WO2020098720A1 - 一类五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

一类五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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WO2020098720A1
WO2020098720A1 PCT/CN2019/118198 CN2019118198W WO2020098720A1 WO 2020098720 A1 WO2020098720 A1 WO 2020098720A1 CN 2019118198 W CN2019118198 W CN 2019118198W WO 2020098720 A1 WO2020098720 A1 WO 2020098720A1
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group
substituted
difluorophenyl
unsubstituted
pyrazolo
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PCT/CN2019/118198
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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 CN201980074711.4A priority Critical patent/CN113166142B/zh
Priority to CA3134396A priority patent/CA3134396A1/en
Priority to AU2019379700A priority patent/AU2019379700A1/en
Priority to US17/439,012 priority patent/US20220144827A1/en
Priority to EP19885079.4A priority patent/EP3919490A4/en
Publication of WO2020098720A1 publication Critical patent/WO2020098720A1/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
    • 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
    • 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 1 , X 2 and X 3 are each independently CR or N;
  • Y is NR 1 , wherein R 1 is selected from the group consisting of H, unsubstituted or C1-C6 alkyl substituted with C1-C4 alkoxy;
  • R is selected from the group consisting of H, D, -OH, -NH 2 , halogen, CN;
  • 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 C1-C6 amine, substituted or unsubstituted having 1-3 selected from N, S and O 5-10 membered heteroaryl groups of hetero atoms, or substituted or unsubstituted 5-12 membered heterocyclic groups having 1-3 heteroatoms selected from N, S and O Or bridge ring);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • the compound of formula I has the structure of the following formula:
  • said L 1 is a substituted or unsubstituted 5-10 membered heterocyclylene having 1-3 heteroatoms selected from N, S and O; preferably, said L 1 is a substituted or unsubstituted 5-7 membered heterocyclylene having 1 or 2 N atoms.
  • R A and R B are connected to form a group selected from the group consisting of substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C1-C8 alkylene-O-, substituted Or unsubstituted C1-C8 alkylene- (5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S, and O), substituted or unsubstituted C1-C8 alkylene-O -(5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O), substituted or unsubstituted C1-C8 alkylene- (having 1-3 selected from N, S 5-10 membered heterocyclic group with hetero atom of O), substituted or unsubstituted C1-C8 alkylene-O- (5-10 membered with 1-3 heteroatoms selected from N, S and O Heterocyclyl).
  • 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:
  • Rb and Rc are independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl; or said Rb Together with Rc and the adjacent N atom, a substituted or unsubstituted 5-12 membered heterocyclic group (including monocyclic, paracyclic, spiro or bridged rings) is formed.
  • the compound has the structure represented by the following formula III:
  • the compound has a structure represented by the following formula:
  • the compound has a structure represented by the following formula:
  • the compound has a structure represented by the following formula:
  • the compound has a structure selected from the group consisting of:
  • 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.
  • 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 heterocyclic group having 1-3 heteroatoms selected from the group consisting of N, S, and O" means having 3-12 ring 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.
  • 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 , X 2 and X 3 are each independently CR or N;
  • Y is NR 1 , wherein R 1 is selected from the group consisting of H, unsubstituted or C1-C6 alkyl substituted with C1-C4 alkoxy;
  • R is selected from the group consisting of H, D, -OH, -NH 2 , halogen, CN;
  • L 2 is selected from the group consisting of substituted or unsubstituted-(X 4 ) z- , wherein each of said X 4 is independently selected from the group consisting of:
  • 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 C1-C6 amine, substituted or unsubstituted having 1-3 selected from N, S and O 5-10 membered heteroaryl groups of heteroatoms, or substituted or unsubstituted 5-12 membered heterocyclic groups having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro ring Or bridge ring);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • X 1 , X 2 , X 3 , L 1 , L 2 , R A and R B are each independently a corresponding group of the compounds in the examples.
  • the compound is selected from the following group:
  • the compound of formula I of the present invention is the compound prepared in the examples.
  • 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 oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), 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.
  • Tetrahydrofuran (150 mL) and zinc powder (6.4 g, 97.2 mmol) were added to a single-necked bottle (500 mL), and the temperature was raised to 80 ° C until the reaction was initiated.
  • Tert-butyl 3-carbonylpyrrolidine-1-carboxylate (15.0 g, 81.0 mmol) and ethyl bromoacetate (13.7 g, 82.0 mmol) were slowly added to the reaction. After incubating for 1 hour, TLC showed that the reaction was completed. The reaction solution was poured into an aqueous solution of ammonium chloride, and extracted with ethyl acetate.
  • Example 1 N- (3-((R) -2- (2,5-difluorophenyl) pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridine-5- Yl) -3-hydroxy-3- (2- (methylamino) -2-oxoethyl) pyrrolidine-1-carboxamide
  • reaction solution was stirred at room temperature for 16 hours. LCMS showed that most of the raw materials remained, and the reaction liquid was reacted at 50 degrees for 72 hours.
  • the reaction solution was purified by preparative high-performance liquid chromatography to obtain the title compound (R) -N- (3- (2- (2,5-difluorophenyl) pyrrolidin-1-yl) -1-((2- ( Trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b] pyridin-5-yl) -6-flunikamide (25 mg, 34%) as a yellow solid.
  • reaction solution was concentrated, and the residue was purified by preparative high-performance liquid chromatography to obtain the target N- (3-((R) -2- (2,5-difluorophenyl) pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl) -6-((S) -3-hydroxypyrrolidin-1-yl) nikamide (8.4 mg, 66%) as a yellow solid.
  • reaction solution was stirred at room temperature for 16 hours. LCMS showed that most of the starting material disappeared.
  • the reaction solution was purified by preparative high-performance liquid chromatography to obtain the title compound 3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1-(( 2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b] pyridine-5-carboxamide (15 mg, yield 52%), as a yellow solid.
  • Example 16 N- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4- b) pyridin-5-yl) -5- (3-hydroxy-3-methylpyrrolidin-1-yl) pyrazine-2-carboxamide
  • Example 615B 3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1-((2- (trimethylsilyl ) Ethoxy) methyl) -1H-pyrazolo [3,4-b] pyridine-5-carbonitrile (70 mg, 0.15 mmol) and 1N tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol) A solution of N, N-dimethylformamide (2mL) was added azidotrimethylsilane (86mg, 0.75mmol). The reaction solution was warmed to 90 degrees and stirred overnight.
  • Example 23 4- (4- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3 , 4-b] pyridin-5-yl) -1H-pyrazol-1-yl) piperidin-2-one
  • Example 25 3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -5- (1-((S) -pyrrolidine- 3-yl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-b] pyridine
  • Example 28 3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -5- (1- (tetrahydro-2H-pyran -4-yl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-b] pyridine
  • Example 32 1- (4- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3 , 4-b] pyridin-5-yl) -1H-pyrazol-1-yl) -2-methylpropane-2-ol
  • Example 33 2- (4- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3 , 4-b) pyridin-5-yl) -1H-pyrazol-1-yl) -N, N-dimethylethane-1-amine
  • Example 36 5- (1- (2,2-difluoroethyl) -1H-pyrazol-3-yl) -3-((2R, 4S) -2- (2,5-difluorophenyl ) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridine
  • Example 37 2- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4- b) pyridin-5-yl) -5- (methoxymethyl) -1,3,4-oxadiazole
  • Example 38 2- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1- (methoxymethyl)- 1H-pyrazolo [3,4-b] pyridin-5-yl) -5- (methoxymethyl) -1,3,4-oxadiazole
  • reaction solution was warmed to 50 degrees, N, N-diisopropylethylamine (308mg, 2.382mmol) was added dropwise, and stirred at 50 degrees for 1 hour.
  • Dichloromethane 50mL was added and washed with water (50mL).
  • Example 40 5- (1- (2,2-difluoroethyl) -4-methyl-1H-pyrazol-3-yl) -3-((2R, 4S) -2- (2,5 -Difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridine
  • Example 41 2- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4- b) pyridin-5-yl) -5-((trifluoromethoxy) methyl) -1,3,4-oxadiazole
  • Example 42 2- (3-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -1H-pyrazolo [3,4- b) pyridin-5-yl) -5- (isopropoxymethyl) -1,3,4-oxadiazole
  • 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.
  • Example 1 Compound TRKA (nm) TRKB (nm) TRKC (nm) Example 1 ⁇ 500 ⁇ 500 ⁇ 500 Example 2 ⁇ 500 ⁇ 500 ⁇ 500 Example 3 ⁇ 50 ⁇ 100 ⁇ 50 Example 4 ⁇ 10 ⁇ 10 ⁇ 10 Example 5 ⁇ 10 ⁇ 10 ⁇ 10 Example 6 ⁇ 50 ⁇ 50 ⁇ 50 Example 7 ⁇ 10 ⁇ 10 ⁇ 10 Example 8 ⁇ 50 ⁇ 10 ⁇ 10 Example 9 ⁇ 50 ⁇ 10 ⁇ 50 Example 10 ⁇ 50 ⁇ 10 ⁇ 10 Example 11 ⁇ 10 ⁇ 1 ⁇ 10 Example 12 ⁇ 10 ⁇ 50 ⁇ 10 Example 13 ⁇ 1 ⁇ 1 ⁇ 1 Example 14 ⁇ 10 ⁇ 10 ⁇ 10 Example 15 ⁇ 10 ⁇ 10 ⁇ 10 Example 16 ⁇ 1 ⁇ 10 ⁇ 10 Example 17 ⁇ 1 ⁇ 1 ⁇ 1 Example 18 ⁇ 500 ⁇ 500 ⁇ 500 Example 19 ⁇ 1 ⁇ 1 ⁇ 1 Example 20 ⁇ 1 ⁇ 1 ⁇ 1 Example 21 ⁇ 1 ⁇ 1 ⁇ 1 Example
  • Example 25 ⁇ 1 ⁇ 1 ⁇ 1 Example 26 ⁇ 1 ⁇ 1 ⁇ 1 Example 27 ⁇ 1 ⁇ 1 ⁇ 1 Example 28 ⁇ 1 ⁇ 1 ⁇ 1 Example 29 ⁇ 1 ⁇ 1 ⁇ 1 Example 30 ⁇ 1 ⁇ 1 ⁇ 1 Example 31 ⁇ 10 ⁇ 1 ⁇ 10 Example 32 ⁇ 1 ⁇ 1 ⁇ 1 Example 33 ⁇ 1 ⁇ 1 ⁇ 1 Example 34 ⁇ 1 ⁇ 1 ⁇ 1 Example 35 ⁇ 1 ⁇ 1 ⁇ 1 Example 36 ⁇ 1 ⁇ 1 ⁇ 1 Example 37 ⁇ 1 ⁇ 1 ⁇ 1 Example 38 ⁇ 100 ⁇ 10 ⁇ 100 Example 39 ⁇ 1 ⁇ 1 ⁇ 1 Example 40 ⁇ 1 ⁇ 1 ⁇ 1 Example 41 ⁇ 1 ⁇ 1 ⁇ 1 Example 42 ⁇ 1 ⁇ 1 ⁇ 1 Example 43 ⁇ 1 ⁇ 1 ⁇ 1
  • the NIH-3T3 cell line stably expressing normal TRKA or TRKB or TRKC was constructed by plasmid transfection.
  • 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 the cell activity and the cells are counted for 72 hours Proliferation inhibition rate.
  • the prism5 was used for statistical analysis and the IC 50 value of the test compound was obtained.
  • 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 3 for details.

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Abstract

一类式I所示的五元并六元杂环化合物，其药物组合物、制备及应用被公开。该化合物具有TRK激酶抑制活性，可以治疗TRK功能异常相关疾病。

Description

一类五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 PCTCN2019118198-appb-000001
其中，
X 1、X 2和X 3各自独立地为CR或N；
Y为NR 1，其中，所述的R 1选自下组：H、未取代或被C1-C4烷氧基取代的C1-C6烷基；
R选自下组：H、D、-OH、-NH 2、卤素、CN；
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-；
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C1-C6胺基、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 PCTCN2019118198-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、苄氧基、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 PCTCN2019118198-appb-000003
C1-C6烷基、C3-C8环烷基、C1-C6胺基、C1-C6酰胺基、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 PCTCN2019118198-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，所述的式I化合物具有下式的结构：
Figure PCTCN2019118198-appb-000005
在另一优选例中，所述的L 1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；较佳地，所述的L 1为取代或未取代的具有1或2个N原子的5-7元亚杂环基。
在另一优选例中，R A和R B相连形成选自下组的基团：取代或未取代的C1-C8亚烷基、取代或未取代的C1-C8亚烷基-O-、取代或未取代的C1-C8亚烷基-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、取代或未取代的C1-C8亚烷基-O-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、取代或未取代的C1-C8亚烷基-(具有1-3个选自N、S和O的杂原子的5-10元杂环基)、取代或未取代的C1-C8亚烷基-O-(具有1-3个选自N、S和O的杂原子的5-10元杂环基)。
在另一优选例中，所述的L 1选自下组：
Figure PCTCN2019118198-appb-000006
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 PCTCN2019118198-appb-000007
其中，所述的
Figure PCTCN2019118198-appb-000008
指R A与L 1的连接位点；
L 2为
Figure PCTCN2019118198-appb-000009
R B为
Figure PCTCN2019118198-appb-000010
其中，所述的
Figure PCTCN2019118198-appb-000011
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 PCTCN2019118198-appb-000012
Figure PCTCN2019118198-appb-000013
其中，所述的Rb和Rc各自独立地选自下组：H、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的5-12元的杂环基(包括单环、并环、螺环或桥环)。
在另一优选例中，所述的化合物具有如下式III所示的结构：
Figure PCTCN2019118198-appb-000014
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2019118198-appb-000015
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2019118198-appb-000016
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2019118198-appb-000017
在另一优选例中，所述的化合物具有选自下组的结构：
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。
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元杂环基”是指具有3-12个环原子的且其中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：
一类如下式I所示的化合物：
Figure PCTCN2019118198-appb-000018
其中，
X 1、X 2和X 3各自独立地为CR或N；
Y为NR 1，其中，所述的R 1选自下组：H、未取代或被C1-C4烷氧基取代的C1-C6烷基；
R选自下组：H、D、-OH、-NH 2、卤素、CN；
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-；
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C1-C6胺基、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 PCTCN2019118198-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、苄氧基、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 PCTCN2019118198-appb-000020
C1-C6烷基、C3-C8环烷基、C1-C6胺基、C1-C6酰胺基、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)；
Figure PCTCN2019118198-appb-000021
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、X 2、X 3、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，所述的化合物选自下组：
Figure PCTCN2019118198-appb-000022
Figure PCTCN2019118198-appb-000023
在另一优选例中，本发明的式I化合物为实施例中所制备的化合物。
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 PCTCN2019118198-appb-000024
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
Figure PCTCN2019118198-appb-000025
)、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种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种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
Figure PCTCN2019118198-appb-000026
(R)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019118198-appb-000027
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 PCTCN2019118198-appb-000028
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 PCTCN2019118198-appb-000029
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0.5h,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)。
3-溴-5-硝基-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000030
将5-硝基-吡咯[3,4-C]吡啶(500mg，3.05mmol)溶于二氧六环和水(20mL/5mL)中，零度下加入氢氧化钠(488mg，12.19mmol)，再缓慢滴加液溴(1.9g，12.19mmol)。室温下搅拌0.5小时。反应完全后，将反应液乙酸乙酯稀释，饱和碳酸氢钠进行润洗。有机相进行硅胶柱纯化，即得到3-溴-5-硝基-1H-吡唑并[3,4-b]吡啶,黄色固体化合物(530mg，收率72％)。
3-溴-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000031
将氢化钠(175mg,4.36mmol)加入四氢呋喃(18mL)中,零度下缓慢加入3-溴-5-硝基-1H-吡唑并[3,4-b]吡啶(530mg,2.18mmol)的四氢呋喃(2mL)溶液。零度下搅拌0.5小时后,缓慢加入SEMCl(545mg,3.27mmol)并反应0.5小时。反应液用冰水进行淬灭,乙酸乙酯进行萃取。有机相用无水硫酸钠干燥,浓缩得粗品。用硅胶过柱纯化(石油醚：乙酸乙酯＝5：1)得3-溴-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶,黄色固体化合物(560mg,收率69％)。
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000032
将3-溴-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(560mg，1.50mmol)，(R)-2-(2,5-二氟苯基)吡咯烷(275mg，1.50mmol)，三(二亚苄基丙酮)二钯(137mg，0.15mmol)，1,1’-联萘-2,2’-双二苯膦(187mg，0.30mmol)和碳酸铯(733mg，2.25mmol)依次加入甲苯(15mL)溶液中。在120度下搅拌过夜。反应完全后，反应液用冰水进行淬灭，乙酸乙酯进行萃取。有机相用无水硫酸钠干燥，浓缩得粗品。用硅胶过柱纯化(石油醚：乙酸乙酯＝3：1)得(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶,黄色固体化合物(403mg，收率56％)。
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺
Figure PCTCN2019118198-appb-000033
在乙醇和水(20mL/5mL)的混合溶液中依次加入(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(403mg，0.85mmol)，氯化铵(400mg)和铁粉(400mg)，反应80度下搅拌3小时。反应完全后。反应液过滤，并将滤液旋干。残留物用乙酸乙酯稀释，并用饱和碳酸氢钠进行洗涤。有机相用无水硫酸钠干燥，浓缩得粗品。将所得粗品硅胶过柱(石油醚：乙酸乙酯＝1：2)得黄色固体化合物(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺(260mg，收率69％)。
MS-ESI:m/z 446[M+H]+.
1H NMR(400MHz,CDCl 3-d):δ(ppm)8.10(d,1H,J＝2.8Hz),7.14-7.07(m,2H),7.03-7.01(m,1H),6.97-6.93(m,1H),5.67-5.63(m,1H),5.45-5.43(m,1H),4.06-4.03(m,1H),3.82-3.78(m,1H),3.66-3.61(m,2H),2.53-2.50(m,1H),2.11-2.04(m,3H),0.99-0.93(m,2H),0.08(s,9H).
中间体B的合成
Figure PCTCN2019118198-appb-000034
(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 PCTCN2019118198-appb-000035
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 PCTCN2019118198-appb-000036
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 PCTCN2019118198-appb-000037
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 PCTCN2019118198-appb-000038
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 PCTCN2019118198-appb-000039
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 PCTCN2019118198-appb-000040
甲基3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯
Figure PCTCN2019118198-appb-000041
将钠氢(47mg，1.17mmol)加入四氢呋喃(18mL)中，零度下缓慢加入3-溴-1H-吡唑并[3,4-b]吡啶-5-羧酸甲酯(200mg，0.78mmol)的四氢呋喃(2mL)溶液。零度下搅拌0.5小时后，缓慢加入2-(三甲基硅烷基)乙氧甲基氯(130mg，1.17mmol)并反应0.5小时。反应液用冰水进行淬灭，乙酸乙酯进行萃取。有机相用无水硫酸钠干燥，浓缩得粗品。用硅胶过柱纯化(石油醚：乙酸乙酯＝10：1)得甲基3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯,黄色固体化合物(180mg，收率60％)。
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯
Figure PCTCN2019118198-appb-000042
将3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(180mg，0.46mmol)，(R)-2-(2,5-二氟苯基)吡咯烷(85mg，0.46mmol)，三(二亚苄基丙酮)二钯(42mg，0.046mmol)，2-双环己基膦-2’,6’-二甲氧基联苯(23mg，0.055mmol)和碳酸铯(300mg，0.92mmol)依次加入甲苯(15mL)溶液中。在120度下搅拌过夜。反应完全后，反应液用冰水进行淬灭，乙酸乙酯进行萃取。有机相用无水硫酸钠干燥，浓缩得粗品。用硅胶过柱纯化(石油醚：乙酸乙酯＝10：1)得C-3,黄色固体化合物(50mg，收率22％)。
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸
Figure PCTCN2019118198-appb-000043
向(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯(50mg,0.10mmol)的四氢呋喃(2mL)溶液中加入氢氧化锂(16mg,0.40mmol)和水(0.5mL).反应液室温搅拌16小时后，TLC显示有大量原料剩余。反应液继续80度搅拌2小时后浓缩得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(100mg粗品,100％)，为黄色固体。
中间体D的合成
Figure PCTCN2019118198-appb-000044
叔-丁基3-(2-乙氧基-2-羰基乙基)-3-羟基吡咯烷-1-羧酸酯
Figure PCTCN2019118198-appb-000045
在单口瓶(500mL)中加四氢呋喃(150mL)和锌粉(6.4g，97.2mmol)，将温度升至80℃直到反应引发。叔-丁基3-羰基吡咯烷-1-羧酸酯(15.0g，81.0mmol)和溴乙酸乙酯(13.7g,82.0mmol)缓慢加入到反应中。保温反应1小时，TLC显示反应完成。将反应液倒入氯化铵水溶液中，用乙酸乙酯萃取。有机相用碳酸氢钠水溶液和饱和食盐水洗涤，干燥，浓缩干，过硅胶柱纯化(石油醚/乙酸乙酯＝10:1)得到黄色油状物(10.2g，收率46％)。
叔-丁基3-羟基-3-(2-(甲基氨基)-2-羰基乙基)吡咯烷-1-羧酸酯
Figure PCTCN2019118198-appb-000046
在微波管(30ml)中加入甲胺醇溶液(7mL，含量30％)，在室温下加入叔-丁基3-(2-乙氧基-2-羰基乙基)-3-羟基吡咯烷-1-羧酸酯(500mg,2.1mmol)，100℃反应2小时。TLC监测反应结束，旋干后得油状产物叔-丁基3-羟基-3-(2-(甲基氨基)-2-羰基乙基)吡咯烷-1-羧酸酯(400mg,收率84％).
2-(3-羟基吡咯烷-3-基)-N-甲基乙酰胺
Figure PCTCN2019118198-appb-000047
在单口瓶(100ml)中加入二氯甲烷(4ml)，加入化合物叔-丁基3-羟基-3-(2-(甲基氨基)-2-羰基乙基)吡咯烷-1-羧酸酯(400mg，1.6mmol)和盐酸二氧六环溶液(6ml,6.0M)，室温下搅拌过夜，LCMS显示反应完成，浓缩干，得到油状物2-(3-羟基吡咯烷-3-基)-N-甲基乙酰胺(240mg，收率97％)。
1H NMR(400MHz,DMSO-d 6):δ(ppm)9.50(s,1H),9.08(s,1H),8.02-7.92(m,1H),3.25-3.12(m,4H),2.65-2.49(m,3H),1.97-1.83(m,2H),1.79(s,2H).
实施例1:N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-羟基-3-(2-(甲基氨基)-2-氧代乙基)吡咯烷-1-甲酰胺
Figure PCTCN2019118198-appb-000048
把三光气(10mg,0.033mmol)的二氯甲烷溶液(1mL)滴加到0度的(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺(10mg,0.023mmol)和N,N-二异丙基乙胺(89mg,0.69mmol)的二氯甲烷溶液(4ml)中,再0度搅拌半小时。反应液用水洗(5ml*1),干燥,过滤。滤液旋干后溶解在二氯甲烷(4mL)中,滴加到0度2-(3-羟基吡咯烷-3-基)-N-甲基乙酰胺(36mg,0.23mmol),N,N-二异丙基乙胺(89mg,0.69mmol)的二氯甲烷溶液(3mL)。反应升到室温反应2个小时，加入盐酸二氧六环溶液(4mL)，反应2个小时.液质监控显示有产物生成。浓缩，残渣通过制备型高效液相色谱纯化获得目标产物N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-羟基-3-(2-(甲基氨基)-2-氧代乙基)吡咯烷-1-甲酰胺(5.5mg,收率47.9％)，为黄色固体。
MS(ESI):m/z＝500[M+H]+.
1H NMR(400MHz,CD 3OD)δ8.32(d,J＝1.6Hz,1H),8.04(dd,J＝5.4,2.3Hz,1H),7.13-7.06(m,1H),6.96–6.88(m,2H),5.35(d,J＝7.3Hz,1H),4.58(s,2H),4.13-4.08(m,1H),3.72(m,1H),3.63–3.53(m,2H),3.48-3.46(m,1H),2.71(s,3H),2.55(s,2H),2.52-2.42(m,1H),2.08–1.92(m,4H).
实施例2:(S)-N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-羟基吡咯烷-1-甲酰胺
Figure PCTCN2019118198-appb-000049
采用类似于实施例1的条件，替换相应的起始原料，得到(S)-N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-羟基吡咯烷-1-甲酰胺(3mg，收率15％)
MS-ESI:m/z＝429[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.16(s,1H),6,01(s,1H),5.88-5.68(m,3H),4.14-4.12(m,1H),3.22-3.20(m,2H),2.95-2.80(m,1H),5.55-2.48(m,1H),2.52-2.31(m,3H),1.60-1.40(m,3H),1.38-1.20(m,2H),0.88-0.75(m,9H).
实施例3:N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺
Figure PCTCN2019118198-appb-000050
(R)-N-(3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-氟尼克酰胺
Figure PCTCN2019118198-appb-000051
向(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺(60mg,0.13mmol)和六氟磷酸2-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基糖醛正离子(274mg,0.72mmol)的无水N,N-二甲基甲酰胺(2mL)溶液中加入6-氟尼古丁酸(92mg,0.65mmol)和N,N-二异丙基乙基胺(134mg,1.04mmol)。反应液室温下搅拌16小时。LCMS显示大部分原料剩余，反应液在50度反应72小时。反应液通过制备型高效液相色谱纯化获得标题化合物(R)-N-(3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-氟尼克酰胺(25mg,34％)，为黄色固体。
MS(ESI):m/z＝439[M+H-130] +。
N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺
Figure PCTCN2019118198-appb-000052
向(R)-N-(3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-氟尼克酰胺(25mg,0.04mmol),(S)-吡咯烷-3-醇(17mg,0.2mmol)的无水N,N-二甲基甲酰胺溶液(1mL)中加入N,N-二异丙基乙基胺(41mg,0.32mmol)，反应液90度搅拌3小时后，残渣通过制备型高效液相色谱纯化获得目标N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺(16mg,57％)，为黄色固体。MS(ESI):m/z＝506[M+H-130] +.
N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺
Figure PCTCN2019118198-appb-000053
冰浴下向N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺(16mg,0.03mmol)的甲醇(1mL)溶液中加入盐酸的二氧六环溶液(2mL，4M)。反应液自然恢复到室温，然后室温搅拌16小时。反应液浓缩，残渣通过制备型高效液相色谱纯化获得目标N-(3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺(8.4mg,66％)，为黄色固体。
MS(ESI):m/z＝506[M+H] +.
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.04(s,1H),8.71(d,J＝2.5Hz,1H),8.55(d,J＝2.2Hz,1H),8.50(d,J＝2.3Hz,1H),8.03(dd,J＝8.9,2.5Hz,1H),7.24-7.17(m,1H),7.07–6.97(m,2H),6.50(d,J＝9.0Hz,1H),5.18(dd,J＝8.4,3.8Hz,1H),5.00(s,1H),4.38(s,1H),4.16-4.09(m,1H),3.63(m,1H),3.55-3.45(m,3H),2.42–2.34(m,1H),2.06–1.76(m,6H).
实施例4:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000054
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000055
向(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(50mg粗品,0.06mmol)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(57mg,0.15mmol)的无水N,N-二甲基甲酰胺(1mL)溶液中加入N,N-二异丙基乙基胺(39mg,0.30mmol)和氯化铵(9mg,0.18mmol).反应液室温搅拌16小时.LCMS显示大部分原料消失。反应液通过制备型高效液相色谱纯化获得标题化合物(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(30mg)，为黄色固体。MS(ESI):m/z＝474[M+H] +.
(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000056
冰浴下向(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(30mg,0.06mmol)的甲醇(1mL)溶液中加入盐酸的二氧六环溶液(2mL，4M).反应液室温搅拌16小时后浓缩。残渣通过制备型高效液相色谱纯化获得标题化合物(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(8.4mg，收率42％)
MS(ESI):m/z＝344[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.47(s,1H),8.85–8.79(m,1H),8.64–8.58(m,1H),8.06(s,1H),7.32(s,1H),7.24–7.17(m,1H),7.08-6.93(m,2H),5.23–5.17(m,1H),4.24–4.16(m,1H),3.67(m,1H),2.43-2.34(m,1H),2.08-1.94(m,2H),1.85-1.76(m,1H).
实施例5:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000057
甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯
Figure PCTCN2019118198-appb-000058
向甲基3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(139mg,0.36mmol),(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(60mg,0.30mmol),碳酸铯(196mg,0.60mmol)的无水甲苯(2mL)溶液中加入三(二苯亚甲基丙酮)二钯(0)(27mg,0.03mmol)和2-二环己基膦-2′,6′-二甲氧基-联苯(16mg,0.04mmol).反应液100度搅拌16小时后浓缩。残渣通过快速分离纯化(石油醚:乙酸乙酯＝8:1)纯化获得目标化合物甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(100mg粗品,66％)，为黄色固体。
MS(ESI):m/z＝506.9[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸
Figure PCTCN2019118198-appb-000059
向甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(100mg,0.20mmol)的四氢呋喃(2mL)溶液中加入氢氧化锂(16mg,0.40mmol)和水(0.5mL).反应液室温搅拌16小时后，TLC显示有大量原料剩余。反应液继续80度搅拌2小时后浓缩得到目标化合物3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(100mg粗品,100％)，为黄色固体。MS(ESI):m/z＝374.9[M-117] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000060
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(40mg粗品,0.06mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(57mg,0.15mmol)的无水N,N-二甲基甲酰胺(1mL)溶液中加入N,N-二异丙基乙基胺(39mg,0.30mmol)和氯化铵(9mg,0.18mmol).反应液室温搅拌16小时.LCMS显示大部分原料消失。反应液通过制备型高效液相色谱纯化获得标题化合物3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(15mg,收率52％)，为黄色固体。
MS(ESI):m/z＝491.9[M+H]+.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000061
冰浴下向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(15mg,0.03mmol)的甲醇(1mL)溶液中加入盐酸的二氧六环溶液(2mL，4M).反应液室温搅拌16小时后浓缩。残渣通过制备型高效液相色谱纯化获得标题化合物3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(3mg,收率27％)，为黄色固体。
MS(ESI):m/z＝362[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.56(s,1H),8.84(d,J＝2.0Hz,1H),8.64(d,J＝2.0Hz,1H),8.08(s,1H),7.37(s,1H),7.24–7.09(m,2H),7.09–7.00(m,1H),5.58-5.45(m,1H),5.32–5.26(m,1H),4.48-4.38(m,1H),4.07–3.95(m,1H),2.77–2.65(m,1H),2.18–2.01(m,1H).
实施例6:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-羟基乙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000062
采用类似于实施例4的条件，替换相应的起始原料，得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-羟基乙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝388[M+H] +.
1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.61(s,1H),7.90(d,J＝8.0Hz,1H),7.76(d,J＝9.8Hz,1H),7.44(s,1H),7.08-6.98(m,2H),6.92-6.86(m,1H),6.69(d,J＝8.8Hz,2H),5.24(d,J＝6.5Hz,1H),3.95-3.85(m,1H),3.55(m,1H),3.27(s,1H),3.11(m,5H),2.42-2.29(m,1H),2.03-1.90(m,2H),1.85-1.76(m,1H).
实施例7:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000063
采用类似于实施例4的条件，替换相应的起始原料，得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝358[M+Na] +
1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.80(d,J＝2.0Hz,1H),8.56(d,J＝2.0Hz,1H),8.53-8.47(m,1H),7.25-7.19(m,1H),7.08–6.95(m,2H),5.21(dd,J＝8.2, 3.3Hz,1H),4.22-4.75(m,1H),3.68(m,1H),2.78(d,J＝4.5Hz,3H),2.44–2.34(m,1H),2.10–1.93(m,2H),1.85-1.77(m,1H).
实施例8:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000064
采用类似于实施例4的条件,替换相应的起始原料,得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝402[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.79(d,J＝2.0Hz,1H),8.53(d,J＝2.0Hz,1H),7.14-7.08(m,1H),6.95-6.89(m,2H),5.39(d,J＝6.5Hz,1H),4.21–4.14(m,1H),3.78(dd,J＝16.1,8.6Hz,1H),3.58-3.53(m,4H),3.37(s,3H),2.51-2.45(m,1H),2.14–2.03(m,2H),2.00-1.93(m,1H).
实施例9:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(3-羟基丙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000065
采用类似于实施例4的条件,替换相应的起始原料,得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(3-羟基丙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝402[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.77(d,J＝2.0Hz,1H),8.51(d,J＝2.0Hz,1H),7.11(td,J＝9.3,4.3Hz,1H),6.97–6.85(m,2H),5.39(d,J＝6.8Hz,1H),4.21–4.13(m,1H),3.78(dd,J＝16.0,8.6Hz,1H),3.64(t,J＝6.3Hz,2H),3.53–3.41(m,2H),2.55-2.44(m,1H),2.17–2.02(m,2H),2.02-1.94(m,1H),1.86-1.79(m,2H).
实施例10:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-羟基-2-甲基丙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000066
采用类似于实施例4的条件,替换相应的起始原料,得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(2-羟基-2-甲基丙基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝416[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.81(d,J＝2.0Hz,1H),8.51(d,J＝2.0Hz,1H),7.11(td,J＝9.2,4.3Hz,1H),6.97–6.86(m,2H),5.40(d,J＝6.6Hz,1H),4.20–4.12(m,1H),3.78(dd,J＝15.9,8.7Hz,1H),3.39(dd,J＝30.2,13.5Hz,2H),2.55–2.43(m,1H),2.14–2.02(m,2H),2.00-1.94(m,1H),1.22(d,J＝2.4Hz,6H).
实施例11:N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺
Figure PCTCN2019118198-appb-000067
采用类似于中间体A的条件,替换相应的起始原料,得到11-1,3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺。
采用类似于实施例3的条件,替换相应的起始原料,得到N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-6-((S)-3-羟基吡咯烷-1-基)尼克酰胺
MS(ESI):m/z＝416[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.24(s,1H),10.07(s,1H),8.73(d,J＝2.4Hz,1H),8.55(dd,J＝10.0,2.4Hz,2H),8.05(dd,J＝9.2,2.4Hz,1H),7.23–7.13(m,1H),7.07–7.02(m,1H),6.51(d,J＝9.2Hz,1H),5.49(d,J＝53.2Hz,1H),5.31–5.27(m,1H),4.98(d,J＝2.8Hz,1H),4.46–4.32(m,2H),3.95–3.86(m,1H),3.54–3.47(m,2H),2.69–2.63(m,1H),2.15–1.86(m,4H).
实施例12:(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-羟基丁基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000068
采用类似于实施例4的条件,替换相应的起始原料,得到(R)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-羟基丁基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝416[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.78(d,J＝2.0Hz,1H),8.50(d,J＝2.0Hz,1H),7.11(td,J＝9.3,4.3Hz,1H),6.97–6.87(m,2H),5.39(d,J＝6.0Hz,1H),4.19–4.11(m,1H), 3.77(dd,J＝15.9,8.7Hz,1H),3.60(t,J＝6.3Hz,2H),3.46–3.34(m,2H),2.57–2.44(m,1H),2.12-2.00(m,2H),2.00-1.93(m,1H),1.71-1.58(m,4H).
实施例13:甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯
Figure PCTCN2019118198-appb-000069
冰浴下向甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(50mg,0.03mmol)的甲醇(1mL)溶液中加入盐酸的二氧六环溶液(2mL,4M).反应液室温搅拌16小时后浓缩。残渣通过制备型高效液相色谱纯化获得甲基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(18.9mg,收率51％),为黄色固体。
MS(ESI):m/z＝377[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.92(d,J＝1.8Hz,1H),8.61(d,J＝1.8Hz,1H),7.14-7.08(m,1H),7.06-7.01(m,1H),6.99–6.89(m,1H),5.51-5.37(m,2H),4.34(ddd,J＝37.7,12.1,3.1Hz,1H),4.13(dd,J＝24.9,11.9Hz,1H),3.91(s,3H),2.92-2.80(m,1H),2.22–2.02(m,1H).
实施例14:3-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)-N-((1s,4S)-4-羟基环己基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000070
MS(ESI):m/z＝442[M+H] +.
1H NMR(400MHz,CD 3ODδ8.77(d,J＝2.0Hz,1H),8.44(d,J＝2.0Hz,1H),7.13(td,J＝9.4,4.3Hz,1H),6.98–6.87(m,2H),5.42(d,J＝6.7Hz,1H),4.18-4.12(m,1H),3.96–3.83(m,2H),3.77(dd,J＝15.9,8.8Hz,1H),3.35-3.30(m,1H),2.56–2.44(m,1H),2.17–1.95(m,3H),1.85-1.60(m,7H).
实施例15:(R)-N-(3-氨基-3-羰基丙基)-3-(2-(2,5-二氟苯基)吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000071
MS(ESI):m/z＝442[M+H] +.
1H NMR(400MHz,CD3OD)δ8.78(d,J＝1.9Hz,1H),8.53(d,J＝2.0Hz,1H),7.12(td,J＝9.3,4.2Hz,1H),6.96–6.85(m,2H),5.38(d,J＝6.6Hz,1H),4.22–4.11(m,1H),3.78(dd,J＝16.0,8.8Hz,1H),3.63(t,J＝7.0Hz,2H),2.57–2.43(m,3H),2.17-1.92(m,3H).
实施例16:N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺
Figure PCTCN2019118198-appb-000072
N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺
Figure PCTCN2019118198-appb-000073
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-胺(93mg,0.2mmol),的N,N-二甲基甲酰胺溶液(3mL)中加入5-氯吡嗪-2-羧酸(48mg,0.3mmol),2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(114mg,0.3mmol)和N,N-二异丙基乙胺(52mg,0.4mmol),室温反应16小时后,加入3-甲基吡咯烷-3-醇盐酸盐(110mg,0.8mmol)和N,N-二异丙基乙胺(52mg,0.4mmol),40度继续反应2小时。向反应液中加入乙酸乙酯,然后水洗,有机相浓缩后经柱层析纯化(0-6％甲醇/二氯甲烷)得到N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺(85mg,收率60％),为黄色固体。
MS(ESI):m/z＝691[M+H] +.
N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺
Figure PCTCN2019118198-appb-000074
向N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺(30mg,0.045mmol)加入到盐酸-甲醇(3M,3mL)溶液中,室温反应1小时,旋蒸移除溶剂,粗产品用 反相柱纯化得到标题化合物563N-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(3-羟基-3-甲基吡咯烷-1-基)吡嗪-2-甲酰胺(9.0mg,收率35.5％),为白色固体。
MS(ESI):m/z＝539[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.75(s,1H),8.59(d,J＝2.2Hz,2H),7.95(s,1H),7.18–6.99(m,2H),6.92(d,J＝8.2Hz,1H),5.53–5.33(m,2H),4.37(dd,J＝36.7,10.8Hz,1H),4.09(dd,J＝25.1,10.7Hz,1H),3.73(s,2H),3.67–3.54(m,1H),3.45(d,J＝11.5Hz,1H),2.85(s,1H),2.08(t,J＝20.5Hz,3H),1.48(s,3H).
实施例17:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-羧酸
Figure PCTCN2019118198-appb-000075
采用类似于实施例13的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-羧酸
MS(ESI):m/z＝363[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.61(s,2H),8.85(d,J＝1.8Hz,1H),8.56(d,J＝1.8Hz,1H),7.26–7.10(m,2H),7.10–6.98(m,1H),5.48(d,J＝52.8Hz,1H),5.36–5.24(m,1H),4.43(dd,J＝38.2,10.6Hz,1H),3.98(dd,J＝25.8,11.9Hz,1H),2.78–2.60(m,1H),2.07(dt,J＝42.1,10.6Hz,1H).
实施例18:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N,N-二甲基-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
Figure PCTCN2019118198-appb-000076
采用类似于实施例4的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N,N-二甲基-1H-吡唑并[3,4-b]吡啶-5-甲酰胺
MS(ESI):m/z＝390[M+H] +.
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.41(d,J＝1.8Hz,1H),8.18(d,J＝1.7Hz,1H),7.24-7.03(m,3H),5.47(d,J＝52.4Hz,1H),5.36–5.21(m,1H),4.39(dd,J＝38.5,11.0Hz,1H),3.95(dd,J＝26.2,12.5Hz,1H),2.97(s,6H),2.76-2.60(m,1H),2.18–1.95(m,1H).
实施例19:异丙基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b] 吡啶-5-羧酸酯
Figure PCTCN2019118198-appb-000077
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(60mg,0.122mmol)的异丙醇(40mL)溶液中加入氯化亚砜(0.5mL)。反应液加热到50度,搅拌5小时。浓缩,制备得到异丙基3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-羧酸酯(21.8mg,收率44.2％),为黄色固体。
MS(ESI):m/z＝405[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.75(s,1H),8.83(d,J＝1.9Hz,1H),8.48(d,J＝1.9Hz,1H),7.28–7.13(m,2H),7.12-7.04(m,1H),5.49(d,J＝53.1Hz,1H),5.40–5.28(m,1H),5.15-5.08(m,1H),4.37(dd,J＝37.9,10.4Hz,1H),4.02(dd,J＝23.8,12.1Hz,1H),2.90-2.67(m,1H),2.17–1.99(m,1H),1.30(dd,J＝6.1,4.2Hz,6H).
实施例20:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000078
5-氯-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000079
向3-溴-5-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(120mg,0.331mmol),(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(66mg,0.331mmol)和碳酸铯(216mg,0.662mmol)的甲苯(6mL)溶液中加入三(二亚苄基丙酮)-二钯(30mg,0.033mmol)和1,1'-联萘-2,2'-双二苯膦(41mg,0.066mmol)。反应液氮气置换3次,加热到100度,搅拌过夜。加入乙酸乙酯(50mL),用水(50mL*2)洗。有机相,干燥,过滤,浓缩,柱层析(石油醚/乙酸乙酯＝8/1)得到5-氯-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(81mg,收率52.6％),为黄色油状物。
MS(ESI):m/z＝365[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000080
向5-氯-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(70mg,0.150mmol),叔-丁基4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-羧酸酯(133mg,0.452mmol)和磷酸钾(159mg,0.750mmol)的水(1mL)和正丁醇(5mL)的溶液中加入三(二亚苄基丙酮)-二钯(27mg,0.030mmol)和2-二环己基磷-2,4,6-三异丙基联苯(29mg,0.060mmol)。反应液氮气置换,加热到125度，搅拌过夜。加入水(50mL),用二氯甲烷(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＝1/1)得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(70mg,收率90.7％)，为黄色固体。
MS(ESI):m/z＝397[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000081
采用类似于实施例13的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝385[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.90(s,1H),12.25(s,1H),8.67(d,J＝2.0Hz,1H),8.24(s,1H),8.22-7.98(m,2H),7.25-7.18(m,1H),7.17-7.12(m,1H),7.09-7.01(m,1H),5.50(d,J＝52.8Hz,1H),5.36–5.27(m,1H),4.44(dd,J＝40.1,12.4Hz,1H),3.98(dd,J＝ 26.7,12.0Hz,1H),2.77-2.60(m,1H),2.18-2.00(m,1H).
实施例21:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(2H-四唑-5-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000082
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲腈
Figure PCTCN2019118198-appb-000083
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰胺(100mg,0.20mmol)和三乙胺(202mg,2.0mmol)的二氯甲烷(3mL)溶液加入三氟乙酸酐(126mg,0.60mmol)，室温搅拌2小时。反应液浓缩，柱层析(石油醚/乙酸乙酯＝4/1)得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲腈(70mg,收率73.9％)，为黄色固体。
MS(ESI):m/z＝356[M-SEM+CH 3] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(2H-四唑-5-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000084
向实施例615B 3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲腈(70mg,0.15mmol)和1N四丁基氟化铵的四氢呋喃(0.75mL,0.75mmol)的N,N-二甲基甲酰胺(2mL)溶液加入叠氮基三甲基硅烷(86mg,0.75mmol)。反应液升温至90度，搅拌过夜。加入乙酸乙酯(50mL),用水(100mL*3)洗.有机相,干燥,浓缩，柱层析(二氯甲烷/甲醇＝10/1)得到3-((2R,4S)-2-(2,5- 二氟苯基)-4-氟吡咯烷-1-基)-5-(2H-四唑-5-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(70mg,收率90.3％)，为黄色固体。
MS(ESI):m/z＝399[M-SEM+CH 3] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(2H-四唑-5-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000085
采用类似于实施例13的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(2H-四唑-5-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝387[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.62(s,1H),8.99(d,J＝1.9Hz,1H),8.71(d,J＝1.5Hz,1H),7.24-7.16(m,2H),7.08-7.03(m,1H),5.53(d,J＝52.8Hz,1H),5.31(dd,J＝9.8,6.8Hz,1H),4.58–4.35(m,1H),4.02(dd,J＝25.8,11.9Hz,1H),2.80–2.66(m,1H),2.21–1.99(m,1H).
实施例22:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000086
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝468[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.65(d,J＝2.0Hz,1H),8.29(s,1H),8.23(d,J＝1.9Hz,1H),7.91(s,1H),7.21(d,J＝4.3Hz,1H),7.18–7.11(m,1H),7.10–7.01(m,1H),5.50(d,J＝53.4Hz,1H),5.31(dd,J＝10.0,6.9Hz,1H),4.55–4.34(m,1H),4.21–4.09(m,1H),3.98(dd,J＝26.2,11.9Hz,1H),3.02(d,J＝12.6Hz,2H),2.77–2.64(m,1H),2.57(t,J＝11.2Hz,1H),2.20–1.92(m,3H),1.83–1.71(m,2H).
实施例23:4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-2-酮
Figure PCTCN2019118198-appb-000087
叔-丁基4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-2-羰基哌啶-1-羧酸酯
Figure PCTCN2019118198-appb-000088
将叔-丁基4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(180mg,0.26mmol),高碘酸钠(280mg,1.30mmol),三氯化钌的水合物(10mg)混合在乙酸乙酯(4mL)和水(4mL)中，室温搅拌1.5小时。有机相分别用硫代硫酸钠，盐水洗涤，干燥，过滤，滤液旋干，柱层析(石油醚/乙酸乙酯＝1/1)得到叔-丁基4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-2-羰基哌啶-1-羧酸酯(68mg,收率37％)。
MS(ESI):m/z＝734[M+Na] +.
4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-2-酮
Figure PCTCN2019118198-appb-000089
采用类似于实施例13的条件,替换相应的起始原料,得到4-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-2-酮
MS(ESI):m/z＝482[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ13.51–13.29(m,1H),8.78(d,J＝2.1Hz,1H),8.57(d,J＝2.1Hz,1H),8.27(s,1H),7.88(s,1H),7.31–7.14(m,2H),7.09(m,1H),5.88–5.81(m,1H),5.69(dt,J＝52.3,7.5Hz,1H),4.28–4.17(m,1H),3.05(d,J＝12.8Hz,2H),3.01–2.84(m,1H),2.69–2.54(m,3H),1.98(d,J＝10.4Hz,2H),1.82(dt,J＝12.1,8.4Hz,2H),
实施例24:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-((R)-吡咯烷-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000090
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-((R)-吡咯烷-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝454[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.14(d,J＝2.0Hz,1H),8.08(s,1H),7.82(s,1H),7.15–7.03(m,2H),6.97-6.88(m,1H),5.58-5.35(m,2H),5.00-4.91(m,1H),4.36(dd,J＝37.9,12.4Hz,1H),4.10(dd,J＝25.2,12.3Hz,1H),3.32-3.30(m,1H),3.26–3.18(m,2H),3.06–2.96(m,1H),2.92-2.80(m,1H),2.40-2.32(m,1H),2.25–1.99(m,2H).
实施例25:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-((S)-吡咯烷-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000091
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-((S)-吡咯烷-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝454[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.14(d,J＝2.0Hz,1H),8.08(s,1H),7.82(s,1H),7.16–7.02(m,2H),6.96-6.90(m,1H),5.55-5.34(m,2H),5.00–4.91(m,1H),4.46–4.26(m,1H),4.10(dd,J＝24.9,12.0Hz,1H),3.27–3.14(m,3H),3.07–2.97(m,1H),2.93–2.78(m,1H),2.42-2.32(m,1H),2.25-2.00(m,2H).
实施例26:5-(1-(吖丁啶-3-基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000092
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(吖丁啶-3-基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝441[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.18–8.12(m,2H),7.89(s,1H),7.16–7.02(m,2H),6.97–6.89(m,1H),5.54–5.34(m,2H),5.34-5.26(m,1H),4.43-4.20(m,1H),4.20–4.13(m,2H),4.13–4.04(m,1H),4.03-3.98(m,2H),2.95–2.78(m,1H),2.19–2.00(m,1H).
实施例27:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(甲磺酰)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000093
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(甲磺酰)-1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000094
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(90mg,0.17mmol)，N,N-二异丙基乙胺(136mg,1.05mmol)的二氯甲烷(5mL)溶液中加入甲基磺酸酐(91mg,0.52mmol)。反应液室温搅拌1小时。加入水(50mL),用二氯甲烷(50mL*2)萃取。合并有机相,干燥,过滤，浓缩得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(甲磺酰)-1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(100mg,收率96.4％)，为黄色油状物。
MS(ESI):m/z＝593[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(甲磺酰)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000095
采用类似于实施例13的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(甲磺酰)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝463[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.66(d,J＝1.9Hz,1H),8.56(s,1H),8.30–8.24(m,2H),7.15–7.02(m,2H),6.97–6.89(m,1H),5.54–5.35(m,2H),4.45-4.32(m,1H),4.12 (dd,J＝24.4,11.5Hz,1H),3.44(s,3H),2.93–2.78(m,1H),2.19–1.99(m,1H).
实施例28:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000096
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝469[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.14(d,J＝2.0Hz,1H),8.10(d,J＝0.5Hz,1H),7.82(d,J＝0.7Hz,1H),7.15–7.03(m,2H),6.97-6.89(m,1H),5.54-5.36(m,2H),4.48–4.28(m,2H),4.16-4.04(m,3H),3.62-3.55(m,2H),2.93-2.80(m,1H),2.19–1.99(m,5H).
实施例29:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(1-甲基吖丁啶-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000097
向5-(1-(吖丁啶-3-基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶(100mg,0.15mmol)，30％甲醛水溶液(0.4mL)的二氯甲烷(5mL)和甲醇(5mL)的混合溶液中加入乙酸(0.05mL)。反应室温搅拌2小时。0度加入三乙酰氧基硼氢化钠(253mg,1.19mmol)并在0度搅拌1小时。浓缩，反相制备得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(1-甲基吖丁啶-3-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶(25mg,收率37.0％)，为黄色固体。
MS(ESI):m/z＝454[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.15(d,J＝0.8Hz,2H),7.87(s,1H),7.14-7.04(m,2H),6.98–6.87(m,1H),5.56–5.34(m,2H),5.09–4.99(m,1H),4.45-4.28(m,1H),4.10(dd,J＝24.1,11.4Hz,1H),3.89(td,J＝7.3,1.7Hz,2H),3.65(t,J＝7.6Hz,2H),2.93–2.79(m,1H),2.49(s,3H),2.19-2.02(m,1H).
实施例30:5-(1-(2,2-二氟乙基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000098
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(2,2-二氟乙基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝449[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝1.9Hz,1H),8.14(d,J＝2.0Hz,1H),8.06(s,1H),7.88(s,1H),7.13-7.02(m,2H),6.96-6.90(m,1H),6.21(tt,J＝55.2,3.8Hz,1H),5.54–5.31(m,2H),4.60(td,J＝14.4,3.8Hz,2H),4.43-4.28(m,1H),4.16-4.04(m,1H),2.98–2.79(m,2H),2.18-2.00(m,1H).
实施例31:5-(1-((苄氧基)甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000099
5-(1-((苄氧基)甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000100
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(100mg,0.194mmol),苄基氯甲基醚(60mg,0.389mmol)的乙腈(5mL)溶液中加入N,N-二异丙基乙胺(124mg,0.97mmol)。反应液加热到80度，并搅拌1小时。加入水(50mL),用乙酸乙酯(50mL*2)萃取.合并有机相,干燥,浓缩，柱层析(石油醚/乙酸乙酯＝3/1)得到5-(1-((苄氧基)甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(100mg,收率81.2％)，为黄色油状物。
MS(ESI):m/z＝635[M+H] +.
5-(1-((苄氧基)甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000101
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-((苄氧基)甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝505[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝1.9Hz,1H),8.15(d,J＝2.1Hz,2H),7.90(s,1H),7.33–7.21(m,5H),7.13–7.03(m,2H),6.95–6.88(m,1H),5.56(s,2H),5.54–5.32(m,2H),4.56(s,2H),4.44-4.28(m,1H),4.11(dd,J＝24.7,11.8Hz,1H),2.92–2.78(m,1H),2.19–2.00(m,1H).
实施例32:1-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇
Figure PCTCN2019118198-appb-000102
采用类似于实施例20的条件,替换相应的起始原料,得到1-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇
MS(ESI):m/z＝457[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.11(d,J＝2.0Hz,1H),7.98(d,J＝0.6Hz,1H),7.80(d,J＝0.7Hz,1H),7.16–7.01(m,2H),6.96-6.90(m,1H),5.57–5.35(m,2H),4.41-4.28(m,1H),4.16–4.05(m,3H),2.93–2.79(m,1H),2.19–1.99(m,1H),1.19(d,J＝1.6Hz,6H).
实施例33:2-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-N,N-二甲基乙烷-1-胺
Figure PCTCN2019118198-appb-000103
采用类似于实施例20的条件,替换相应的起始原料,得到2-(4-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)-N,N-二甲基乙烷-1-胺
MS(ESI):m/z＝456[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.57(d,J＝2.0Hz,1H),8.13(d,J＝2.0Hz,1H),8.03 (d,J＝0.7Hz,1H),7.80(d,J＝0.8Hz,1H),7.15–7.03(m,2H),6.96–6.89(m,1H),5.55–5.34(m,2H),4.43–4.26(m,3H),4.15-4.05(m,1H),2.93–2.79(m,3H),2.30(s,6H),2.19-2.01(m,1H).
实施例34:5-(1-(吖丁啶-3-基甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000104
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(吖丁啶-3-基甲基)-1H-吡唑-4-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝454[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),8.62(d,J＝2.0Hz,1H),8.20–8.11(m,2H),7.86(s,1H),7.25–7.10(m,2H),7.08–7.00(m,1H),5.61–5.36(m,2H),4.52-4.36(m,1H),4.33(d,J＝7.4Hz,2H),4.02(dd,J＝26.1,11.8Hz,1H),3.56(t,J＝7.6Hz,2H),3.37-3.32(m,2H),3.10-3.04(m,1H),2.80–2.69(m,1H),2.22–2.05(m,1H).
实施例35:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000105
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝467[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.30(s,1H),8.66(d,J＝2.0Hz,1H),8.33(s,1H),8.28(d,J＝1.9Hz,1H),8.09(s,1H),7.25–7.09(m,2H),7.09–6.98(m,1H),5.58-5.42(m,1H),5.36-5.29(m,1H),5.15(q,J＝9.1Hz,2H),4.52–4.36(m,1H),4.00(dd,J＝26.7,11.8Hz,1H),2.77–2.61(m,1H),2.18-2.00(m,1H).
实施例36:5-(1-(2,2-二氟乙基)-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000106
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000107
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
5-(1-(2,2-二氟乙基)-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000108
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(1H-吡唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(30mg,0.078mmol)，碳酸铯(63mg,0.194mmol)的N,N-二甲基甲酰胺(1mL)溶液中加入2,2-二氟乙基甲磺酸酯(37mg,0.233mmol)。反应液加热到80度，搅拌3小时。加入水(50mL),用乙酸乙酯(50mL)萃取。有机相,干燥,过滤，浓缩得到5-(1-(2,2-二氟乙基)-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(40mg,收率88.6％)，为黄色油状物。
MS(ESI):m/z＝601[M+H] +.
5-(1-(2,2-二氟乙基)-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000109
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(2,2-二氟乙基)-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝450[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.38(s,1H),8.84(d,J＝1.9Hz,1H),8.38(d,J＝1.8Hz,1H),7.84(d,J＝2.3Hz,1H),7.28–7.11(m,2H),7.11–7.00(m,1H),6.84(d,J＝2.3Hz,1H),6.53–6.27(m,1H),5.57-5.43(m,1H),5.36-5.31(m,1H),4.66(td,J＝15.0,3.8Hz,2H),4.50–4.35(m,1H),4.04-3.94(m,1H),2.79–2.65(m,1H),2.17–1.98(m,1H).
实施例37:2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑
实施例38:2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-(甲氧基甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000110
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-(2-甲氧基乙酰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
Figure PCTCN2019118198-appb-000111
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(200mg,0.406mmol),甲氧基乙酸肼(126mg,1.218mmol)和N,N-二异丙基乙胺(262mg,2.06mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(308mg,0.812mmol)。反应液室温搅拌16小时。加入二氯甲烷(50mL),用水(50mL)洗.有机相,干燥,过滤,浓缩，柱层析(二氯甲烷/甲醇＝20/1)得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-(2-甲氧基乙酰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼(230mg,收率97.9％)，为黄色固体。
MS(ESI):m/z＝601[M+Na] +.
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000112
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-(2-甲氧基乙酰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼(230mg,0.397mmol),4-二甲氨基吡啶(7mg,0.060mmol)的乙腈(6mL)溶液中加入4-甲苯磺酰氯(227mg,1.19mmol)。反应液升温至50度,滴加N,N-二异丙基乙胺(308mg,2.382mmol),在50度搅拌1小时。加入二氯甲烷(50mL),用水(50mL)洗.有机相,干燥,过滤,浓缩，柱层析(石油醚/乙酸乙酯＝1/1)得到2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑(150mg,收率67.4％)，为黄色固体。
MS(ESI):m/z＝561[M+H] +.
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000113
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-(甲氧基甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000114
在0度，向2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑(100mg,0.178mmol)的乙酸乙酯(4mL)溶液中滴加4N盐酸二氧六环(4mL)。反应液0度搅拌2小时。浓缩，用甲醇(5mL)稀释,7N氨甲醇中和，浓缩反向制备得到2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑(14mg,收率18.3％)，为黄色固体。
MS(ESI):m/z＝432[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ8.95(d,J＝2.0Hz,1H),8.61(d,J＝2.0Hz,1H),7.28–7.15(m,2H),7.09-7.03(m,1H),6.03(s,1H),5.51(d,J＝53.2Hz,1H),5.36-5.32(m, 1H),4.72(s,2H),4.54–4.39(m,1H),4.09-4.00(m,1H),3.38(m,3H),2.78–2.68(m,1H),2.18–2.01(m,1H).
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-(甲氧基甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(甲氧基甲基)-1,3,4-噁二唑(17mg,收率20.1％)，为黄色固体。
MS(ESI):m/z＝476[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ9.02(d,J＝1.9Hz,1H),8.63(d,J＝2.0Hz,1H),7.25-7.18(m,2H),7.09-7.03(m,1H),5.59-5.46(m,2H),5.41-5.35(m,2H),4.73(s,2H),4.53-4.39(m,1H),4.15-4.06(m,1H),3.38(s,3H),3.06(s,3H),2.83–2.70(m,1H),2.22–2.04(m,1H).
实施例39:3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
Figure PCTCN2019118198-appb-000115
采用类似于实施例20的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
MS(ESI):m/z＝377[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.56(s,1H),9.90(s,1H),8.79(d,J＝2.0Hz,1H),8.60(d,J＝1.8Hz,1H),7.23-7.17(m,1H),7.16-7.11(m,1H),7.09(s,1H),7.08-7.04(m,1H),6.96(s,1H),5.52(d,J＝52.5Hz,1H),5.32-5.27(m,1H),4.92(s,2H),4.47-4.35(m,1H),4.07-3.98(m,1H),2.78–2.65(m,1H),2.20-2.02(m,1H).
实施例40:5-(1-(2,2-二氟乙基)-4-甲基-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000116
3-溴-1-(2,2-二氟乙基)-4-甲基-1H-吡唑
Figure PCTCN2019118198-appb-000117
采用类似于实施例36的条件,替换相应的起始原料,得到3-溴-1-(2,2-二氟乙基)-4-甲基-1H-吡唑
MS(ESI):m/z＝227[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000118
向5-氯-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(200mg,0.414mmol)，双联硼酸频那醇酯(315mg,1.240mmol)和醋酸钾(122mg,1.242mmol)的二氧六环(8mL)溶液中加入三(二亚苄基丙酮)-二钯(38mg,0.0414mmol)和三环己基膦(23mg,0.828mmol)。反应液氮气置换3次,加热到85度，搅拌过夜。反应液得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶直接用于下一步。
MS(ESI):m/z＝575[M+H] +.
5-(1-(2,2-二氟乙基)-4-甲基-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000119
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(2,2-二氟乙基)-4-甲基-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝593[M+H] +.
5-(1-(2,2-二氟乙基)-4-甲基-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2019118198-appb-000120
采用类似于实施例20的条件,替换相应的起始原料,得到5-(1-(2,2-二氟乙基)-4-甲基-1H-吡唑-3-基)-3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶
MS(ESI):m/z＝464[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.64(d,J＝2.0Hz,1H),8.17(d,J＝1.9Hz,1H),7.64(s,1H),7.26–7.11(m,2H),7.07-7.03(m,1H),6.50–6.20(m,1H),6.00(s,1H),5.41-5.32(m,2H),4.58(td,J＝15.0,3.6Hz,2H),4.44-4.32(m,1H),4.06–3.95(m,1H),2.80–2.66(m,1H),2.11(s,3H),2.08–1.95(m,1H).
实施例41:2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-((三氟甲氧基)甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000121
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
Figure PCTCN2019118198-appb-000122
采用类似于实施例4的条件,替换相应的起始原料,得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
MS(ESI):m/z＝507[M+H] +.
3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-(2-(三氟甲氧基)乙酰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼
Figure PCTCN2019118198-appb-000123
向3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼(382mg,0.75mmol),2-(三氟甲氧基)乙酸(162mg,1.13mmol)和三乙胺(380mg,3.75mmol)的二氧六环(10mL)溶液中加入50％1-丙基磷酸酐的乙酸乙酯(2.3mL,1.13mmol)溶液。反应液40度搅拌16小时。加入二氯甲烷 (50mL),用水(50mL*2)洗.有机相,干燥,过滤,浓缩，柱层析(石油醚/乙酸乙酯＝1/1)得到3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N'-(2-(三氟甲氧基)乙酰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-甲酰肼(377mg,收率79.5％)，为黄色固体。
MS(ESI):m/z＝533[M-SEM+CH 2OH] +.
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-((三氟甲氧基)甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000124
采用类似于实施例37的条件,替换相应的起始原料,得到2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-((三氟甲氧基)甲基)-1,3,4-噁二唑
MS(ESI):m/z＝615[M+H] +.
2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-((三氟甲氧基)甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000125
采用类似于实施例37的条件,替换相应的起始原料,得到2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-((三氟甲氧基)甲基)-1,3,4-噁二唑
MS(ESI):m/z＝486[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.88(s,1H),8.95(d,J＝2.0Hz,1H),8.61(d,J＝2.0Hz,1H),7.24-7.17(m,2H),7.08-7.04(m,1H),5.58-5.44(m,3H),5.41–5.30(m,1H),4.46(dd,J＝39.4,11.7Hz,1H),4.05(dd,J＝25.3,12.2Hz,1H),2.81–2.67(m,1H),2.17-2.02(m,1H).
实施例42:2-(3-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(异丙氧基甲基)-1,3,4-噁二唑
Figure PCTCN2019118198-appb-000126
采用类似于实施例41的条件,替换相应的起始原料,得到2-(3-((2R,4S)-2-(2,5-二氟苯 基)-4-氟吡咯烷-1-基)-1H-吡唑并[3,4-b]吡啶-5-基)-5-(异丙氧基甲基)-1,3,4-噁二唑
MS(ESI):m/z＝460[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.83(s,1H),8.93(d,J＝1.9Hz,1H),8.59(d,J＝1.9Hz,1H),7.28–7.14(m,2H),7.12–6.99(m,1H),5.51(d,J＝52.7Hz,1H),5.36-5.32(m,1H),4.74(s,2H),4.53-4.39(m,1H),4.04(dd,J＝24.9,12.1Hz,1H),3.80-3.74(m,1H),2.80–2.68(m,1H),2.18-2.01(m,1H),1.16(t,J＝11.6Hz,6H).
实施例43:((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)(4-(((1R,2R)-2-羟基环戊基)氨基)-1H-吡唑并[3,4-b]吡啶-3-基)甲酮
Figure PCTCN2019118198-appb-000127
4-(((1R,2R)-2-羟基环戊基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-羧酸
Figure PCTCN2019118198-appb-000128
把甲基4-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-羧酸酯(300mg,0.880毫摩尔),(1R,2R)-2-氨基环戊烷-1-醇盐酸盐(121mg,0.880mmol)和N,N-二异丙基乙胺(341mg,2.62mmol)的N-甲基吡咯烷酮(8mL)溶液封管加热到120度搅拌20小时。反应液浓缩，反相制备得到4-(((1R,2R)-2-羟基环戊基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-羧酸(240mg,收率69.5％)，为黄色固体。
MS(ESI):m/z＝393[M+H] +.
((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)(4-(((1R,2R)-2-羟基环戊基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-基)甲酮
Figure PCTCN2019118198-appb-000129
向4-(((1R,2R)-2-羟基环戊基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-羧酸(240mg,0.61mmol),(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(368mg,1.83mmol)和N,N-二异丙基乙胺(394mg,3.05mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(464mg,1.22mmol),室温搅拌3小时。反应液加入二氯甲烷(50mL),用水(50mL)洗.有机相,干燥,过滤,浓缩，柱层析(石油醚/乙酸乙酯＝1/1)浓缩，得到((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)(4-(((1R,2R)-2-羟基环戊基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(332mg,收率94.5％)，为黄色固体。
MS(ESI):m/z＝572[M+H] +.
((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)(4-(((1R,2R)-2-羟基环戊基)氨基)-1H-吡唑并[3,4-b]吡啶-3-基)甲酮
Figure PCTCN2019118198-appb-000130
采用类似于实施例20的条件,替换相应的起始原料,得到((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)(4-(((1R,2R)-2-羟基环戊基)氨基)-1H-吡唑并[3,4-b]吡啶-3-基)甲酮
MS(ESI):m/z＝447[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.00-7.89(m,1H),7.15–6.69(m,3H),6.38–6.20(m,1H),5.61–5.28(m,2H),4.83-4.73(m,1H),4.43-4.29(m,1H),4.12–3.94(m,1H),3.75-3.68(m,1H),2.88–2.71(m,1H),2.35–1.44(m,7H).
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。
表1
Compound TRKA(nm) TRKB(nm) TRKC(nm)
实施例1 <500 <500 <500
实施例2 <500 <500 <500
实施例3 <50 <100 <50
实施例4 <10 <10 <10
实施例5 <10 <10 <10
实施例6 <50 <50 <50
实施例7 <10 <10 <10
实施例8 <50 <10 <10
实施例9 <50 <10 <50
实施例10 <50 <10 <10
实施例11 <10 <1 <10
实施例12 <10 <50 <10
实施例13 <1 <1 <1
实施例14 <10 <10 <10
实施例15 <10 <10 <10
实施例16 <1 <10 <10
实施例17 <1 <1 <1
实施例18 <500 <500 <500
实施例19 <1 <1 <1
实施例20 <1 <1 <1
实施例21 <1 <1 <1
实施例22 <1 <1 <1
实施例23 <10 <10 <10
实施例24 <10 <500 <100
实施例25 <1 <1 <1
实施例26 <1 <1 <1
实施例27 <1 <1 <1
实施例28 <1 <1 <1
实施例29 <1 <1 <1
实施例30 <1 <1 <1
实施例31 <10 <1 <10
实施例32 <1 <1 <1
实施例33 <1 <1 <1
实施例34 <1 <1 <1
实施例35 <1 <1 <1
实施例36 <1 <1 <1
实施例37 <1 <1 <1
实施例38 <100 <10 <100
实施例39 <1 <1 <1
实施例40 <1 <1 <1
实施例41 <1 <1 <1
实施例42 <1 <1 <1
实施例43 <1 <1 <1
生物测试例2: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正常TRKA或TRKB或TRKC的NIH-3T3细胞株。
第一天接种细胞于96孔细胞培养板,10000细胞/孔于正常培养基中(DMEM+10％FBS)。第二天换含有0.5％FBS的培养基饥饿过夜。第三天加不同浓度的待测化合物处理细胞1个小时,然后用100ng/ul生长因子刺激10分钟(NGF用于激活TRKA,BDNF用于激活TRKB,NT-3用于激活TRKC)。将细胞培养板置于冰上；去掉上清,用预冷的PBS润洗一次。用双蒸水稀释elisa试剂盒中附带的裂解液(Cellsignaling Technology)并加入蛋白酶和磷酸酶抑制剂。将配置好的细胞裂解液加入孔板中,冰上静置20分钟。排枪吹打细胞裂解液数次,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Cellsignaling Technology #7212C中所描述)。
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IC 50值。
结果显示,本发明化合物能够有效的抑制KM12-LUC细胞的增殖，具体见表2。
表2
Figure PCTCN2019118198-appb-000131
生物测试例4 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3。
表3
Figure PCTCN2019118198-appb-000132
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 (10)

  1. 一类如下式I所示的化合物：
    Figure PCTCN2019118198-appb-100001
    其中，
    X 1、X 2和X 3各自独立地为CR或N；
    Y为NR 1，其中，所述的R 1选自下组：H、未取代或被C1-C4烷氧基取代的C1-C6烷基；
    R选自下组：H、D、-OH、-NH 2、卤素、CN；
    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-；
    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C1-C6胺基、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 PCTCN2019118198-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、苄氧基、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 PCTCN2019118198-appb-100003
    C1-C6烷基、C3-C8环烷基、C1-C6胺基、C1-C6酰胺基、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 PCTCN2019118198-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 PCTCN2019118198-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 PCTCN2019118198-appb-100006
    其中，所述的
    Figure PCTCN2019118198-appb-100007
    指R A与L 1的连接位点；
    L 2为
    Figure PCTCN2019118198-appb-100008
    R B为
    Figure PCTCN2019118198-appb-100009
    其中，所述的
    Figure PCTCN2019118198-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 PCTCN2019118198-appb-100011
    其中，所述的Rb和Rc各自独立地选自下组：H、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基；或所述的Rb和Rc与相邻的N原子共同构成取代或未取代的5-12元的杂环基(包括单环、并环、螺环或桥环)。
  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III所示的结构：
    Figure PCTCN2019118198-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 PCTCN2019118198-appb-100013
    Figure PCTCN2019118198-appb-100014
    Figure PCTCN2019118198-appb-100015
    Figure PCTCN2019118198-appb-100016
  6. 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。
  7. 如权利要求6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。
  8. 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6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。
  9. 如权利要求8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。
  10. 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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