test compound c-MET IC 50 (nM) Example 1-2 1.09 Example 7 15.50 Example 2-2 9.33 Example 8-2 3.79 Example 4 6.16 Example 10 69.50 Example 5 2.90 Example 11 5.00 Example 6 4.37
  • Cell culture DMEM medium, fetal bovine serum, DPBS
  • Detection reagent live cell detection kit CellTiter-Glo
  • the amount of ATP directly reflects the number of cells and the state of the cells, and the number of living cells can be detected by quantitatively measuring ATP.
  • the live cell assay kit contains luciferase and its substrate. Through the participation of ATP, luciferase can catalyze the substrate, emit a stable optical signal, and determine the amount of ATP in the cell by detecting the intensity of the signal. The light signal is proportional to the amount of ATP in the cell, and ATP is positively correlated with the number of living cells, so that the cell proliferation can be detected.
  • the assay plate was analyzed using PE company's Envision.
  • MHCC97-H cells were separately seeded in 384-well plates containing 500 cells per well. The cell plates were placed in a carbon dioxide incubator for overnight culture.
  • Compounds were transferred to cell plates at a starting concentration of 10 uM.
  • the cell plates were incubated in a carbon dioxide incubator for 3 days.
  • the Promega CellTiter-Glo reagent was added to the cell plate and incubated for 10 minutes at room temperature to stabilize the luminescence signal. Readings were performed using a PerkinElmer Envision multi-label analyzer.
  • the compounds of the present invention show good inhibitory activity against MHCC97H cells.
  • Test compound MHCC97H cell IC 50 (nM) Test compound MHCC97H cell IC 50 (nM)
  • Example 1-2 8.80 Example 7 22.30
  • Example 9-2 22.10 Example 3-2 19.0
  • Example 10 166.00
  • Example 4 72.90
  • Example 11 93.80
  • Example 5 58.80
  • Example 12 51.40
  • Example 6 32.90
  • MHCC97H cells were cultured in vitro in a single layer, cultured in RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin-streptomycin double antibody, and cultured at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
  • mice BALB/c nude mice, male. 6-8 weeks old, weighing 18-22 grams.
  • 0.2 ml of a cell suspension containing 5 x 10 ⁇ 6 MHCC97H was subcutaneously inoculated into the right back of each mouse.
  • Group administration was initiated when the average tumor volume reached approximately 172 mm3.
  • the experimental grouping and dosing schedule are shown in the table below.
  • the antitumor effect (TGI) of the compounds was evaluated by T-C (days) and T/C (%).
  • the compounds of the present invention show better tumor inhibition than Tepotinib in the pharmacodynamic experiments of the subcutaneous xenograft tumor model of MHCC97H hepatoma cells.
  • the b.p value is calculated from the tumor volume.
  • the compounds of the invention have better metabolic stability than tepotinib.
  • t 1/2 of liver particle metabolism in human, rat, and mouse species was 62.1 minutes, 36.5 minutes, and 49.1 minutes, respectively, under the same conditions, tepotinib in human, rat, and mouse.
  • the t 1/2 of liver particle metabolism of the three species was 48.3 minutes, 10.5 minutes, and 12.4 minutes, respectively.
  • the compound of the present invention has an increased half-life, an extended action time for the target, enhanced metabolic stability, and more excellent inhibitory activity. The prolongation of the half-life will keep the blood concentration for a longer period of time. It can be predicted that the compound will be used in tumor treatment, and the patient's medication dose or dose will be reduced compared with the same drug, and patient compliance will be significantly improved.
  • c-MET binds to HGF, it activates MAPK, PI3K/AKT, Cdc42/Rac1 and other pathways, resulting in cancer cell survival and proliferation, thereby accelerating tumor growth. Therefore, pyridone compounds as c-MET inhibitors are targeted therapeutic drugs for liver cancer, non-small cell lung cancer, and gastric cancer. It has a large application prospect. Especially in the treatment of liver cancer, this compound has a precise therapeutic effect on liver cancer with high expression of c-MET. Therefore, the compound of the present invention, as a c-MET inhibitor of pyridone, is expected to be a new drug which is more effective than similar products in view of its remarkable inhibitory activity in vivo and in vitro and good metabolic stability.

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Abstract

本发明公开了一类作为c-MET抑制剂的吡啶酮类化合物，具体公开了式(Ⅰ)所示化合物或其药学上可接受的盐。

Description

作为c-MET抑制剂的吡啶酮类化合物 技术领域
本发明涉及一类作为c-MET抑制剂的吡啶酮类化合物，具体公开了式(Ⅰ)所示化合物或其药学上可接受的盐。
背景技术
原癌基因Met编码的c-Met是一种具有高度结合性的受体酪氨酸激酶，属于RON亚族，是散射因子或肝细胞生长因子(HGF)唯一已知的受体。c-Met蛋白是由50kD的α亚基和145kD的β亚基通过二硫键相连的异二聚体，分为胞外域和胞内域。胞外域包含有3个功能不同的结构域:覆盖整个α链和部分β链的N-端配体结合域(SEMA区域)、有4个保守二硫键的胱氨酸富集区域、以及免疫球蛋白样结构域。胞内域同样由3个调控区域组成:有Tyr1003磷酸化位点的近膜结构域、有Tyr1234和Tyr1235磷酸化位点的酪氨酸激酶催化结构域、以及有Tyr1349和Tyr1356结合酪氨酸的C-端多功能结合区域
HGF与c-Met胞外域结合后，诱导c-Met发生磷酸化，在C-端多功能区域募集多种细胞间质因子，如GAB1(生长因子受体结合蛋白-1)、GAB2(生长因子受体结合蛋白-2)等，进一步吸引SHP2、PI3K等分子结合在此，由此激活RAS/MAPK、PI3K/AKT、JAK/STAT通路等，从而调控着细胞的生长、迁移、增殖和存活。c-Met通路异常会诱发肿瘤的发生和转移，在多种人类恶性肿瘤如膀胱癌、胃癌、肺癌、乳腺癌中发现异常高水平表达的c-Met。此外，c-Met还与肿瘤对多种激酶抑制剂的耐药性相关。
c-Met和多种膜受体之间存在相互作用(crosstalk)，构成了复杂的网络体系。c-Met和黏附受体CD44之间的相互作用，放大了信号肽的应答作用；与脑蛋白受体从蛋白的相互作用激活了非依赖配体HGF的c-Met，增强了侵袭作用；与促凋亡受体FAS之间的相互作用加快了细胞凋亡；与多种受体酪氨酸激酶如EGFR、VEGFR等的作用使得彼此间激活受到调控，血管生成过程受到影响。c-Met与这些膜受体之间的相互作用促进了肿瘤的发生和转移，诱导产生耐药性。
转录因子HIF-1α是肿瘤细胞适应低氧环境压力的主要调节因子。VEGFR抑制剂在治疗初期造成肿瘤缺氧，在低氧环境中，HIF-1α上调c-Met水平，c-Met浓度的增加促进肿瘤细胞转移，使得肿瘤区域性扩张或转移，造成肿瘤逃离氧气缺乏环境，建立更具侵袭性和生长能力的克隆体系。肿瘤对EGFR抑制剂产生耐药性的原因可能与配体HGF水平上调相关。在4％～20％对吉非替尼和厄洛替尼耐药的非小细胞肺癌患者中检测到了c-Met的扩增，HGF通过GAB1调节PI3K/AKT和ERK通路直接对EGFR激酶抑制剂产生耐药性。在BRAF突变的黑色素瘤细胞系中，研究人员发现HGF的上调对BRAF抑制剂ramurafenib的作用产生抵抗。因此，c-Met和膜受体间的相互作用诱导出现激酶靶点治疗的耐药性。
目前已上市的抗肿瘤药物较多，如烷化剂药物、抗代谢药物、抗肿瘤抗生素、免疫调节剂等，但是大多由于毒性较大，病人不耐受。随着肿瘤分子生物学研究的深入，对肿瘤的发生发展的分子机制越来越清楚，分子靶向治疗多种恶性肿瘤受到了广泛的关注和高度重视。分子靶向药物具有选择性高、广谱有效，其安全性优于细胞毒性化疗药物，是目前肿瘤治疗领域发展的新方向。
目前针对c-Met通路的抗肿瘤治疗药物有两种:一种是抗HGF或c-Met的单克隆抗体；一种是针对c-Met的小分子抑制剂。在研的或已进入临床研究的c-Met小分子抑制剂有PF-2341066、EMD-1214063、XL-184或ARQ-197等。
其中，Tepotinib(EMD1214063)(WO2009006959,公开日2009.1.15)抗肿瘤活性最优，对多种c-MET高表达的肿瘤细胞有很强的抑制作用(c-MET酶活性IC50＝3.67nM,MHCC97H细胞IC50＝6.2nM)，目前已经进入临床Ⅱ期研究阶段。
但是，Tepotinib(EMD1214063)虽然具有高选择性，其仍然存在代谢稳定性不高、体内清除率大的缺点。因此，临床亟需代谢稳定的c-Met抑制剂来弥补这一缺憾。
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2017107964-appb-000001
R1选自H、F；
R2选自H、CH3；
当R2不为H时，与R2相连的碳原子为R构型或S构型；
A选自任选被1、2或3个R3取代的：苯基、吡啶基、吡唑基、异恶唑基、异噻唑基或噻唑基；
R3选自CN、卤素、C(＝O)NH2，或选自任选被1、2或3个R0取代的：C1-6烷基、C1-6杂烷基或C3-6环烷基；
R0选自F、Cl、Br、I、OH、CN、NH2、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3杂烷基；
R’选自F、Cl、Br、I、CN、OH、NH2、CH3、CH3CH2、CF3、CHF2、CH2F。
“C1-3杂烷基”、“C1-6杂烷基”所述之“杂”选自：-O-、-C(＝O)NR’-、-C(＝O)NH-、-NR’-、-NH-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
在本发明的一些方案中，上述R0选自F、Cl、Br、I、OH、CN、NH2、C(＝O)NH2、CH3、CH3CH2、CF3、CHF2、CH2F、NH2CH2、(NH2)2CH、CH3O、CH3CH2O、CH3OCH2、CH3NH、(CH3)2N。
在本发明的一些方案中，上述R1选自H。
在本发明的一些方案中，上述R1选自F。
在本发明的一些方案中，上述R2选自H。
在本发明的一些方案中，上述R2选自CH3。
在本发明的一些方案中，上述与R2相连的碳原子为R构型。
在本发明的一些方案中，上述与R2相连的碳原子为S构型。
在本发明的一些方案中，上述R3选自CN、卤素、C(＝O)NH2，或选自任选被1、2或3个R0取代的：C1-3烷基或C1-3杂烷基。
在本发明的一些方案中，上述R3选自CN、F、Cl、Br、CH3、CH3CH2、CF3、CHF2、CH2F、CH3O、C(＝O)NH2。
在本发明的一些方案中，上述A选自任选被1、2或3个R3取代的：
Figure PCTCN2017107964-appb-000002
Figure PCTCN2017107964-appb-000003
在本发明的一些方案中，上述A选自：
Figure PCTCN2017107964-appb-000004
Figure PCTCN2017107964-appb-000005
在本发明的一些方案中，上述A选自：
Figure PCTCN2017107964-appb-000006
Figure PCTCN2017107964-appb-000007
在本发明的一些方案中，上述A选自：
Figure PCTCN2017107964-appb-000008
Figure PCTCN2017107964-appb-000009
在本发明的一些方案中，上述化合物，选自：
Figure PCTCN2017107964-appb-000010
Figure PCTCN2017107964-appb-000011
本发明还提供一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗肿瘤药物中的应用。
技术效果
本发明着重对易代谢位点进行了精确的结构修饰，使目标化合物代谢稳定性得到很较大程度地提高。另外，设计并合成出了全新的吡啶酮母核结构，使得目标化合物与c-MET酶的结合力显著增强，进而获得了更优良的抑制肿瘤生长的活性。同时，体内药效结果显示，同等剂量下，给予本发明化合物小鼠的肿瘤生长速度较Tepotinib(EMD1214063)明显降低，进一步证明了本发明化合物具有更好的肿瘤抑制活性。本发明化合物半衰期增大，针对靶点的作用时间延长，代谢稳定性增强，具有更优异的抑制活性。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液 或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2017107964-appb-000012
表示一个立体中心的绝对构型，用
Figure PCTCN2017107964-appb-000013
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发 明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化 合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2017107964-appb-000014
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基，可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC 代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017107964-appb-000015
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1(1-1和1-2)
Figure PCTCN2017107964-appb-000016
步骤A：
中间体7C(合成方法见实施例7)(20.4克，50.88毫摩尔)和二氧化锰(44.23克，508.7毫摩尔)在DCM(300毫升)溶液中室温搅拌16小时。反应完毕，将反应液过滤，浓缩得到中间体1A(18.4克)直接用于下一步。LCMS(ESI)m/z:398(M+1).
步骤B：
0℃下，往中间体1A(23.0克，57.87毫摩尔)的THF(200毫升)溶液中加入甲基溴化镁(3M，38.58毫升)。反应液在室温下搅拌1小时。反应完毕后，反应液用饱和氯化铵溶液(300毫升)淬灭，乙酸乙酯萃取(200毫升*2)，无水硫酸钠干燥，过滤，浓缩。得到中间体1B(22.76克，95.11％收率)。LCMS(ESI)m/z:414(M+1).HNMR(400MHz,CHLOROFORM-d)δ＝8.46(s,2H),8.38-8.33(m,1H),8.26(td,J＝1.9,6.9Hz,1H),7.53-7.44(m,2H),5.02(q,J＝6.4Hz,1H),4.31-4.12(m,2H),3.95(d,J＝6.4Hz,2H),2.78(br t,J＝12.1Hz,2H),2.13(br s,1H),2.08-1.96(m,1H),1.86(br d,J＝12.9Hz,2H),1.58(d,J＝6.5Hz,3H),1.49(s,9H),1.39-1.29(m,2H).
步骤C：
0℃下，往中间体1B(22.76克，55.04毫摩尔)的DCM(300毫升)溶液中加入二异丙基乙胺(21.34克，165.12毫摩尔)和甲烷磺酰氯(9.12克，79.62毫摩尔)。反应液在室温下搅拌1小时。薄层色谱显示反应完毕。将反应液用饱和的氯化铵溶液(200毫升)洗涤两次，无水硫酸钠干燥，过滤，浓缩。得到中间体1C(30g，粗品)直接用于下一步。
步骤D：
室温下，往中间体1C(19克，38.65毫摩尔)的DMF(100毫升)溶液中加入碳酸钾(10.68克，77.30毫摩尔)，碘化钾(641.58毫克，3.86毫摩尔)和5-溴-3-氟-1H-吡啶-2-酮(11.13克，57.97毫摩尔)。反应液在90℃下搅拌3小时。反应完毕后，往反应液中加入乙酸乙酯(300毫升)并用饱和食盐水(500毫升)洗涤3次。有机相用无水硫酸钠干燥，过滤，浓缩。得到中间体1D(5.8克，25.54％收率)。HNMR(400MHz,CHLOROFORM-d)δ＝8.47(s,2H),8.41-8.32(m,2H),7.55-7.47(m,1H),7.39(d,J＝7.7Hz,1H),7.15(dd,J＝2.4,8.4Hz,1H),7.11-7.07(m,1H),6.52(q,J＝7.0Hz,1H),4.31-4.12(m,2H),4.01-3.93(m,2H),2.87-2.72(m,2H),2.09-1.98(m,1H),1.89-1.80(m,5H),1.49(s,9H),1.39-1.30(m,2H).
步骤E：
在室温氮气保护下，将中间体1D(2.0克，3.4毫摩尔)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,3,2-二氧杂戊硼烷(1.04克，4.09毫摩尔)，乙酸钾(668.21毫克，6.81毫摩尔)和Pd(dppf)Cl2(498.20毫克，680.87微摩尔)溶于二氧六环(30毫升)。反应液在90℃下搅拌2小时。反应完毕后，得到中间体1E的二氧六环溶液30毫升，将该反应液直接用于下一步。
步骤F(1F-1、1F-2)：
在室温氮气保护下，将中间体1E的二氧六环溶液30毫升(1.92克，3.03毫摩尔)，碳酸钠(642.30毫克，6.06毫摩尔)，2-溴-5-氰基吡啶(665.42毫克，3.64毫摩尔)和Pd(dppf)Cl2(443.43毫克，606.0微摩尔)溶于二氧六环(40毫升)和水(6毫升)中。反应液在90℃下搅拌3小时。反应完毕，将反应液过滤，在滤液中加水(100毫升)并用乙酸乙酯(60毫升*3)萃取。有机相用无水硫酸钠干燥，过滤，浓缩。粗产品用制备板纯化，产品用SFC(柱型:AS(250mm*30mm,10um)；流动相：[B：0.1％NH3H2O ETOH]；B％:55％-55％,10min；200minmin)分离得中间体1F-1(t＝2.819,490毫克，26.04％收率)和中间体1F-2(t＝3.933,480毫克，25.95％收率)。
LCMS(ESI)m/z:611(M+1).
HNMR(中间体1F-1)(400MHz,METHANOL-d4)δ＝8.73(dd,J＝0.9,5.0Hz,1H),8.55(s,2H),8.39(s, 1H),8.34-8.26(m,2H),8.17-8.08(m,2H),7.58-7.49(m,3H),6.50(q,J＝7.2Hz,1H),4.15(br d,J＝13.3Hz,2H),4.06(d,J＝6.3Hz,2H),2.84(br s,2H),2.14-2.01(m,1H),1.97(d,J＝7.3Hz,3H),1.87(br d,J＝11.9Hz,2H),1.48(s,9H),1.35-1.28(m,2H).
HNMR(中间体1F-2)(400MHz,METHANOL-d4)δ＝8.73(dd,J＝0.8,5.0Hz,1H),8.55(s,2H),8.39(s,1H),8.34-8.26(m,2H),8.16-8.09(m,2H),7.61-7.49(m,3H),6.50(q,J＝7.2Hz,1H),4.15(br d,J＝13.2Hz,2H),4.06(d,J＝6.3Hz,2H),2.84(br s,2H),2.12-2.01(m,1H),1.99-1.95(m,3H),1.87(br d,J＝10.9Hz,2H),1.48(s,9H),1.35-1.29(m,2H).
步骤G(1G-1、1G-2)：
0℃下，往中间体1F-1(490毫克，786.01微摩尔)的DCM(10毫升)溶液中加入三氟乙酸(3毫升)。反应液在室温下搅拌1小时。反应完毕后，将反应液浓缩旋干，得到中间体1G-1(502毫克，粗品)直接用于下一步。如中间体1G-1的制备方法得到中间体1G-2(491毫克，粗品)。
步骤H：
0℃下，往中间体1G-1(502.00毫克，803.74毫摩尔)的DCM(10毫升)溶液中加入甲醛水溶液(326.27毫克，4.02毫摩尔，37％纯度)和三乙酰氧基硼氢化钠(511.03毫克,2.41毫摩尔)。反应液在室温下搅拌2小时。反应完毕后，反应液用水(50毫升)淬灭并用DCM(30毫升*2)。有机相用无水硫酸钠干燥，过滤，浓缩。得到的粗产品用制备型HPLC纯化。得到实施例1-1(150毫克，35.41％收率)。
如实施例1-1的制备方法由中间体1G-2得到实施例1-2(100.6毫克，23.91％收率)。。
实施例1-1：
LCMS(ESI)m/z:525(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.73(d,J＝4.9Hz,1H),8.56(s,2H),8.49(s,1H),8.39(s,1H),8.34-8.26(m,2H),8.18-8.09(m,2H),7.61-7.49(m,3H),6.50(q,J＝7.2Hz,1H),4.13(d,J＝5.8Hz,2H),3.53(br d,J＝12.4Hz,2H),3.03(br t,J＝12.4Hz,2H),2.87(s,3H),2.27-2.08(m,3H),1.97(d,J＝7.2Hz,3H),1.81-1.63(m,2H).
实施例1-2：
LCMS(ESI)m/z:525(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.72(dd,J＝0.8,5.0Hz,1H),8.61-8.46(m,3H),8.38(s,1H),8.33-8.25(m,2H),8.16-8.08(m,2H),7.58-7.47(m,3H),6.49(q,J＝7.1Hz,1H),4.12(d,J＝5.9Hz,2H),3.50(br d,J＝12.2Hz,2H),3.05-2.93(m,2H),2.83(s,3H),2.22-2.06(m,3H),1.96(d,J＝7.2Hz,3H),1.80-1.62(m,2H).
实施例2(2-1和2-2)
Figure PCTCN2017107964-appb-000017
Figure PCTCN2017107964-appb-000018
步骤A：
在室温氮气保护下，将中间体1D(1.0克*2，1.70毫摩尔)，3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)异噻唑(1.15克，5.10毫摩尔)，磷酸钾(1M，3.4毫升)和1,1-二(叔丁基磷)二茂铁二氯化钯(110.80毫克，170.00微摩尔)溶于THF(10毫升)中。反应液在70℃下搅拌16小时。将反应液过滤并加水(50毫升)。混合溶液用乙酸乙酯(30毫升*3)萃取。有机相用无水硫酸钠干燥，过滤，浓缩。得到的粗产品用制备型HPLC纯化。产品用SFC(柱型：AS(250mm*30mm,10um)；流动相：[0.1％NH3H2O ETOH]；B％:35％-35％,7.2min；200minmin)分离得到中间体2A-1(t＝2.529，560毫克，24.28％收率)和中间体2A-2(t＝3.494，500毫克，27.19％收率)。
LCMS(ESI)m/z:605(M+1)。
HNMR(中间体2A-1)(400MHz,METHANOL-d4)δ＝8.61-8.50(m,2H),8.41-8.26(m,2H),7.76(d,J＝2.1Hz,1H),7.70(dd,J＝2.1,10.0Hz,1H),7.57-7.50(m,2H),7.29(s,1H),6.45(q,J＝7.1Hz,1H),4.16(br d,J＝13.3Hz,2H),4.07(d,J＝6.1Hz,2H),2.85(br s,2H),2.45(s,3H),2.08(br s,1H),1.96-1.84(m,5H),1.48(s,9H),1.37-1.29(m,2H).
HNMR(中间体2A-2)(400MHz,METHANOL-d4)δ＝8.59-8.53(m,2H),8.41-8.27(m,2H),7.76(s,1H),7.73-7.66(m,1H),7.58-7.49(m,2H),7.28(d,J＝2.8Hz,1H),6.45(q,J＝6.9Hz,1H),4.16(br d,J＝13.6Hz,2H),4.06(dd,J＝3.9,6.1Hz,2H),2.94-2.78(m,2H),2.44(d,J＝2.1Hz,3H),2.07(td,J＝3.7,9.6Hz,1H),1.96-1.84(m,5H),1.48(s,9H),1.36-1.27(m,2H).
步骤B：如中间体1G-1的方法制备得到中间体2B-1和中间体2B-2
步骤C：同实施例1的方法制备得到实施例2-1和2-2。
实施例2-1：
LCMS(ESI)m/z:520(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.73(s,2H),8.35(s,1H),8.29(d,J＝7.2Hz,1H),7.86-7.81(m,1H),7.72(dd,J＝2.3,10.0Hz,1H),7.64-7.58(m,2H),7.36(s,1H),6.45(q,J＝7.1Hz,1H),4.21(d,J＝5.9Hz,2H),3.63(br d,J＝12.4Hz,2H),3.15(br t,J＝11.9Hz,2H),2.92(s,3H),2.47(s,3H),2.33-2.06(m,3H),1.99(d,J＝7.2Hz,3H),1.86-1.73(m,2H).
实施例2-2：
LCMS(ESI)m/z:520(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.75(s,2H),8.37(s,1H),8.28(d,J＝7.2Hz,1H),7.88-7.81(m,1H),7.70(dd,J＝2.3,10.0Hz,1H),7.65-7.56(m,2H),7.34(s,1H),6.42(q,J＝7.1Hz,1H),4.20(d,J＝5.9Hz, 2H),3.62(br d,J＝12.4Hz,2H),3.12(br t,J＝11.9Hz,2H),2.91(s,3H),2.45(s,3H),2.33-2.08(m,3H),1.96(d,J＝7.2Hz,3H),1.87-1.70(m,2H).
实施例3
Figure PCTCN2017107964-appb-000019
步骤A：
如中间体1D的方法制备得到中间体3D。
步骤B：
如中间体1F的方法制备得到中间体3E。产品用SFC(柱型：AS(250mm*30mm,10um)；流动相：[0.1％NH3H2O ETOH]；B％:40％-40％,5min；80minmin)分离得到中间体3E-1(t＝2.805，33毫克，33.0％收率)和中间体3E-2(t＝3.255，33毫克，33.0％收率)。LCMS(ESI)m/z:588(M+1).
步骤C：
如中间体1G的方法制备得到中间体3F-1(580毫克，粗品)、3F-2(520毫克，粗品)。
步骤D：
如实施例1的方法制备得到实施例3-1和3-2。
实施例3-1：
LCMS(ESI)m/z:502(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.62-8.49(m,3H),8.36(s,1H),8.31(br d,J＝6.8Hz,1H),7.91(s,1H),7.77(br d,J＝9.4Hz,1H),7.57-7.49(m,2H),7.26(s,1H),6.71(d,J＝9.4Hz,1H),6.42(q,J＝6.6Hz,1H),4.13(br d,J＝5.1Hz,2H),3.50(br d,J＝11.9Hz,2H),2.97(br t,J＝12.2Hz,2H),2.83(s,3H),2.44(s,3H),2.24-2.06(m,3H),1.91(br d,J＝7.1Hz,3H),1.80-1.61(m,2H).
实施例3-2：
LCMS(ESI)m/z:502(M+1).
HNMR(400MHz,METHANOL-d4)δ＝8.56(s,2H),8.49(br s,1H),8.36(s,1H),8.30(br d,J＝6.7Hz,1H),7.91(d,J＝2.4Hz,1H),7.77(dd,J＝2.4,9.4Hz,1H),7.56-7.49(m,2H),7.26(s,1H),6.70(d,J＝9.4Hz,1H),6.41(q,J＝7.1Hz,1H),4.13(d,J＝5.7Hz,2H),3.54(br d,J＝12.3Hz,2H),3.05(br t,J＝11.9Hz,2H),2.87(s,3H),2.44(s,3H),2.21-2.08(m,3H),1.91(d,J＝7.1Hz,3H),1.79-1.67(m,2H).
实施例4
Figure PCTCN2017107964-appb-000020
步骤A：
如中间体1D的方法制备得到中间体4A。
步骤B：
如中间体1E的方法制备得到中间体4B。
步骤C：
如中间体1F的方法制备得到中间体4C。
步骤D：
如中间体1G的方法制备得到中间体4D。
步骤E：
如实施例1的方法制备得到实施例4。LCMS(ESI)m/z:510(M+1)。HNMR(400MHz,METHANOL-d4)δ＝8.59-8.47(m,3H),8.37(s,1H),8.32-8.24(m,1H),8.17(d,J＝2.5Hz,1H),7.95(dd,J＝2.0,7.3Hz,1H),7.85-7.73(m,2H),7.51-7.46(m,2H),7.41(dd,J＝8.6,10.5Hz,1H),6.70(d,J＝9.5Hz,1H),5.37(s,2H),4.12(d,J＝5.8Hz,2H),3.52(br d,J＝12.8Hz,2H),3.08-2.96(m,2H),2.85(s,3H),2.26-2.09(m,3H),1.79-1.63(m,2H).
实施例5
Figure PCTCN2017107964-appb-000021
步骤A：
如中间体1D的方法制备得到中间体5A。
步骤B：
如中间体1F的方法制备得到中间体5B。
步骤C：
如中间体1G的方法制备得到中间体5C。
步骤D：
如实施例1的方法制备得到实施例5。LCMS(ESI)m/z:506(M+1)。HNMR(400MHz,METHANOL-d4)δ＝8.58-8.49(m,3H),8.37-8.26(m,2H),8.16(dd,J＝1.3,2.1Hz,1H),7.74(dd,J＝2.2,10.2Hz,1H),7.50(d,J＝5.3Hz,2H),7.34(s,1H),5.40(s,2H),4.12(d,J＝5.8Hz,2H),3.51(br d,J＝12.4Hz,2H),3.06-2.94(m,2H),2.84(s,3H),2.47(s,3H),2.23-2.07(m,3H),1.80-1.62(m,2H).
实施例6
Figure PCTCN2017107964-appb-000022
步骤A：
如中间体1E的方法制备得到中间体6A。
步骤B：
如中间体1F的方法制备得到中间体6B。
步骤C：
如中间体1G的方法制备得到中间体6C。
步骤D：
如实施例1的方法制备得到实施例6。LCMS(ESI)m/z:493(M+1)。HNMR(400MHz,METHANOL-d4)δ＝8.75(d,J＝5.0Hz,1H),8.69(d,J＝2.4Hz,1H),8.58-8.43(m,3H),8.34(s,1H),8.30-8.22(m,2H),8.13(s,1H),7.55(dd,J＝1.1,5.0Hz,1H),7.51-7.44(m,2H),6.71(d,J＝9.5Hz,1H),5.39(s,2H),4.10(d,J＝5.9Hz,2H),3.54(br d,J＝12.0Hz,2H),3.04(br t,J＝12.0Hz,2H),2.87(s,3H),2.23-2.07(m,3H),1.79-1.65(m,2H).
实施例7
Figure PCTCN2017107964-appb-000023
Figure PCTCN2017107964-appb-000024
步骤A：
0℃氮气保护，搅拌下，向叔丁基-4-(羟甲基)哌啶-1-甲酸酯(68.00克，315.85毫摩尔)和二异丙基乙基胺(81.64克，631.71毫摩尔)的二氯甲烷(800毫升)溶液中滴加甲烷磺酰氯(45.15克，394.15毫摩尔)。滴加完毕后在25℃下搅拌2小时。薄层色谱检测反应完毕。反应液用饱和氯化铵溶液(500毫升*2)和饱和食盐水(300毫升*2)洗涤，无水硫酸钠干燥，过滤并浓缩，得到中间体7A(红色油状液体，95.00克，100％收率)直接用于下一步骤无需进一步纯化。
步骤B：
25℃氮气保护下，往中间体7A(94.40克，321.77毫摩尔)和2-氯嘧啶-5-醇(35.00克，268.14毫摩尔)的DMF(1.00升)液中，加入碳酸钾(74.12克，536.28毫摩尔)。反应液在80℃下反应16小时，薄层色谱检测反应完毕。将反应液冷却到室温，浓缩，往残余物中加入水(500毫升)，用乙酸乙酯(300毫升*3)萃取，有机相用饱和食盐水(400毫升*2)洗涤，有机层用无水硫酸钠干燥，过滤，浓缩，残余物通过柱色谱纯化得到中间体7B(淡黄色固体，84.00克，95.05％收率)。LCMS(ESI)m/z:327.7(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.08-1.25(m,2H)1.40(s,9H)1.69-1.78(m,2H)1.88-2.03(m,1H)2.58-2.88(m,2H)3.89-4.05(m,4H)8.50-8.57(m,2H)
步骤C：
氮气保护下，中间体7B(84.00克，254.85毫摩尔)，[3-(羟甲基)苯基]硼酸(42.60克，280.34毫摩尔)，Pd(PPh3)2Cl2(17.89克，25.49毫摩尔)和碳酸钾(70.45克，509.71毫摩尔)在1,4-二氧六环(1.00升)和水(200.00毫升)的混合溶液中，80℃搅拌反应16小时。反应液冷却至室温，过滤，二氯甲烷(500毫升*3)萃取，合并有机层，饱和食盐水(500毫升*2)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物通过甲醇重结晶得到中间体7C(白色固体，77.60克，76.22％收率)。LCMS(ESI)m/z:400.1(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.14-1.31(m,2H)1.45(s,9H)1.75-1.87(m,2H)1.95-2.10(m,1H)2.66-2.93(m,2H)3.94-4.22(m,4H)4.63(d,J＝5.62Hz,2H)5.34(t,J＝5.81Hz,1H)7.41-7.54(m,2H)8.21(d,J＝7.46Hz,1H)8.35(s,1H)8.68(s,2H)
步骤D：
0℃氮气保护，搅拌下，向中间体7C(10.00克，25.03毫摩尔)和二异丙基乙基胺(6.47克，50.06毫摩尔)的二氯甲烷(100.00毫升)溶液中滴加甲烷磺酰氯(3.44克，30.04毫摩尔)。滴加完毕后在25℃下搅拌2小时。薄层色谱检测反应完毕。反应液用饱和氯化铵溶液(500毫升*2)和饱和食盐水(300毫升*2)洗涤，无水硫酸钠干燥，过滤并浓缩，得到中间体7D(灰色固体，14.00克，100％收率)直接用于下一步骤无需进一步纯化。LCMS(ESI)m/z:478.1(M+1).
步骤E：
25℃氮气保护下，往中间体7D(12.00克，25.13毫摩尔)和5-溴-3-氟-1-氢-吡啶-2-酮(5.79克，30.16毫摩尔)的DMF(100.00毫升)溶液中，加入碳酸钾(6.95克，50.26毫摩尔)。反应液在90℃下反应3小时，薄层色谱检测反应完毕。将反应液冷却到室温，浓缩，往残余物中加入水(100毫升)，用乙酸乙酯(100毫升*3)萃取，有机相用饱和食盐水(200毫升*2)洗涤，有机层用无水硫酸钠干燥，过滤，浓缩，残余物通过柱色谱纯化得到中间体7E(黄色固体，9.60克，66.62％收率)。LCMS(ESI)m/z:574.9(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.09-1.27(m,2H)1.41(s,9H)1.77(br d,J＝11.13Hz,2H)1.90-2.10(m,1H)2.62-2.91(m,2H)3.87-4.14(m,4H)5.16-5.30(m,2H)7.39-7.52(m,2H)7.76(dd,J＝9.66,2.45Hz,1H)8.14-8.19(m,1H)8.24(d,J＝7.58Hz,1H)8.28(s,1H)8.65(s,2H)
步骤F：
氮气保护下，中间体7E(200.00毫克，348.77微摩尔)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,3,2-二氧杂戊硼烷(92.99毫克，366.21微摩尔)，Pd(dppf)Cl2(25.52毫克，34.88微摩尔)和乙酸钾(102.68毫克，1.05毫摩尔)在1,4-二氧六环(10.00毫升)的混合溶液中，70℃搅拌反应2小时得到中间体7F的二氧六环溶液。反应液直接用于下一步反应无需处理。
步骤G：
氮气保护下，中间体7F的二氧六环溶液(210.00毫克，338.43微摩尔)，2-溴吡啶-4-甲腈(185.81毫克,1.02毫摩尔)，Pd(dppf)Cl2·CH2Cl2(55.28毫克，67.69微摩尔)和碳酸钾(93.55毫克，676.86微摩尔)在1,4-二氧六环(10.00毫升)和水(2.00毫升)的混合溶液中，80℃搅拌反应3小时。反应液冷却至室温，过滤，浓缩，残余物加水(50mL)溶解，乙酸乙酯(30毫升*3)萃取，合并有机层，饱和食盐水(30毫升*2)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物通过制备薄层色谱纯化得到中间体7G(黄色固体，50.00毫克，24.76％收率)。LCMS(ESI)m/z:619.2(M+23).
步骤H：
0℃氮气保护下，往中间体7G(50.00毫克，83.80微摩尔)的二氯甲烷(10.00毫升)溶液中滴加三氟乙酸(4.62克，40.52毫摩尔，3.00毫升)。反应物在25℃搅拌1小时。将反应物浓缩干，得到中间体7H(棕黑色油状液体，60.00毫克，100％收率，三氟乙酸盐)直接用于下一步骤无需进一步纯化。LCMS(ESI)m/z:497.2(M+1).
步骤I：
0℃氮气保护下，往中间体7H(50.00毫克，100.70微摩尔)的二氯甲烷(5.00毫升)溶液中加入甲醛(40.87毫克，503.50微摩尔，37.50微升，37％水溶液)和三乙酰氧基硼氢化钠(64.03毫克，302.10微摩尔)。混合物在25℃反应16小时，浓缩，残余物通过制备型HPLC纯化得到实施例7(21.70毫克，38.48％收率，甲酸盐)。LCMS(ESI)m/z:511.1(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.27-1.43(m,2H)1.77(br d,J＝9.78Hz,3H)1.99(br t,J＝11.43Hz,2H)2.22(s,3H)2.85(br d,J＝11.37Hz,2H)4.05(d,J＝5.99Hz,2H)5.39(s,2H)7.50(d,J＝5.01Hz,2H)7.75(dd,J＝5.01,1.22Hz,1H)8.18-8.26(m,2H)8.28(s,1H)8.33(s,1H)8.40(s,1H)8.64(s,2H)8.78(d,J＝1.34Hz,1H)8.82(d,J＝5.01Hz,1H)
实施例8(8-1和8-2)
Figure PCTCN2017107964-appb-000025
步骤A：
氮气保护下，中间体1D(1.50克，2.55毫摩尔)，三丁基(1-乙氧基乙烯)锡(1.14克，3.16毫摩尔， 1.07毫升)和Pd(PPh3)2Cl2(358.43毫克，510.66微摩尔)在甲苯(10.00毫升)的溶液中，100℃搅拌反应3小时。反应液冷却至室温，加入盐酸(10.21毫升，1N水溶液)，25℃搅拌1小时。过滤，浓缩。残余物通过柱色谱纯化得到中间体8A(黄色油状液体，1.13克，80.48％收率)。LCMS(ESI)m/z:573.1(M+23).1HNMR(400MHz,CHLOROFORM-d)δppm 1.50(s,9H)1.89(d,J＝7.03Hz,6H)1.98-2.10(m,2H)2.31(s,3H)2.72-2.86(m,2H)3.98(d,J＝6.27Hz,2H)4.12-4.31(m,2H)6.54(q,J＝7.28Hz,1H)7.42(br d,J＝7.65Hz,1H)7.61(dd,J＝9.66,2.26Hz,1H)7.65-7.74(m,1H)7.84(d,J＝1.38Hz,1H)8.38(d,J＝7.78Hz,1H)8.42(s,1H)8.47(s,2H)
步骤B：
氮气保护下，中间体8A(1.13克，2.05毫摩尔)在1,1-二甲氧基-N,N-二甲基-乙烷(5.00毫升)的溶液中，120℃搅拌反应3小时。反应液冷却至室温，将反应物浓缩干，得到中间体8B(棕黑色油状液体，1.27克，100％收率)直接用于下一步骤无需进一步纯化。LCMS(ESI)m/z:620.1(M+1).
步骤C：
氮气保护下，往中间体8B(1.27克，2.05毫摩尔)的乙醇(20.00毫升)溶液中加入羟胺(213.61毫克，3.08毫摩尔，盐酸盐)。混合物在80℃反应16小时，浓缩，残余物通过制备型HPLC纯化，消旋体经制备型SFC(柱型：AS(250mm*30mm,10um)；流动相：[0.1％NH3-H2O ETOH]；B％：0％-55％，5.2min；150minmin)拆分得到中间体8C-1(白色固体，380.00毫克，31.44％收率，100％ee值，Rt＝2.431min)和中间体8C-2(白色固体，350.00毫克，28.95％收率，100％ee值，Rt＝3.299min)。LCMS(ESI)m/z:590.4(M+1).1HNMR(中间体8C-1)(400MHz,CHLOROFORM-d)δppm 1.31-1.38(m,2H)1.50(s,9H)1.82-1.94(m,5H)1.97-2.12(m,1H)2.29(s,3H)2.79(br t,J＝12.23Hz,2H)3.98(d,J＝6.36Hz,2H)4.21(br s,2H)6.06(s,1H)6.59(d,J＝6.97Hz,1H)7.33(dd,J＝9.41,2.20Hz,1H)7.40-7.46(m,1H)7.48-7.55(m,1H)7.56-7.62(m,1H)8.36(d,J＝7.70Hz,1H)8.43(s,1H)8.47(s,2H).
1HNMR(中间体8C-2)(400MHz,CHLOROFORM-d)δppm 1.30-1.37(m,2H)1.49(s,9H)1.81-1.94(m,5H)1.96-2.10(m,1H)2.29(s,3H)2.79(br t,J＝12.10Hz,2H)3.98(d,J＝6.24Hz,2H)4.20(br s,2H)6.06(s,1H)6.59(q,J＝7.05Hz,1H)7.33(dd,J＝9.29,2.20Hz,1H)7.41-7.46(m,1H)7.48-7.54(m,1H)7.59(d,J＝1.59Hz,1H)8.36(d,J＝7.82Hz,1H)8.42(s,1H)8.47(s,2H)
步骤D：
如中间体1G描述的方法制备得到中间体8D-1,8D-2。
步骤E：
如实施例1的方法制备得到实施例8-1、8-2
实施例8-1
LCMS(ESI)m/z:504.1(M+1).
1HNMR(400MHz,DMSO-d6)δppm 1.54-1.72(m,2H)1.85-2.13(m,6H)2.24(s,3H)2.69-2.80(m,3H)2.86-3.16(m,2H)3.19-3.52(m,2H)4.09(d,J＝6.27Hz,2H)6.29(q,J＝7.07Hz,1H)6.78(s,1H)7.47-7.60(m,2H)7.92(dd,J＝10.42,2.13Hz,1H)8.08(s,1H)8.21-8.35(m,2H)8.62-8.75(m,2H)10.37-10.80(m,1H)
实施例8-2
LCMS(ESI)m/z:504.1(M+1).
1HNMR(400MHz,DMSO-d6)δppm 1.57-1.74(m,2H)1.81-2.12(m,6H)2.23(s,3H)2.62-2.79(m,3H)2.86-3.05(m,2H)3.41(br d,J＝11.92Hz,2H)4.09(d,J＝6.27Hz,2H)6.29(q,J＝6.99Hz,1H)6.79(s,1H)7.53(d,J＝5.02Hz,2H)7.92(dd,J＝10.48,2.07Hz,1H)8.08(s,1H)8.20-8.34(m,2H)8.61-8.73(m,2H)10.75(br s,1H)
实施例9
Figure PCTCN2017107964-appb-000026
步骤A：
氮气保护下，中间体3D(1.00克，1.76毫摩尔)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,3,2-二氧杂戊硼烷(469.28毫克，1.85毫摩尔)，Pd(dppf)Cl2(128.78毫克，176.00微摩尔)和乙酸钾(518.18毫克，5.28毫摩尔)在1,4-二氧六环(15.00毫升)的混合溶液中，80℃搅拌反应2小时。得到中间体9A的二氧六环溶液，反应液直接用于下一步反应无需处理。
步骤B：
氮气保护下，中间体9A二氧六环溶液(1.09克，1.77毫摩尔)，2-溴吡啶-4-甲腈(485.89毫克，2.66毫摩尔)，Pd(dppf)Cl2·CH2Cl2(289.09毫克，354.00微摩尔)和碳酸钾(489.26毫克，3.54毫摩尔)在1,4-二氧六环(20.00毫升)和水(4.00毫升)的混合溶液中，80℃搅拌反应3小时。反应液冷却至室温，过滤，浓缩。残余物通过制备薄层色谱纯化，制备型SFC(柱型：AS(250mm*30mm,10um)；流动相：[0.1％NH3-H2O ETOH]；B％：55％-55％，8.2min；100minmin)拆分得到中间体9B-1(黄色油状液体，200.00毫克，100％ee值，19.06％收率，Rt＝2.973min)和中间体9B-2(黄色油状液体，200.00毫克，100％ee值，19.06％收率，Rt＝3.605min)。LCMS(ESI)m/z:593.1(M+1).
步骤C：
如中间体1G描述的方法制备得到中间体9C-1,9C-2。
步骤D：
如实施例1描述的方法制备得到实施例9-1,9-2。
实施例9-1
LCMS(ESI)m/z:507.1(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.29-1.45(m,2H)1.80(br d,J＝10.54Hz,3H)1.88(d,J＝7.28Hz,3H)2.14(br t,J＝11.17Hz,2H)2.30(s,3H)2.94(br d,J＝11.29Hz,2H)4.05(d,J＝6.02Hz,2H)6.32(d,J＝7.15Hz,1H)6.62(d,J＝9.66Hz,1H)7.46-7.55(m,2H)7.69(dd,J＝5.02,1.25Hz,1H)8.19-8.26(m,3H)8.27(s,1H)8.43(t,J＝1.07Hz,1H)8.49(d,J＝2.38Hz,1H)8.64(s,2H)8.77(dd,J＝5.02,0.88Hz,1H)
实施例9-2
LCMS(ESI)m/z:507.1(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.27-1.46(m,2H)1.81(br d,J＝10.54Hz,3H)1.89(d,J＝7.28Hz,3H)2.17(br t,J＝11.17Hz,2H)2.31(s,3H)2.96(br d,J＝11.29Hz,2H)4.09(d,J＝6.02Hz,2H)6.35(d,J＝7.15Hz,1H)6.65(d,J＝9.66Hz,1H)7.42-7.57(m,2H)7.66(dd,J＝5.02,1.25Hz,1H)8.21-8.27(m,3H)8.29(s,1H)8.45(t,J＝1.07Hz,1H)8.51(d,J＝2.38Hz,1H)8.67(s,2H)8.79(dd,J＝5.02,0.88Hz,1H)
实施例10
Figure PCTCN2017107964-appb-000027
步骤A:
氮气保护下，中间体4A(200.00毫克，346.53微摩尔)，1-甲基-4-(，4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡唑(108.15毫克，519.80微摩尔)，Pd(dppf)Cl2(25.36毫克，34.65微摩尔)和碳酸钠(110.19毫克，1.04毫摩尔)在1,4-二氧六环(10.00毫升)的溶液中，80℃搅拌反应2小时。反应液冷却至室温，过滤，浓缩，残余物加水(60毫升)溶解，乙酸乙酯(50毫升*3)萃取，合并有机层，饱和食盐水(80毫升*2)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经制备薄层色谱得到中间体10B(黄色油状液体，200.00毫克，95.45％收率)。LCMS(ESI)m/z:557.3(M+1).
步骤B:
如中间体1G描述的方法制备得到中间体10C。
步骤C:
如实施例1描述的方法制备得到实施例10。LCMS(ESI)m/z:471.2(M+1).1HNMR(400MHz,METHANOL-d4):1.63-1.80(m,2H)2.09-2.25(m,3H)2.88(s,3H)3.05(t,J＝12.17Hz,2H)3.55(d,J＝12.67Hz,2H)3.91(s,3H)4.12(d,J＝5.90Hz,2H)5.34(s,2H)6.67(d,J＝9.41Hz,1H)7.42-7.51(m,2H)7.75(s,1H)7.81(dd,J＝9.35,2.57Hz,1H)7.88(s,1H)8.05(d,J＝2.38Hz,1H)8.25-8.29(m,1H)8.33(s,1H)8.47(s,1H)8.55(s,2H).
实施例11
Figure PCTCN2017107964-appb-000028
步骤A:
0℃氮气保护下，向3-甲基异噻唑-5胺(5.00克，33.19毫摩尔，盐酸盐)的水(14.00毫升)和硫酸(10.00毫升，98％纯度)的混合溶液中，逐滴加入亚硝酸钠(2.52克，36.51毫摩尔)的水(50毫升)溶液，反应液在0℃下搅拌1小时，加入碘化钾(6.06克，36.51毫摩尔)的水(35毫升)溶液，80℃反应1小时。反应液冷却至室温，加水(100毫升)稀释，二氯甲烷(50毫升*2)萃取，合并有机层，饱和食盐水(25毫升*2)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物通过柱色谱纯化得到中间体11A(黄色固体，4.00克，53.55％收率)。LCMS(ESI)m/z:225.9(M+1).1HNMR(400MHz,CHLOROFORM-d)δppm 2.39-2.48(m,3H)7.04-7.13(m,1H)
步骤B:
-25℃氮气保护下，向中间体11A(1.00克，4.44毫摩尔)和2-异丙氧基-4,4,5,5,-1,3,2-二氧杂戊硼烷(850毫克，4.57毫摩尔)的四氢呋喃(5.00毫升)溶液中，逐滴加入异丙基氯化镁-氯化锂复合物(3.66毫升，1.3M四氢呋喃溶液)，反应液在-25℃下搅拌0.5小时。反应完毕，滴加乙酸(0.24毫升)的四氢呋喃(0.67毫升)溶液淬灭，反应液中加入石油醚(48毫升)和叔丁基甲醚(24毫升)，过滤，滤液中加入叔丁基甲醚(32毫升)，过滤，浓缩。得到中间体11B(黄色油状液体，512毫克，51.22％收率)直接用于下一步骤无需进一步纯化。1HNMR(400MHz,CHLOROFORM-d)δppm 1.28(s,12H)2.46-2.48(m,3H)7.31(s,1H)。
步骤C:
氮气保护下，中间体11B(283.69毫克，1.26毫摩尔)，中间体4A(500.00毫克，900.15微摩尔)，1,1-二(叔丁基磷)二茂铁氯化钯(58.67毫克,90.02微摩尔)和三水合磷酸钾(479.44毫克，1.80毫摩尔)在四氢呋喃(5.00毫升)和水(1.00毫升)的混合溶液中，65℃搅拌反应12小时。反应液冷却至室温，过滤，浓缩，残余物加水(50毫升)溶解，乙酸乙酯(100毫升*2)萃取，合并有机层，饱和食盐水(50毫升*2)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经制备薄层色谱得到中间体11C(黄色固体，266.00毫克，51.51％收率)。LCMS(ESI)m/z:574.2(M+1).1HNMR(400MHz,CHLOROFORM-d)δppm 1.27-1.34(m,6H)1.60-1.64(m,10H)1.60-1.65(m,10H)1.83-1.91(m,2H)1.95(s,1H)2.46-2.52(m,3H)3.95-4.01(m,2H)5.28-5.31(m,2H)6.71-6.77(m,1H)6.94-6.97(m,1H)7.39-7.56(m,3H)7.63-7.68(m,1H)8.37(s,2H)8.47(s,2H)
步骤D:
如中间体1F描述的方法制备制备得到中间体11D。LCMS(ESI)m/z:474.2(M+1).
步骤E:
如实施例1描述的方法制备得到实施例11。LCMS(ESI)m/z:488.2(M+1).1HNMR(400MHz,DMSO-d6)δppm 1.37(br d,J＝10.54Hz,2H)1.79(br d,J＝10.04Hz,3H)2.11(br s,2H)2.26-2.31(m,3H)2.40-2.44(m,3H)2.89-2.97(m,2H)4.01-4.09(m,2H)5.25(s,2H)6.57(d,J＝9.41Hz,1H)7.45(d,J＝11.80Hz,3H)7.79(dd,J＝9.41,2.64Hz,1H)8.20-8.26(m,2H)8.29(s,1H)8.53-8.56(m,1H)8.62-8.66(m,2H).
实施例12
Figure PCTCN2017107964-appb-000029
Figure PCTCN2017107964-appb-000030
步骤A:
向异氰酸苯酯(830.74毫克，6.97毫摩尔)的硝基乙烷(261.77毫克，3.49毫摩尔，249.30微升)溶液中加入三乙胺(32.08毫克，317.00微摩尔，43.94微升)，在50℃搅拌30分钟，然后再加入三丁基(乙炔基)锡烷(1.00克，3.17毫摩尔)的甲苯(8.00毫升)溶液，反应液在50℃下反应5小时。薄层色谱检测反应完毕。向反应液加水(100毫升)，用乙酸乙酯(100毫升)萃取。有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，旋转蒸发仪浓缩干，残余物通过柱色谱纯化得到中间体12A(黄色油状液体，700.00毫克，42.13％收率)。LCMS(ESI)m/z:373.14(M+1).1H NMR(400MHz,CHLOROFORM-d)δppm 0.82-0.85(m,9H)0.97-1.11(m,6H)1.20-1.34(m,12H)1.49-1.52(m,3H)7.18-7.20(m,1H)
步骤B:
在20℃下，向中间体4A(200.00毫克，360.06微摩尔)的二氧六环(4.00毫升)溶液加入中间体12A(200.00毫克，348.77微摩尔)和Pd(PPh3)2Cl2(25.27毫克，36.01微摩尔)，然后在氮气保护下加热至100℃搅拌12小时。薄层色谱检测反应完毕。向反应液加水(50毫升)，用乙酸乙酯(50毫升*2)萃取。有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，旋转蒸发仪浓缩干，残余物通过柱色谱纯化得到中间体12B(黄色固体，110.00毫克，42.18％收率)。LCMS(ESI)m/z:557.26(M+1).1H NMR(400MHz,CHLOROFORM-d)δppm 1.21-1.31(m,4H)1.40(s,9H)1.72-1.81(m,2H)1.89-1.98(m,1H)2.22(s,3H)2.70(br s,2H)3.88(d,J＝6.36Hz,2H)5.21(s,2H)6.02(s,1H)6.63(d,J＝9.54Hz,1H)7.33-7.37(m,1H)7.50(dd,J＝9.54,2.57Hz,1H)7.57-7.64(m,1H)7.83(d,J＝2.32Hz,1H)8.23-8.31(m,2H)8.38(s,2H)
步骤C:
如中间体1G描述的方法制备得到中间体12C。LCMS(ESI)m/z:457.21(M+1).
步骤D:
如实施例1描述的方法制备得到实施例12。LCMS(ESI)m/z:471.23(M+1).1H NMR(400MHz,DMSO-d6)δppm 1.14-1.21(m,2H)1.49(br s,2H)1.79-1.95(m,3H)1.99(s,2H)2.24(s,3H)2.38-2.38(m,1H)2.46(s,3H)3.12(br d,J＝10.92Hz,2H)5.29(s,2H)6.65(s,1H)7.47(br s,1H)7.82-7.90(m,1H)8.29(br s,2H)8.63(s,2H)
实验例1:c-MET酶结合活性实验
试剂和耗材:
cMET(invitrogen PV3143)
Tracer 236(Lot Number:10815978)
Eu-Anti-His AB(MAb Anti 6HIS-K)
PerkinElmer公司Envison检测665nm和615nm
384孔板_检测板(PerkinElmer#6007299)
实验原理:
本实验利用LanthaScreenTM Eu激酶结合实验(LanthaScreenTM Eu Kinase Binding Assay)，如图1所示，通过添加Eu标记抗体检测Alexa Fluor偶联物或激酶“示踪剂”结合。示踪剂和抗体与激酶的结合导致高度的FRET，反之使用激酶抑制化合物代替示踪剂会造成FRET丢失。
实验方法:
1)稀释抗体Eu-Anti-His AB，酶cMET，示踪剂Tracer236。
2)化合物配制：将10mM受试化合物及参考化合物用100％DMSO稀释至0.667mM，使用全自动微孔板预处理系统ECHO进行3倍稀释，8个浓度梯度，设置双复孔，每孔75nL。
3)在化合物板中加入7.5uL抗体(1/375nM)与激酶(10nM)混合物，再加入7.5uL Tracer(60nM)。反应终浓度：cMET:5nM，Tracer 236:30nM，Eu-Anti-His AB(MAb Anti 6HIS-K):1/750nM。
4)4℃孵育60分钟后，用多标记微孔板检测仪Envision读数(将665nm/615nm信号值用Prism 5进行数据分析；Ex激发光:Laser mirror446Em发射光:615and 665nM)。
实验结果:见表1。
结论：本发明化合物对c-MET酶有较强的抑制活性。
表1
待测化合物 c-MET IC50(nM) 待测化合物 c-MET IC50(nM)
实施例1-2 1.09 实施例7 15.50
实施例2-2 9.33 实施例8-2 3.79
实施例4 6.16 实施例10 69.50
实施例5 2.90 实施例11 5.00
实施例6 4.37    
实验例2:细胞增殖的抑制效应测试
试剂和耗材:
1.细胞培养：DMEM培养基、胎牛血清、DPBS
2.细胞系：MHCC97-H
3.检测试剂：活细胞检测试剂盒CellTiter-Glo
4.其他主要耗材及试剂：化合物稀释板，中间板，检测板，DMSO
实验原理:
ATP的含量直接反应了细胞的数量及细胞状态，通过对ATP进行定量测定可以检测活细胞的数目。活细胞检测试剂盒含有萤光素酶及其底物，通过ATP的参与，荧光素酶可以催化底物，发出稳定的光学信号，通过检测信号的强度来测定细胞中ATP的数量。其中光信号和细胞中ATP量成正比，而ATP又和活细胞数正相关，从而可以检测出细胞的增殖情况。检测板使用PE公司的Envision进行分析。
实验方法:
1.制备细胞板
将MHCC97-H细胞分别种于384孔板中，每孔包含500个细胞。细胞板置于二氧化碳培养箱中过夜培养。
2.准备化合物
用Echo进行4倍稀释，9个化合物浓度，设置双复孔实验。
3.化合物处理细胞
将化合物转移到细胞板中，化合物起始浓度为10uM。细胞板置于二氧化碳培养箱中培养3天。
4.检测
向细胞板中加入Promega CellTiter-Glo试剂，室温孵育10分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
实验结果:见表2。
结论：本发明化合物对MHCC97H细胞的显示出较好的抑制活性。
表2
待测化合物 MHCC97H cell IC50(nM) 待测化合物 MHCC97H cell IC50(nM)
实施例1-2 8.80 实施例7 22.30
实施例2-2 13.80 实施例9-2 22.10
实施例3-2 19.0 实施例10 166.00
实施例4 72.90 实施例11 93.80
实施例5 58.80 实施例12 51.40
实施例6 32.90    
实验例3：MHCC97H肝癌细胞皮下异种移植肿瘤模型的药效实验
细胞培养：
MHCC97H细胞体外单层培养，培养条件为RPMI1640培养基中加10％热灭活胎牛血清、1％青霉素-链霉素双抗，37℃ 5％CO2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞呈指数生长期时，收取细胞，计数，接种。
动物：
BALB/c裸小鼠，雄性。6－8周龄，体重18-22克。
肿瘤接种：
将0.2ml含5x10^6个MHCC97H的细胞悬液皮下接种于每只小鼠的右后背。肿瘤平均体积达到约172mm3时开始分组给药。实验分组和给药方案见下表。
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(％)评价。
实验结果:见表3。
结论：本发明化合物在MHCC97H肝癌细胞皮下异种移植肿瘤模型的药效实验中显示比Tepotinib更好的肿瘤抑制作用。
表3受试药物对人肝癌MHCC97H细胞异种移植瘤模型的抑瘤药效评价
(基于给药后第24天肿瘤体积计算得出)
Figure PCTCN2017107964-appb-000031
注：
a.平均值±SEM。
b.p值根据肿瘤体积计算。
本发明化合物比tepotinib有更好的代谢稳定性。例如实施例1-2在人、大鼠、和小鼠三个物种肝微粒代谢的t1/2分别为62.1分钟、36.5分钟、49.1分钟，同等条件下，tepotinib在人、大鼠和小鼠三个物种肝微粒代谢的t1/2分别为48.3分钟、10.5分钟、12.4分钟。本发明化合物半衰期增大，针对靶点的作用时间延长，代谢稳定性增强，具有更优异的抑制活性。半衰期的延长将会使血药浓度维持更长时间，由此可以预测，该化合物运用于肿瘤治疗，与同类药物相比，将减少病人的服药量或服药次数，病人依从性将得到显著提高。
由于c-MET与HGF结合后,激活MAPK、PI3K/AKT、Cdc42/Rac1等通路,导致癌细胞存活与增殖,从而加速肿瘤生长。因此，作为c-MET抑制剂的吡啶酮类化合物在肝癌、非小细胞肺癌、胃癌等靶向治疗药物 中具有较大的应用前景。特别是在治疗肝癌上，该类化合物对c-MET高表达的肝癌具有精准的治疗作用。所以，本发明化合物作为吡啶酮类的c-MET抑制剂，鉴于其在体内外的显著的抑制活性及良好的代谢稳定性，有望成为比同类产品治疗效果更好的新药。

Claims (17)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017107964-appb-100001
    R1选自H、F；
    R2选自H、CH3；
    当R2不为H时，与R2相连的碳原子为R构型或S构型；
    A选自任选被1、2或3个R3取代的：苯基、吡啶基、吡唑基、异恶唑基、异噻唑基或噻唑基；
    R3选自CN、卤素、C(＝O)NH2，或选自任选被1、2或3个R0取代的：C1-6烷基、C1-6杂烷基或C3-6环烷基；
    R0选自F、Cl、Br、I、OH、CN、NH2、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3杂烷基；
    R’选自F、Cl、Br、I、CN、OH、NH2、CH3、CH3CH2、CF3、CHF2、CH2F；
    “C1-3杂烷基”、“C1-6杂烷基”所述之“杂”选自：-O-、-C(＝O)NR’-、-C(＝O)NH-、-NR’-、-NH-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  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，R0选自F、Cl、Br、I、OH、CN、NH2、C(＝O)NH2、CH3、CH3CH2、CF3、CHF2、CH2F、NH2CH2、(NH2)2CH、CH3O、CH3CH2O、CH3OCH2、CH3NH、(CH3)2N。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R1选自H。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R1选自F。
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R2选自H。
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R2选自CH3。
  7. 根据权利要求6所述的化合物或其药学上可接受的盐，其中，与R2相连的碳原子为R构型。
  8. 根据权利要求6所述的化合物或其药学上可接受的盐，其中，与R2相连的碳原子为S构型。
  9. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R3选自CN、卤素、C(＝O)NH2，或选自任选被1、2或3个R0取代的：C1-3烷基或C1-3杂烷基。
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中，R3选自CN、F、Cl、Br、CH3、CH3CH2、CF3、CHF2、CH2F、CH3O、C(＝O)NH2。
  11. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，A选自任选被1、2或3个R3取代的：
    Figure PCTCN2017107964-appb-100002
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中，A选自：
    Figure PCTCN2017107964-appb-100003
    Figure PCTCN2017107964-appb-100004
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其中，A选自：
    Figure PCTCN2017107964-appb-100005
    Figure PCTCN2017107964-appb-100006
  14. 根据权利要求10或13所述的化合物或其药学上可接受的盐，其中，A选自：
    Figure PCTCN2017107964-appb-100007
    Figure PCTCN2017107964-appb-100008
  15. 根据权利要求1所述的化合物，选自：
    Figure PCTCN2017107964-appb-100009
    Figure PCTCN2017107964-appb-100010
  16. 一种药物组合物，其含有治疗有效量的根据权利要求1～15任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  17. 根据权利要求1～15任意一项所述的化合物或其药学上可接受的盐或根据权利要求16所述的药物组合物在制备治疗肿瘤药物中的应用。
PCT/CN2017/107964 2016-10-27 2017-10-27 作为c-MET抑制剂的吡啶酮类化合物 Ceased WO2018077227A1 (zh)

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