WO2020098723A1 - 一类六元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途 - Google Patents

一类六元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途 Download PDF

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WO2020098723A1
WO2020098723A1 PCT/CN2019/118217 CN2019118217W WO2020098723A1 WO 2020098723 A1 WO2020098723 A1 WO 2020098723A1 CN 2019118217 W CN2019118217 W CN 2019118217W WO 2020098723 A1 WO2020098723 A1 WO 2020098723A1
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group
substituted
unsubstituted
compound
difluorophenyl
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PCT/CN2019/118217
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English (en)
French (fr)
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江磊
冯志勇
金贤
乔智
寿建勇
尚珂
吴淡宜
许灵灵
徐圆
张淑芸
张毅
张宇星
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上海轶诺药业有限公司
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Priority to US17/293,592 priority Critical patent/US20220017512A1/en
Priority to CA3120430A priority patent/CA3120430C/en
Priority to AU2019379213A priority patent/AU2019379213B2/en
Priority to CN201980074704.4A priority patent/CN113166141B/zh
Priority to EP19883726.2A priority patent/EP3882247A4/en
Publication of WO2020098723A1 publication Critical patent/WO2020098723A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of small molecule medicines.
  • the present invention relates to a class of TRK kinase inhibitors and their preparation and use.
  • Tropomyosin receptor kinase (tropomyosin-receptorkinase, TRK) is a type of nerve growth factor receptor, which belongs to the receptor tyrosine kinase family, mainly including three highly homologous members TRKA, TRKB and TRKC, respectively It is encoded by the three genes NTRK1, NTRK2 and NTRK3. These receptor tyrosine kinases are mainly expressed in nerve tissues, and play an important role in the development and physiological functions of the nervous system through the activation of neurotrophins (neurotrophins). TRK acts as a tyrosine kinase receptor, and each TRK has its corresponding ligand to bind and activate its downstream signaling pathway.
  • NGF nerve growth factor
  • TRKB ligands include BDGF (brain-derived growth factor) and NT-4 / 5 (neurotrophin-4 / 5); NT-3 specifically binds and activates TRKC . All three TRK receptors contain an extracellular domain for ligand binding, a transmembrane domain, and an intracellular domain with kinase activity.
  • a specific ligand When a specific ligand binds to the extracellular domain of the corresponding receptor, it will trigger oligomerization of the receptor and phosphorylation of specific tyrosine residues in the intracytoplasmic kinase domain, resulting in downstream signaling pathways such as Ras /
  • downstream signaling pathways such as Ras /
  • the activation of MAPK, PLC ⁇ / PKC and PI3K / AKT signaling pathways regulates a series of physiological processes such as neural cell proliferation, differentiation and survival (Bergman, et al. 1999).
  • the TRK signaling pathway is usually precisely regulated, and its abnormal activation is closely related to tumorigenesis (Amatu, et al. 2016).
  • the object of the present invention is to provide a new class of TRK kinase inhibitors.
  • X is H, halogen, D, CN, -CONH 2 ;
  • X 1 is CR or N
  • R is selected from the group: H, D, fluorine, chlorine, -OH, -NH 2 ;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, -COOH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, Or a substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro or bridged rings);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • said L 1 is selected from the following group:
  • n is selected from the group: 0, 1, 2 or 3;
  • R 2 , R 2a and R 2b are each independently selected from the group consisting of H, OH, halogen, substituted or unsubstituted C 1 -C 8 alkyl;
  • R A is Among them, the Refers to the connection site of R A and L 1 ;
  • R B is Among them, the Is the connection site of R B and L 2 ;
  • R 3 is selected from the group consisting of H, halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of H, OH, halogen, C 1 -C 6 alkyl OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1- C 6 alkylamido,-(C 1 -C 6 alkyl) -NH- (C 1 -C 6 alkyl), -C 1 -C 6 alkylamido-(C 1 -C 6 alkyl) ;
  • R 6a , R 6b , R 7a , R 7b are each independently selected from the group consisting of H, OH, halogen; or R 6a , R 6b , R 7a , R 7b and the carbon atom to which they are connected together constitute 1-3 5-12 membered heterocyclic group from hetero atom of N, S and O.
  • the compound has the structure represented by the following formula II:
  • X 2 is selected from the group consisting of C ⁇ O, —CH 2 —, O, NH.
  • the compound has the structure represented by the following formula IIIa:
  • X is H, D or halogen
  • X 1 is CR or N
  • R is selected from the group: H, D, fluorine, chlorine, -OH, -NH 2 ;
  • L 2 is a substituted or unsubstituted 5-10 membered heterocyclylene having 1-3 heteroatoms selected from N, S, and O, and 5 having 1-3 heteroatoms selected from N, S, and O -10 membered heteroaryl;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, -COOH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, Or a substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro or bridged rings);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • the compound has the structure represented by the following formula V:
  • X 2 is selected from the group consisting of C ⁇ O, —CH 2 —, O, NH.
  • the compound has the structure represented by the following formula IIIa:
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or Pharmaceutically acceptable salts, hydrates or solvates; (2) pharmaceutically acceptable carriers.
  • the pharmaceutical composition is an injection, sachet, tablet, pill, powder, or granule.
  • the disease is selected from the group consisting of cancer, proliferative diseases, pain, skin diseases or disorders, metabolic diseases, muscle diseases, neurological diseases, autoimmune diseases, pruritus caused by dermatitis, inflammation-related Diseases, bone-related diseases.
  • the cancer is selected from cancers (including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • cancers including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • TRK dysfunction TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion
  • the disease is selected from the group consisting of cancer, proliferative diseases, pain, skin diseases or disorders, metabolic diseases, muscle diseases, neurological diseases, autoimmunity Itching caused by disease, dermatitis.
  • a class of TRK inhibitors comprising the compound of the first aspect of the present invention, or stereoisomers or tautomers thereof, or pharmaceutically acceptable Salt, hydrate or solvate.
  • Figure 1 is the percentage of the inhibition rate of the test compound on cells in the cell experiment
  • Figure 2 is the curve of the tumor volume of mice with time after administration of the test compound in the mouse model test.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (including)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl includes linear or branched alkyl groups.
  • C 1 -C 8 alkyl represents a linear or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes straight-chain or branched alkenyl.
  • C 2 -C 6 alkenyl refers to straight-chain or branched alkenyl with 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
  • alkynyl includes linear or branched alkynyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C 3 -C 8 cycloalkyl means a cycloalkyl group having 3-8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a double ring, such as a bridge ring or a spiro ring.
  • C 1 -C 8 alkoxy refers to a linear or branched alkoxy group having 1-8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • the term "3-12 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to having 3-12 atoms and of which 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the group consisting of N, S, and O. It may be a single ring or a double ring, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, and O” refers to having 5-10 atoms and wherein 1-3 atoms are selected from Cyclic aromatic groups of heteroatoms of N, S and O in the lower group. It can be monocyclic or fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2, 4) -Triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention can be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxy, amino, C 1 -C 6 alkyl-amine, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogen Substituted C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkane Group, C 1 -C 6 alkoxy-carbonyl group, phenoxycarbonyl group, C 2 -C 6 alkynyl-carbonyl group, C 2 -C 6 alkenyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halo” means substituted with an atom selected from F, Cl, Br, and I.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformers)): for example, containing asymmetry The R and S configurations of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformers) are within the scope of the present invention.
  • tautomer means that structural isomers with different energies can exceed the low energy barrier and thus convert to each other.
  • proton tautomers ie, proton shift
  • Valence tautomers include interconversion through some bond-forming electron recombination.
  • solvate refers to a compound of the present invention that coordinates with a solvent molecule to form a complex in a specific ratio.
  • the present invention provides a class of compounds represented by the following formula I:
  • X 1 is CR or N
  • R is selected from the group: H, D, fluorine, chlorine, -OH, -NH 2 ;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, -COOH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, Or a substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro or bridged rings);
  • z and w are independently selected from the group: 1, 2, 3, 4, 5, 6, or 7;
  • Art 1 is selected from the group consisting of substituted or unsubstituted benzene rings, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O;
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • X 1 , L 1 , L 2 , R A and R B are each independently a corresponding group of the compound in the examples.
  • the compound of the present invention has a structure represented by the following formula:
  • X is H, halogen, CN, -CONH 2 ;
  • X 1 is CR or N
  • R is selected from the group: H, D, fluorine, chlorine, -OH, -NH 2 ;
  • L 2 is a substituted or unsubstituted 5-10 membered heterocyclylene having 1-3 heteroatoms selected from N, S, and O;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, -COOH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, Or a substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro or bridged rings);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • the compound of formula I of the present invention is a compound shown in the following table.
  • the compound of formula I of the present invention can be prepared by the following method:
  • Lg and Lg ' are leaving groups, preferably Tf, fluorine, chlorine, bromine or iodine.
  • the compound of the present invention Since the compound of the present invention has excellent TRK kinase inhibitory activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention as the main active ingredient
  • the pharmaceutical composition of can be used to prevent and / or treat diseases (eg, cancer) related to TRK kinase activity or expression level.
  • the pharmaceutical composition of the present invention contains the compound of the present invention within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound / dose of the present invention, and more preferably, 10-200 mg of the compound / dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, for example, cetyl alcohol and
  • Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in this composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oil,
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more other pharmaceutically acceptable compounds.
  • One or more of the other pharmaceutically acceptable compounds can be administered simultaneously, separately, or sequentially with the compounds of the present invention.
  • a safe and effective amount of the compound of the present invention is suitable for mammals in need of treatment (such as humans), wherein the dose when administered is the pharmaceutically effective dose, for 60kg body weight
  • the dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (100 mL ⁇ 2), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate
  • the diphenyl ether-biphenyl eutectic (170 mL) was heated to 190 degrees, and 5-[(6-methoxy-pyridin-3-ylamino) -methylene] -2,2-dimethyl- [ 1,3] Dioxane-4,6-dione (17g, 61.5mmol) was added to the above solution in batches. After the addition, the reaction solution was maintained at 190 degrees and stirred for 0.5 hour.
  • Example 8 N- (6-((R) -2- (2,5-difluorophenyl) pyrrolidin-1-yl) -1,5-diazanaphthalen-4-yl) -2- ((S) -3-hydroxypyrrolidin-1-yl) pyrimidine-5-carboxamide
  • Example 12 2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (tetrahydro-2H-pyran -4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 13 2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (1-methylpiperidine- 4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 14 2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (1-isopropylpiperidine -4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 16 7-chloro-2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (piperidine- 4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 17 2-((R) -2- (2,5-difluorophenyl) pyrrolidin-1-yl) -8- (1- (2,2-dimethylpiperidin-4-yl ) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 18 2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (2,2-dimethyl Piperidin-4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 19 4- (4- (6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1,5-diaza Naphthalene-4-yl) -1H-pyrazol-1-yl) piperidin-2-one
  • Example 20 2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -7-fluoro-8- (1- (piperidine- 4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 22 8- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -7-chloro-2-((2R, 4S) -2- (2,5-di Fluorophenyl) -4-fluoropyrrolidin-1-yl) -1,5-diazanna
  • Example 23 7-chloro-2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (1-methyl Azetidine-3-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 25 7-chloro-2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (methanesulfonyl ) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • Example 32 2- (4- (4- (3-chloro-6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl)- 1,5-Diazanaphthalen-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethane-1-ol
  • Example 36 6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -4- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1,5-naphthyridine-3-carbonitrile
  • Example 38 7-chloro-2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (1- (3-methyl Oxy-3-methylcyclobutyl) -1H-pyrazol-4-yl) -1,5-naphthyridine
  • reaction solution was washed with saturated sodium bicarbonate, extracted with ethyl acetate (100 mL x 2), the organic layers were combined, washed sequentially with water (80 mL), saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was under reduced pressure
  • reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (100 mL x 2), the organic layers were combined, washed with water (80 mL), saturated brine (80 mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized
  • Example 46 6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -4- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyrido [3,2-d] pyrimidine
  • Example 726A 6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -3-nitromethylpyridineamide (2.0 g, 5.46 To the mixed solution of ethanol (40 mL) and water (10 mL), iron powder (1.5 g, 27.3 mmol) and ammonium chloride (1.46 g, 27.3 mmol) were added. The reaction solution was heated to 60 degrees and stirred for 2 hours. LCMS showed that the raw materials had reacted.
  • Example 51 3- (3-chloro-6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1,5-diazepine Heteraphthalene-4-yl) -5- (piperidin-4-yl) -1,2,4-oxadiazole
  • Example 63 7-chloro-2-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -8- (6- (piperidine- 4-yl) pyridin-3-yl) -1,5-naphthyridine
  • dichloromethane (S) -3-((tert-butyldimethylsilyl) oxo) pyrrolidine (2.01g, 10mmol) and triethylamine (3.03g, 30.0mmol) in dichloromethane ( 20mL) solution was added sulfonyl chloride (2.68g, 20mmol) in portions, reacted for 1 hour under ice bath, and then reacted at room temperature for 5 hours.
  • Example 816C (40 mg, 0.065 mmol) in tetrahydrofuran (1 mL) was added pyridine hydrofluoric acid solution (0.3 mL), and the reaction was carried out at room temperature for 1 hour.
  • Example 95 1- (6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1,5-diazanaphthalene-4 -Yl) -3- (piperidin-4-yl) -1,3-dihydro-2H-imidazol-2-one
  • TRKA, TRKB, and TRKC proteins were purchased from Carna Biosciences.
  • HTRFkinEASETK is purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to a three-fold concentration gradient dilution with a final concentration of 1 ⁇ M to 0.05 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA protein kinase 1 ⁇ M TK Substrate-biotin peptide substrate, 14.68 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • TRKB protein kinase 1 ⁇ M TK Substrate-biotin peptide substrate, 4.77 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 50 minutes, and the reaction system was 10 ⁇ l.
  • TRKC protein kinase 0.037ng / ⁇ l TRKC protein kinase, 1 ⁇ M TK Substrate-biotin peptide substrate, 25.64 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 IC50 (nM) data measured by parameter curve fitting, see Table 1 for details.
  • TRKA G595R
  • TRKA G667C
  • TRKC G623R
  • HTRFkinEASETK is purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to 4-fold concentration gradient dilution, with a final concentration of 1 ⁇ M to 0.004 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA TRKA (G595R) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate
  • 4.5 ⁇ M ATP 1 ⁇ enzymatic buffer
  • 5 mM MgCl 2 1 mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • TRKA TRKA (G667C) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate
  • 5.5 ⁇ M ATP 1 ⁇ enzymatic buffer
  • 5 mM MgCl 2 1 mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 IC50 (nM) data measured by parameter curve fitting, see Table 1 for details.
  • Human colon cancer cell line KM12-LUC (LUC, stably expressing Luciferace) containing the TPM3-NTRK1 fusion gene was used as a model for evaluating the efficacy of the test compounds at the cytological level.
  • the TRK fusion gene in KM12-LUC cells makes it independent of extracellular growth factor stimulation, and can continue to spontaneously activate and activate its downstream signaling pathways MAPK-ERK, PI3K-AKT and other signaling pathways that are closely related to cell proliferation. Therefore, inhibition of TRK activity in KM12-LUC cells can significantly inhibit cell proliferation.
  • the method is as follows: on the first day, cells are seeded in a 384-well plate at 2000 cells / well; on the second day, different concentrations of the test compound are added; on the fifth day, CellTiter-Glo (Promega) is added to detect cell viability and the cells are counted for 72 hours Proliferation inhibition rate. Use prism5 to perform statistical analysis and obtain the inhibition rate of the test compound, as shown in Figure 1.
  • the NIH-3T3 cell line stably expressing ⁇ TRKA or ⁇ TRKA (G595R) was constructed by plasmid transfection.
  • mice ⁇ TRKA (G595R) / 3T3 cells (5 ⁇ 10 6 ) were injected subcutaneously into the dorsal area of mice.
  • the tumor volume was monitored by measuring the diameter with a caliper, and calculated by the following formula: length ⁇ (width 2 ) / 2.
  • mice are randomly selected to receive the diluent, 30 mg / kg / dose test compound.
  • the test compound is administered once a day by oral administration for 14 days. After the last administration, the mice were weighed, and 2 hours after the administration, tissues and blood were collected.
  • ICR mice were administered intravenously (IV) and orally (PO) with a single test compound, and blood samples were collected at different time points.
  • LC-MS / MS was used to determine the concentration of the test substance in the mouse plasma and related parameters were calculated. The details are as follows: take the required amount for the test product, dissolve it in 5% DMSO + 10% Solutol + 85% water for injection, and prepare a solution of the required concentration for intravenous or oral administration. The animals were about 6-8 weeks old at the beginning of the dosing experiment. Venous blood collection time: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.
  • Oral blood collection time 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
  • Example 20 C max ng / mL 714 448 AUC 0-24hr hr * ng / mL 3229 2705 T 1/2 hr 2.34 2.82 F % 107 144

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Abstract

本发明提供了一类六元并六元杂环化合物的制备和应用，具体地，本发明提供了一类如下式I所示的化合物，其中，各基团的定义如说明书中所述。所述的化合物具有TRK激酶抑制活性，可以作为治疗TRK功能异常相关疾病的药物组合物。(I)

Description

一类六元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途 技术领域
本发明涉及小分子药物领域，具体地，本发明涉及一类TRK激酶抑制剂及其制备和用途。
背景技术
原肌球蛋白受体激酶(tropomyosin-receptor kinase,TRK)是一类神经生长因子受体，隶属于受体酪氨酸激酶家族，主要包括高度同源的TRKA、TRKB和TRKC三个成员，分别由NTRK1、NTRK2和NTRK3三个基因编码而成。这些受体酪氨酸激酶主要在神经组织中表达，并通过神经营养因子NTs(neurotrophins)的激活在神经系统的发育和生理功能中发挥重要作用。TRK作为酪氨酸激酶受体，每个TRK都有与其相对应的配体结合并激活其下游的信号通路。NGF(nerve growth factor)特异性结合并激活TRKA；TRKB的配体包括有BDGF(brain-derived growth factor)和NT-4/5(neurotrophin-4/5)；NT-3特异性结合并激活TRKC。三种TRK受体均含有用于配体结合的细胞外结构域、跨膜结构域和具有激酶活性的胞内结构域。
当特定配体与相应受体的胞外结构域相结合，会引发受体的寡聚化和胞质内激酶结构域中特定酪氨酸残基的磷酸化，从而引起下游信号通路如Ras/MAPK、PLCγ/PKC和PI3K/AKT信号通路的激活，进而调控神经细胞的增殖、分化和存活等一系列生理过程(Bergman,et al.1999)。TRK信号通路通常被精确调控，而它的异常激活则与肿瘤发生密切相关(Amatu,et al.2016)。研究结果表明，引起TRK通路异常激活的机制有很多，包括基因融合、蛋白质过度表达和单核苷酸突变，这些异常与肿瘤的发病机制密切相关，特别是NTRK基因融合已被证实是导致多种肿瘤发生的重要要因素，且不依赖于肿瘤的组织来源和类型。在当前二代测序技术和精准医疗的迅猛发展下，越来越多的NTRK融合基因被发现，例如ETV6-NTRK3、MPRIP–NTRK1、CD74–NTRK1等。近年来的临床试验结果表明，这些融合基因是非常有效的抗癌靶点，且含有NTRK融合基因的肿瘤对TRK抑制剂有非常显著的响应率(Drilon,et al.2018)。因此，越来越多的TRK靶点抑制剂被报道，如(WO2010048314,WO2011146336,WO2017004342)。同时，在临床试验阶段，已经发现有部分接受治疗的患者出现了耐药现象，并被证实是由酶活区域的部分碱基突变引起，例如NTRK1G595R或G667C突变，NTRK3的G623R或G696A突变，而新一代TRK激酶抑制剂的研制有望解决这些问题。
综上所述，本领域迫切需要开发新一代TRK激酶抑制剂。
发明内容
本发明的目的是提供一类新型TRK激酶抑制剂。
本发明的第一方面，提供了一类如下式I所示的化合物：
Figure PCTCN2019118217-appb-000001
其中，
X为H、卤素、D、CN、-CONH 2；
X 1为CR或N；
R选自下组：H、D、氟、氯、-OH、-NH 2；
L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
L 2选自下组：取代或未取代的-(X 4) z-，其中各个所述的X 4各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-、-CONH-、-NHCO-、-NHCS-、-NHCONH-、-NHS(＝O)-、-NHS(＝O) 2-；
y选自下组：1或2；z选自下组：0、1或2；
R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
Figure PCTCN2019118217-appb-000002
或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
Figure PCTCN2019118217-appb-000003
C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基(包括 单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)；
Figure PCTCN2019118217-appb-000004
为基团的连接位点；
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中，所述的L 1选自下组：
Figure PCTCN2019118217-appb-000005
n选自下组：0、1、2或3；
R 2、R 2a和R 2b各自独立地选自下组：H、OH、卤素、取代或未取代的C 1-C 8烷基；
X选自下组：NH、O、-CONH-、-NHCO-、S、-S(＝O) 2-、-NHS(＝O)-、-NHS(＝O) 2-；
R A为
Figure PCTCN2019118217-appb-000006
其中，所述的
Figure PCTCN2019118217-appb-000007
指R A与L 1的连接位点；
L 2为
Figure PCTCN2019118217-appb-000008
R B为
Figure PCTCN2019118217-appb-000009
其中，所述的
Figure PCTCN2019118217-appb-000010
为R B与L 2的连接位点；
R 3选自下组：H、卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基；
R 4、R 5各自独立地选自下组：H、OH、卤素、C 1-C 6烷基OH、C 1-C 6烷氧基、C 1-C 6烷基胺基、C 1-C 6烷基酰胺基、-(C 1-C 6烷基)-NH-(C 1-C 6烷基)、-C 1-C 6烷基酰胺基-(C 1-C 6烷基)；
R 6a、R 6b、R 7a、R 7b各自独立地选自下组：H、OH、卤素；或R 6a、R 6b、R 7a、R 7b与其相连的碳原子共同构成具有1-3个选自N、S和O的杂原子的5-12元杂环基。
在另一优选例中，所述的化合物具有如下式II所示的结构：
Figure PCTCN2019118217-appb-000011
其中，所述的X 2选自下组：C＝O、-CH 2-、O、NH。
在另一优选例中，所述的化合物具有如下式IIIa所示的结构：
Figure PCTCN2019118217-appb-000012
本发明的另一方面，提供了一类如下式IV所示的化合物：
Figure PCTCN2019118217-appb-000013
其中，
X为H、D或卤素；
X 1为CR或N；
R选自下组：H、D、氟、氯、-OH、-NH 2；
L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
L 2为取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
y选自下组：1或2；z选自下组：0、1或2；
R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
Figure PCTCN2019118217-appb-000014
或取代或未取代的选自下组的基团：未取代或被一个或多个羟基取代的C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、未取代或被一个或多个羟基取代的C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、C1-C6酰胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
Figure PCTCN2019118217-appb-000015
为基团的连接位点；
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中，所述的化合物具有如下式V所示的结构：
Figure PCTCN2019118217-appb-000016
其中，所述的X 2选自下组：C＝O、-CH 2-、O、NH。
在另一优选例中，所述的化合物具有如下式IIIa所示的结构：
Figure PCTCN2019118217-appb-000017
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒，炎症相关疾病，骨相关的疾病。
在另一优选例中，所述的癌症选自TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的癌症(包括但不仅限于)：神经母细胞瘤，前列腺癌，甲状腺癌，肺癌卵巢癌，胰腺癌、结直肠癌症、非小细胞肺癌、纤维肉瘤等。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如本发明第二方面所述的药物组合物的用途，用于制备预防和/或治疗与TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的疾病的药物组合物。
在另一优选例中，所述的疾病选自下组：所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒。
本发明的第四方面，提供了一类TRK抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为细胞实验中待测化合物对于细胞的抑制率百分比；
图2为小鼠模型试验中施用待测化合物后，小鼠的肿瘤体积随时间变化曲线。
具体实施方式
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-12元杂环烷基”是指具有3-12个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯 丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一类如下式I所示的化合物：
Figure PCTCN2019118217-appb-000018
其中，
X 1为CR或N；
R选自下组：H、D、氟、氯、-OH、-NH 2；
L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
L 2选自下组：取代或未取代的-(X 4) z-，其中各个所述的X 4各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-、-CONH-、-NHCO-、-NHCONH-、-NHS(＝O)-、-NHS(＝O) 2-，或L 2为无；
y选自下组：1或2；z选自下组：0、1或2；
R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取 代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
Figure PCTCN2019118217-appb-000019
或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、C1-C6酰胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
或R A和-L 2-R B相连形成：-Art 1-L 4-L 3-；其中，L 3选自下组：取代或未取代的-(X 4) z-，其中所述的各个X 4各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-、-CONH-、-NHCO-、-NHCONH-、-NHS(＝O)-、-NHS(＝O) 2-；
L 4选自下组：取代或未取代的-(X 5) w-，其中所述的各个X 5各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-、-CONH-、-NHCO-、-NHCONH-、-NHS(＝O)-、-NHS(＝O) 2-、取代或未取代的C3-C8亚环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元亚杂环基；
z和w各自独立地选自下组：1、2、3、4、5、6或7；
且z与w之和≤10；
Art 1选自下组：取代或未取代的苯环、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
Figure PCTCN2019118217-appb-000020
为基团的连接位点；
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中，X 1、L 1、L 2、R A和R B各自独立地为实施例中化合物的对应基团。
在另一优选例中，本发明的化合物具有如下式所示的结构：
Figure PCTCN2019118217-appb-000021
其中，
X为H、卤素、CN、-CONH 2；
X 1为CR或N；
R选自下组：H、D、氟、氯、-OH、-NH 2；
L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取 代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
L 2为取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基；
y选自下组：1或2；z选自下组：0、1或2；
R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
Figure PCTCN2019118217-appb-000022
或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、未取代或被一个或多个羟基取代的C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、C1-C6酰胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
Figure PCTCN2019118217-appb-000023
为基团的连接位点；
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中，本发明的式I化合物为下表中所示的化合物。
Figure PCTCN2019118217-appb-000024
Figure PCTCN2019118217-appb-000025
Figure PCTCN2019118217-appb-000026
Figure PCTCN2019118217-appb-000027
Figure PCTCN2019118217-appb-000028
Figure PCTCN2019118217-appb-000029
Figure PCTCN2019118217-appb-000030
Figure PCTCN2019118217-appb-000031
Figure PCTCN2019118217-appb-000032
Figure PCTCN2019118217-appb-000033
式I化合物的制备
本发明的式I化合物可以通过以下方法制备：
Figure PCTCN2019118217-appb-000034
其中，Lg和Lg'为离去基团，优选为Tf、氟、氯、溴或碘。
药物组合物和施用方法
由于本发明化合物具有优异的TRK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与TRK激酶活性或表达量相关的疾病(例如，癌症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019118217-appb-000035
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
联合给药时，所述药物组合物还包括与一类或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一类或多种可与本发明的化合物同时、分开或顺序地给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
中间体A的合成：(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000036
8-氯-1,5-二氮杂萘-2-醇盐酸盐
Figure PCTCN2019118217-appb-000037
向8-氯-2-甲氧基-1,5-二氮杂萘(900mg,4.62mmol)加入4N盐酸二氧六环溶液(60mL).升温至100度搅拌30小时。反应液浓缩，得标题化合物8-氯-1,5-二氮杂萘-2-醇盐酸盐(1.17g,收率100％)，为白色固体。
MS(ESI):m/z＝181[M+H]+
8-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯
Figure PCTCN2019118217-appb-000038
向8-氯-1,5-二氮杂萘-2-醇盐酸盐(1.17g,4.62mmol),三乙胺(3.2mL,23.1mmol)的N,N-二甲基甲酰胺(28mL)溶液中加入N-苯基双(三氟甲烷磺酰)亚胺(2.48g,6.93mmol),室温并搅拌一个小时。加入水(100mL),用乙酸乙酯萃取(100mL*2)。合并有机相,干燥,浓缩，柱层析(石油醚:乙酸乙酯＝2:1)到得标题化合物8-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯.(1.4g,97.0％)，为白色固体。
MS(ESI):m/z＝313[M+H] +
(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000039
向8-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯(500mg,1,60mmol),(R)-2-(2,5-二氟苯基)吡咯烷(293mg,1.60mmol),碳酸铯(1.04g,3.20mmol)的甲苯溶液(10mL)中加入双(二亚苄基丙酮)钯(146mg,0.16mmol)和2-二环己基膦-2′,6′-二甲氧基-联苯(131mg,0.32 mmol)，反应液加热到90℃，并搅拌2小时。加入水(100mL),用二氯甲烷萃取(100mL*2).合并有机相,干燥,浓缩，柱层析(石油醚:乙酸乙酯＝4:1)到得标题化合物(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(257mg,收率46.5％)，为黄色油状物。
MS(ESI):m/z＝346[M+H]+.
中间体B的合成
Figure PCTCN2019118217-appb-000040
(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019118217-appb-000041
将(R)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(30g,122.45mmol)于室温下加入到饱和溴化钠(480mL)的水溶液中,加入In(42g,367.35mmol),然后加入烯丙基溴化镁(42mL,489.8mmol),室温反应6小时,TLC监测反应完毕，用饱和碳酸氢钠溶液淬灭，过滤，滤液用乙酸乙酯萃取，饱盐水洗涤，无水硫酸钠干燥，旋干得(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺,黄色固体(35g).
(S)-N-((1S)-1-(2,5-二氟苯基)-2-(环氧乙烷-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019118217-appb-000042
将(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺(35g,121.95mmol)溶于二氯甲烷(800mL)中,于室温下分批加入间氯过氧苯甲酸(80g,365.85mmol),室温搅拌过夜，TLC监测反应完毕，反应液用饱和碳酸氢钠与饱和硫代硫酸钠溶液洗涤，饱盐水洗涤，无水硫酸钠干燥，旋干得(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺，黄色固体(31g,收率：79％).
(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇
Figure PCTCN2019118217-appb-000043
将(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺(31g,97.18mmol)溶于N,N-二甲基甲酰胺(300mL)中，室温下加入碳酸钾(40g,291.53mmol),碘化钾(16g,97.18mmol),加热至100℃反应1小时，TLC监测反应完毕，待反应液冷却至室温，过滤，滤液打入水中，用乙酸乙酯萃取，合并有机相，饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝10/1—5/1)得到化合物(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇(7.5g)。
(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷
Figure PCTCN2019118217-appb-000044
将(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇(2.0g,6.27mmol)溶于二氯甲烷(50ml)中，冷却至零下60℃，将DAST(2ml)滴加入体系，然后自然升至室温并搅拌过夜，LCMS监测反应完毕，反应液加入二氯甲烷稀释，将其缓慢倒入冰水中，分液，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝10/1)得到(2R，4S)-1-(叔丁基磺酰基)-2-(2,5-二氟苯基)-4-氟，黄色固体(1.2g,收率：60％)。
(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷
Figure PCTCN2019118217-appb-000045
向2R，4S)-1-(叔丁基磺酰基)-2-(2,5-二氟苯基)-4-氟(500mg，1.55mmol)的二氯甲烷溶液(20mL)中加入三氟甲磺酸(0.7mL)，反应2小时，溶剂旋干，用2M的氢氧化钠溶液洗涤，加入乙酸乙酯萃取，分液，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝4/1)得到(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷，黄色固体(305mg,收率：99％)。
中间体C的合成
Figure PCTCN2019118217-appb-000046
(R)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019118217-appb-000047
将2,5-二氟苯(甲)醛(5g,35.2mmol)与(R)-2-甲基丙烷-2-亚磺酰胺(4.47g,36.9mmol)溶于二氯甲烷(50ml)中，室温下加入碳酸铯(8.0g,24.6mmol),然后升温至50℃反应3h，TLC显示反应完毕，过滤，滤饼用二氯甲烷洗涤，滤液用盐水洗涤，Na 2SO 4干燥，旋干得(R)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺，为黄色油状液体(9g)。
(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019118217-appb-000048
将镁屑(2g,83.3mmol)溶于四氢呋喃(72ml)中，氮气保护，于40℃下将Dibal-H(0.1ml,1.5M,0.15mmol)滴加入体系，40℃反应0.5h,然后将2-(2-溴乙基)-1,3-二噁烷(14.3g,73.47mmol)的四氢呋喃(40ml)溶液缓慢滴加入体系并控制温度在40-50℃，滴完后保持40℃搅拌1h。撤掉加热，将反应体系冷却至-30℃，然后将(R,E)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(9g,36.73mmol)的四氢呋喃(40ml)溶液滴加入体系，控制其温度在-30℃-20℃，滴完后，于-30℃搅拌2h,TLC显示反应完毕,用10％的柠檬酸水溶液淬灭并控制温度在10℃，用二氯甲烷萃取，有机相用饱盐水洗涤，Na 2SO 4干燥，旋干得(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺，无色油状液体(15.8g)。(R)-2-(2,5-二氟苯基)吡咯烷
Figure PCTCN2019118217-appb-000049
室温下将(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺(15.8g,43.76mmol)加入到三氟乙酸(32mL)与水(8mL)的混合溶液中，室温搅拌1h,然后将三氟乙酸(60mL)加入到体系，三乙基硅烷(15.2g,131.1mmol)滴加入体系，反应室温过夜，LCMS监测反应完毕，旋掉大部分三氟乙酸,剩余溶于盐酸(1N,100mL)并搅拌0.5小时,用甲基叔丁基醚萃取，有机相用盐酸(1N,50mL)洗涤，合并水相，水相用40％氢氧化钠水溶液调节pH＝11,然后用二氯甲烷萃取，合并有机相，饱盐水洗涤，无水硫酸钠干燥，旋干得(R)-2-(2,5-二氟苯基)吡咯烷，油状液体(6.7g)。
中间体D的合成
Figure PCTCN2019118217-appb-000050
2-(1-乙氧基乙烯基)-6-甲氧基-3-硝基吡啶
Figure PCTCN2019118217-appb-000051
将化合物2-氯-6-甲氧基-3-硝基吡啶(16.4g,86.8mmol)溶于乙腈(150mL)中,加入三丁基(1-乙氧基乙烯)锡(37.5g,103.9mmol)，双三苯基磷二氯化钯(3.05g,4.3mmol)，氮气置换后，反应液于80度下搅拌16小时。LCMS检测反应结束后，反应混合液降至室温,反应液倒入冰水/乙酸乙酯(150mL/100mL)中，用乙酸乙酯(100mL x 2)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝10/1)得到淡黄色液体化合物(29g,收率99％).
MS(ESI):m/z＝225[M+H]+.
2-氟-1-(6-甲氧基-3-硝基吡啶-2-基)乙酮
Figure PCTCN2019118217-appb-000052
将2-(1-乙氧基乙烯基)-6-甲氧基-3-硝基吡啶(23g,66.7mmol)溶于乙腈(100mL)和水 (50mL)中,加入选择性氟试剂(30.75g,86.8mmol)，反应液于室温下搅拌16小时。LCMS检测反应结束后，反应液倒入冰水(100mL)中，用乙酸乙酯(100mL x 2)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝6/1)，并用石油醚(150mL)打浆得到白色固体化合物(3)(13.76g,收率75％).
MS(ESI):m/z＝215[M+H]+.
3-(6-甲氧基-3-硝基吡啶-2-基)-3-羰基丙腈
Figure PCTCN2019118217-appb-000053
将2-氟-1-(6-甲氧基-3-硝基吡啶-2-基)乙酮(9.76g,45.61mmol)溶于甲苯(60mL)中,加入N,N-二甲基甲酰胺二甲基缩醛(30ml)，反应液于50度下搅拌16小时。LCMS检测反应结束后，反应液降至室温,大量的固体析出，过滤，滤饼用石油醚洗涤,干燥,得到黄色固体(10.61g,收率86％).
MS(ESI):m/z＝270[M+H]+.
3-氟-6-甲氧基-1,5-二氮杂萘-4-醇
Figure PCTCN2019118217-appb-000054
将3-(6-甲氧基-3-硝基吡啶-2-基)-3-羰基丙腈(10.61g,39.4mmol)溶于N,N-二甲基甲酰胺(50mL)中，加入10％Pd/C(3.2g)，氢气置换后，反应液于40度在氢气氛围下搅拌16h。LCMS检测反应结束后，滤除Pd/C，滤液减压下蒸除溶剂，得到黄色固体(8.76g，收率80％)
MS(ESI):m/z＝195[M+H]+.
8-溴-7-氟-2-甲氧基-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000055
将3-氟-6-甲氧基-1,5-二氮杂萘-4-醇(8.76g,44.9mmol)溶于N,N-二甲基甲酰胺(50mL)中,控温在0度下滴加三溴化磷(14.73g,54.3mmol)，滴完，反应液于25度下搅拌2小时。LCMS检测反应结束后，反应液倒入冰水(100mL)中，用饱和碳酸氢钠中和至pH～8。用乙酸乙酯(40mL x 5)萃取，合并有机层，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝6/1)得到浅黄色固体6(5.96g,收率52％).
MS(ESI):m/z＝257[M+H]+.
8-溴-7-氟-1,5-二氮杂萘-2-醇
Figure PCTCN2019118217-appb-000056
将8-溴-7-氟-2-甲氧基-1,5-二氮杂萘(5.96g,23.2mmol)溶于氢溴酸溶液(30mL)中,反应液于80度下搅拌3小时。LCMS检测反应结束后，用饱和碳酸氢钠溶液中和 至pH～8，过滤，得到类白色固体(4.76g,收率85％).
8-溴-7-氟-1,5-二氮杂萘-2-基三氟甲磺酸酯
Figure PCTCN2019118217-appb-000057
将8-溴-7-氟-1,5-二氮杂萘-2-醇(3.0g,12.4mmol)，吡啶(2.2mL,27.3mmol)溶于二氯甲烷(50mL)中，反应液冷却至0度，向上述反应液滴加Tf 2O(2.5mL,14.8mmol)，反应液在室温搅拌1h。LCMS检测反应结束后，用盐酸调至pH～2，用二氯甲烷(30mL x 3)萃取，粗品用柱纯化(石油醚/乙酸乙酯＝5/1)得到白色固体(4.0g,收率86％).
MS(ESI):m/z＝375[M+H]+.
中间体E的合成
Figure PCTCN2019118217-appb-000058
5-[(6-甲氧基-吡啶-3-基氨基)-亚甲基]-2,2-二甲基-[1,3]二噁烷-4,6-二酮
Figure PCTCN2019118217-appb-000059
将6-甲氧基吡啶-3-胺(25g,201.61mmol)溶于乙醇(150mL)中,加入丙二酸亚异丙酯(31.9g,221.77mmol)，原甲酸三乙酯(29.84g,201.61mmol)，反应液加热至回流5小时。LCMS检测反应结束后，反应液降至室温,大量的固体析出，过滤，滤饼用乙醇洗涤,干燥,得到黑褐色固体(90.4g,收率90％).
1H-NMR(CDCl 3,400MHz):δ8.51(d,J＝14.4Hz,1H),8.13(d,J＝2.8Hz,1H),7.54-7.51(m,1H),6.84(d,J＝8.8Hz,1H),3.95(s,3H),1.75(s,6H).
6-甲氧基-[1,5]二氮杂萘-4-醇
Figure PCTCN2019118217-appb-000060
将二苯醚-联苯共晶(170mL)加热至190度,将5-[(6-甲氧基-吡啶-3-基氨基)-亚甲 基]-2,2-二甲基-[1,3]二噁烷-4,6-二酮(17g,61.5mmol)分批加入上述溶液，加完，反应液维持190度搅拌0.5小时。LCMS检测反应结束后，反应液降至室温,加入乙醚(170mL)，大量的固体析出，过滤，滤饼用乙醚洗涤,干燥,得到褐色固体(6.5g,收率60％).
MS(ESI):m/z＝177[M+H]+.
3-氯-6-甲氧基-1,5-二氮杂萘-4-醇
Figure PCTCN2019118217-appb-000061
将6-甲氧基-[1,5]二氮杂萘-4-醇(19.4g,110.23mmol)溶解在醋酸(330mL)中,加入N-氯代丁二酰亚胺(16.87g,126.76mmol),反应液于30度搅拌16小时。LCMS检测反应结束后,反应液降至室温，大量的固体析出，过滤，滤饼分别用乙醚，正庚烷洗涤,干燥,得到类白色固体(10g,收率43％).
MS(ESI):m/z＝211[M+H]+.
8-溴-7-氯-2-甲氧基-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000062
采用类似于8-溴-7-氟-2-甲氧基-1,5-二氮杂萘的条件，替换相应的起始原料,得化合物8-溴-7-氯-2-甲氧基-1,5-二氮杂萘(1.1g,收率84％).
MS(ESI):m/z＝273[M+H]+.
8-溴-7-氯-1,5-二氮杂萘-2-醇
Figure PCTCN2019118217-appb-000063
采用类似于8-溴-7-氟-1,5-二氮杂萘-2-醇的条件，替换相应的起始原料,得化合物8-溴-7-氯-1,5-二氮杂萘-2-醇(1.6g,收率>100％)。
MS(ESI):m/z＝261[M+H]+.
8-溴-7-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯
Figure PCTCN2019118217-appb-000064
采用类似于8-溴-7-氟-1,5-二氮杂萘-2-基三氟甲磺酸酯的条件，替换相应的起始原料,得化合物8-溴-7-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯(13.3g,收率81％).MS(ESI):m/z＝393[M+H]+.
实施例1：3-((6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)环戊烷-1-醇
Figure PCTCN2019118217-appb-000065
向(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(68mg,0.197mmol),3-氨基环戊烷-1-醇盐酸盐(81mg,0.59mmol),碳酸铯(321mg,0.985mmol)的甲苯溶液(5mL)中加入双(二亚苄基丙酮)钯(18mg,0.020mmol)和2-二环己基膦-2′,6′-二甲氧基-联苯(16mg,0.039mmol)，反应液加热到110度，并搅拌2小时。反应液浓缩，反相制备到得标题化合物3-((6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)环戊烷-1-醇(10mg,收率2.4％)，为黄色固体。
MS(ESI):m/z＝411[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.09(d,J＝7.8Hz,1H),7.88(d,J＝9.6Hz 1H),7.21-7.14(m,2H),7.00-6.93(m,1H),6.90-6.80(m,1H),6.75(d,J＝7.0Hz,1H),5.48-5.42(m,1H),4.45-4.37(m,1H),4.30-4.20(m,1H),4.05-3.95(m,1H),3.80-3.70(m,1H),2.60-2.50(m,1H),2.30–2.08(m,4H),2.08-2.00(m,1H),1.99-1.80(m,3H),1.79–1.68(m,1H).
实施例2：3-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)环戊烷-1-醇
Figure PCTCN2019118217-appb-000066
8-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000067
采用类似于(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘的条件，替换相应的起始原料,得化合物8-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘(137mg,收率47.1％)，为无色油状物。
MS(ESI):m/z＝364[M+H]+.
3-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)环戊烷-1-醇
Figure PCTCN2019118217-appb-000068
采用类似于实施例1的条件，替换相应的起始原料,得化合物3-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)环戊烷-1-醇(10mg,收率11.8％)，为白色油状物。
MS(ESI):m/z＝429[M+H]+
1H NMR(400MHz,CD 3OD)δ8.09(d,J＝5.4Hz,1H),7.88(dd,J＝9.2,2.3Hz,1H),7.19(m,1H),7.10–6.91(m,3H),6.47(d,J＝5.5Hz,1H),5.52-5.37(m,2H),4.39-4.33(m,1H),4.22-4.10(m,2H),4.01–3.93(m,1H),2.93–2.81(m,1H),2.45–2.24(m,2H),2.23–2.06(m,2H),1.96-1.80(m,2H),1.76–1.52(m,2H).
实施例3： (R)-1-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-3- 醇
Figure PCTCN2019118217-appb-000069
向(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(50mg,0.144mmol),N,N-二异丙基乙胺(186mg,1.44mmol)的N,N-二甲基甲酰胺溶液(2mL)中加入(R)-吡咯烷-3-醇盐酸(38mg,0.433mmol)，反应液加热到110度，并搅拌16小时。反应液浓缩，反相制备到得标题化合物(R)-1-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-3-醇(12mg,收率21.0％)，为黄色固体。
MS(ESI):m/z＝396.9[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.00(d,J＝5.6Hz,1H),7.86(d,J＝9.2Hz,1H),7.15-7.09(m,1H),7.04–6.88(m,2H),6.82-6.78(m,1H),6.35(d,J＝5.7Hz,1H),5.53(d,J＝8.0Hz,1H),4.35-4.28(m,1H),4.00-3.93(m,1H),3.92-3.83(m,2H),3.67–3.50(m,2H),3.48-3.42(m,1H),2.51–2.38(m,1H),2.15-2.02(m,2H),2.01-1.93(m,1H),1.90-1.82(m,2H).
实施例4：(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-N,N-二甲基-1,5-二氮杂萘-4-胺。
Figure PCTCN2019118217-appb-000070
采用类似于实施例3的条件，替换相应的起始原料,得化合物(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-N,N-二甲基-1,5-二氮杂萘-4-胺(16mg,收率31.4％)，为黄色固体。
MS(ESI):m/z＝355[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.10(d,J＝5.5Hz,1H),7.90(d,J＝9.2Hz,1H),7.15–7.05(m,1H),7.00(d,J＝9.4Hz,1H),6.99-6.92(m,1H),6.80-6.75(m,1H),6.61(d,J＝5.5Hz,1H),5.51(d,J＝8.4Hz,1H),4.00-3.96(m,1H),3.71-3.63(m,1H),3.07(s,6H),2.52–2.40(m,1H),2.16–2.02(m,2H),2.02–1.94(m,1H).
实施例5：(S)-1-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-3- 醇
Figure PCTCN2019118217-appb-000071
采用类似于实施例3的条件，替换相应的起始原料,得化合物(S)-1-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-3-醇(30mg,收率52.6％)，为黄色固体。
MS(ESI):m/z＝397[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.00(d,J＝5.6Hz,1H),7.86(d,J＝9.2Hz,1H),7.12(m,1H),7.01–6.89(m,2H),6.80-6.74(m,,1H),6.35(d,J＝5.7Hz,1H),5.49(d,J＝8.1Hz,1H),4.40-4.35(m,1H),4.01–3.91(m,2H),3.90-3.80(m,1H),3.72-3.60(m,3H),2.52–2.38(m,1H),2.12-1.88(m,5H).
实施例6：(R)-2-((6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)乙烷-1-醇
Figure PCTCN2019118217-appb-000072
向(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(50mg,0.144mmol),N,N-二异丙基乙胺(186mg,1.44mmol)的二甲基亚砜溶液(2mL)中加入2-氨基乙烷-1-醇(26mg,0.433mmol)，反应液加热到140度，并搅拌24小时。反应液浓缩，反相制备到得标题化合物(R)-2-((6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)乙烷-1-醇(15mg,收率28.1％)，为黄色固体。
MS(ESI):m/z＝371[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.07(d,J＝5.4Hz,1H),7.83(d,J＝9.2Hz,1H),7.17–7.08(m,1H),6.95-6.92(m,2H),6.84-6.82(m,1H),6.49(d,J＝5.4Hz,1H),5.42(d,J＝5.2Hz,1H),4.04–3.94(m,1H),3.80–3.67(m,3H),3.45–3.32(m,2H),2.54–2.44(m,1H),2.17–2.07(m,2H),2.04–1.95(m,1H).
实施例7：(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000073
叔-丁基(R)-4-(4-(6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000074
将(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(50mg,0.14mmol),叔-丁基4-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(106mg,0.28mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5.7mg,0.007mmol)和碳酸钾(38mg,0.28mmol)与1,4-二氧六环(1mL),水(0.2mL)混合，氮气保护下，加热到100度搅拌过夜。加入水(50mL),用乙酸乙酯(50mL*2)萃取。合并有机相,干燥,过滤，浓缩，柱层析(石油醚/乙酸乙酯＝1/2)得到黄色固体(70mg,收率89％)。
MS(ESI):m/z＝561[M+H]+.
(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000075
将叔-丁基(R)-4-(4-(6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(70mg,0.12mmol)溶解在二氯甲烷(5mL)中，冷却到0度，加入三氟甲磺酸(0.5mL)，室温反应1小时。溶解旋干，反向制备得到白色固体(48mg,收率87％)。
MS(ESI):m/z＝461[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝4.7Hz,1H),8.41–7.87(m,3H),7.77(d,J＝3.9Hz,1H),7.38–7.26(m,1H),7.14–7.05(m,1H),6.91–6.83(m,1H),5.51(s,1H),4.17–3.98(m,2H),3.66(s,1H),3.05(d,J＝12.4Hz,2H),2.61(t,J＝12.1Hz,2H),2.14–2.03(m,1H),2.00–1.73(m,5H).
实施例8：N-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-2-((S)-3-羟基吡咯烷-1-基)嘧啶-5-甲酰胺
实施例9：(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-甲氧苄基)-1,5-二氮杂萘-4-胺
Figure PCTCN2019118217-appb-000076
(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-甲氧苄基)-1,5-二氮杂萘-4-胺
Figure PCTCN2019118217-appb-000077
将(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(76mg,0.56mmol),对甲氧基苄胺(72mg,0.56mmol)，N,N-二异丙基乙胺(72mg,0.56mmol)混合在N-甲基吡咯烷酮(2mL),加热到150度过夜。冷却到室温后，反向制备得到(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-甲氧苄基)-1,5-二氮杂萘-4-胺(117mg,收率94％)。
MS(ESI):m/z＝447[M+H]+.
(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-胺
Figure PCTCN2019118217-appb-000078
采用类似于实施例7的条件，替换相应的起始原料,得化合物(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-胺(83mg,收率98％)。
MS(ESI):m/z＝327[M+H]+.
N-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-2-((S)-3-羟基吡咯烷-1-基)嘧啶-5-甲酰胺
Figure PCTCN2019118217-appb-000079
向(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-胺(83mg,0.25mmol),的N,N-二甲基甲酰胺溶液(2mL)中加入5-氯吡嗪-2-羧酸(79mg,0.25mmol),2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(144mg,0.38mmol)和N,N-二异丙基乙胺(129 mg,1.0mmol),室温反应16小时后,加入(S)-吡咯烷-3-醇盐酸盐(87mg,1.0mmol)室温继续反应2小时。反向制备得到N-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-2-((S)-3-羟基吡咯烷-1-基)嘧啶-5-甲酰胺(70mg,收率54％),为黄色固体。
MS(ESI):m/z＝518[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ9.61(s,1H),8.58(s,2H),8.44(d,J＝4.6Hz,1H),8.28(s,1H),8.06(s,1H),7.43–6.92(m,3H),6.90–6.80(m,1H),5.78–5.53(m,1H),5.04(s,1H),4.41(s,1H),3.79–3.51(m,4H),2.01(d,J＝44.0,4H).
实施例10：(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-甲酰胺
Figure PCTCN2019118217-appb-000080
甲基(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-羧酸酯
Figure PCTCN2019118217-appb-000081
将(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(152mg,1.12mmol),三乙胺(339mg,3.36mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(84mg,0.11mmol)的甲醇(5nL)在一氧化碳氛围下加热50度反应过夜，反应完毕后旋干，柱层析得到甲基(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-羧酸酯(315mg,收率76％)。
(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-甲酰胺
Figure PCTCN2019118217-appb-000082
将甲基(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-羧酸酯(40mg,0.11mmol)和甲醇的胺溶液(2mL,7N)混合，微波80度反应2小时，过滤得到白色固体为产物(20mg,收率51％)。
MS(ESI):m/z＝355[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ10.31(s,1H),9.28(s,1H),8.63(d,J＝3.8Hz,1H),8.25–8.02(m,2H),7.74(s,1H),7.44–6.74(m,4H),5.38(d,J＝8.1Hz,1H),4.12–3.99(m,1H),3.72–3.58(m,1H),2.13–1.79(m,3H).
实施例11：2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000083
采用类似于实施例7的条件，替换相应的起始原料,得化合物2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(53mg,收率57％)。
MS(ESI):m/z＝479[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.58-8.44(m,2H),8.20(s,1H),8.03(d,J＝9.1Hz,1H),7.77(d,J＝4.8Hz,1H),7.29-7.23(m,1H),7.15-6.95(m,3H),5.61–5.43(m,2H),4.25-4.14(m,3H),3.08(d,J＝11.8Hz,2H),2.98-2.85(m,1H),2.64(t,J＝12.0Hz,2H),2.33-2.12(m,2H),2.00-1.76(m,4H).
实施例12：2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000084
采用类似于实施例7的条件，替换相应的起始原料,得化合物2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(54mg,收率56％)。
MS(ESI):m/z＝480[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.52(s,1H),8.44(d,J＝4.8Hz,1H),8.23(s,1H),8.02(d,J＝9.2Hz,1H),7.78(d,J＝4.8Hz,1H),7.15(ddd,J＝21.4,13.2,6.6Hz,2H),6.94(dd,J＝18.0,8.8Hz,2H),5.62(t,J＝7.9Hz,1H),5.46(d,J＝53.1Hz,1H),4.45(t,J＝11.5Hz,1H),4.29(dt,J＝12.6,10.8Hz,2H),4.14(dd,J＝25.4,7.3Hz,2H),3.62(t,J＝11.5Hz,2H),3.01(dd,J＝22.2,11.7Hz,1H),2.34–1.97(m,5H).
实施例13： 2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-甲基哌啶-4-基)- 1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000085
向2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)- 1,5-二氮杂萘(60mg,0.125mmol),甲醛水溶液(0.5mL)的甲醇(5mL)溶液中加入冰醋酸(0.05mL)。反应液室温搅拌1小时后加入三乙酰氧基硼氢化钠(133mg,0.627mmol)。反应液室温搅拌1小时。LCMS显示原料反应完了。反应液浓缩，反向制备得到2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(32mg,收率52.0％)，为黄色固体。
MS(ESI):m/z＝493[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.62-8.45(m,2H),8.21(s,1H),8.03(d,J＝9.1Hz,1H),7.77(d,J＝4.4Hz,1H),7.29-7.24(m,1H),7.15-6.95(m,3H),5.61–5.42(m,2H),4.30-4.02(m,3H),2.98-2.83(m,3H),2.34-2.10(m,4H),2.11–1.80(m,6H).
实施例14：2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-异丙基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000086
采用类似于实施例13的条件，替换相应的起始原料,得化合物2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-异丙基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(18mg,收率16％)。
MS(ESI):m/z＝521[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.60-8.50(s,1H),8.46(d,J＝4.7Hz,1H),8.21(s,1H),8.03(d,J＝8.6Hz,1H),7.77(d,J＝4.5Hz,1H),7.30–7.21(m,1H),7.15-6.98(m,3H),5.60–5.43(m,2H),4.30–4.05(m,3H),3.00-2.84(m,3H),2.78–2.67(m,1H),2.35-2.12(m,3H),2.06–1.85(m,4H),0.98(d,J＝6.5Hz,6H).
实施例15：(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000087
叔-丁基4-(5-氟-4-碘-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000088
将叔-丁基4-(4-碘-1H-吡唑-1-基)哌啶-1-羧酸酯(800mg,2.1mmol)溶解在四氢呋喃(15mL),冷却到-78度，氮气保护下，加入LDA溶液(2.1mL,4.2mmol)并在此温度下反应30分钟，加入select-F试剂(2.6g,8.4mmol)的四氢呋喃(10mL)溶液，反应1小时。加入饱和氯化铵淬灭反应，加入水(150mL),用乙酸乙酯(150mL*2)萃取。合并有机相,干燥,过滤，浓缩，柱层析(石油醚/乙酸乙酯＝1/2)得到白色固体(390mg,收率47％)。
MS(ESI):m/z＝340[M+H]+.
(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000089
将(R)-8-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘(100mg,0.29mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(110mg,0.43mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(12mg,0.015mmol)和醋酸钾(57mg,0.58mmol)混合在1,4-二氧六环(2mL),加热到100度反应过夜，反应液浓缩，柱层析(乙酸乙酯)得到棕色固体(60mg,收率47％)。
MS(ESI):m/z＝356[M+H]+.
叔-丁基(R)-4-(4-(6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-5-氟-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000090
采用类似于实施例7的条件，替换相应的起始原料,得化合物叔-丁基(R)-4-(4-(6-(2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-5-氟-1H-吡唑-1-基)哌啶-1-羧酸酯(75mg,收率93％)。
MS(ESI):m/z＝579[M+H]+.
(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000091
采用类似于实施例7的条件，替换相应的起始原料,得化合物(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(51mg,收率82％)。
MS(ESI):m/z＝479[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.48(d,J＝4.6Hz,1H),8.03(s,1H),7.79–7.44(m,2H),7.31–7.19(m,1H),7.14–6.99(m,1H),6.89–6.75(m,1H),5.46(s,1H),4.23(s,1H),4.08–3.96(m,1H),3.63(s,1H),3.09–2.82(m,3H),2.59(t,J＝11.5Hz,2H),2.43–2.32(m,1H),2.12–1.99(m,1H),1.99–1.70(m,6H).
实施例16：7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000092
8-溴-7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000093
向8-溴-7-氯-1,5-二氮杂萘-2-基三氟甲磺酸酯(3.0g,7.67mmol)和(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(1.6g,8.05mmol)的乙腈溶液中加入N,N-二异丙基乙胺(2.0g,15.34mmol)，80度反应16小时，旋蒸除去溶剂后，粗产品用正相柱纯化(乙酸乙酯/石油醚＝2/1)得到8-溴-7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘(3.1,收率91％)，为无色油状物。
MS(ESI):m/z＝442[M+H]+.
叔-丁基4-(4-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000094
采用类似于实施例7的条件，替换相应的起始原料,得化合物叔-丁基4-(4-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
MS(ESI):m/z＝613[M+H]+.
7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000095
采用类似于实施例7的条件，替换相应的起始原料,得化合物7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝513[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.50(s,1H),8.25(s,1H),8.00(d,J＝9.2Hz,2H),7.10(td,J＝9.2,4.1Hz,1H),7.03(s,1H),6.93(s,1H),6.84(s,1H),5.55–5.31(m,2H),4.45–4.22(m,2H),4.09(ddd,J＝35.7,12.7,3.0Hz,1H),3.24(s,2H),2.92(s,1H),2.84(t,J＝12.6Hz,2H),2.31–2.11(m,3H),2.04(ddd,J＝24.5,12.2,3.6Hz,2H).
实施例17：2-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(2,2-二甲基哌啶-4-基)-1H-吡 唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000096
叔-丁基4-羟基-2,2-二甲基哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000097
冰浴下向叔-丁基2,2-二甲基-4-羰基哌啶-1-羧酸酯(1.0g,4.405mmol)的甲醇(10mL)溶液中分批加入硼氢化钠(1.0g,4.405mmol)，室温反应30分钟，加水淬灭反应，旋蒸移除甲醇后，加入乙酸乙酯，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂后得到标题化合物叔-丁基4-羟基-2,2-二甲基哌啶-1-羧酸酯(790mg,收率78.3％)，为无色油状.
MS(ESI):m/z＝230[M+H]+.
叔-丁基2,2-二甲基-4-(甲苯磺酰氧代)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000098
向叔-丁基4-羟基-2,2-二甲基哌啶-1-羧酸酯(229mg,1.0mmol)的二氯甲烷(10mL)溶液中加入对甲苯磺酰氯(287mg,1.5mmol)，三乙胺(201mg,2.0mmol)和4-二甲氨基吡啶(24mg,0.2mmol)。40度反应16小时，加入二氯甲烷稀释，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物经正相柱层析(乙酸乙酯/石油醚＝1/4)得到叔-丁基2,2-二甲基-4-(甲苯磺酰氧代)哌啶-1-羧酸酯(315mg,收率82.2％)，为浅黄色固体。
MS(ESI):m/z＝284[M-Boc+H]+.
(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000099
采用类似于实施例7的条件，替换相应的起始原料,得化合物(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1H-吡唑-4-基)-1,5-二氮杂萘(217mg,收率82％)。
MS(ESI):m/z＝378[M+H]+.
叔-丁基4-(4-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)-2,2-二甲基哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000100
向(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1H-吡唑-4-基)-1,5-二氮杂萘(136mg,0.36mmol)和叔-丁基2,2-二甲基-4-(甲苯磺酰氧代)哌啶-1-羧酸酯(138mg,0.36mmol)的N,N-二甲基乙酰胺(5mL)溶液中加入碳酸铯(176mg；0.54mmol)，120度反应3小时，加入乙酸乙酯稀释，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物经正相柱层析(乙酸乙酯/石油醚＝7/3)得到标题化合物叔-丁基4-(4-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)-2,2-二甲基哌啶-1-羧酸酯(60mg,收率29.3％)，为黄色固体。
MS(ESI):m/z＝589[M+H]+.
2-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000101
采用类似于实施例7的条件，替换相应的起始原料,得化合物2-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(33mg,收率66％)。
MS(ESI):m/z＝489[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.51(s,1H),8.41(d,J＝4.8Hz,1H),8.29–8.14(m,1H),8.02(s,1H),7.77(s,1H),7.20(dd,J＝9.6,4.9Hz,2H),6.98(s,1H),6.77(s,1H),5.61(s,1H),4.67(s,1H),4.08(s,1H),3.76(s,2H),3.42(s,2H),2.54(s,1H),2.20(d,J＝9.4Hz,4H),2.08(d,J＝7.4Hz,2H),1.54(s,3H),1.47(d,J＝5.5Hz,3H).
实施例18：2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000102
采用类似于实施例17的条件，替换相应的起始原料,得化合物2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝507[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.55(s,1H),8.43(d,J＝4.8Hz,1H),8.22(s,1H),8.01(d,J＝9.3Hz,1H),7.81–7.73(m,1H),7.14(ddd,J＝17.7,13.4,9.1Hz,2H),7.02–6.86(m,2H),5.62(s,1H),5.47(d,J＝52.8Hz,1H),4.57(d,J＝3.8Hz,1H),4.40–4.14(m,2H),3.17–2.94(m,3H),2.34–2.09(m,2H),2.05(d,J＝12.3Hz,1H),1.89(dt,J＝20.9,10.5Hz,2H),1.33(d,J＝3.1Hz,3H),1.26(d,J＝4.8Hz,3H).
实施例19： 4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂 萘-4-基)-1H-吡唑-1-基)哌啶-2-酮
Figure PCTCN2019118217-appb-000103
叔-丁基4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H- 吡唑-1-基)-2-羰基哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000104
向叔-丁基4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(156mg,0.27mmol)的乙酸乙酯(8mL)和水(2mL)混合溶液中加入高碘酸钠(288mg,1.35mmol)和氧化钌(4mg,0.03mmol)。反应液25度反应3小时。LCMS显示原料反应完了。加入水(50mL),用乙酸乙酯萃取(50mL*2).合并有机相,干燥,浓缩，柱层析(乙酸乙酯)得到叔-丁基4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(40mg,收率25％)，为白色固体。
MS(ESI):m/z＝593[M+H]+.
4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-2-酮
Figure PCTCN2019118217-appb-000105
采用类似于实施例7的条件，替换相应的起始原料,得化合物4-(4-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-2-酮
MS(ESI):m/z＝493[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.76-8.73(m,2H),8.48(d,J＝9.2Hz,1H),8.38(s,1H),8.04(s,1H),7.87(d,J＝4.7Hz,1H),7.28–7.19(m,1H),7.09–7.00(m,1H),6.95–6.86(m,1H),6.28(d,J＝8.8Hz,1H),5.74-5.54(m,1H),4.25-4.15(m,1H),3.07(d,J＝9.8Hz,2H),3.00-2.80(m,2H),2.69–2.56(m,3H),1.95-1.80(m,4H).
实施例20：2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-7-氟-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000106
采用类似于实施例16的条件，替换相应的起始原料,得化合物2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-7-氟-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝493[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.52(s,1H),8.48(d,J＝2.8Hz,1H),8.31(d,J＝9.32Hz,1H),7.14(td,J＝9.4,4.3Hz,1H),7.10–7.00(m,1H),7.00–6.86(m,2H),5.61(t,J＝7.7Hz,1H),5.46(d,J＝52.8Hz,1H),4.64–4.54(m,1H),4.41–4.12(m,2H),3.60–3.50(m,2H),3.23–3.12(m,2H),3.06–2.93(m,1H),2.42–2.10(m,5H).
实施例21：(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-7-氟-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000107
采用类似于实施例21的条件，替换相应的起始原料,得化合物(R)-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-7-氟-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝479[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.99–8.66(m,1H),8.54(d,J＝2.2Hz,1H),8.46–7.77(m,3H),7.37–7.24(m,1H),7.18–7.03(m,1H),6.91–6.80(m,1H),5.70–5.06(m,2H),4.31–3.96(m,2H),3.80–3.53(m,1H),3.04(d,J＝12.4Hz,1H),2.59(t,J＝13.5Hz,1H),2.14–1.64(m,7H).
实施例22：8-(1-(吖丁啶-3-基)-1H-吡唑-4-基)-7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000108
采用类似于实施例21的条件，替换相应的起始原料,得化合物8-(1-(吖丁啶-3-基)-1H-吡唑-4-基)-7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘
MS(ESI):m/z＝485[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.06–8.04(m,3H),7.18–6.93(m,4H),5.55–5.26(m,3H),4.27–3.82(m,6H),2.87–2.63(m,1H),2.29–2.07(m,1H).
实施例23：7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-甲基吖丁啶-3-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000109
采用类似于实施例13的条件，替换相应的起始原料,得化合物7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(1-甲基吖丁啶-3-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝500[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.50(s,1H),8.48(s,1H),8.04–7.95(m,3H),7.11–7.03(m,2H),6.91–6.87(m,1H),6.77–6.75(m,1H),5.53–5.21(m,3H),4.27-4.02(m,6H),2.96–2.85(m,1H),2.75(s,3H),2.26–2.08(m,1H).
实施例24：(R)-7-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000110
采用类似于实施例21的条件，替换相应的起始原料,得化合物(R)-7-氯-2-(2-(2,5-二氟苯基)吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝495[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.73(s,1H),8.28–7.77(m,3H),7.19–7.16(m,1H),6.98-6.96(m,1H),6.74–6.71(m,1H),5.56–5.54(m,1H),4.64–4.56(m,1H),4.12–4.08(m,1H),3.77–3.61(m,3H),2.54–2.03(m,8H).
实施例25：7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(甲磺酰)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000111
采用类似于实施例21的条件，替换相应的起始原料,得化合物7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(甲磺酰)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝509[M+H]+.
实施例26：(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-甲酰胺
Figure PCTCN2019118217-appb-000112
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺
Figure PCTCN2019118217-appb-000113
采用类似于实施例8-2的条件，替换相应的起始原料,得化合物6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺
(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-甲酰胺
Figure PCTCN2019118217-appb-000114
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺(80mg,0.233mmol)的二氯甲烷(5mL)溶液中加入N,N-二异丙基乙胺(150mg,1.165mmol)和对硝基苯基氯甲酸酯(140mg,0.698mmol)，室温搅拌16小时，向反应液中加入(S)-吡咯烷-3-醇(101mg,1.165mmol)，继续室温反应1小时。加入二氯甲烷和水，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物用反相柱纯化得到(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-甲酰胺(64mg,收率60％)，为白色固体
MS(ESI):m/z＝458[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.34(d,J＝5.3Hz,1H),8.16(d,J＝5.3Hz,1H),8.01(d,J＝9.2Hz,1H),7.24–7.09(m,2H),6.98(ddd,J＝9.0,7.4,3.6Hz,1H),6.86(s,1H),5.63(t,J＝7.8Hz,1H),5.43(d,J＝53.2Hz,1H),4.49(s,1H),4.32–4.05(m,2H),3.65–3.35(m,4H),3.08–2.94(m,1H),2.31–1.98(m,3H).
实施例27：(S)-N-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-甲酰胺
Figure PCTCN2019118217-appb-000115
采用类似于实施例26的条件，替换相应的起始原料,得化合物(S)-N-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-甲酰胺
MS(ESI):m/z＝440[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ7.50(d,J＝5.2Hz,1H),7.32(d,J＝5.2Hz,1H),7.19(d,J＝8.7Hz,1H),6.54–6.22(m,2H),6.22–6.12(m,1H),5.99–5.90(m,1H),4.76(s,1H),3.66(s,1H),3.19(t,J＝8.3Hz,1H),3.00–2.50(m,5H),1.77–1.62(m,1H),1.47–1.10(m,5H).
采用类似于实施例的条件，替换相应的起始原料，得到如下表中所示的化合物：
Figure PCTCN2019118217-appb-000116
Figure PCTCN2019118217-appb-000117
Figure PCTCN2019118217-appb-000118
Figure PCTCN2019118217-appb-000119
Figure PCTCN2019118217-appb-000120
Figure PCTCN2019118217-appb-000121
Figure PCTCN2019118217-appb-000122
Figure PCTCN2019118217-appb-000123
Figure PCTCN2019118217-appb-000124
Figure PCTCN2019118217-appb-000125
Figure PCTCN2019118217-appb-000126
Figure PCTCN2019118217-appb-000127
Figure PCTCN2019118217-appb-000128
实施例32：2-(4-(4-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-基)乙烷-1-醇
Figure PCTCN2019118217-appb-000129
将7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘(46mg,0.08mmol),2-溴乙烷-1-醇(21mg,0.01mmol),碳酸钾(35mg,0.25mmol)和N,N-二甲基甲酰胺(4mL)混合，室温搅拌3天，固体过滤，滤液用反向制备得到2-(4-(4-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-基)乙烷-1-醇(14.5mg,收率31％)，为白色固体。
MS(ESI):m/z＝558[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.50(s,1H),8.25(s,1H),8.04–7.80(m,2H),7.10(td,J＝9.3,4.2Hz,1H),7.05–6.98(m,1H),6.93(t,J＝8.3Hz,1H),6.83(s,1H),5.52–5.32(m,2H),4.38–4.19(m,2H),4.09(ddd,J＝35.7,12.7,3.1Hz,1H),3.71(t,J＝6.0,Hz,2H),3.15(d,J＝11.9Hz,2H),2.97–2.85(m,1H),2.61(t,J＝6.0Hz,2H),2.41–2.11(m,6H).
实施例36：6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘-3-甲腈
Figure PCTCN2019118217-appb-000130
2-溴-1-(6-甲氧基-3-硝基吡啶-2-基)乙酮
Figure PCTCN2019118217-appb-000131
将2-(1-乙氧基乙烯基)-6-甲氧基-3-硝基吡啶(9.5g,42.4mmol)溶于四氢呋喃(100mL)和水(40mL)中,加入N-溴代丁二酰亚胺(7.5g,42.4mmol)，反应液于室温下搅拌16小时。LCMS检测反应结束后，反应液倒入冰水(200mL)中，用乙酸乙酯(100mL x2)萃取，合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝6/1)得到黄色固体化合物(3)(9.8g,收率85％).
MS(ESI):m/z＝275[M+H]+.
3-(6-甲氧基-3-硝基吡啶-2-基)-3-羰基丙腈
Figure PCTCN2019118217-appb-000132
将2-溴-1-(6-甲氧基-3-硝基吡啶-2-基)乙酮(4.2g,15.2mmol)溶于甲苯(40mL)和乙腈(40mL)中,加入18-冠醚-6(8.1g,30.4mmol)，氰化钾(1.98g,30.4mmol)，反应液于室温下搅拌20分钟。LCMS检测反应结束后，LCMS检测反应结束后，反应液倒入冰水(80mL)中，用乙酸乙酯(100mL)萃取，有机层丢弃，水层用醋酸调pH＝6-7,用乙酸乙酯(100mL x 2)萃取,合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫 酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝3/1)得到黑色油状物(1.1g,收率33％).
MS(ESI):m/z＝221[M+H]+.
中间体36-3,36-4，36-5采用类似于中间体D的条件。
叔-丁基4-(4-(3-氰基-6-甲氧基-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000133
采用类似于实施例16的条件，得到目标产物。
MS(ESI):m/z＝435[M+H]+.
叔-丁基4-(4-(3-氰基-6-羟基-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000134
将叔-丁基4-(4-(3-氰基-6-甲氧基-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(300mg,0.69mmol)和氢溴酸水溶液混合，加热到85度，反应2小时，旋干，粗产品溶解在二氯甲烷(10mL),加入三乙胺(281mg,2.81mmol)和二碳酸二叔丁酯(202mg,0.93mmol),室温反应1小时，旋干，粗品用柱纯化(石油醚/乙酸乙酯＝1/3)得到无色油状物(170mg).
MS(ESI):m/z＝443[M+H]+.
叔-丁基4-(4-(3-氰基-6-(((三氟甲基)磺酰)氧代)-1,5-二氮杂萘-4-基)-1H-吡唑-1-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000135
采用类似于中间体D的条件，得到目标产物。
MS(ESI):m/z＝497[M-56+H]+.
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,5-二氮杂萘-3-甲腈
Figure PCTCN2019118217-appb-000136
采用类似于实施例16的条件，得到目标产物。
MS(ESI):m/z＝504[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.75(s,1H),8.10–7.95(m,3H),7.23–7.06(m,4H),5.57–5.44(m,2H),4.35–4.09(m,3H),3.10–2.89(m,2H),2.84–2.82(m,1H),2.73–2.62(m,2H),2.29–1.85(m,5H).
实施例38：7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(3-甲氧基-3-甲基环丁基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000137
4-碘-1-(5,8-二氧杂螺[3.4]辛烷-2-基)-1H-吡唑
Figure PCTCN2019118217-appb-000138
将4-碘-1H-吡唑(1.67g,8.63mmol),2-溴-5,8-二氧杂螺[3.4]辛烷(2.0g,10.4mmol),碳酸铯(5.64g,17.3mmol)和N,N-二甲基甲酰胺(20mL)混合，加热到60度过夜，LCMS检测反应结束后，反应液倒入冰水(80mL)中，用乙酸乙酯(100mL),用乙酸乙酯(100mL x 2)萃取,合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝4/1)得到白色固体(1.7g,收率64％).
3-(4-碘-1H-吡唑-1-基)环丁烷-1-酮
Figure PCTCN2019118217-appb-000139
将4-碘-1-(5,8-二氧杂螺[3.4]辛烷-2-基)-1H-吡唑(890mg,2.91mmol),TsOH H 2O(110mg,0.58mmol)和丙酮(10mL),水(1mL)混合加热到50度反应2天。反应液用饱和碳酸氢钠洗涤，用乙酸乙酯(100mL x 2)萃取,合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝2/1)得到无色油状物(691mg,收率90％).
3-(4-碘-1H-吡唑-1-基)-1-甲基环丁烷-1-醇
Figure PCTCN2019118217-appb-000140
将3-(4-碘-1H-吡唑-1-基)环丁烷-1-酮(691mg,2.64mmol)的四氢呋喃(10mL)溶液冷却到0度，滴加甲基格氏试剂(3.1mL,1M的四氢呋喃溶液),室温搅拌1小时，反应液用饱和氯化铵淬灭，用乙酸乙酯(100mL x 2)萃取,合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝2/1)得到白色固体(291mg,收率40％).
4-碘-1-(3-甲氧基-3-甲基环丁基)-1H-吡唑
Figure PCTCN2019118217-appb-000141
将3-(4-碘-1H-吡唑-1-基)-1-甲基环丁烷-1-醇(120mg,0.43mmol)溶解在N,N-二甲基甲酰胺(5mL)中，0度下加入氢化钠(19mg,60％含量)，搅拌30分钟，加入碘甲烷(123mg,0.86mmol),室温反应1小时。反应液用饱和氯化铵淬灭，用乙酸乙酯(100mL x 2)萃取,合并有机层，依次用水(80mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱纯化(石油醚/乙酸乙酯＝4/1)得到白色固体(100mg,收率79％).
7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(3-甲氧基-3-甲基环丁基)-1H-吡唑-4-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000142
采用类似于实施例15的条件，替换相应的起始原料,得化合物7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(1-(3-甲氧基-3-甲基环丁基)-1H-吡唑-4-基)-1,5-二氮杂萘
MS(ESI):m/z＝528[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.50(s,1H),8.22(s,1H),8.05–7.87(m,2H),7.14–6.96(m,2H),6.90(s,1H),6.79(s,1H),5.56–5.32(m,2H),4.72–4.60(m,1H),4.33–4.19(m,1H),4.10(ddd,J＝36.6,12.7,3.2Hz,1H),3.27(s,3H),2.98–2.83(m,1H),2.80–2.68(m,2H),2.63–2.54(m,2H),2.30–2.11(m,1H),1.47(s,3H).
实施例46：6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶并[3,2-d]嘧啶
Figure PCTCN2019118217-appb-000143
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-3-硝基甲基吡啶酰胺
Figure PCTCN2019118217-appb-000144
向6-氯-3-硝基甲基吡啶酰胺(1.1g,5.47mmol),(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(1.1g,5.47mmol)的N,N-二甲基甲酰胺(18mL)溶液中加入N,N-二异丙基乙胺(2.1g,16.41mmol)。反应液加热到110度并搅拌过夜。LCMS显示原料反应完了。加入乙酸乙酯(50mL),用水(100mL*3)洗.有机相,干燥,浓缩，柱层析(石油醚/乙酸乙酯＝1/2)得到6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-3-硝基甲基吡啶酰胺(2.0g,收率99.8％)， 为黄色固体。
MS(ESI):m/z＝367[M+H]+.
3-氨基-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)甲基吡啶酰胺
Figure PCTCN2019118217-appb-000145
向实施例726A 6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-3-硝基甲基吡啶酰胺(2.0g,5.46mmol)的乙醇(40mL)和水(10mL)的混合溶液中加入铁粉(1.5g,27.3mmol)和氯化铵(1.46g,27.3mmol)。反应液加热到60度，搅拌2小时。LCMS显示原料反应完了。反应液浓缩,加入二氯甲烷(100mL),干燥,过滤,浓缩，得到3-氨基-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)甲基吡啶酰胺(1.83g,收率99.7％)，为棕色固体。
MS(ESI):m/z＝337[M+H]+.
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡啶并[3,2-d]嘧啶-4-酚
Figure PCTCN2019118217-appb-000146
向3-氨基-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)甲基吡啶酰胺(1.83g,5.44mmol)的原甲酸三乙酯(110mL)的溶液中加入冰醋酸(0.7mL)。反应液加热到150度，搅拌3小时。LCMS显示原料反应完了。反应液浓缩,柱层析(石油醚/乙酸乙酯＝1/2)得到6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡啶并[3,2-d]嘧啶-4-酚(1.07g,收率56.8％)，为棕色固体。
MS(ESI):m/z＝347[M+H]+.
4-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡啶并[3,2-d]嘧啶
Figure PCTCN2019118217-appb-000147
把6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡啶并[3,2-d]嘧啶-4-酚(1.07g,3.09mmol)的三氯氧磷(15mL)的溶液加热到110度，搅拌2小时。LCMS显示原料反应完了。反应液浓缩,冰浴下加入二氯甲烷(10mL)稀释后滴加到冰水(100mL)中。加入二氯甲烷(100mL),再加入饱和碳酸氢钠水溶液(80mL*1)洗，水(80mL*1)洗。有机相,干燥,浓缩得到4-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡啶并[3,2-d]嘧啶(820mg,收率72.8％)，为棕色固体。
MS(ESI):m/z＝365[M+H]+.
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶并[3,2-d]嘧啶
Figure PCTCN2019118217-appb-000148
采用类似于实施例7的条件，替换相应的起始原料,得化合物6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶并[3,2-d]嘧啶
MS(ESI):m/z＝480[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ8.84(s,1H),8.59(s,1H),8.31(s,1H),8.05-7.98(m,1H),7.40-7.23(m,2H),7.15-7.03(m,2H),5.68-5.45(m,2H),4.32-4.15(m,3H),3.12-3.01(m,2H),3.00-2.85(m,2H),2.68-2.55(m,2H),2.32-2.14(m,1H),2.00-1.78(m,4H).
实施例51：3-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-5-(哌啶-4-基)-1,2,4-噁二唑
Figure PCTCN2019118217-appb-000149
3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-甲腈
Figure PCTCN2019118217-appb-000150
向8-溴-7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘(503mg,1.14mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入氰化锌(133mg,1.14mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(93mg,0.114mmol)，氩气保护下120度反应16小时，冷却至室温，加入30mL乙酸乙酯，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物用正相柱纯化(乙酸乙酯:石油醚＝1:1)得到3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-甲腈(193mg,收率43.6％)， 为黄色固体。
MS(ESI):m/z＝389.0[M+H]+.
(Z)-3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-羟基-1,5-二氮杂萘-4-碳杂氧杂脒
Figure PCTCN2019118217-appb-000151
向3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-甲腈(193mg,0.497mmol)的乙醇(5mL)溶液中加入盐酸羟胺(52mg,0.746mmol)和N,N-二异丙基乙胺(128mg,0.994mmol)，80度反应16小时，旋蒸移除溶剂，残留物用正相柱纯化(甲醇:二氯甲烷＝1:20)得到(Z)-3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-羟基-1,5-二氮杂萘-4-碳杂氧杂脒(195mg,收率93.1％)，为黄色泡沫状固体。
MS(ESI):m/z＝422.1[M+H]+.
叔-丁基4-(((Z)-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)(肟基)甲基)氨基甲酰)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000152
1-boc-哌啶-4-羧酸(106mg,0.463mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入O-(7-偶氮苯并三氮唑-1-氧)-N,N”,N”-四甲基脲六氟磷酸酯(194mg,0.509mmol,1.1equiv)和N,N-二异丙基乙胺(179mg,1.389mmol)，室温反应5分钟后加入实施例758B(195mg,0.463mmol,)，继续室温反应5小时，加入乙酸乙酯，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，得到的粗产品直接用于下一步。
MS(ESI):m/z＝633.2[M+H]+.
叔-丁基4-(3-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1,2,4-噁二唑-5-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000153
叔-丁基4-(((Z)-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)(肟基)甲基)氨基甲酰)哌啶-1-羧酸酯得到的粗产品溶于二氧六环(5mL)，120度反应5小时，旋蒸移除溶剂，残留物用正相柱纯化(乙酸乙酯:石油醚＝1:3)得到标题化合物(190mg,收率66.7％)，为黄色固体。
MS(ESI):m/z＝615.2[M+H]+.
3-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-5-(哌啶-4-基)-1,2,4-噁二唑
Figure PCTCN2019118217-appb-000154
采用实施例7的方法，替换替换相应的起始原料，得到3-(3-氯-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-5-(哌啶-4-基)-1,2,4-噁二唑(94mg,收率59.1％)，为黄色固体。
MS(ESI):m/z＝515.4[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.61(s,1H),8.11(d,J＝8.7Hz,1H),7.21(s,1H),7.04(s,1H),6.90(s,1H),6.76(s,1H),5.54–5.24(m,2H),4.23–3.91(m,2H),3.53–3.42(m,1H),3.34(d,J＝3.5Hz,2H),3.01(t,J＝12.1Hz,2H),2.77(s,1H),2.34(t,J＝16.2Hz,2H),2.23–1.92(m,3H).
实施例63：7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(6-(哌啶-4-基)吡啶-3-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000155
叔-丁基5-溴-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯
Figure PCTCN2019118217-appb-000156
向2,5-二溴吡啶(1.63g,10.0mmol)和叔-丁基4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3,6-二氢吡啶-1(2H)-羧酸酯(3.40g,11.0mmol)的二氧六环(30mL)溶液中加入碳酸钠溶液(7mL,14.0mmol)和四(三苯基膦)钯(0.817g,1.0mmol)，氩气保护下，100度反应16小时，冷却至室温，加入30mL乙酸乙酯稀释，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物用正相柱纯化(乙酸乙酯:石油醚＝1:5)得到叔-丁基5-溴-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯(2.7g,收率79.1％)，为黄色油状。
MS(ESI):m/z＝283[M-56+H]+.
叔-丁基5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯
Figure PCTCN2019118217-appb-000157
向叔-丁基5-溴-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯(1.69g,5.0mmol)的二氧六环(10mL)溶液中，加入联硼酸频那醇酯(1.52g,6.0mmol)，乙酸钾(1.47g,15.0mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.41g,0.5mmol)，氩气保护下100度反应16小时，加入乙酸乙酯稀释，有机相用水洗和盐洗，硫酸钠干燥，过滤，旋蒸除去溶剂，残留物用正相柱纯化(甲醇:二氯甲烷＝1:20)得到叔-丁基5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯(1.49g,收率77.4％)，为黑色固体。
MS(ESI):m/z＝305[boric acid+H]+.
叔-丁基4-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000158
向叔-丁基5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸酯(309mg,0.8mmol)的甲醇(10mL)溶液中加入钯碳(100mg)，氢气保护下室温反应2小时，过滤，滤液减压浓缩得到叔-丁基4-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)哌啶-1-羧酸酯(279mg，收率90％)，为棕色固体。
MS(ESI):m/z＝307[Boric acid+H]+.
7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(6-(哌啶-4-基)吡啶-3-基)-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000159
采用实施例16的合成方法，得到7-氯-2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-(6-(哌啶-4-基)吡啶-3-基)-1,5-二氮杂萘(206mg,92.4％)，为黄色固体。
MS(ESI):m/z＝524[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.59(s,1H),8.38(s,1H),8.11(d,J＝9.0Hz,1H),7.59(s,1H),7.38(s,1H),7.19(s,1H),6.90(d,J＝38.5Hz,2H),6.55(s,1H),5.49–5.17(m,2H),4.20–3.92(m,2H),3.59(d,J＝12.6Hz,2H),3.26(s,1H),3.25–3.16(m,2H),2.74(s,1H),2.38–2.22(m,2H),2.22–2.08(m,2H),2.01(s,1H).
实施例69：(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-磺酰胺
Figure PCTCN2019118217-appb-000160
(S)-3-((叔-丁基二甲基甲硅烷基)氧代)吡咯烷
Figure PCTCN2019118217-appb-000161
冰浴下向(S)-吡咯烷-3-醇(1.044g,12.0mmol)和咪唑(1.632g,24.0mmol)的二氯甲烷(20mL)溶液中滴加叔丁基二甲基氯硅烷(2.16g,14.4mmol)，室温反应15小时后，加入饱和碳酸氢钠溶液，用二氯甲烷萃取，有机相用硫酸钠干燥，过滤，浓缩得2.2g产物，为黄色油状，直接用于下一步。
MS(ESI):m/z＝202[M+H]+.
(S)-3-((叔-丁基二甲基甲硅烷基)氧代)吡咯烷-1-磺酰氯
Figure PCTCN2019118217-appb-000162
冰浴下向(S)-3-((叔-丁基二甲基甲硅烷基)氧代)吡咯烷(2.01g,10mmol)和三乙胺(3.03g,30.0mmol)的二氯甲烷(20mL)溶液中分批加入磺酰氯(2.68g,20mmol)，冰浴下反应1小时，然后室温反应5小时。向反应液中加入水淬灭反应，用二氯甲烷萃取，水洗，盐洗，硫酸钠干燥，过滤，浓缩，残留物用正相柱纯化(乙酸乙酯:石油醚＝1:6)得到标题化合物(350mg,收率11.7％)，为黄色油状。
(S)-3-((叔-丁基二甲基甲硅烷基)氧代)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-1-磺酰胺
Figure PCTCN2019118217-appb-000163
向(S)-3-((叔-丁基二甲基甲硅烷基)氧代)吡咯烷-1-磺酰氯(299mg,1mmol)和6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺(69mg,0.2mmol)的二氯甲烷(5mL)溶液中加入三乙胺(101mg,5mmol)和4-二甲氨基吡啶(24mg,0.2mmol)，40度反应16小时。加入10mL二氯甲烷稀释，有机相用水洗，盐洗，硫酸钠干燥，过滤，浓缩，残留物用正相柱纯化(乙酸乙酯:石油醚＝1:3)得到(S)-3-((叔-丁基二甲基甲硅烷基)氧代)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)吡咯烷-1-磺酰胺(40mg,收率32.5％)，为黄色油状。
MS(ESI):m/z＝608[M+H]+.
(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯 烷-1-磺酰胺
Figure PCTCN2019118217-appb-000164
向实施例816C(40mg,0.065mmol)的四氢呋喃(1mL)溶液中加入氢氟酸吡啶溶液(0.3mL)，室温反应1小时，旋蒸除掉溶剂，残留物经高效液相制备色谱纯化得到标题化合物816(S)-N-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-羟基吡咯烷-1-磺酰胺(25mg,收率78.4％)，为白色固体。
MS(ESI):m/z＝494[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.33(d,J＝5.1Hz,1H),8.01(d,J＝9.2Hz,1H),7.45(d,J＝5.2Hz,1H),7.28–7.12(m,2H),7.04(ddd,J＝8.9,5.7,3.2Hz,1H),7.01–6.91(m,1H),5.60–5.38(m,2H),4.34–4.09(m,3H),3.45–3.32(m,2H),3.26–3.20(m,1H),2.95–2.79(m,1H),2.35–2.14(m,1H),1.97–1.84(m,1H),1.80(s,1H).
实施例95:1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(哌啶-4-基)-1,3-二氢-2H-咪唑-2-酮
Figure PCTCN2019118217-appb-000165
叔-丁基4-((22-二甲氧基乙基)氨基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000166
向叔-丁基4-羰基哌啶-1-羧酸酯(1.99g,10mmol)的1,2-二氯乙烷(20ml)溶液中加入2,2-二甲氧基乙烷-1-胺(1.47g,14mmol)，回流反应2小时，冷却至室温后加入三乙酰氧基硼氢化钠(3.18g,15mmol)，室温继续反应16小时，过滤，滤液用稀盐酸溶液萃取，水相用碳酸氢钠水溶液调节至碱性，用二氯甲烷萃取三次，有机相用硫酸钠干燥、浓缩后，残留物用硅胶柱纯化(甲醇:二氯甲烷＝1:10)得到叔-丁基4-((2,2-二甲氧基乙基)氨基)哌啶-1-羧酸酯(1.2g,产率41.6％)，为无色油状物。
MS(ESI):m/z＝289[M+H]+.
叔-丁基4-(3-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1-(2,2-二甲氧基乙基)脲基)哌啶-1-羧酸酯
Figure PCTCN2019118217-appb-000167
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺(80mg,0.233mmol)的二氯甲烷(5mL)溶液中加入N,N-二异丙基乙胺(150mg,1.165mmol)和对硝基苯基氯甲酸酯(104mg,0.513mmol)，室温反应16小时，加入叔-丁基4-((2,2-二甲氧基乙基)氨基)哌啶-1-羧酸酯(168mg,0.583mmol)，室温继续反应1小时。加入水和二氯甲烷，有机相用水洗、盐洗，硫酸钠干燥后，柱层析纯化(乙酸乙酯:石油醚＝2:1)得到叔-丁基4-(3-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1-(2,2-二甲氧基乙基)脲基)哌啶-1-羧酸酯(104mg,产率64.4％)，为无色固体。
MS(ESI):m/z＝659[M+H]+.
1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(哌啶-4-基)-1,3-二氢-2H-咪唑-2-酮
Figure PCTCN2019118217-appb-000168
叔-丁基4-(3-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-1-(2,2-二甲氧基乙基)脲基)哌啶-1-羧酸酯(104mg,0.158mmol)加入到甲磺酸(1mL)和水(1mL)中，100度反应2小时，反应液冷却至室温后用碳酸钠水溶液调节至碱性，加入乙酸乙酯，有机相用水洗、盐洗，硫酸钠干燥，旋蒸浓缩得到的残留物用反相柱纯化得到1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(哌啶-4-基)-1,3-二氢-2H-咪唑-2-酮(35mg,产率44.3％)，为白色固体。
MS(ESI):m/z＝495[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.55(d,J＝5.0Hz,1H),8.11(d,J＝9.0Hz,1H),7.81(d,J＝4.9Hz,1H),7.22(s,1H),7.12(td,J＝9.4,4.2Hz,1H),6.91(d,J＝19.4Hz,2H),6.82–6.63(m,1H),6.57(s,1H),5.58–5.31(m,2H),4.12(dd,J＝37.3,12.5Hz,3H),3.23(d,J＝1.5Hz,1H),2.87(t,J＝11.2Hz,3H),2.28–1.81(m,6H).
实施例98:(R)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇
实施例99:(S)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇
Figure PCTCN2019118217-appb-000169
2-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-8-异硫氰基-1,5-二氮杂萘
Figure PCTCN2019118217-appb-000170
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-胺(80mg,0.233mmol)的二氯甲烷(5mL)溶液中加入1,1'-硫羰基双(吡啶-2(1H)-酮)(59mg,0.256mmol)，40度反应3小时，反应所得粗产品直接用于下一步。
MS(ESI):m/z＝387[M+H] +.
1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(2,3-二羟基丙基)硫代脲
Figure PCTCN2019118217-appb-000171
向实施例882A的反应液中加入3-氨基丙烷-1,2-二醇(106mg,1.165mmol)，室温反应1小时，旋蒸除去溶剂，残留物用反相柱纯化得到1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(2,3-二羟基丙基)硫代脲(80mg,产率71.7％)，为黄色固体。
MS(ESI):m/z＝478.1[M+H] +.
(R)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇
(S)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇
Figure PCTCN2019118217-appb-000172
向1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)-3-(2,3-二羟基丙基)硫代脲(80mg,0.167mmol)的乙腈(3mL)溶液中加入1-(3-二甲氨基丙基)-3-乙基甲二酰亚胺盐酸盐(80mg,0.418mmol)和三乙胺(59mg,0.585mmol)，40度反应16小时，冷却至室温后加入乙酸乙酯和水，有机相用水洗和盐洗，硫酸钠干燥，浓缩所得 残留物经制备型高效液相色谱纯化得到(R)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇(14mg,产率18.5％)，为白色固体。
MS(ESI):m/z＝444[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.32(d,J＝5.3Hz,1H),8.02–7.92(m,2H),7.19–7.05(m,3H),6.99–6.89(m,1H),5.57–5.38(m,2H),4.77(t,J＝12.4Hz,1H),4.29–4.08(m,2H),3.98(dd,J＝12.7,9.4Hz,1H),3.87–3.74(m,2H),3.68(dd,J＝12.4,5.0Hz,1H),2.94–2.80(m,1H),2.38–2.18(m,1H).
同时得到另一个异构体(S)-2-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1,5-二氮杂萘-4-基)氨基)-5,6-二氢-4H-1,3-噁嗪-5-醇(14mg,产率18.5％)，为白色固体。
MS(ESI):m/z＝444[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.32(d,J＝5.3Hz,1H),7.98(t,J＝7.7Hz,2H),7.23(td,J＝9.5,4.3Hz,1H),7.15–7.01(m,2H),6.98–6.90(m,1H),5.58–5.38(m,2H),4.82–4.74(m,1H),4.27–4.09(m,2H),4.00(dd,J＝12.8,9.5Hz,1H),3.83–3.65(m,3H),2.94–2.80(m,1H),2.37–2.16(m,1H).
生物测试例1 TRKA，TRKB，TRKC激酶体外活性测试
实验材料
重组人源TRKA，TRKB，TRKC蛋白购自Carna Biosciences。HTRF kinEASE TK kit购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行3倍浓度梯度稀释，终浓度为1μM到0.05nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA酶反应：
0.2ng/μl TRKA蛋白激酶，1μM TK Substrate-biotin多肽底物，14.68μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
TRKB酶反应：
0.037ng/μl TRKB蛋白激酶，1μM TK Substrate-biotin多肽底物，4.77μM ATP，1×enzymatic buffer，5mM MgCl 2，1mMMnCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
TRKC酶反应：
0.037ng/μl TRKC蛋白激酶，1μM TK Substrate-biotin多肽底物，25.64μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值通过下列公式将读数转化成抑制率(％)＝(1-Ratio test/Ratio max)×100％。Ratio max为不含检测化合物的阳性对照，Ratio test为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表1。
生物测试例2 突变的TRKA(G595R),TRKA(G667C)and TRKC(G623R)激酶体外活性测试
实验材料
重组人源TRKA(G595R)，TRKA(G667C)，TRKC(G623R)蛋白购自SignalChem。HTRF kinEASE TK kit购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行4倍浓度梯度稀释，终浓度为1μM到0.004nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA(G595R)酶反应：
0.12ng/μlTRKA(G595R)蛋白激酶，1μM TK Substrate-biotin多肽底物，4.5μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKA(G667C)酶反应：
0.026ng/μlTRKA(G667C)蛋白激酶，1μM TK Substrate-biotin多肽底物，5.5μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKC(G623R)酶反应：
1.0ng/μlTRKC(G623R)蛋白激酶，1μM TK Substrate-biotin多肽底物，62.9μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值减去不含酶的阴性对照孔数值后通过下列公式将读数转化成抑制率(％)＝(1-Ratio test/Ratio max)×100％。Ratio max为不含检测化合物的阳性对照，Ratio test为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表1。
表1
Figure PCTCN2019118217-appb-000173
Figure PCTCN2019118217-appb-000174
Figure PCTCN2019118217-appb-000175
生物测试例3:KM12-LUC细胞增殖实验
含有TPM3-NTRK1融合基因的的人结肠癌细胞株KM12-LUC(LUC,稳定表达Luciferace)用于待测化合物细胞学水平药效评估的模型。KM12-LUC细胞中的TRK融合基因使其不依赖于胞外生长因子的刺激，可以持续自发激活并激活其下游信号通路MAPK-ERK、PI3K-AKT等与细胞增殖密切相关的信号通路。因此，在KM12-LUC细胞中抑制TRK活性可显著抑制细胞的增殖。方法如下：第一天，在384孔板中接种细胞，2000细胞/孔；第二天加不同浓度的待测化合物；第五天，加CellTiter-Glo(Promega)检测细胞活性，计算细胞72小时增殖抑制率。用prism5来进行统计分析并得出待测化合物的抑制率，具体见图1。
结果显示，本发明化合物能够有效的抑制KM12-LUC细胞的增殖。
生物测试例4:用elisa方法检测细胞学水平TRK激酶活性
通过质粒转染构建稳定表达ΔTRKA或ΔTRKA(G595R)的NIH-3T3细胞株。
第一天接种细胞于96孔细胞培养板，10000细胞/孔于培养基中(DMEM+10％BS)。第二天加不同浓度的待测化合物处理细胞2个小时后将细胞培养板置于冰上；去掉上清，用预冷的PBS润洗一次。用含有蛋白酶和磷酸酶抑制剂的NP40裂解液裂解细胞，并将其转移至抗体预包被的板条中，封板并4度过夜孵育。剩余步骤参照elisa试剂盒中提供的方法进行(例如R&DDYC2578-2中所描述)，具体见表2。
结果显示，本发明化合物能够在细胞学水平有效的抑制ΔTRKA/NIH-3T3细胞或ΔTRKA(G595R)/NIH-3T3细胞TRKA的磷酸化水平。
表2
Figure PCTCN2019118217-appb-000176
生物测试例5:本发明中小分子抑制剂治疗肿瘤体内药效实验
建立皮下移植肿瘤的小鼠模型，以检查这些化合物对肿瘤生长的体内抑制效果。方法如下：
将ΔTRKA(G595R)/3T3细胞(5×10 6)皮下注射到小鼠的背侧区域。通过用卡尺测量直径来监测肿瘤体积，并通过下式计算：长度×(宽度 2)/2。当肿瘤大小在150和200mm 2之间时，随机选择小鼠以接受稀释剂，30mg/kg/剂量待测化合物。通过口服给药每天一次施用待测化合物，持续14天。最后一次给药后，称量小鼠体重，并在给药后2小时，收集组织和血液。计算肿瘤抑制率，检测肿瘤及血液样本中待测化合物浓度，检测肿瘤样本中TRKA磷酸化水平及其下游信号分子如ERK或AKT磷酸化水平。结果如图2中所示，结果显示，本发明化合物给药的情况下，小鼠的肿瘤体积保持在较低的水平。
结果显示，本发明化合物能够在荷瘤小鼠中有效抑制肿瘤生长。
生物测试例6：本发明中小分子抑制剂小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予ICR小鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，溶于5％DMSO+10％Solutol+85％注射用水中，配成所需浓度的溶液，用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。口服采血时间：给药后0.25h，0.5h，1h，2h，4h，6h，8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数，如AUC(0-t)，AUC(0-∞)，T1/2，Cmax，Tmax和MRT等。
小鼠药代动力学(5mg/kg，P.O.)
参数 单位 实施例16 实施例20
C max ng/mL 714 448
AUC 0-24hr hr*ng/mL 3229 2705
T 1/2 hr 2.34 2.82
F ％ 107 144
结果显示，本发明化合物具有优异的药代动力学性质。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 一类如下式I所示的化合物：
    Figure PCTCN2019118217-appb-100001
    其中，
    X为H、卤素、D、CN、-CONH 2；
    X 1为CR或N；
    R选自下组：H、D、氟、氯、-OH、-NH 2；
    L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
    L 2选自下组：取代或未取代的-(X 4) z-，其中各个所述的X 4各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-、-CONH-、-NHCO-、-NHCS-、-NHCONH-、-NHS(＝O)-、-NHS(＝O) 2-；
    y选自下组：1或2；z选自下组：0、1或2；
    R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
    R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
    Figure PCTCN2019118217-appb-100002
    或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳 基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
    Figure PCTCN2019118217-appb-100003
    C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)；
    Figure PCTCN2019118217-appb-100004
    为基团的连接位点；
    附加条件是式I化合物为化学上稳定的结构。
  2. 如权利要求1所述的化合物，其特征在于，所述的L 1选自下组：
    Figure PCTCN2019118217-appb-100005
    n选自下组：0、1、2或3；
    R 2、R 2a和R 2b各自独立地选自下组：H、OH、卤素、取代或未取代的C 1-C 8烷基；
    X选自下组：NH、O、-CONH-、-NHCO-、S、-S(＝O) 2-、-NHS(＝O)-、-NHS(＝O) 2-；
    R A为
    Figure PCTCN2019118217-appb-100006
    其中，所述的
    Figure PCTCN2019118217-appb-100007
    指R A与L 1的连接位点；
    L 2为
    Figure PCTCN2019118217-appb-100008
    R B为
    Figure PCTCN2019118217-appb-100009
    其中，所述的
    Figure PCTCN2019118217-appb-100010
    为R B与L 2的连接位点；
    R 3选自下组：H、卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基；
    R 4、R 5各自独立地选自下组：H、OH、卤素、C 1-C 6烷基OH、C 1-C 6烷氧基、C 1-C 6烷基胺基、C 1-C 6烷基酰胺基、-(C 1-C 6烷基)-NH-(C 1-C 6烷基)、-C 1-C 6烷基酰胺基-(C 1-C 6烷基)；
    R 6a、R 6b、R 7a、R 7b各自独立地选自下组：H、OH、卤素；或R 6a、R 6b、R 7a、R 7b与其相连的碳原子共同构成具有1-3个选自N、S和O的杂原子的5-12元杂环基。
  3. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式II所示的结构：
    Figure PCTCN2019118217-appb-100011
    其中，所述的X 2选自下组：C＝O、-CH 2-、O、NH。
  4. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式IIIa所示的结构：
    Figure PCTCN2019118217-appb-100012
  5. 如权利要求1所述的化合物，其特征在于，所述的化合物具有选自下组的结构：
    Figure PCTCN2019118217-appb-100013
    Figure PCTCN2019118217-appb-100014
    Figure PCTCN2019118217-appb-100015
    Figure PCTCN2019118217-appb-100016
    Figure PCTCN2019118217-appb-100017
    Figure PCTCN2019118217-appb-100018
    Figure PCTCN2019118217-appb-100019
    Figure PCTCN2019118217-appb-100020
  6. 一类如下式IV所示的化合物：
    Figure PCTCN2019118217-appb-100021
    其中，
    X为H、D或卤素；
    X 1为CR或N；
    R选自下组：H、D、氟、氯、-OH、-NH 2；
    L 1选自下组：取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、或取代或未取代的-(X 3) y-，其中各个所述的X 3各自独立地选自下组：取代或未取代的C 1-C 8亚烷基、-O-、-C(＝O)-、-CONH-、-NHCO-、-S-、-S(＝O)-、-S(＝O) 2-、-NH-；
    L 2为取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元亚杂环基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
    y选自下组：1或2；z选自下组：0、1或2；
    R A选自下组：H、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
    R B选自下组：H、NH 2、OH、-COOH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺 基)、
    Figure PCTCN2019118217-appb-100022
    或取代或未取代的选自下组的基团：未取代或被一个或多个羟基取代的C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括单环、并环、螺环或桥环)、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、未取代或被一个或多个羟基取代的C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、C1-C6酰胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
    Figure PCTCN2019118217-appb-100023
    为基团的连接位点；
    附加条件是式I化合物为化学上稳定的结构。
  7. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式V所示的结构：
    Figure PCTCN2019118217-appb-100024
    其中，所述的X 2选自下组：C＝O、-CH 2-、O、NH。
  8. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式VI所示的结构：
    Figure PCTCN2019118217-appb-100025
  9. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下表：
    Figure PCTCN2019118217-appb-100026
    Figure PCTCN2019118217-appb-100027
    Figure PCTCN2019118217-appb-100028
  10. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  11. 如权利要求10所述的用途，其特征在于，所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起 的瘙痒，炎症相关疾病，骨相关的疾病。
  12. 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如权利要求9所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的疾病的药物组合物。
  13. 如权利要求12所述的用途，其特征在于，所述的疾病选自下组：所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒。
  14. 一类TRK抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
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CA3120430A1 (en) 2020-05-22
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AU2019379213B2 (en) 2023-02-02
AU2019379213A1 (en) 2021-07-01
EP3882247A1 (en) 2021-09-22
CA3120430C (en) 2024-04-09
US20220017512A1 (en) 2022-01-20
CN111171020A (zh) 2020-05-19
EP3882247A4 (en) 2022-08-03

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