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WO2019037761A1 - 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途 - Google Patents

含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途 Download PDF

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Publication number
WO2019037761A1
WO2019037761A1 PCT/CN2018/101960 CN2018101960W WO2019037761A1 WO 2019037761 A1 WO2019037761 A1 WO 2019037761A1 CN 2018101960 W CN2018101960 W CN 2018101960W WO 2019037761 A1 WO2019037761 A1 WO 2019037761A1
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WO
WIPO (PCT)
Prior art keywords
group
amino
alkyl
compound
fluoro
Prior art date
Application number
PCT/CN2018/101960
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English (en)
French (fr)
Inventor
戴丽光
段小伟
杨艳青
刘希杰
李红娟
赵娜
孙颖慧
孔凡胜
张久庆
朱益忠
杨玲
刘飞
Original Assignee
正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
连云港润众制药有限公司
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Publication date
Priority to FIEP18849368.8T priority Critical patent/FI3674307T3/fi
Priority to PL18849368.8T priority patent/PL3674307T3/pl
Application filed by 正大天晴药业集团股份有限公司, 北京赛林泰医药技术有限公司, 连云港润众制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to AU2018320021A priority patent/AU2018320021C1/en
Priority to DK18849368.8T priority patent/DK3674307T3/da
Priority to MX2020001979A priority patent/MX2020001979A/es
Priority to CA3071032A priority patent/CA3071032A1/en
Priority to KR1020207008187A priority patent/KR102619444B1/ko
Priority to BR112020003783-4A priority patent/BR112020003783A2/pt
Priority to CN201880053972.3A priority patent/CN110945000B/zh
Priority to EP18849368.8A priority patent/EP3674307B1/en
Priority to RU2020108770A priority patent/RU2779497C2/ru
Priority to JP2020511268A priority patent/JP7239563B2/ja
Priority to US16/641,187 priority patent/US11098060B2/en
Priority to ES18849368T priority patent/ES2951427T3/es
Publication of WO2019037761A1 publication Critical patent/WO2019037761A1/zh
Priority to ZA2020/01442A priority patent/ZA202001442B/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—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 three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present application relates to macrocyclic compounds containing aminopyrazolopyrimidines, processes for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of Trk kinase mediated diseases.
  • NTRK/TRK Tropomyosin receptor kinase
  • a neurotrophic factor tyrosine kinase receptor is a member of the receptor tyrosine kinase family.
  • the Trk family consists mainly of three members, NTRK1/TrkA, NTRK2/TrkB and NTRK3/TrkC; wherein NGF (nerve growth factor) binds to TrkA, BDNF (derived neurotrophic factor) binds to TrkB, and NT3 (neurotrophic factor 3) Combined with TrkC.
  • Trk kinase plays an important physiological role in the development of nerves.
  • a large number of studies have shown that the activation of Trk signal transduction pathway is also strongly correlated with the occurrence and development of tumors.
  • Activated Trk signaling proteins are found in neuroblastoma, lung adenocarcinoma, pancreatic cancer, breast cancer and the like.
  • the discovery of various Trk fusion proteins in recent years has further demonstrated its biological function of promoting tumorigenesis. The earliest TPM3-TrkA fusion protein was found in colon cancer cells.
  • Trk fusion proteins such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, were found in different types of patients with tumors such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, and glioma. ETV6-NTRK3 and BTB1-NTRK3, etc. These different NTRK fusion proteins are themselves in a highly activated state of kinase activity without the need for ligand binding, thereby continuously phosphorylating downstream signaling pathways, inducing cell proliferation, promoting tumorigenesis and progression, and In preclinical models of cancer, Trk inhibitors are effective in inhibiting tumor growth and preventing tumor metastasis.
  • Trk fusion proteins have become an effective anti-cancer target, for example, WO 2010048314, WO2012116217, WO2010033941, WO2011146336, WO2017035354, etc. all disclose Trk kinase inhibitors having different mother nucleus.
  • Trk kinase inhibitors In view of the important physiological functions of Trk kinase, it is necessary to find effective Trk kinase inhibitors.
  • the application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • X is selected from the group consisting of a bond, -O-, -S- or -NR 4 -;
  • Y is selected from Wherein "*" represents one end of the Y group attached to the aminopyrazolopyrimidine ring;
  • R 1 and R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, hydroxy, cyano or amino, wherein C 1 -C 6 alkyl and a C 1 -C 6 alkoxy group is optionally substituted by one or more substituents independently selected from halogen, nitro, hydroxy, cyano or amino;
  • R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, hydroxy, cyano or amino, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy Substituents are optionally substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano or amino;
  • R 4 and R 5 are independently selected from hydrogen or C 1 -C 6 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n is selected from 0, 1, 2, 3, 4, 5, 6 or 7;
  • Cy is selected from the group consisting of a 6-10 member aromatic ring, a 5-10 membered aromatic heterocyclic ring, a 3-10 membered alicyclic ring or a 3-10 membered cycloalkane, wherein a 6-10 membered aromatic ring and a 5-10 membered aromatic heterocyclic ring are used.
  • the 3-10 membered alicyclic or 3-10 membered cycloalkane is optionally one or more independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Substituted by a halogen, a nitro group, a hydroxyl group, a cyano group or an amino group.
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application.
  • the present application relates to a method of treating a Trk kinase mediated disease in a mammal comprising administering to a mammal in need thereof, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable compound thereof Salt, or a pharmaceutical composition thereof.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by Trk kinase.
  • the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a disease mediated by Trk kinase.
  • the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • X is selected from the group consisting of a bond, -O-, -S- or -NR 4 -;
  • Y is selected from Wherein "*" represents one end of the Y group attached to the aminopyrazolopyrimidine ring;
  • R 1 and R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, hydroxy, cyano or amino, wherein C 1 -C 6 alkyl and a C 1 -C 6 alkoxy group is optionally substituted by one or more substituents independently selected from halogen, nitro, hydroxy, cyano or amino;
  • R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, hydroxy, cyano or amino, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy Substituents are optionally substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano or amino;
  • R 4 and R 5 are independently selected from hydrogen or C 1 -C 6 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n is selected from 0, 1, 2, 3, 4, 5, 6 or 7;
  • Cy is selected from the group consisting of a 6-10 member aromatic ring, a 5-10 membered aromatic heterocyclic ring, a 3-10 membered alicyclic ring or a 3-10 membered cycloalkane, wherein a 6-10 membered aromatic ring and a 5-10 membered aromatic heterocyclic ring are used.
  • the 3-10 membered alicyclic or 3-10 membered cycloalkane is optionally one or more independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Substituted by a halogen, a nitro group, a hydroxyl group, a cyano group or an amino group.
  • X is selected from a bond or -O-.
  • R 4 is selected from hydrogen or C 1 -C 3 alkyl, preferably hydrogen.
  • Y is selected from Wherein "*" denotes the end to which the Y group is attached to the aminopyrazolopyrimidine ring.
  • R 5 is selected from hydrogen or C 1 -C 3 alkyl. In some typical embodiments, R 5 is selected from hydrogen or methyl.
  • Y is selected from the group consisting of *-CONH-, *-CON(CH 3 )- or *-CONHO-, wherein "*" indicates that the Y group is attached to the aminopyrazolopyrimidine ring. One end.
  • R 1 and R 2 are, independently, selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluoro, chloro, bromo, iodo, nitro, hydroxy, cyano, or An amino group, wherein the C 1 -C 3 alkyl group and the C 1 -C 3 alkoxy group are optionally one or more independently selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, hydroxy, cyano or amino. Substituent substitution.
  • R 1 and R 2 are independently selected from hydrogen, fluoro or C 1 -C 3 alkyl. In some more typical embodiments, R 1 and R 2 are independently selected from hydrogen, fluoro or methyl.
  • n is selected from 1, 2, 3, 4, or 5. In some typical embodiments, m is selected from 2, 3 or 4.
  • the structural unit Selected from Where ** indicates a structural unit One end connected to X.
  • the structural unit Selected from Where ** indicates a structural unit One end connected to X.
  • R 3 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluoro, chloro, bromo, iodo, nitro, hydroxy, cyano or amino, wherein C 1 - The C 3 alkyl group and the C 1 -C 3 alkoxy group are optionally substituted by one or more substituents independently selected from fluorine, chlorine, bromine, iodine, nitro, hydroxy, cyano or amino.
  • R 3 is selected from the group consisting of fluorine, chlorine, bromine, iodine, or hydroxyl. In some more typical embodiments, R 3 is selected from fluoro or hydroxy.
  • n is selected from 0, 1, 2, or 3. In some typical embodiments, n is selected from 0 or 1.
  • Cy is selected from the group consisting of a benzene ring, a naphthalene ring, a pyrrole, a furan, a thiophene, an imidazole, an oxazole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, a quinoline, an isoquinoline, a benzofuran, a benzothiophene.
  • hydrazine isoindole, ethylene oxide, tetrahydrofuran, dihydrofuran, pyrrolidine, dihydropyrrolidine, 2H-pyridine, piperidine, piperazine, pyrazolidine, tetrahydropyran, morpholine, sulfur Dimorpholine, tetrahydrothiophene, cyclopropane, cyclopentane or cyclohexane, each optionally one or more independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, Substituted by a group of fluorine, chlorine, bromine, iodine, nitro, hydroxy, cyano or amino.
  • Cy is selected from the group consisting of a benzene ring, a pyridine, or a 1,2-2H-pyridine, each of which is optionally independently selected from fluorine or one or more Replaced by the group.
  • Cy is selected from Each of which is optionally independently selected from fluorine or Replaced by the group.
  • Cy is selected from
  • the compound of formula (I) above is selected from the group consisting of a compound of formula (II),
  • the aforementioned compound of formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the present application is directed to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • compositions of the present application can be prepared by combining a compound of formula (I) of the present application with a suitable pharmaceutically acceptable excipient, for example, as a solid, semi-solid, liquid or gaseous preparation, such as tablets, pills, Capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable excipient for example, as a solid, semi-solid, liquid or gaseous preparation, such as tablets, pills, Capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, ocular Internal, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of formula (I) of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, serum suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions are also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the present application relates to a method of treating a disease mediated by a Trk kinase in a mammal comprising administering to a mammal in need thereof, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable compound thereof Salt, or a pharmaceutical composition thereof.
  • the daily dose is from 0.01 to 300 mg/kg body weight, preferably from 10 to 300 mg/kg body weight, more preferably from 25 to 200 mg/kg body weight, in a single dose or Administration in separate doses.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by Trk kinase.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease mediated by Trk kinase.
  • the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a disease mediated by Trk kinase.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compounds of formula (II) of the present application can be prepared by one skilled in the art of organic synthesis by standard synthetic methods described below, using standard methods in the art, including but not Limited to:
  • R a is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R b is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably ethyl;
  • R c is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably methyl;
  • R 1 , R 2 , R 3 , R 5 , Cy and m are as defined in the above compound of the formula (II).
  • R a is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R b is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably ethyl;
  • R c is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably methyl;
  • R a is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R b is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably ethyl;
  • R c is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably methyl;
  • R d is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R a is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R b is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably ethyl;
  • R c is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably methyl;
  • R 1 , R 2 , R 3 , Cy and m are as defined in the above compound of the formula (II).
  • R a is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • R b is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably ethyl;
  • R c is selected from C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl, further preferably methyl;
  • P is selected from 0, 1, 2, 3 or 4.
  • R 1 , R 2 , R 3 , R 5 and Cy are as defined in the above compound of the formula (II).
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted and the oxo does not occur on the aryl group.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2 , etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C m -C n herein means that the moiety has an integer number of carbon atoms in a given range.
  • C 1 -C 6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent.
  • each R has an independent option; for example, when the structural unit In the case of m ⁇ 2, R 1 and R 2 in each repeating unit have independent options; for example, when the structural unit In the case of n ⁇ 2, each R 3 has an independent option.
  • X is selected from a bond, meaning that X in the compound of formula (I) is absent, ie, the Cy group and the structural unit in the compound of formula (I) Connect directly through covalent bonds.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino means -NH 2 group.
  • nitro refers to a -NO 2 group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C 1 -C 6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl) , tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety i.e., alkyl
  • alkyl in the alkoxy group, alkylamino group, dialkylamino group, alkylsulfonyl group, and alkylthio group has the same definition as defined above.
  • alkoxy refers to -O-alkyl
  • cycloalkane refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkanes include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[2.2.2]octane, adamantane, and the like.
  • aliphatic heterocycle refers to a non-aromatic ring which is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and which may exist as a monocyclic, bicyclic or spiro ring.
  • the heterocyclic ring is typically a 3 to 6 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • Non-limiting examples of aliphatic heterocycles include, but are not limited to, ethylene oxide, tetrahydrofuran, dihydrofuran, pyrrolidine, N-methylpyrrolidine, dihydropyrrole, piperidine, piperazine, pyrazolidine, 4H-pyridyl Methane, morpholine, thiomorpholine, tetrahydrothiophene, and the like.
  • aromatic heterocyclic ring refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred aromatic heterocycles have a single 4- to 8-membered ring, especially a 5- to 8-membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms.
  • Non-limiting examples of aromatic heterocycles include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, pyrazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, benzofuran, benzothiophene, hydrazine , different, etc.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing Or an amount of a compound of the present application that delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • pharmaceutically acceptable is in the sense of those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • h means hour
  • V V means the volume ratio
  • DCM dichloromethane
  • EA means ethyl acetate
  • PE means petroleum ether
  • MeOH means methanol
  • THF means tetrahydrofuran
  • ACN means acetonitrile
  • Toluene means toluene
  • DMF means N,N-dimethylformamide
  • DMSO means dimethyl sulfoxide
  • TEA means triethylamine
  • EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBT refers to 1-hydroxybenzotriazole
  • Ti(OEt) 4 means tetraethyl titanate
  • DMAP 4-dimethylaminopyridine
  • DIAD means diisopropyl azodicarboxylate
  • PPh 3 means triphenylphosphine
  • Pd(PPh 3 ) 4 means tetrakis(triphenylphosphine)palladium
  • PdCl 2 means palladium chloride
  • CuI means cuprous iodide
  • TFA means trifluoroacetic acid
  • TBDMSCl means tert-butyldimethylchlorosilane
  • NaBH 4 means sodium borohydride
  • LiHMDS refers to lithium hexamethyldisilazide
  • (BOC) 2 O means di-tert-butyl dicarbonate
  • NBS means N-bromosuccinimide
  • Dess-Martin means Dess-Martin oxidizer
  • DAST diethylaminosulfur trifluoride
  • HATU O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIEA means N,N-diisopropylethylamine
  • FDPP means pentafluorophenyl diphenyl phosphate
  • LC-MS refers to liquid chromatography coupled with mass spectrometry
  • HMPA hexamethylphosphoric triamide
  • Cs 2 CO 3 means cesium carbonate
  • LiH refers to lithium hydride
  • TLC refers to thin layer chromatography
  • M means a molar concentration unit mol / L, for example 2M means 2mol / L;
  • mM means a molar concentration of unit mmol / liter, for example 2 mM means 2mmol / L;
  • N means an equivalent concentration, for example, 1N HCl means hydrochloric acid having a concentration of 1 mol/L; 2N NaOH means sodium hydroxide having a concentration of 2 mol/L;
  • Ts means p-methylbenzenesulfonyl
  • TsCl means p-toluenesulfonyl chloride
  • Et means ethyl
  • Me means methyl
  • PMB means p-methoxybenzyl
  • Boc means a tert-butoxycarbonyl group
  • TBS means tert-butyldimethylsilyl.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • Non-limiting examples of tautomers include, but are not limited to,
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is substituted by at least one hydrazine.
  • deuterated compounds include, but are not limited to,
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by the use of chiral starting materials or chiral reagents.
  • Non-limiting examples of stereoisomers include, but are not limited to,
  • Step A-1 Synthesis of 2-(3-butyn-1-yl)isoindole-1,3-dione
  • Step B-1 Synthesis of 2-(4-(5-fluoro-2-methoxypyridin-3-yl)-3-butyn-1-yl)isoindole-1,3-dione
  • Step C-1 Synthesis of 4-(5-fluoro-2-methoxypyridin-3-yl)-3-butyn-1-amine
  • Step D-1 Synthesis of 3-(3,4-dihydro-2H-pyrrole-5-yl)-5-fluoro-2-methoxypyridine
  • Step E-1 5-Fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine
  • Step A-2 Synthesis of 4-chloro-N-methoxy-N-methylbutanamide
  • Step B-2 Synthesis of 4-chloro-1-(5-fluoro-2-methoxypyridin-3-yl)butan-1-one
  • n-Butyllithium (2.5 M in hexane) (43 mL) was added dropwise to a solution of 3-bromo-5-fluoro-2-methoxypyridine (20.0 g) in THF (200 mL). During the dropwise addition, the temperature of the reaction system was maintained at -90 ° C. After the completion of the dropwise addition, the mixture was stirred at -90 ° C for 2 h, and 4-chloro-N-methoxy-N-methylbutyramide was added dropwise to the reaction mixture. 17.7g) THF (100mL) solution, the temperature of the reaction system is maintained at -90 ° C during the dropwise addition. After the addition is completed, the temperature is gradually increased to 10 ° C.
  • reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. (100mL ⁇ 3).
  • the organic phase was washed with water and saturated brine.
  • the organic phase was dried over anhydrous sodium sulfate and filtered and evaporated.
  • the residue was purified to silicagel elut elut elut elut elut elut elut elut
  • Step C-2 (S,E)-N-(4-Chloro-1-(5-fluoro-2-methoxypyridin-3-yl)butylene)-2-methylpropane-2-sulfin Amide synthesis
  • Step D-2 (S)-N-(4-Chloro-1-(5-fluoro-2-methoxypyridin-3-yl)butyl)-2-methylpropane-2-sulfinamide synthesis
  • Step E-2 3-((R)-1-((S)-tert-butylsulfinyl)pyrrolidin-2-yl)-5-fluoro-2-methoxypyridine and 3-((S Synthesis of 1-((S)-tert-butylsulfinyl)pyrrolidin-2-yl)-5-fluoro-2-methoxypyridine
  • Step F-2 Synthesis of (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine hydrochloride
  • Step A-3 Synthesis of 4-chloro-1-(5-fluoro-2-methoxyphenyl)butan-1-one
  • Steps B-3, C-3 and D-3 are sequentially carried out with reference to steps C-2, D-2 and E-2 in the synthesis method shown in Intermediate 2.
  • Step E-3 Synthesis of (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine
  • the racemic product of the step D-5 in the intermediate 5 is used as a starting material, and is synthesized by referring to the synthetic step E-5.
  • Step A-9 Synthesis of (R,E)-N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfenamide
  • Step B-9 (R)-N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)but-3-enyl)-2-methylpropane-2- Synthesis of sulfenamide
  • Step C-9 Synthesis of (R)-1-(5-fluoro-2-methoxypyridin-3-yl)but-3-en-1-amine
  • Step D-9 Synthesis of (R)-N-(1-(5-fluoro-2-methoxypyridin-3-yl)but-3-enyl)acetamide
  • Step E-9 Synthesis of (5R)-5-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-3-ylacetate
  • Step F-9 Synthesis of (2R)-4-acetoxy-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Boc anhydride (56.0 mL) was added dropwise to the solution, followed by the addition of aq. sodium hydroxide aqueous solution (50 mL), stirred for 3 h, and 1 L of water was added to the reaction system, ethyl acetate was extracted (100 mL ⁇ 3), and the organic phase was combined.
  • the title compound (45.0 g) was obtained.
  • Step G-9 Synthesis of (2R,4RS)-2-(5-fluoro-2-methoxypyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step H-9 Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-3-yl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
  • Step I-9 Synthesis of (2R,4R)-2-(5-fluoro-2-methoxypyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step J-9 Synthesis of (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step A-10 Synthesis of (Z)-3-amino-4,4,4-trichloro-2-cyano-butenoic acid ethyl ester
  • Triethylamine (2.0 g) was added dropwise to a solution of ethyl cyanoacetate (41.22 g) and trichloroacetonitrile (100 g) in ethanol (120 mL). Stir at 0 ° C for 2 hours, slowly increase to room temperature and continue stirring for 30 minutes. The solvent was evaporated to dryness.
  • Step B-10 Synthesis of 3,5-diamino-1H-pyrazole-4-carboxylic acid ethyl ester
  • Step C-10 Synthesis of 2-amino-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step D-10 Synthesis of 2-amino-5-chloropyrazole [1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step A-13 Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one
  • Step B-13 Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester
  • Step C-13 (2R)-2-((tert-Butyldimethylsilyl)oxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamic acid Synthesis of butyl ester
  • Step D-13 Synthesis of (4R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step E-13 Synthesis of (2R,4R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step F-13 Synthesis of (3R,5R)-5-(5-fluoro-2-hydroxyphenyl)pyrrolidin-3-ol
  • Step G-13 Synthesis of (2R,4R)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Boc 2 O (476 mg) and triethylamine were added dropwise to a solution of (3R,5R)-5-(5-fluoro-2-hydroxyphenyl)pyrrolidin-3-ol (391 mg) in dichloromethane at room temperature. (602 mg), stirred at room temperature overnight. After the completion of the reaction, the title compound (330 mg) was obtained.
  • Step H-13 Synthesis of (2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step I-13 Synthesis of 4-fluoro-2-((2R,4S)-4fluoropyrrolidin-2-yl)phenol
  • Example 1 (1 3 E,1 4 E)-1 2 -amino-3 5 -fluoro-4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a Synthesis of pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidine cycloxan-8-one
  • Step Aa 2-Amino-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Synthesis of ethyl ester
  • Step Ba 2-Amino-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxamide
  • Step Ca (1 3 E,1 4 E)-1 2 -amino-3 5 -fluoro-4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a] Pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidine cyclophanan-8-one
  • Example 1 The following examples were synthesized by referring to the method shown in Example 1.
  • Example 12 (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa-8-aza-1 (5, 3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolidine cyclo-9-one
  • Step Bb 2-Amino-5-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxylate
  • Step Cb 2-Amino-5-((2R,4S)-2-(2-(3-(tert-butoxycarbonylamino)propoxy)-5-fluoropyridin-3-yl)-4-fluoropyrrole Synthesis of Ethyl-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step Db 2-Amino-5-((2R,4S)-2-(2-(3-(tert-butoxycarbonyl)propoxy)-5-fluoropyridin-3-yl)-4-fluoropyrrolidine Synthesis of -1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step Eb 2-Amino-5-((2R,4S)-2-(2-(3-aminopropoxy)-5-fluoropyridin-3-yl)-4-fluoropyrrolidin-1-yl) Synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step Fb (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa-8-aza-1 (5,3 Synthesis of pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclo-9-one
  • Step Bc (S)-2-Amino-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid synthesis
  • Step Cc (S)-2-Amino-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1, Synthesis of 5-a]pyrimidine-3-carboxamide
  • Step Dc (S, 1 3 E, 1 4 E)-1 2 -amino-3 5 -fluoro-4-oxa-7-aza-1(5,3)-pyrazolo[1,5- Synthesis of ⁇ ]pyrimidine-2(1,2)-pyrrolidine-3(1,2)-benzocycloindan-8-one
  • Example 22 (1 3 E,1 4 E,2 2 R)-1 2 -amino-3 5 -fluoro-3 1 ,3 2 -dihydro-7-aza-1(5,3)-pyridyl Zizo[1,5-a]pyrimidin-3(3,1)-pyridine-2(1,2)-pyrrolidinecycloxanthene-3 2 ,8-dione
  • Step Bd (R)-2-Amino-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine Synthesis of 3-carboxylic acid
  • Step Cd (R)-2-Amino-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-hydroxypropyl)pyrr Synthesis of oxazo[1,5-a]pyrimidine-3-carboxamide
  • Step Dd (R)-2-Amino-N-(3-chloropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyridin Synthesis of oxazo[1,5-a]pyrimidine-3-carboxamide
  • Step Ed (R, 1 3 E, 1 4 E)-1 2 -amino-3 5 -fluoro-4-oxa-8-aza-1(5,3)-pyrazolo[1,5- a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidine cyclo-9-one and (1 3 E,1 4 E,2 2 R)-1 2 -amino-3 5 -fluoro-3 1 ,3 2 -dihydro-7-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,1)-pyridine-2 (1, Synthesis of 2)-pyrrolidine cycloxanthene-3 2 ,8-dione
  • Example 23 (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-3 1 ,3 2 -dihydro-7-aza- 1 (5,3) - pyrazolo [1,5-a] pyrimidin-3 (3,1) - pyridin-2 (1,2) - pyrrolidine Fan cyclooctadiene -32, 8-dione synthesis
  • Step Ae 2-Amino-5-((2R,4S)-2-(1-(3-(1,3-dioxoisoindoline-2-yl)propyl)-5-fluoro- Synthesis of Ethyl 2-oxo-1,2-dihydropyridin-3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step Be 2-amino-5-((2R,4S)-2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl) Synthesis of ethyl 4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step De (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-3 1 ,3 2 -dihydro-7-aza-1 (5,3) - pyrazolo [1,5-a] pyrimidin-3 (3,1) - pyridin-2 (1,2) - pyrrolidine Fan cyclooctadiene -32, 8-dione synthesis
  • Example 26 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 6R)-1 2 -amino-2 4 ,3 5 -difluoro-6-methyl-7-aza-1 ( Synthesis of 5,3)-pyrazolo[1,5- ⁇ ]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinylcyclooctan-8-one
  • Step Af 2-Amino-5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(trifluoromethylsulfonyloxy)pyridin-3-yl)pyrrolidine-1- Synthesis of pyridyl[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step Bf 2-Amino-5-((2R,4S)-2-(2-((R)-3-(tert-butoxycarbonylamino)but-1-yn-1-yl)-5-fluoro Synthesis of ethyl pyridin-3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step Cf 2-Amino-5-((2R,4S)-2-(2-((R)-3-(tert-butoxycarbonylamino)butyl)-5-fluoropyridin-3-yl)- Synthesis of ethyl 4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Steps D-f, E-f and F-f are carried out with reference to steps D-b, E-b and F-b in Example 12.
  • Example 26 The following examples were synthesized by referring to the method shown in Example 26.
  • Example 1 The following examples were synthesized by referring to the method shown in Example 1.
  • the TrkA WT kinase activity assay platform was established by homogeneous phase time-resolved fluorescence (HTRF) method for the determination of compound activity.
  • the compound was diluted 5 times with 100% DMSO starting from 200 ⁇ M for 8 times (9 concentrations in total), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM HEPES, pH 7.4, 5 mM MgCl 2 , 0.1).
  • mM NaVO 3 0.001% Tween-20, 0.01% BAS, 1 mM DTT
  • 2*TrkA kinase (final concentration 1 nM) was prepared using reaction buffer, and 4* substrate (ATP+TK peptide) (TK peptide) was prepared using reaction buffer.
  • KinEASE TM -TK purchased from Cisbio, TK peptide, final concentration 1 ⁇ M, ATP final concentration 40 ⁇ M).
  • TrkA G667C KerkA domain kinase was expressed in Sf9 cells using pIEX-Bac-4 and purified by affinity chromatography on AKTA Purifier (GE).
  • the kinase activity assay platform of TrkA G667C was established by homogeneous phase and time-resolved fluorescence (HTRF) method to determine the activity of the compound.
  • the compound was diluted 5 times with 100% DMSO starting from 200 ⁇ M (8 concentrations in total), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM HEPES, pH 7.4, 5 mM MgCl 2 , 0.1 mM NaVO).
  • TrkA G595R KerkA domain kinase was expressed in Sf9 cells using pIEX-Bac-4 and purified by affinity chromatography on AKTA Purifier (GE).
  • the kinase activity assay platform of TrkA G595R was established by homogeneous phase and time-resolved fluorescence (HTRF) method to determine the activity of the compound.
  • the compound was diluted 5 times with 100% DMSO starting from 200 ⁇ M (8 concentrations in total), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM HEPES, pH 7.4, 5 mM MgCl 2 , 0.1 mM NaVO 3 ).
  • the "*” means multiplication, indicating a multiple.
  • “2*TrkA G595R kinase (final concentration 0.2 nM)” refers to a TrkA G595R kinase at a concentration of 0.4 nM.
  • gradient dilution is, for example, "5 times gradient dilution" means adding 4 volumes of the diluted solution to 1 volume of the stock solution 1 to obtain the stock solution 2; taking 1 volume of the stock solution 2, and adding 4 volumes of the diluted solution, The stock solution 3 was obtained; and so on, different concentrations of the solution were obtained.
  • TrkA WT refers to tropomyosin-like kinase A, a wild type.
  • TrkA G667C refers to the mutation of glycine at position 667 of TrkA WT to cysteine.
  • TrkA G595R refers to the mutation of glycine at position 595 of TrkA WT to arginine.
  • HPES 4-hydroxyethylpiperazineethanesulfonic acid
  • MgCl 2 means magnesium chloride
  • NaVO 3 refers to sodium vanadate.
  • Tween-20 means that the volume ratio of Tween 20 to the reaction buffer is 0.001%.
  • 0.01% BAS refers to the mass to volume ratio of bovine serum albumin to reaction buffer, such as 0.01 g of BSA in 100 mL of buffer.
  • DTT refers to dithiothreitol.
  • SEB refers to an enzymatic reaction buffer supplement
  • mM millimoles per liter
  • mice Male SD rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Rats were divided into groups of 3, and a suspension of the test sample (5 mg/kg, suspension of 10% EtOH, 40% PEG 400 and 50% H 2 O) was administered orally by a single oral administration. ). Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, respectively. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4000 rpm for 5 min at 4 ° C, and the plasma was transferred to a centrifuge tube and placed in a centrifuge tube. Store at -80 ° C until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS. The results are shown in Table 2.
  • Example compound 14 15 33 Dose (mg/kg) 5 5 5 T 1/2 (hr) 1.81 1.53 4.22 Tmax(hr) 1.0 0.58 0.50 Cmax(ng/mL) 140 285 142 AUC0-inf(hr*ng/mL) 504 494 513

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Abstract

本申请涉及式(I)所示的含有氨基吡唑并嘧啶的大环化合物、其药物组合物及其在抑制Trk激酶的活性以及治疗哺乳动物的由Trk激酶介导的疾病中的用途。

Description

含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途
相关申请的引用
本申请要求于2017年8月23日向中华人民共和国知识产权局提交的申请号为201710728132.X的中国发明专利申请的权益，在此将它的全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及含有氨基吡唑并嘧啶的大环化合物、其制备方法、含有该化合物的药物组合物及其在治疗Trk激酶介导的疾病中的用途。
背景技术
NTRK/TRK(Tropomyosin receptor kinase)，神经营养因子酪氨酸激酶受体，隶属于受体酪氨酸激酶家族。Trk家族主要包括3个成员，NTRK1/TrkA，NTRK2/TrkB和NTRK3/TrkC；其中，NGF(神经生长因子)结合TrkA，BDNF(衍生的神经营养因子)结合TrkB，以及NT3(神经营养因子3)结合TrkC。
Trk激酶在神经的发育过程中发挥重要的生理功能。大量的研究表明Trk信号转导通途的活化与肿瘤的发生发展也有很强的相关性，在神经细胞瘤、肺腺癌、胰腺癌、乳腺癌等中都发现了活化的Trk信号蛋白。近几年来多种Trk融合蛋白的发现，更显示了其促进肿瘤发生的生物学功能。最早的TPM3-TrkA融合蛋白是在结肠癌细胞中发现的。后来在不同类型的患有如肺癌，头颈癌、乳腺癌、甲状腺癌、神经胶质瘤等肿瘤的病人样本中发现了不同类型的Trk融合蛋白，如CD74-NTRK1、MPRIP-NTRK1、QKI-NTRK2、ETV6-NTRK3和BTB1-NTRK3等。这些不同的NTRK融合蛋白在不需要配体结合的情况下，自身处于高度活化的激酶活性状态，因而能够持续性地磷酸化下游的信号途径，诱导细胞增殖，促进肿瘤的发生、发展，而且在癌症的临床前模型中，Trk抑制剂在抑制肿瘤生长与阻止肿瘤转移中有效。因此，近几年来，Trk融合蛋白已经成为一个有效的抗癌靶点，例如WO2010048314、WO2012116217、WO2010033941、WO2011146336、WO2017035354等均公开了具有不同母核的Trk激酶抑制剂。
鉴于Trk激酶的重要生理功能，寻找有效的Trk激酶抑制剂是十分必要的。
发明概述
一方面，本申请涉及式(I)化合物或其药学上可接受的盐，
Figure PCTCN2018101960-appb-000001
其中，X选自键、-O-、-S-或-NR 4-；
Y选自
Figure PCTCN2018101960-appb-000002
Figure PCTCN2018101960-appb-000003
其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端；
R 1和R 2独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
或R 1和R 2共同构成
Figure PCTCN2018101960-appb-000004
R 3选自C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
R 4和R 5独立地选自氢或C 1-C 6烷基；
m选自0、1、2、3、4、5或6；
n选自0、1、2、3、4、5、6或7；
Cy选自6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃，其中，6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃任选地被一个或多个独立地选自C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2018101960-appb-000005
卤素、硝基、羟基、氰基或氨基的取代基取代。
另一方面，本申请涉及药物组合物，其包含本申请的式(I)化合物或其药学上可接受的盐。
再一方面，本申请涉及治疗哺乳动物的由Trk激酶介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，施用治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。
再一方面，本申请涉及式(I)化合物或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗由Trk激酶介导的疾病的药物中的用途。
还一方面，本申请涉及用于预防或者治疗由Trk激酶介导的疾病的式(I)化合物或其药学上可接受的盐、或其药物组合物。
发明详述
本申请涉及式(I)化合物或其药学上可接受的盐，
Figure PCTCN2018101960-appb-000006
其中，X选自键、-O-、-S-或-NR 4-；
Y选自
Figure PCTCN2018101960-appb-000007
Figure PCTCN2018101960-appb-000008
其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端；
R 1和R 2独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
或R 1和R 2共同构成
Figure PCTCN2018101960-appb-000009
R 3选自C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
R 4和R 5独立地选自氢或C 1-C 6烷基；
m选自0、1、2、3、4、5或6；
n选自0、1、2、3、4、5、6或7；
Cy选自6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃，其中，6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃任选地被一个或多个独立地选自C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2018101960-appb-000010
卤素、硝基、羟基、氰基或氨基的取代基取代。
在一些实施方案中，X选自键或-O-。
在一些实施方案中，R 4选自氢或C 1-C 3烷基，优选为氢。
在一些实施方案中，Y选自
Figure PCTCN2018101960-appb-000011
其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端。
在一些实施方案中，R 5选自氢或C 1-C 3烷基。在一些典型的实施方案中，R 5选自氢或甲基。
在一些更为典型的实施方案中，Y选自*-CONH-、*-CON(CH 3)-或*–CONHO-，其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端。
在一些实施方案中，R 1和R 2独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基、氟、氯、溴、碘、硝基、羟基、氰基或氨基，其中，C 1-C 3烷基和C 1-C 3烷氧基任选地被一个或多个独立地选自氟、氯、溴、碘、硝基、羟基、氰基或氨基的取代基取代。
在一些典型的实施方案中，R 1和R 2独立地选自氢、氟或C 1-C 3烷基。在一些更为典型的实施方案中，R 1和R 2独立地选自氢、氟或甲基。
在一些实施方案中，m选自1、2、3、4或5。在一些典型的实施方案中，m选自2、3或4。
在一些最为典型的实施方案中，结构单元
Figure PCTCN2018101960-appb-000012
选自
Figure PCTCN2018101960-appb-000013
Figure PCTCN2018101960-appb-000014
其中**表示结构单元
Figure PCTCN2018101960-appb-000015
与X相连接的一端。
在一些最为典型的实施方案中，结构单元
Figure PCTCN2018101960-appb-000016
选自
Figure PCTCN2018101960-appb-000017
Figure PCTCN2018101960-appb-000018
Figure PCTCN2018101960-appb-000019
其中**表示结构单元
Figure PCTCN2018101960-appb-000020
与X相连接的一端。
在一些实施方案中，R 3选自C 1-C 3烷基、C 1-C 3烷氧基、氟、氯、溴、碘、硝基、羟基、氰基或氨基，其中，C 1-C 3烷基和C 1-C 3烷氧基任选地被一个或多个独立地选自氟、氯、溴、碘、硝基、羟基、氰基或氨基的取代基取代。
在一些典型的实施方案中，R 3选自氟、氯、溴、碘或羟基。在一些更为典型的实施方案中，R 3选自氟或羟基。
在一些实施方案中，n选自0、1、2或3。在一些典型的实施方案中，n选自0或1。
在一些实施方案中，Cy选自苯环、萘环、吡咯、呋喃、噻吩、咪唑、噁唑、吡唑、吡啶、嘧啶、吡嗪、喹啉、异喹啉、苯并呋喃、苯并噻吩、吲哚、异吲哚、环氧乙烷、四氢呋喃、二氢呋喃、吡咯烷、二氢吡咯烷、2H-吡啶、哌啶、哌嗪、吡唑烷、四氢吡喃、吗啉、硫代吗啉、四氢噻吩、环丙烷、环戊烷或环己烷，各自任选地被一个或多个独立地选自C 1-C 3烷基、C 1-C 3烷氧基、
Figure PCTCN2018101960-appb-000021
氟、氯、溴、碘、硝基、羟基、氰基或氨基的基团取代。
在一些典型的实施方案中，Cy选自苯环、吡啶或1,2-2H-吡啶，各自任选地被一个或多个独立地选自氟或
Figure PCTCN2018101960-appb-000022
的基团取代。
在一些更为典型的实施方案中，Cy选自
Figure PCTCN2018101960-appb-000023
Figure PCTCN2018101960-appb-000024
各自任选地被一个多个独立地选自氟 或
Figure PCTCN2018101960-appb-000025
的基团取代。
在一些更为典型的实施方案中，Cy选自
Figure PCTCN2018101960-appb-000026
Figure PCTCN2018101960-appb-000027
在本申请的一些实施方案中，前述式(I)化合物选自式(II)所示化合物，
Figure PCTCN2018101960-appb-000028
其中，X、R 1、R 2、R 3、R 5、Cy、m和n如前述式(I)化合物中所定义。
在本申请的一些实施方案中，前述式(I)化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
Figure PCTCN2018101960-appb-000029
Figure PCTCN2018101960-appb-000030
Figure PCTCN2018101960-appb-000031
另一方面，本申请涉及药物组合物，其包含本申请的式(I)化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
本申请的药物组合物可通过将本申请的式(I)化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
施用本申请的式(I)化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的式(I)化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。合适的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
另一方面，本申请涉及治疗哺乳动物的由Trk激酶介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，施用治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。
本文所述的式(I)化合物的所有施用方法中，每天给药的剂量为0.01-300mg/kg体重，优选为10-300mg/kg体重，更优选25-200mg/kg体重，以单独剂量或分开剂量的形式给药。
另一方面，本申请涉及式(I)化合物或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗由Trk激酶介导的疾病的药物中的用途。
另一方面，本申请涉及式(I)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗由Trk激酶介导的疾病中的用途。
另一方面，本申请涉及用于预防或者治疗由Trk激酶介导的疾病的式(I)化合物或其药学上可接受的盐、或其药物组合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请的具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域中合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献通过援引方式整体上 并入本申请。
在一些实施方案中，本申请的式(II)化合物可以由有机合成领域的技术人员通过下述示例性的合成方案，用本领域的标准方法来制备，所述示例性的合成方案包括但不限于：
合成方案一：
Figure PCTCN2018101960-appb-000032
其中，R a选自卤素，优选氟、氯、溴或碘；
R b选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选乙基；
R c选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选甲基；
R 1、R 2、R 3、R 5、Cy和m如前述式(II)化合物中所定义。
合成方案二：
Figure PCTCN2018101960-appb-000033
其中，R a选自卤素，优选氟、氯、溴或碘；
R b选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选乙基；
R c选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选甲基；
R 1、R 2、R 3、R 5、Cy和m如前述式(II)化合物中所定义。 合成方案三：
Figure PCTCN2018101960-appb-000034
其中，R a选自卤素，优选氟、氯、溴或碘；
R b选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选乙基；
R c选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选甲基；
R d选自卤素，优选氟、氯、溴或碘；
R 1、R 2、R 3、R 5、Cy和m如前述式(II)化合物中所定义。合成方案四：
Figure PCTCN2018101960-appb-000035
其中，R a选自卤素，优选氟、氯、溴或碘；
R b选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选乙基；
R c选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选甲基；
R 1、R 2、R 3、Cy和m如前述式(II)化合物中所定义。
合成方案五：
Figure PCTCN2018101960-appb-000036
其中，R a选自卤素，优选氟、氯、溴或碘；
R b选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选乙基；
R c选自C 1-C 6烷基，优选C 1-C 3烷基，进一步优选甲基；
P选自0、1、2、3或4。
R 1、R 2、R 3、R 5和Cy如前述式(II)化合物中所定义。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选的”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选地”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-C n表示该部分具有给定范围中的整数个碳原子。例如“C 1-C 6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项；又例如，当结构单元
Figure PCTCN2018101960-appb-000037
中的m≥2时，各个重复单元中的R 1和R 2都有独立的选项；再例如，当结构单元
Figure PCTCN2018101960-appb-000038
中的n≥2时，每个R 3都有独立的选项。
X选自键，即意味着式(I)化合物中的X不存在，即式(I)化合物中Cy基团与结构单元
Figure PCTCN2018101960-appb-000039
直接通过共价键连接。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“氨基”指-NH 2基团。
术语“硝基”指-NO 2基团。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-C 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基中的烷基部分(即烷基)具有上述相同定义。
术语“烷氧基”指-O-烷基。
术语“环烷烃”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3元至10元环。环烷烃的非限制性实例包括但不限于环丙烷、环丁烷、环戊烷、环己烷、双环[2.2.2]辛烷、金刚烷等。
术语“脂杂环”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、双环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至6元环。脂杂环的非限制性实例包括但不限于环氧乙烷、四氢呋喃、二氢呋喃、吡咯烷、N-甲基吡咯烷、二氢吡咯、哌啶、哌嗪、吡唑烷、4H-吡喃、吗啉、硫代吗啉、四氢噻吩等。
术语“芳杂环”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的芳杂环具有单个4元至8元环，尤其是5元至8元环，或包含6个至14个，尤其是6个至10个环原子的多个稠合环。芳杂环的非限制性实例包括但不限于吡咯、呋喃、噻吩、咪唑、噁唑、吡唑、吡啶、嘧啶、吡嗪、喹啉、异喹啉、苯并呋喃、苯并噻吩、吲哚、异吲哚等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，并且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即，遏制其发展；
(iii)缓解疾病或疾病状态，即，使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、疾病状态或障碍，(ii)减轻、改善或消除特定疾病、疾病状态或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、疾病状态或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体施用本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
在本申请中，除非特别定义，所采用的缩略语的含义如下所示：
min是指分钟；
h是指小时；
℃是指摄氏度；
V:V是指体积比；
DCM是指二氯甲烷；
Ac 2O是指醋酸酐；
EA是指乙酸乙酯；
PE是指石油醚；
MeOH是指甲醇；
THF是指四氢呋喃；
ACN是指乙腈；
Toluene是指甲苯；
DMF是指N,N-二甲基甲酰胺；
DMSO是指二甲基亚砜；
TEA是指三乙胺；
EDCI是指1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；
HOBT是指1-羟基苯并三唑；
Ti(OEt) 4是指钛酸四乙酯；
DMAP是指4-二甲氨基吡啶；
DIAD是指偶氮二甲酸二异丙酯；
PPh 3是指三苯基膦；
Pd(PPh 3) 4是指四(三苯基膦)钯；
PdCl 2是指氯化钯；
CuI是指碘化亚铜；
TFA是指三氟乙酸；
TBDMSCl是指叔丁基二甲基氯硅烷；
NaBH 4是指硼氢化钠；
LiHMDS是指六甲基二硅基胺基锂；
(BOC) 2O是指二碳酸二叔丁酯；
NBS是指N-溴代琥珀酰亚胺；
Dess-Martin是指戴斯-马丁氧化剂；
DAST是指二乙胺基三氟化硫；
HATU是指O-(7-氮杂苯并三唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
DIEA是指N,N-二异丙基乙胺；
FDPP是指五氟苯基二苯基磷酸酯；
LC-MS是指液相色谱与质谱联用；
HMPA是指六甲基磷酰三胺；
Cs 2CO 3是指碳酸铯；
LiH是指氢化锂；
TLC是指薄层色谱；
M是指摩尔浓度单位mol/L，例如2M是指2mol/L；
mM是指摩尔浓度单位毫摩尔/升，例如2mM是指2mmol/L；
N是指当量浓度，例如1N HCl是指浓度为1mol/L的盐酸；2N NaOH是指浓度为2mol/L的氢氧化钠；
Ts是指对甲基苯磺酰基；
TsCl是指对甲苯磺酰氯；
Et是指乙基；
Me是指甲基；
Ac是指乙酰基；
PMB是指对甲氧基苄基；
Boc是指叔丁氧碳基；
TBS是指叔丁基二甲基硅基。
本申请的中间体和化合物还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。互变异构体的非限制性实例包括但不限于，
Figure PCTCN2018101960-appb-000040
Figure PCTCN2018101960-appb-000041
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然界中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。氘代化合物的非限制性实例包括但不限于，
Figure PCTCN2018101960-appb-000042
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物中拆分，或通过使用手性原料或手性试剂合成。立体异构体的非限制性实例包括但不限于，
Figure PCTCN2018101960-appb-000043
Figure PCTCN2018101960-appb-000044
为了清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
具体实施例
中间体的制备
中间体1:5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶合成
Figure PCTCN2018101960-appb-000045
步骤A-1:2-(3-丁炔-1-基)异吲哚-1,3-二酮的合成
在0℃下，向邻苯二甲酰亚胺(20.0g)、3-丁炔-1-醇(10.5g)和三苯基膦(39.3g)的甲苯(200mL)混合溶液中缓慢滴加DIAD(34.0g)，滴加完毕后升至室温并继续搅拌1h。向反应混合物中加入甲醇(50mL)并搅拌1h，有大量白色固体析出，过滤，用甲醇洗涤滤饼，得标题化合物(15.6g)；将滤液浓缩，残留物用甲醇打浆，过滤得标题化合物(7.95g)。
1H NMR(400MHz,CDCl 3)δ7.88-7.81(m,4H),3.69(t,J＝6.8Hz,2H),3.80(t,J＝2.8Hz,1H),2.55-2.51(m,2H)。
步骤B-1:2-(4-(5-氟-2-甲氧基吡啶-3-基)-3-丁炔-1-基)异吲哚-1,3-二酮的合成
室温下，将3-溴-5-氟-2-甲氧基吡啶(24.4g)、2-(3-丁炔-1-基)异吲哚-1,3-二酮(23.6g)和三 乙胺(66mL)溶于DMF(200mL)中，向反应体系通氮气10分钟后加入四(三苯基膦)钯(7.0g)和碘化亚铜(2.3g)。氮气保护下，混合物加热至90℃并搅拌2h，冷却至室温，加入甲醇(100mL)，析出大量固体，过滤，用甲醇洗涤滤饼，真空干燥得标题化合物(38.3g)。
1H NMR(400MHz,CDCl 3)δ7.89-7.86(m,3H),7.75-7.73(m,2H),7.35-7.30(m,1H),3.99(t,J＝7.2Hz,2H),3.85(s,3H),2.90(t,J＝7.2Hz,2H)。
步骤C-1:4-(5-氟-2-甲氧基吡啶-3-基)-3-丁炔-1-胺的合成
室温下，向2-(4-(5-氟-2-甲氧基吡啶-3-基)3-丁炔-1-基)异吲哚-1,3-二酮(38.3g)的甲醇(120mL)和二氯甲烷(600mL)中的混合溶液中缓慢滴加水合肼(12.0g,纯度80％)，室温搅拌12h，过滤，二氯甲烷洗涤滤饼，向滤液加入水(500mL)，分液，将有机相用无水硫酸钠干燥后，过滤，滤液减压浓缩得标题化合物(17.6g)。
步骤D-1:3-(3,4-二氢-2H-吡咯-5-基)-5-氟-2-甲氧基吡啶的合成
室温下，将4-(5-氟-2-甲氧基吡啶-3-基)-3-丁炔-1-胺(17.6g)和氯化钯(178mg)在乙腈(200mL)和水(70mL)中的溶液于80℃下搅拌5h，冷却至室温，减压浓缩除去乙腈，用二氯甲烷萃取(200mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液浓缩，将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝20:1(V:V))纯化，得标题化合物(11.2g)。
1H NMR(400MHz,CDCl 3)δ8.04(d,J＝3.2Hz,1H),7.92(dd,J＝8.4,2.8Hz,1H),4.05-3.96(m,5H),3.03-2.98(m,2H),2.04-1.96(m,2H)。
步骤E-1:5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶
在0℃下，向3-(3,4-二氢-2H-吡咯-5-基)-5-氟-2-甲氧基吡啶(11.2g)的甲醇(100mL)和水(25mL)中的混合溶液中分批加入NaBH 4(4.4g)，加料完毕后缓慢升至室温并搅拌2h，用2N盐酸水溶液淬灭反应，减压浓缩除去甲醇，再用饱和的氢氧化钠水溶液将反应体系的pH值调至8，用二氯甲烷萃取(100mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(11.3g)。
1H NMR(400MHz,CDCl 3)δ7.83(d,J＝3.2Hz,1H),7.56(dd,J＝8.8,3.2Hz,1H),4.28(t,J＝7.6Hz,1H),3.92(s,3H),3.15-3.01(m,2H),2.28-2.19(m,1H),1.95-1.78(m,3H),1.59-1.52(m,1H)。
中间体2：(R)-5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶盐酸盐的合成
Figure PCTCN2018101960-appb-000046
步骤A-2:4-氯-N-甲氧基-N-甲基丁酰胺的合成
0℃搅拌下，向N,O-二甲基羟胺盐酸盐(100.0g)的DCM(1500mL)溶液中加入吡啶(250mL)，并继续搅拌30min。然后向该混合物中滴加4-氯丁酰氯(145.0g)，滴加结束后将反应混合物升至室温并继续搅拌2h。将反应混合物倒入水中(250mL)，用二氯甲烷萃取(100mL×3)，将有机相分别用1N盐酸、水洗，然后饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物(125.1g)。
步骤B-2:4-氯-1-(5-氟-2-甲氧基吡啶-3-基)丁-1-酮的合成
-90℃下，将正丁基锂(2.5M在己烷中)(43mL)滴加到3-溴-5-氟-2-甲氧基吡啶(20.0g)的THF(200mL)溶液中，滴加过程中维持反应体系温度在-90℃，滴加完毕后，在-90℃下搅拌2h，向该反应混合物中滴加4-氯-N-甲氧基-N-甲基丁酰胺(17.7g)的THF(100mL)溶液，滴加过程中维持反应体系温度在-90℃，滴加完毕后逐渐升温至10℃，将反应混合物用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取(100mL×3)。将有机相用水和饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液石油醚:乙酸乙酯＝20:1(V:V))纯化，得标题化合物(3.82g)。
1H NMR(400MHz,CDCl 3)δ8.17(d,J＝3.2Hz,1H),7.88(dd,J＝8.0,3.2Hz,1H),4.05(s,3H),3.66(t,J＝6.4Hz,2H),3.22(t,J＝7.2Hz,2H),4.19(dd,J＝13.2,6.4Hz,2H)。
步骤C-2:(S,E)-N-(4-氯-1-(5-氟-2-甲氧基吡啶-3-基)亚丁基)-2-甲基丙烷-2-亚磺酰胺的合成
室温并且搅拌下，向4-氯-1-(5-氟-2-甲氧基吡啶-3-基)丁-1-酮(3.82g)和(S)-2-甲基丙烷-2-亚磺酰胺(3.01g)的THF(20mL)溶液中加入钛酸四乙酯(5.66g)。将混合物在70℃下继续搅拌5h。然后将反应混合物冷却至室温，用饱和氯化铵水溶液淬灭，过滤，滤饼用乙酸乙酯洗涤。将滤液分液，有机相用水和饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(5.09g)。
步骤D-2:(S)-N-(4-氯-1-(5-氟-2-甲氧基吡啶-3-基)丁基)-2-甲基丙烷-2-亚磺酰胺的合成
-78℃下，向(S,E)-N-(4-氯-1-(5-氟-2-甲氧基吡啶-3-基)亚丁基)-2-甲基丙烷-2-亚磺酰胺(5.09g)的THF(20mL)溶液中分批加入NaBH 4(576mg)，加料过程中维持反应体系温度不高于-78℃，滴加完毕后缓慢升温至室温并搅拌1h，反应液缓慢倒入冰水中淬灭，用乙酸乙酯萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(5.12g)。
步骤E-2:3-((R)-1-((S)-叔丁基亚硫酰基)吡咯烷-2-基)-5-氟-2-甲氧基吡啶和3-((S)-1-((S)-叔丁基亚硫酰基)吡咯烷-2-基)-5-氟-2-甲氧基吡啶的合成
Figure PCTCN2018101960-appb-000047
-78℃下，向(S)-N-(4-氯-1-(5-氟-2-甲氧基吡啶-3-基)丁基)-2-甲基丙烷-2-亚磺酰胺(5.12g)的THF(30mL)溶液中缓慢滴加入LiHMDS(1M在THF中)(23mL)，滴加过程中维持反应体系温度不高于-78℃，滴加完毕后缓慢升温至室温，在室温下搅拌2h，用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚：乙酸乙酯＝20:1(V：V))纯化，分别得到所述的两种标题化合物(1.1g)。
E-2-1: 1H NMR(400MHz,CDCl 3)δ7.88(d,J＝3.2Hz,1H),7.32(dd,J＝8.4,3.2Hz,1H),4.96(t,J＝6.8Hz,1H),3.94(s,3H),3.91-3.85(m,1H),3.00-2.94(m,1H),2.25-2.20(m,1H),1.91-1.83(m,2H),1.75-1.68(m,1H),1.18(s,9H).m/z＝301[M+1] +。
E-2-2: 1H NMR(400MHz,CDCl 3)δ7.87(d,J＝2.8Hz,1H),7.32(dd,J＝8.4,2.8Hz,1H),5.22(d,J＝8.0Hz,1H),3.93(s,3H),3.65-3.54(m,2H),2.14-2.09(m,1H),1.93-1.88(m,1H),1.75-1.68(m,2H),1.18(s,9H).m/z＝301[M+1] +。
步骤F-2:(R)-5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶盐酸盐的合成
-10℃下，将化合物E-2-1(2.25g)固体溶于二氯甲烷(20mL)中，缓慢滴加入HCl的1,4-二氧六环溶液(4M，10mL)，滴加完毕后升至室温，并搅拌10min，析出大量白色固体，过 滤，用二氯甲烷洗涤滤饼，真空干燥得标题化合物(1.75g)。
1H NMR(400MHz,DMSO-d 6)δ10.07(brs,1H),9.31(brs,1H),8.18(d,J＝3.2Hz,1H),7.32(dd,J＝8.8,3.2Hz,1H),4.62(t,J＝7.6Hz,1H),3.89(s,3H),3.28-3.24(m,2H),2.30-2.24(m,1H),2.10-1.91(m,3H).m/z＝197[M+1] +。
中间体3和4：(R)-2-(5-氟-2-甲氧基苯基)吡咯烷(中间体3)和(S)-2-(5-氟-2-甲氧基苯基)吡咯烷(中间体4)的合成
Figure PCTCN2018101960-appb-000048
步骤A-3:4-氯-1-(5-氟-2-甲氧基苯基)丁-1-酮的合成
-50℃下，将异丙基氯化镁(2M)的THF(54mL)溶液滴加到2-溴-4-氟苯甲醚(23.5g)的THF(150mL)溶液中。滴加完毕，升至室温并继续搅拌1h。将反应混合物再次冷却至-50℃。搅拌下，向该反应混合液中滴加4-氯-N-甲氧基-N-甲基丁酰胺(9.0g)的THF(30mL)溶液，滴加完毕后逐渐升温至30℃并在30℃下继续搅拌2h。将反应混合物用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取(100mL×3)。有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝20:1(V:V))纯化，得到标题化合物(7.6g)。 1H NMR(400MHz,CDCl 3)δ7.33(dd,J＝9.0,3.2Hz,1H),7.07-7.02(m,1H),6.83(dd,J＝9.0,4.0Hz,1H),3.81(s,3H),3.55(t,J＝6.4Hz,2H),3.07(t,J＝7.0Hz,2H),2.12-2.15(m,2H)。
步骤B-3，C-3和D-3依次参照中间体2中所示的合成方法中的步骤C-2、D-2和E-2实施。
步骤E-3：(R)-2-(5-氟-2-甲氧基苯基)吡咯烷的合成
在0℃下，向(R)-1-((S)-叔丁基亚磺酰基)-2-(5-氟-2-甲氧基苯基)吡咯烷(2.8g)的1,4-二氧六环溶液(25mL)中缓慢滴加入HCl的1,4-二氧六环溶液(4M，14mL)，滴加完毕后升至室温并继续搅拌1h，之后用NaOH水溶液调PH为8，用乙酸乙酯萃取(100mL×3)。有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得中间体3化合物(1.8g)。
中间体3: 1H NMR(400MHz,CDCl 3)δ7.19(dd,J＝9.6,3.0Hz,1H),6.92–6.83(m,1H),6.75(dd,J＝8.8,4.4Hz,1H),4.38(t,J＝7.6Hz,1H),3.80(s,3H),3.19-3.14(m,1H),3.10–2.98(m,1H),2.89(brs,1H),2.34–2.12(m,1H),1.96–1.76(m,2H),1.72–1.52(m,1H)。
中间体4：参照步骤E-3的方法，以(S)-1-((S)-叔丁基亚磺酰基)-2-(5-氟-2-甲氧基苯基)吡咯烷为原料，制备得到中间体4化合物。
1H NMR(400MHz,CDCl 3)δ7.19(dd,J＝9.6,3.0Hz,1H),6.92–6.83(m,1H),6.75(dd,J＝8.8,4.4Hz,1H),4.38(t,J＝7.6Hz,1H),3.80(s,3H),3.19-3.14(m,1H),3.10–2.98(m,1H),2.89(brs,1H),2.34–2.12(m,1H),1.96–1.76(m,2H),1.72–1.52(m,1H)。
中间体5：(R)-2-甲氧基-3-(吡咯烷-2-基)吡啶的合成
Figure PCTCN2018101960-appb-000049
以2-甲氧基-3-溴吡啶为原料，参照中间体3和中间体4所示的合成步骤实施。
Figure PCTCN2018101960-appb-000050
中间体5： 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝4.0Hz,1H),7.69(d,J＝7.2Hz,1H),6.85(dd,J＝7.2,5.2Hz,1H),4.28(t,J＝7.6Hz,1H),3.96(s,3H),3.14-3.19(m,1H),3.06-3.00(m,1H),2.16-2.24(m,2H),1.82-1.89(m,2H),1.60-1.65(m,1H)。
中间体6：(R,S)-2-甲氧基-3-(吡咯烷-2-基)吡啶的合成
以中间体5中步骤D-5的消旋体产物为原料参照合成步骤E-5合成。
Figure PCTCN2018101960-appb-000051
1H NMR(400MHz,CDCl 3)δ8.03(d,J＝4.0Hz,1H),7.69(d,J＝7.2Hz,1H),6.85(dd,J＝7.2,5.2Hz,1H),4.28(t,J＝7.6Hz,1H),3.96(s,3H),3.14-3.19(m,1H),3.06-3.00(m,1H),2.16-2.24(m,2H),1.82-1.89(m,2H),1.60-1.65(m,1H)
中间体7：2-甲氧基-6-(吡咯烷-2-基)吡啶的合成
Figure PCTCN2018101960-appb-000052
以2-甲氧基-6-溴吡啶为原料，参照中间体1所示的合成步骤实施。
Figure PCTCN2018101960-appb-000053
中间体7： 1H NMR(400MHz,CDCl 3)δ7.50(t,J＝8.0Hz,1H),6.85(d,J＝7.6Hz,1H),6.58(d,J＝8.4Hz,1H),4.14(t,J＝7.2Hz,1H),3.92(s,3H),3.26-3.20(m,1H),3.01-2.95(m,1H),2.48(brs,1H),2.18-2.13(m,1H),1.89-1.74(m,3H)。
中间体8：(R)-4-甲氧基-3-(吡咯烷-2-基)吡啶的合成
Figure PCTCN2018101960-appb-000054
以3-溴-4-甲氧基吡啶为原料，参照中间体3和中间体4所示的合成步骤实施。
Figure PCTCN2018101960-appb-000055
中间体8： 1H NMR(400MHz,CDCl 3)δ8.51(s,1H),8.40(d,J＝5.6Hz,1H),6.76(d,J＝6.0Hz,1H),4.33(t,J＝7.6Hz,1H),3.88(s,3H),3.71(brs,1H),3.22-3.16(m,1H),3.05-2.99(m,1H),2.21-2.14(m,2H),1.91-1.85(m,1H),1.75-1.68(m,1H)。
中间体9：5-氟-3-((2R,4S)-4-氟吡咯烷-2-基)-2-甲氧基吡啶的合成
Figure PCTCN2018101960-appb-000056
步骤A-9:(R,E)-N-((5-氟-2-甲氧基吡啶-3-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺的合成
0℃下，向5-氟-2-甲氧基烟醛(54g)的四氢呋喃(250mL)溶液中加入(R)-叔丁基亚磺酰胺(54.8g)，然后向反应体系中滴加钛酸四乙酯(103.2g),滴加完毕后，升至室温并继续搅拌3h。将反应体系冷却至0℃后，滴加饱和食盐水(80mL)，继续搅拌20min，过滤，滤饼用二氯甲 烷洗涤，洗涤液和滤液合并，分液，有机相用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝20:1(V:V))纯化，得标题化合物(88.0g)。
1H NMR(400MHz,CDCl 3)δ8.89(d,J＝2.4Hz,1H),8.15(d,J＝3.2Hz,1H),7.98(dd,J＝8.0,2.8Hz,1H),4.01(s,3H),1.27(s,9H)。
步骤B-9:(R)-N-((R)-1-(5-氟-2-甲氧基吡啶-3-基)丁-3-烯基)-2-甲基丙烷-2-亚磺酰胺的合成
0℃下，向(R,E)-N-((5-氟-2-甲氧基吡啶-3-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(88.0g)的六甲基磷酰三胺(400mL)溶液中依次加入3-溴丙烯(59.2ml)、锌粉(44.7g)和水(6.15ml)，加完撤去冰浴，升温至25℃并搅拌过夜。冷却至0℃，向反应体系中加入水(500ml)，搅拌20min，再加入甲基叔丁基醚(500mL)和10％柠檬酸溶液(100mL)，继续搅拌30min。抽滤，滤液分液，有机相用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝20:1(V:V))纯化，得标题化合物(48.4g)。
1H NMR(400MHz,CDCl 3)δ7.90(d,J＝3.2Hz,1H),7.34(dd,J＝8.0,2.8Hz,1H),5.69-5.60(m,1H),5.08-5.03(m,2H),4.50(dd,J＝14.8,7.2Hz,1H),4.07(d,J＝8.0Hz,1H),3.97(s,3H),2.65-1.72(m,2H),1.21(s,9H)。
步骤C-9:(R)-1-(5-氟-2-甲氧基吡啶-3-基)丁-3-烯-1-胺的合成
室温下，向(R)-N-((R)-1-(5-氟-2-甲氧基吡啶-3-基)丁-3-烯基)-2-甲基丙烷-2-亚磺酰胺(48.4g)的甲醇(250mL)溶液中加入HCl的1,4-二氧六环溶液(4M,67.5mL)，搅拌2h，减压浓缩，残留物倒入水中(250mL)，用饱和碳酸氢钠水溶液调节pH为8，用乙酸乙酯萃取(200mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(40.0g)。
步骤D-9:(R)-N-(1-(5-氟-2-甲氧基吡啶-3-基)丁-3-烯基)乙酰胺的合成
0℃下，向(R)-1-(5-氟-2-甲氧基吡啶-3-基)-丁-3-烯-1-胺(40.0g)的二氯甲烷(200mL)溶液中加入吡啶(19.5mL)和乙酸酐(16mL)，升温至室温并搅拌过夜。将反应液倒入饱和碳酸氢钠水溶液中(500mL)，二氯甲烷萃取(200mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(37.9g)。
1H NMR(400MHz,CDCl 3)δ7.90(d,J＝2.8Hz,1H),7.30(dd,J＝8.0,2.8Hz,1H),6.22(d,J＝8.0Hz,1H),5.67-5.58(m,1H),5.13-5.04(m,3H),3.98(s,3H),2.56-2.52(m,2H),2.00(s,3H)。
步骤E-9:(5R)-5-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-3-基乙酸酯的合成
室温下，向(R)-N-(1-(5-氟-2-甲氧基吡啶-3-基)丁-3-烯基)乙酰胺(37.6g)在四氢呋喃(360mL)和水(84mL)中的溶液中加入碘(113.7g)，搅拌过夜，向反应液中加入饱和碳酸氢钠水溶液(100mL)和饱和亚硫酸钠水溶液(100mL)，乙酸乙酯萃取(100mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(43.0g)。
步骤F-9:(2R)-4-乙酰氧基-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-甲酸叔丁酯的合成
室温下，向(5R)-5-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-3-基乙酸酯(43.0g)的1,4-二氧六环(250)溶液中滴加Boc酸酐(56.0mL)，随后加入pH为9的氢氧化钠水溶液(50mL)，搅拌3h，向反应体系中加入1L水，乙酸乙酯萃取(100mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(45.0g)。
步骤G-9:(2R，4RS)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯的合成
室温下，向(2R)-4-乙酰氧基-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-甲酸叔丁酯(45.0g)的甲醇(500mL)溶液中加入氢氧化钠溶液(2N,88mL)，搅拌1h，减压浓缩除去溶剂，向残余物中加入盐酸(1N,180mL)，二氯甲烷萃取(150mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化，得标题化合物(34.0g)。
步骤H-9:(R)-2-(5-氟-2-甲氧基吡啶-3-基)-4-氧代吡咯烷-1-甲酸叔丁酯的合成
将(2R,4RS)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯(15.1g)溶于二氯甲烷(200mL)中，室温下，加入碳酸氢钠(4.06g)，接着加入Dess-Martin氧化剂(92g)，搅拌过夜。向反应液中加入饱和碳酸氢钠水溶液调节pH至7，二氯甲烷萃取(150mL×3)，有机相合并， 用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化，得标题化合物(10.1g)。
1H NMR(400MHz,CDCl 3)δ7.92(brs,1H),7.30(brs,1H),5.30-5.16(m,1H),4.09-3.88(m,5H),3.06(dd,J＝18.4,10.8Hz,1H),2.56(d,J＝18.0Hz,1H),1.47-1.29(m,9H)。
步骤I-9:(2R,4R)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯的合成
0℃下，向(R)-2-(5-氟-2-甲氧基吡啶-3-基)-4-氧代吡咯烷-1-甲酸叔丁酯(14g)的甲醇(100mL)溶液中分批加入硼氢化钠(1.42g)，维持在0℃，并搅拌45min。向反应液中加入饱和氯化铵水溶液(100mL)，随后逐渐升至室温，二氯甲烷萃取(150mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化，得标题化合物(13.6g)。
1H NMR(400MHz,CDCl 3)δ7.84(brs,1H),7.35-7.19(m,1H),5.09-4.92(m,1H),4.44(d,J＝2.8Hz,1H),3.91(s,3H),3.73-3.70(m,1H),3.62-3.55(m,1H),2.50(brs,1H),1.95(dd,J＝14.0,1.2Hz,1H),1.57-1.18(m,10H)。
步骤J-9:(2R,4S)-4-氟-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-甲酸叔丁酯的合成
-78℃下，向(2R,4R)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯(5.1g)的二氯甲烷(50mL)溶液中加入三氟化二乙氨基硫(5.27g)，保持-78℃并搅拌20min，逐渐升温至室温，并搅拌过夜。向反应体系中加入饱和碳酸氢钠水溶液(100mL)，二氯甲烷萃取(100mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：石油醚:乙酸乙酯＝10:1(V:V))纯化，得标题化合物(3.71g)。
1H NMR(400MHz,CDCl 3)δ7.88(brs,1H),7.23-2.16(m,1H),5.29-5.02(m,2H),4.13-4.04(m,1H),3.94(s,3H),3.71-3.58(m,1H),2.84-2.61(m,1H),2.09-1.80(m,1H),1.50-1.12(m,9H)。步骤K-9:5-氟-3-((2R,4S)-4-氟吡咯烷-2-基)-2-甲氧基吡啶的合成
向(2R,4S)-4-氟-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-甲酸叔丁酯(3.71g)中加入氯化氢的1,4-二氧六环溶液(4M,25mL)，室温搅拌30min，用饱和氢氧化钠水溶液调节pH为8，用乙酸乙酯萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩得标题化合物(3.0g)。
1H NMR(400MHz,CDCl 3)δ7.85(d,J＝3.2Hz,1H),7.62(dd,J＝8.8,3.2Hz,1H),5.33-5.17(m,1H),4.61(t,J＝7.2Hz,1H),3.94(s,3H),3.35(dd,J＝25.6,13.6Hz,1H),3.23-3.10(m,1H),3.71-2.60(m,2H),1.74-0.96(m,1H)。
中间体10：2-氨基-5-氯吡唑[1,5-a]嘧啶-3-甲酸乙酯的合成
Figure PCTCN2018101960-appb-000057
步骤A-10:(Z)-3-氨基-4,4,4-三氯-2-氰基-丁烯酸乙酯的合成
0℃下，向氰基乙酸乙酯(41.22g)和三氯乙腈(100g)的乙醇(120mL)溶液中滴加三乙胺(2.0g)。0℃下搅拌2小时，慢慢升至室温后继续搅拌30分钟。浓缩除去溶剂，残余物用硅胶柱色谱纯化(二氯甲烷洗脱)，得标题化合物(93.0g)。
1H NMR(400MHz,CDCl 3)δ10.20(brs,1H),6.93(brs,1H),4.30(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H)。
步骤B-10:3,5-二氨基-1H-吡唑-4-甲酸乙酯的合成
向(Z)-3-氨基-4,4,4-三氯-2-氰基-丁烯酸乙酯(92.1g)的DMF(250mL)溶液中缓慢滴加水合联氨(50g，浓度80％)，将反应混合物加热到100℃并搅拌1.5小时。浓缩除去溶剂，残余物用二氯甲烷打浆，抽滤，固体用二氯甲烷洗涤、干燥得标题化合物(41.0g)。
1H NMR(400MHz,DMSO-d 6)δ10.4(brs,1H),5.35(brs,4H),4.13(q,J＝7.2Hz,2H),1.24(t,J＝7.2Hz,3H)。
步骤C-10:2-氨基-5-氧代-4,5-二氢吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
Figure PCTCN2018101960-appb-000058
在室温下，向乙醇钠(33.2g)的乙醇(500mL)溶液中依次加入3,5-二氨基-1H-吡唑-4-甲酸乙酯(20.8g)和1,3-二甲基嘧啶-2,4(1H,3H)-二酮(17.0g)。将反应液在90℃下搅拌12小时。将反应液冷却到室温，用1N的盐酸调节体系pH值到7，过滤，固体用乙醇洗涤，干燥得标题化合物(18.4g)。
1H NMR(400MHz,DMSO-d 6)δ11.17(brs,1H),8.24(d,J＝8.0Hz,1H),5.93(s,2H),5.90(d,J＝8.0Hz,1H),4.26(q,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H)。
步骤D-10:2-氨基-5-氯吡唑[1,5-a]嘧啶-3-甲酸乙酯的合成
室温下，向2-氨基-5-氧代-4,5-二氢吡唑并[1,5-a]嘧啶-3-甲酸乙酯(33.6g)的乙腈(500mL)溶液中加入三氯氧磷(110mL)，加热至40℃后并继续搅拌5小时。冷却至室温，减压浓缩，向残余物中加入饱和碳酸氢钠水溶液(250mL)，用乙酸乙酯萃取(200mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法(洗脱液：乙酸乙酯/石油醚＝2:1(V：V))纯化，得标题化合物(4.5g)。
1H NMR(400MHz,CDCl 3)δ8.29(d,J＝7.2Hz,1H),6.80(d,J＝7.2Hz,1H),5.51(brs,2H),4.43(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。
中间体11：5-氟-3-((2R,4R)-4氟吡咯烷-2-基)-2-甲氧基吡啶的合成
Figure PCTCN2018101960-appb-000059
以中间体9的步骤G-9中所得到的(2R,4S)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯为原料，参照中间体9的合成中步骤J-9和步骤K-9合成
1H NMR(400MHz,DMSO-d 6)δ9.45(brs,1H),8.13(d,J＝2.8Hz,1H),7.93(dd,J＝9.2,2.8,Hz,1H),5.60-5.42(m,1H),4.87(d,J＝8.4Hz,1H),3.90(s,3H),3.58-3.36(m,2H),2.77-2.60(m,1H),2.49-2.36(m,1H)。
中间体12：(3R,5R)-5-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-3-醇的合成
Figure PCTCN2018101960-appb-000060
以中间体9的步骤G-9中所得到的(2R,4R)-2-(5-氟-2-甲氧基吡啶-3-基)-4-羟基吡咯烷-1-甲酸叔丁酯为原料，参照中间体9的合成中步骤K-9合成。
1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),9.28(s,1H),8.21(d,J＝3.2Hz,1H),8.01(dd,J＝3.2,9.2Hz,1H),4.80(t,J＝7.2Hz,1H),4.48-4.53(m,1H),3.91(s,3H),3.29-3.34(m,1H),3.01-3.18(m,1H),2.46-2.55(m,1H),2.07-2.14(m,1H)。
中间体13：4-氟-2-((2R,4S)-4-氟吡咯烷-2-基)苯酚的合成
Figure PCTCN2018101960-appb-000061
步骤A-13：(R)-4-((叔丁基二甲基硅基)氧基)吡咯烷-2-酮的合成
将(R)-4-羟基-2-吡咯烷酮(6.0g)溶于DMF(60mL)中，0℃下，加入TBDMSCl(9.8g)和咪唑(6.05g)，升至室温，搅拌3h。监测反应完毕，向反应体系中加入水，有固体析出，过滤，红外灯下干燥过夜，得标题化合物(10.7g)。
1H NMR(400MHz,CDCl 3)δ7.45(s,1H),4.44(m,1H),3.42(m,1H),2.93(m,1H),2.40(m,1H),1.85(m,1H),0.79(s,9H),0.00(s,6H)。
步骤B-13：(R)-4-((叔丁基二甲基硅基)氧基)-2-氧代吡咯烷-1-甲酸叔丁酯的合成
0℃下，向(R)-4-((叔丁基二甲基硅基)氧基)吡咯烷-2-酮(10.67g)的乙腈溶液中加入三乙胺(8.26mL)和DMAP(3.0g)，氮气保护下滴加(Boc) 2O(15mL),加完，搅拌5min，升至室温并继续搅拌过夜。反应体系倒入水中，乙酸乙酯萃取，柱层析(PE/EA＝10/1)，得标题化合物(14.5g)。
1H NMR(400MHz,CDCl 3)δ4.38-4.40(m,1H),3.86(dd,J＝11.4,5.6Hz,1H),3.62(dd,J＝11.4,3.2Hz,1H),2.71(dd,J＝15.6,5.6Hz,1H),2.48(dd,J＝3.4,5.6Hz,1H),1.56(s,9H),0.89(m,9H),0.08(m,6H)。
步骤C-13：(2R)-2-((叔丁基二甲基硅基)氧基)-4-(5-氟-2-甲氧基苯基)-4-羟基丁基氨基甲酸叔丁酯的合成
将5-氟-2-甲氧基-溴苯(9.75g)溶于干燥后的四氢呋喃，冷却至0℃，加入异丙基氯化镁(2M,23.5mL)，反应体系升至70℃，搅拌2h；然后再冷却至0℃，向体系中加入(R)-4-((叔丁基二 甲基硅基)氧基)-2-氧代吡咯烷-1-甲酸叔丁酯(15.0g)的四氢呋喃溶液，再次升至室温，搅拌2h。0℃，加入甲醇，随后加入硼氢化钠(1.78g)，搅拌2h，反应完毕，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，柱层析(PE/EA＝13/1)，得标题化合物(4.2g)。
步骤D-13：(4R)-4-(叔丁基二甲基硅基氧基)-2-(5-氟-2-甲氧基苯基)吡咯烷-1-甲酸叔丁酯的合成
将(2R)-2-((叔丁基二甲基硅基)氧基)-4-(5-氟-2-甲氧基苯基)-4-羟基丁基氨基甲酸叔丁酯(4.2g)溶于二氯甲烷中，冷却至-60℃，滴加三乙胺(3.95mL)和甲基磺酰氯(0.807mL)，保持该温度搅拌1h，加入DBU(2.1mL)，升至室温并继续搅拌3h，监测反应完毕，将反应体系倒入水中，二氯甲烷萃取(50mL×3)，有机相用饱和食盐水洗，硫酸钠干燥，柱层析(PE/EA＝15/1)，得标题化合物(3.18g)。
步骤E-13：(2R,4R)-2-(5-氟-2-甲氧基苯基)-4-羟基吡咯烷-1-甲酸叔丁酯的合成
将(4R)-4-(叔丁基二甲基硅基氧基)-2-(5-氟-2-甲氧基苯基)吡咯烷-1-甲酸叔丁酯(3.18g)溶于四氢呋喃中，0℃下加入三水合四丁基氟化铵(3.5g)，搅拌1h，监测反应完毕，将反应体系倒入冰水中，乙酸乙酯萃取(×2)，柱层析(洗脱液梯度洗脱：PE/EA＝20/1-10/1-1/1(V:V))纯化，得到目标化合物(1.2g)。
步骤F-13:(3R,5R)-5-(5-氟-2-羟基苯基)吡咯烷-3-醇的合成
0℃下，向(2R,4R)-2-(5-氟-2-甲氧基苯基)-4-羟基吡咯烷-1-甲酸叔丁酯(600mg)的二氯甲烷溶液中滴加三溴化硼溶液(0.746mL)，升至室温并搅拌过夜。LCMS及TLC监测反应完毕，将反应体系倒入冰水中，DCM/iPrOH＝3/1(V/V)的混合溶剂萃取(150ml×3)，有机相以硫酸钠干燥，过滤，滤液除去溶剂，得到(3R,5R)-5-(5-氟-2-羟基苯基)吡咯烷-3-醇(391mg)。
1H NMR(400MHz,CDCl 3)δ6.83-6.95(m,2H),6.63-6.66(m,1H),4.26-4.33(m,2H),3.32(s,1H),3.01-3.04(m,1H),2.76-2.79(m,1H),2.38-2.45(m,1H),1.55-1.62(m,1H)。。
步骤G-13：(2R,4R)-2-(5-氟-2-羟基苯基)-4-羟基吡咯烷-1-甲酸叔丁酯的合成
室温下，向(3R,5R)-5-(5-氟-2-羟基苯基)吡咯烷-3-醇(391mg)的二氯甲烷溶液中滴加Boc 2O(476mg)和三乙胺(602mg)，室温搅拌过夜。监测反应完毕，除去溶剂，柱层析(洗脱液梯度洗脱：PE/EA＝3/1-1/1(V/V))纯化，得到标题化合物(330mg)。
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),7.16(s,1H),6.72-6.76(m,1H),6.62-6.66(m,1H),5.15(s,1H),4.55(s,1H),3.77-3.81(m,1H),3.53-3.56(m,1H),2.58-2.66(m,1H),2.04-2.15(m,1H),1.41(s,9H)。。
步骤H-13：(2R,4S)-4-氟-2-(5-氟-2-羟基苯基)吡咯烷-1-甲酸叔丁酯的合成
-78℃下，向(2R,4R)-2-(5-氟-2-羟基苯基)-4-羟基吡咯烷-1-甲酸叔丁酯(330mg)的二氯甲烷溶液中滴加DAST(359mg)试剂，保持该温度下搅拌2h，逐渐升至室温并搅拌过夜。0℃下，加入饱和碳酸氢钠溶液淬灭，二氯甲烷萃取(200ml×2)，有机相以饱和食盐水洗，硫酸钠干燥，柱层析(洗脱液：PE/EA＝7/1(V/V)纯化，得到标题化合物(145mg)。
1H NMR(400MHz,CDCl 3)δ6.82-7.02(m,1H),6.62-6.80(m,2H),5.10-5.40(m,2H),3.90-4.20(m,2H),3.81-3.50(m,1H),3.60-3.78(m,1H),2.18-2.6(m,1H),1.35(s,9H)。
步骤I-13：4-氟-2-((2R,4S)-4氟吡咯烷-2-基)苯酚的合成
室温下，向(2R,4S)-4-氟-2-(5-氟-2-羟基苯基)吡咯烷-1-甲酸叔丁酯(145mg)的二氯甲烷溶液中加入4N氯化氢的1,4-二氧六环溶液(3mL)，搅拌1h，监测反应完毕，除去溶剂无需进一步纯化，即得到4-氟-2-((2R,4S)-4氟吡咯烷-2-基)苯酚(100mg)。
实施例化合物
实施例1：(1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环辛蕃-8-酮的合成
Figure PCTCN2018101960-appb-000062
步骤A-a:2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
向反应管中的2-氨基-5-氯吡唑[1,5-a]嘧啶-3-甲酸乙酯(3.3g)和2-(2-甲氧基-5-氟吡啶基)吡咯烷(3.0g)的正丁醇(50mL)溶液中加入DIEA(5.39g)，封管，升至160℃反应5h。冷却至室温，减压浓缩去除溶剂，残留物用硅胶柱层析纯化(洗脱液：石油醚:乙酸乙酯＝4:1(V:V))，得标题化合物(5.2g)。
1H NMR(400MHz,CDCl 3)δ7.89-8.07(m,2H),7.04(s,1H),5.63(s,1H),5.22-5.30(m,2H),5.03(m,1H),3.50-4.50(m,7H),2.45(s,1H),1.86-2.04(m,3H),1.40-1.48(m,2H),1.13-1.20(m,1H)。
步骤B-a:2-氨基-5-(2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)-N-(2-羟乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺的合成
向反应管中的2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(600mg)的正丁醇(3mL)溶液中加入乙醇胺(4mL)，封管，加热至160℃反应16h，减压浓缩去除溶剂，残留物用硅胶柱层析纯化得标题化合物(263mg)。
步骤C-a:(1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环辛蕃-8-酮
0℃下，向三苯基膦(344mg)和2-氨基-5-(2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)-N-(2-羟乙基)吡唑并[1,5-α]嘧啶-3-甲酰胺(263mg)的四氢呋喃(10mL)溶液中加入偶氮二甲酸二异丙酯(265mg)，升至室温搅拌过夜，减压浓缩去除溶剂，残留物用硅胶柱层析纯化(二氯甲烷:甲醇＝20:1)，得标题化合物(66.0mg)。
1HNMR(400MHz,CDCl 3)δ8.85-8.93(brs,1H),7.99(d,J＝7.6Hz,1H),7.85(d,J＝3.2Hz,1H),7.23(dd,J＝8.4,2.8Hz,1H),6.02(d,J＝7.2Hz,1H),5.66-5.70(m,1H),5.12-5.21(brs,2H),5.06-5.11(m,1H),4.32-4.38(m,1H),3.83-3.95(m 2H),3.64-3.69(m 2H),2.35-2.57(m,2H),2.16-2.27(m,1H),1.91-1.99(m 1H)。
以下实施例参照实施例1所示方法合成
Figure PCTCN2018101960-appb-000063
Figure PCTCN2018101960-appb-000064
Figure PCTCN2018101960-appb-000065
Figure PCTCN2018101960-appb-000066
实施例12：(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-4-氧杂-8-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环壬蕃-9-酮
Figure PCTCN2018101960-appb-000067
步骤A-b:2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
参照实施例1中的步骤A-a实施，将2-(2-甲氧基-5-氟吡啶基)吡咯烷替换成5-氟-3-((2R,4S)-4-氟吡咯烷-2-基)-2-甲氧基吡啶。
步骤B-b:2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
向2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(1.0g)中加入HCl的1,4-二氧六环溶液(3.5M,4mL)，加热至100℃并封管反应3h，降至室温后减压浓缩得标题化合物(0.6g)。
步骤C-b:2-氨基-5-((2R,4S)-2-(2-(3-(叔丁氧羰基氨基)丙氧基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
0℃下，向三苯基膦(778mg)的四氢呋喃(15mL)溶液中加入偶氮二甲酸二异丙酯(600mg)，搅拌20min，加入2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(400mg)，升至室温搅拌过夜，减压浓缩去除溶剂，残留物用硅胶柱层析纯化(洗脱液：二氯甲烷:甲醇＝20:1(V:V))，得标题化合物(250mg)。
步骤D-b:2-氨基-5-((2R,4S)-2-(2-(3-(叔丁氧羰基)丙氧基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
向2-氨基-5-((2R,4S)-2-(2-(3-(叔丁氧羰基氨基)丙基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(375mg)的甲醇(10mL)溶液中加入饱和氢氧化钠水溶液(2mL)，加热至80℃搅拌3h，除去甲醇，用稀盐酸调节pH小于5，用二氯甲烷/异丙醇(V/V＝3/1)混合溶剂萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物(310mg)。
步骤E-b:2-氨基-5-((2R,4S)-2-(2-(3-氨基丙氧基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
将2-氨基-5-((2R,4S)-2-(2-(3-(叔丁氧羰基)丙基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(310mg)溶于二氯甲烷(100mL)中，加入HCl的1,4-二氧六环溶液(4M,30mL)，反应10min，减压浓缩得标题化合物(205mg)。
步骤F-b:(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-4-氧杂-8-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环壬蕃-9-酮的合成
将2-氨基-5-((2R,4S)-2-(2-(3-氨基丙氧基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(20mg)溶于DMF(2mL)中，0℃下加入五氟苯基二苯基磷酸酯(20mg)和二异丙基 乙基胺(31mg)，升至室温并搅拌过夜。将反应液倒入水中(50mL)，用乙酸乙酯萃取(25mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压下浓缩。将残留物用硅胶柱色谱法纯化(二氯甲烷:甲醇＝20:1)，得标题化合物(8.2mg)。
1HNMR(400MHz,CDCl 3)δ8.05(d,J＝7.6Hz,1H),7.91-7.98(m,1H),7.86(d,J＝2.8Hz,1H),7.13(dd,J＝8.4,2.8Hz,1H),6.02(d,J＝7.6Hz,1H),5.83-5.88(m,1H),5.41-5.55(m,3H),5.23-5.28(m,1H),3.97-4.24(m,3H),3.40-3.48(m,1H),2.80-2.91(m,1H),2.26-2.36(m,1H),1.90-2.09(m,3H)。
以下实施例参照实施例12所示方法合成
Figure PCTCN2018101960-appb-000068
Figure PCTCN2018101960-appb-000069
实施例20:(S,1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-α]嘧啶-2(1,2)-吡咯烷-3(1,2)-苯并环辛蕃-8-酮的合成
Figure PCTCN2018101960-appb-000070
步骤A-c:(S)-2-氨基-5-(2-(5-氟-2-甲氧基苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
参照实施例1中的步骤A-a实施。
1H NMR(400MHz,CDCl 3)δ7.81(d,J＝6.4,1H),6.91–6.71(m,3H),5.64(d,J＝6.4,1H),5.20-5.14(m,3H),4.38(m,2H),4.06-3.94(m,2H),3.88(s,3H),2.44(m,1H),2.05-1.96(m,3H),1.46(m,3H)。
步骤B-c:(S)-2-氨基-5-(2-(5-氟-2-羟基苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
0℃下，向(S)-2-氨基-5-(2-(5-氟-2-甲氧基苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(160mg)的二氯甲烷(10mL)溶液中加入三溴化硼(193μL)。升至室温并搅拌过夜，加入饱和碳酸氢钠水溶液调至碱性(pH＝8)，再用1N的盐酸溶液调pH值至4，用二氯甲烷萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物(95.3mg)。
步骤C-c:(S)-2-氨基-5-(2-(5-氟-2-羟基苯基)吡咯烷-1-基)-N-(2-羟基乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺的合成
0℃下，向(S)-2-氨基-5-(2-(5-氟-2-羟基苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(160mg)和乙醇胺(72mg)的DMF(8mL)溶液中加入EDCI(224mg)、HOBt(158mg)和三乙胺(272μL)，升至室温并搅拌过夜，加入水(10mL)，用乙酸乙酯萃取(50mL×3)，有机相合并，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化(洗脱液：二氯甲烷:甲醇＝20:1(V:V))，得标题化合物(66mg)。
步骤D-c:(S,1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-α]嘧啶-2(1,2)-吡咯烷-3(1,2)-苯并环辛蕃-8-酮的合成
Figure PCTCN2018101960-appb-000071
参照实施1中的步骤C-a实施。
1HNMR(400MHz,CDCl 3)δ9.13-9.20(brs,1H),7.92(d,J＝7.6Hz,1H),6.75-6.81(m,3H),5.96(d,J＝7.2Hz,1H),5.80-5.83(m,1H),5.07(s,2H),4.41-4.47(m,1H),4.26-4.31(m,1H),3.78-3.85(m,2H),3.55-3.61(m,2H),2.33-2.43(m,2H),2.08-2.15(m,1H),1.83-1.89(m,1H)。
实施例21和实施例22的合成
实施例21：(R,1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-8-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环壬蕃-9-酮
实施例22:(1 3E,1 4E,2 2R)-1 2-氨基-3 5-氟-3 1,3 2-二氢-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,1)-吡啶-2(1,2)-吡咯烷环辛蕃-3 2,8-二酮
Figure PCTCN2018101960-appb-000072
步骤A-d:(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
参照实施例1的步骤A-a实施。
1H NMR(400MHz,CDCl 3)δ8.20-7.81(m,2H),7.05(brs,1H),6.22-5.48(m,1H),5.23(brs,2H),5.03(brs,1H),4.45-4.26(m,1H),4.20-3.42(m,6H),2.45(brs,1H),2.10-1.81(m,3H),1.45(brs,2H),1.23(brs,1H).m/z＝401[M+1] +。
步骤B-d:(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温下，将氢氧化锂一水合物(500mg)加入到(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(896mg)、水(2mL)和甲醇(10mL)的混合物中，加热至80℃并回流5小时。减压浓缩除去甲醇，向残留物中加入水(20mL)，用1N盐酸水溶液调节pH值为2，析出大量白色固体，过滤，将固体真空干燥，得标题化合物(656mg)。
步骤C-d:(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)-N-(3-羟基丙基)吡唑并[1,5-a]嘧啶-3-甲酰胺的合成
氮气保护下，向(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(325mg)和3-氨基丙醇(100mg)的干燥DMF(9mL)溶液中依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(502mg,)、1-羟基苯并三唑(354mg)和三乙胺(441mg)。加完室温搅拌过夜。加入水(20mL)和乙酸乙酯(100mL)，搅拌5分钟，分液，有机相用无水硫酸钠干燥，过滤，滤液浓缩得标题化合物(137mg)。
步骤D-d:(R)-2-氨基-N-(3-氯丙基)-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺合成
将(R)-2-氨基-5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)-N-(3-羟基丙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(130mg)和HCl的1,4-二氧六环溶液(4M，6mL)的混合物密封于加压管中，加热至100℃并继续反应1小时，冷却至室温后，减压浓缩除去1,4-二氧六环，得标题化合物(110mg)。步骤E-d:(R,1 3E,1 4E)-1 2-氨基-3 5-氟-4-氧杂-8-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环壬蕃-9-酮和(1 3E,1 4E,2 2R)-1 2-氨基-3 5-氟-3 1,3 2-二氢-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,1)-吡啶-2(1,2)-吡咯烷环辛蕃-3 2,8-二酮的合成
将(R)-2-氨基-N-(3-氯丙基)-5-(2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(110mg)、碳酸铯(414mg)和DMF(6mL)的混合物加热到80℃并搅拌6h，加入水(20mL)和乙酸乙酯(100mL)，搅拌5分钟，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(洗脱液：二氯甲烷:甲醇＝20:1(V:V))，分别得到标题所述的两种化合物(15mg)。
Figure PCTCN2018101960-appb-000073
1H NMR(400MHz,CDCl 3)δ7.99(d,J＝7.6Hz,2H),7.84(brs,1H),7.14(d,J＝8.4Hz,1H),6.02(d,J＝7.6Hz,1H),5.76-5.74(m,1H),5.41(brs,2H),5.24-5.20(m,1H),4.20(d,J＝8.8Hz,1H),4.02-3.95(m,1H),3.92-3.86(m,1H),3.65(dd,J＝17.2,7.6Hz,1H),3.46(t,J＝6.8Hz,1H),2.49-2.19(m,4H),2.061.95(m,1H),1.90-1.83(m,1H).m/z＝398[M+1] +。
Figure PCTCN2018101960-appb-000074
1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.6Hz,1H),7.37(brs,1H),7.05-6.98(brs,2H),6.01(d,J＝7.6Hz,1H),5.51(t,J＝7.2Hz,1H),5.41(brs,2H),5.07(t,J＝12.4Hz,1H),4.39-4.31(m,1H),3.81-3.65(m,2H),3.43-3.31(m,2H),2.56-2.53(m,1H),2.39-1.98(m,3H),1.94-1.76(m,2H).m/z＝398[M+1] +。
实施例23:(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-3 1,3 2-二氢-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,1)-吡啶-2(1,2)-吡咯烷环辛蕃-3 2,8-二酮的合成
Figure PCTCN2018101960-appb-000075
步骤A-e:2-氨基-5-((2R,4S)-2-(1-(3-(1,3-二氧代异二氢吲哚-2-基)丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
Figure PCTCN2018101960-appb-000076
0℃下，向2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(380mg)的DMF(8mL)溶液中加入氢化锂(12mg)，搅拌5min后加入N-溴代丙基邻苯二甲酰胺(500mg)，升至室温并搅拌4h。加入水(20mL)，用二氯甲烷萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩去除溶剂得粗产品，无需纯化，直接投入下一步。
步骤B-e:2-氨基-5-((2R,4S)-2-(1-(3-氨基丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
室温下向2-氨基-5-((2R,4S)-2-(1-(3-(1,3-二氧代异二氢吲哚-2-基)丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(120mg)的甲醇(8mL)溶液中加入水合联氨(0.5mL，浓度80％)，加热至50℃并搅拌5h，减压浓缩除去溶剂得粗产品，无需纯化，直接投入下一步。
步骤C-e:2-氨基-5-((2R,4S)-2-(1-(3-氨基丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温下向2-氨基-5-((2R,4S)-2-(1-(3-氨基丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的甲醇(8mL)溶液中加入氢氧化钠(300mg)，加热至70℃并搅拌1h，用浓盐酸调节pH为5，过滤，将固体干燥得粗产品，无需纯化，直接投入下一步。
步骤D-e:(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-3 1,3 2-二氢-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,1)-吡啶-2(1,2)-吡咯烷环辛蕃-3 2,8-二酮的合成
将2-氨基-5-((2R,4S)-2-(1-(3-氨基丙基)-5-氟-2-氧代-1,2-二氢吡啶-3-基)-4-氟吡咯烷-1-基基)吡唑并[1,5-a]嘧啶-3-甲酸、N,N-二异丙基乙胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑溶于N,N-二甲基甲酰胺和二氯甲烷的混合溶剂中(50mL，V:V＝1:1)，室温搅拌4h，除去溶剂后经柱层析纯化(洗脱液：二氯甲烷:甲醇＝20:1(V:V))得到目标产物(2mg)。
1H NMR(400MHz,CD 3OD)δ8.15(d,J＝7.6Hz,1H),7.62-7.64(m,1H),7.50-7.52(m,1H),7.44-7.46(m,1H),6.29(d,J＝7.6Hz,1H),5.43-5.62(m,2H),4.92-4.98(m,1H),4.11-4.25(m,2H),3.91-4.00(m,1H),3.64-3.68(m,1H),3.30-3.37(m,1H),2.78-2.80(m,1H),2.05-2.23(m,2H),1.78-1.81(m,1H).m/z＝416[M+1] +。
以下实施例参照实施例23所示方法合成
Figure PCTCN2018101960-appb-000077
Figure PCTCN2018101960-appb-000078
实施例26：(1 3E,1 4E,2 2R,2 4S,6R)-1 2-氨基-2 4,3 5-二氟-6-甲基-7-氮杂-1(5,3)-吡唑并[1,5-α]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷基环辛蕃-8-酮的合成
Figure PCTCN2018101960-appb-000079
步骤A-f:2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-(三氟甲基磺酰氧基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
向2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(1.8g)和三乙胺(1.43mL)的DMF(15mL)溶液中加入N-苯基双(三氟甲烷)磺酰亚胺(1.76g)。室温搅拌过夜，加入水(100mL)淬灭反应，乙酸乙酯萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(洗脱液：二氯甲烷:甲醇＝20:1(V:V))得标题化合物(1.6g)。
步骤B-f:2-氨基-5-((2R,4S)-2-(2-((R)-3-(叔丁氧基羰基氨基)丁-1-炔-1-基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
在室温和氮气保护下，向2-氨基-5-((2R,4S)-4-氟-2-(5-氟-2-(三氟甲基磺酰氧基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(600mg)和N-[(1R)-1-甲基-2-丙炔-1-基]氨基甲酸叔丁酯(378mg)的DMF(8mL)溶液中加入碘化亚铜(43mg)、双三苯基磷二氯化钯(157mg)、 二异丙乙基胺(417uL)。加热至65℃并搅拌9小时，减压浓缩除去DMF，残留物用硅胶柱层析纯化(二氯甲烷:甲醇＝20:1)得标题化合物(563mg)。
1H NMR(400MHz,CDCl 3)δ8.37(s,1H),8.04-8.01(m,1H),7.28-7.23(m,1H),5.80–5.30(m,4H),4.85-4.79(m,3H),4.33(m,2H),4.13-4.10(m,2H),3.05(m,1H),2.05(m,1H),1.54-1.44(m,15H).m/z＝556[M+1] +。
步骤C-f:2-氨基-5-((2R,4S)-2-(2-((R)-3-(叔丁氧基羰基氨基)丁基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
向2-氨基-5-((2R,4S)-2-(2-((R)-3-(叔丁氧基羰基氨基)丁-1-炔-1-基)-5-氟吡啶-3-基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(563mg)的甲醇(100mL)溶液中加入氢氧化钯碳(20％)(860mg)，氢气置换三次，氢气球保护，室温搅拌过夜，抽滤，将滤液减压浓缩得标题化合物。
步骤D-f、E-f和F-f参照实施例12中的步骤D-b、E-b和F-b实施。
Figure PCTCN2018101960-appb-000080
1HNMR(400MHz,CDCl 3)δ8.35(d,J＝2.8Hz,1H),8.09(d,J＝7.6Hz,1H),7.43(d,J＝7.2Hz,1H),7.19(dd,J＝9.2,2.8Hz,1H),6.06(d,J＝7.6Hz,1H),5.62-5.67(m,1H),5.47(dt,J＝52.0,2.8Hz,1H),5.28-5.39(brs,2H),4.27-4.33(m,1H),3.98-4.18(m,2H),3.67-3.73(m,1H),2.95-3.00(m,1H),2.66-2.84(m,2H),2.32-2.40(m,1H),1.91-2.07(m,1H),1.28(d,J＝6.8Hz,3H)。
以下实施例参照实施例26所示方法合成。
Figure PCTCN2018101960-appb-000081
Figure PCTCN2018101960-appb-000082
Figure PCTCN2018101960-appb-000083
以下实施例参照实施例1所示方法合成。
Figure PCTCN2018101960-appb-000084
以下实施例参照实施例12所示方法合成。
Figure PCTCN2018101960-appb-000085
Figure PCTCN2018101960-appb-000086
生物活性实验
TrkA激酶抑制活性(IC 50)检测
1.TrkA WT激酶抑制活性(IC 50)检测
采取匀相时间分辨荧光(HTRF)方法建立了TrkA WT激酶活性检测平台，进行化合物活性的测定。将化合物从200μM开始用100％DMSO进行5倍的梯度稀释8次(共9个浓度)，每个浓度取4μL加入到96μL的反应缓冲液中(50mM HEPES，pH7.4，5mM MgCl 2，0.1mM NaVO 3，0.001％Tween-20，0.01％BAS，1mM DTT)，混匀，作为4*化合物待用。使用反应缓冲液配制2*TrkA激酶(终浓度为1nM)，用反应缓冲液配制4*底物(ATP+TK peptide)(TK peptide,
Figure PCTCN2018101960-appb-000087
KinEASE TM-TK,购买于Cisbio，TK肽，终浓度为1μM，ATP终浓度为40μM)。取2.5μL的4*化合物加入到384孔板(OptiPlate-384,购买于PerkinElmer)，然后加入5μL的2*TrkA激酶，离心混匀，再加入2.5μL的4*底物混合物启动反应(总反应体积为10μL)。将384孔板放于孵育箱中在23℃下反应60分钟，然后加入5μL的Eu3+cryptate-labled anti-phosphotyrosine antibody
Figure PCTCN2018101960-appb-000088
KinEASE TM-TK,购买于Cisbio)，5μL的Streptavidin-XL-665(
Figure PCTCN2018101960-appb-000089
KinEASE TM-TK,购买于Cisbio)停止反应。在孵育箱中孵育1小时后，在Envision(购买于PerkinElmer)上读取荧光值(320nm激发，检测665nm与620nm的发射光，二者比值为酶活性)。每个化合物分别在9个浓度下测定酶的活性，数据使用GraFit6.0软件(Erithacus Software)计算得到该化合物的IC 50值。
2.TrkA G667C激酶抑制活性(IC 50)检测
TrkA G667C(Kinase domain)激酶使用pIEX-Bac-4在Sf9细胞中进行表达，在AKTA Purifier(GE公司)上使用亲和层析法进行纯化。采取匀相、时间分辨荧光(HTRF)方法建立了TrkA G667C的激酶活性检测平台，进行化合物活性的测定。将化合物从200μM开始用100％DMSO进行5倍的梯度稀释(共8个浓度)，每个浓度取4μL加入到96μL的反应缓冲液中(50mM HEPES，pH7.4，5mM MgCl 2，0.1mM NaVO 3，0.001％Tween-20，0.01％BAS，1mM DTT)，混匀，作为4*化合物待用。使用反应缓冲液配制2*TrkA G667C激酶(终浓度为0.5nM)，4*底物(ATP+TK peptide)(TK peptide，
Figure PCTCN2018101960-appb-000090
KinEASE TM-TK,购买于Cisbio，终浓度为1μM，ATP终浓度为15μM)待用。取2.5μL的4*化合物加入到384孔板(OptiPlate-384，购买于PerkinElmer)，然后加入5μL的2*TrkA G667C激酶，离心混匀，再加入2.5μL的4*底物混合物启动反应(总反应体积为10μL)。将384孔板放于孵育箱中在23℃下反应60min，然后加入5μL的Eu3+cryptate-labled anti-phosphotyrosine antibody(
Figure PCTCN2018101960-appb-000091
KinEASE TM-TK，购买于Cisbio)，5μL的Streptavidin-XL-665(
Figure PCTCN2018101960-appb-000092
KinEASE TM-TK，购买于Cisbio)停止反应。在孵育箱中孵育60min后，在Envision(购买于PerkinElmer)上读取荧光值(320nm激发，检测665nm与620nm的发射光，二者比值为酶活性)。每个化合物分别在8个浓度下测定酶的活性，数据使用GraFit6.0软件(Erithacus Software)计算得到该化合物的IC 50值。
3.TrkA G595R激酶抑制活性(IC 50)检测
TrkA G595R(Kinase domain)激酶使用pIEX-Bac-4在Sf9细胞中进行表达，在AKTA Purifier(GE公司)上使用亲和层析法进行纯化。采取匀相、时间分辨荧光(HTRF)方法建立了TrkA G595R的激酶活性检测平台，进行化合物活性的测定。将化合物从200μM开始用100％DMSO进行5倍的梯度稀释(共8个浓度)，每个浓度取4μL加入到96μL的反应缓冲液(50mM HEPES，pH7.4，5mM MgCl 2，0.1mM NaVO 3，0.001％Tween-20，0.01％BAS，1mM DTT，50nM SEB)中，混匀，作为4*化合物待用。使用反应缓冲液配制2*TrkA G595R激酶(终浓度为0.2nM)，4*底物(ATP+TK peptide)(TK peptide,
Figure PCTCN2018101960-appb-000093
KinEASE TM-TK,购买于Cisbio,终浓度为1μM，ATP终浓度5μM)待用。取2.5μL的4*化合物加入到384孔板(OptiPlate-384，购买于PerkinElmer)，然后加入5μL的2*TrkA G595R激酶，离心混匀，再加入2.5μL的4*底物混合物启动反应(总反应体积为10μL)。将384孔板放于孵育箱中在23℃下反应120分钟，然后加入5μL的Eu3+cryptate-labled anti-phosphotyrosine antibody(
Figure PCTCN2018101960-appb-000094
KinEASE TM-TK，购买于Cisbio)，5μL的Streptavidin-XL-665(
Figure PCTCN2018101960-appb-000095
KinEASE TM-TK，购买于Cisbio)停止反应。在孵育箱中孵育60min，在Envision(购买于PerkinElmer)上读取荧光值(320nm激发，检测665nm与620nm的发射光，二者比值为酶活性)。每个化合物分别在8个浓度下测定酶的活性，数据使用GraFit6.0软件(Erithacus Software)计算得到该化合物的IC 50值。
在本申请的激酶抑制活性检测试验中，所述“*”是指乘，表示倍数。示例性地，“2*TrkA G595R激酶(终浓度为0.2nM)”是指浓度为0.4nM的TrkA G595R激酶。
梯度稀释的示例性含义例如，“5倍的梯度稀释”是指往1体积的原液1中加入4体积的稀释溶液，得到原液2；再取1体积的原液2，加入4体积的稀释溶液，得到原液3；以此类推，得到不同浓度的溶液。
术语“TrkA WT”是指原肌球蛋白样激酶A，野生型。
术语“TrkA G667C”是指TrkA WT的667位甘氨酸突变为半胱氨酸。
术语“TrkA G595R”是指TrkA WT的595位甘氨酸突变为精氨酸。
术语“HEPES”是指4-羟乙基哌嗪乙磺酸。
术语“MgCl 2”是指氯化镁。
术语“NaVO 3”是指钒酸钠。
术语“0.001％Tween-20”是指吐温20与反应缓冲液的体积比是0.001％。
术语“0.01％BAS”是指牛血清白蛋白与反应缓冲液的质量体积比，比如100mL的缓冲液中BSA的质量为0.01g。
术语“DTT”是指二硫苏糖醇。
术语“SEB”是指酶学反应缓冲液添加物。
“mM”是指毫摩尔/升。
根据本申请所述的生物学方法对上述实施例制备的化合物进行分析，其结果如表1所示：
表1 化合物对野生型和突变型TrkA激酶的抑制活性(IC 50)
Figure PCTCN2018101960-appb-000097
其中，“---”是指未测。
药代动力学实验
雄性SD大鼠来源于北京维通利华实验动物技术有限公司。将大鼠分组，每组3只，分别口服单次灌胃给予待测样品的混悬液(5mg/kg，混悬剂为10％EtOH、40％PEG 400和50％H 2O的混合溶液)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。分别于给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛取0.3mL全血，放于肝素抗凝管中，样品于4℃下、以4000rpm离心5min，血浆转移至离心管中，并放于-80℃下保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。其结果如表2所示。
表2 实施例化合物的药代动力学数据
实施例化合物 14 15 33
剂量(mg/kg) 5 5 5
T 1/2(hr) 1.81 1.53 4.22
Tmax(hr) 1.0 0.58 0.50
Cmax(ng/mL) 140 285 142
AUC0-inf(hr*ng/mL) 504 494 513

Claims (15)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2018101960-appb-100001
    其中，X选自键、-O-、-S-或-NR 4-；
    Y选自
    Figure PCTCN2018101960-appb-100002
    Figure PCTCN2018101960-appb-100003
    其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端；
    R 1和R 2独立地选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
    或R 1和R 2共同构成
    Figure PCTCN2018101960-appb-100004
    R 3选自C 1-C 6烷基、C 1-C 6烷氧基、卤素、硝基、羟基、氰基或氨基，其中，C 1-C 6烷基和C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、硝基、羟基、氰基或氨基的取代基取代；
    R 4和R 5独立地选自氢或C 1-C 6烷基；
    m选自0、1、2、3、4、5或6；
    n选自0、1、2、3、4、5、6或7；
    Cy选自6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃，其中，6-10元芳香环、5-10元芳杂环、3-10元脂杂环或3-10元环烷烃任选地被一个或多个独立地选自C 1-C 6 烷基、C 1-C 6烷氧基、
    Figure PCTCN2018101960-appb-100005
    卤素、硝基、羟基、氰基或氨基的取代基取代。
  2. 如权利要求1所述的化合物，其中X选自键或-O-。
  3. 如权利要求1或2所述的化合物，其中Y选自
    Figure PCTCN2018101960-appb-100006
    Figure PCTCN2018101960-appb-100007
    其中“*”表示Y基团与氨基吡唑并嘧啶环相连接的一端。
  4. 如权利要求1-3中任一项所述的化合物，其中R 5选自氢或C 1-C 3烷基；优选地，R 5选自氢或甲基。
  5. 如权利要求1-4中任一项所述的化合物，其中R 1和R 2独立地选自氢、C 1-C 3烷基、C 1-C 3烷氧基、氟、氯、溴、碘、硝基、羟基、氰基或氨基，其中，C 1-C 3烷基和C 1-C 3烷氧基任选地被一个或多个独立地选自氟、氯、溴、碘、硝基、羟基、氰基或氨基的取代基取代；优选地，R 1和R 2独立地选自氢、氟或C 1-C 3烷基；进一步优选地，R 1和R 2独立地选自氢、氟或甲基。
  6. 如权利要求1-5中任一项所述的化合物，其中m选自1、2、3、4或5；优选地，m选自2、3或4。
  7. 如权利要求1-6中任一项所述的化合物，其中R 3选自C 1-C 3烷基、C 1-C 3烷氧基、氟、氯、溴、碘、硝基、羟基、氰基或氨基，其中，C 1-C 3烷基和C 1-C 3烷氧基任选地被一个或多个独立地选自氟、氯、溴、碘、硝基、羟基、氰基或氨基的取代基取代；优选地，R 3选自氟、氯、溴、碘或羟基；进一步优选地，R 3选自氟或羟基。
  8. 如权利要求1-7中任一项所述的化合物，其中n选自0、1、2或3；优选地，n选自0或1。
  9. 如权利要求1-8中任一项所述的化合物，其中，Cy选自苯环、萘环、吡咯、呋喃、噻吩、咪唑、噁唑、吡唑、吡啶、嘧啶、吡嗪、喹啉、异喹啉、苯并呋喃、苯并噻吩、吲哚、异吲哚、环氧乙烷、四氢呋喃、二氢呋喃、吡咯烷、二氢吡咯烷、2H-吡啶、哌啶、哌嗪、吡唑烷、四氢吡喃、吗啉、硫代吗啉、四氢噻吩、环丙烷、环戊烷或环己烷，各自任选地被一个或多个独立地选自C 1-C 3烷基、C 1-C 3烷氧基、
    Figure PCTCN2018101960-appb-100008
    氟、氯、溴、碘、硝基、羟基、氰基或氨基的基团取代；优选地，Cy选自苯环、吡啶或1,2-2H-吡啶，各自任选地被一个或多个独立地选自氟或
    Figure PCTCN2018101960-appb-100009
    的基团取代的。
  10. 如权利要求1-9中任一项所述的化合物，其中，式(I)化合物选自式(II)所示化合物，
    Figure PCTCN2018101960-appb-100010
    其中X、R 1、R 2、R 3、R 5、Cy、m和n如权利要求1-9中任一项所定义的。
  11. 如权利要求1-9中任一项所述的化合物，其中，式(I)化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，
    Figure PCTCN2018101960-appb-100011
    Figure PCTCN2018101960-appb-100012
    Figure PCTCN2018101960-appb-100013
  12. 一种药物组合物，其包含权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐。
  13. 一种治疗哺乳动物的由Trk激酶介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐、或权利要求12所述的药物组合物。
  14. 权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐、或权利要求12所述的药物组合物在制备用于预防或者治疗由Trk激酶介导的疾病的药物中的用途。
  15. 一种治疗或者预防由Trk激酶介导的疾病的权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐或权利要求12所述的药物组合物。
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JP2021502413A (ja) * 2017-11-10 2021-01-28 エンジェクス ファーマシューティカル インコーポレイテッド Ｔｒｋキナーゼ阻害剤としての大環状化合物およびその使用
CN110386944A (zh) * 2018-04-16 2019-10-29 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白激酶活性的二(杂)芳基大环化合物
CN110386944B (zh) * 2018-04-16 2021-10-29 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白激酶活性的二(杂)芳基大环化合物
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CN112110938A (zh) * 2019-06-21 2020-12-22 成都海博为药业有限公司 一种作为蛋白质激酶抑制剂的化合物及其制备方法和用途
CN112110938B (zh) * 2019-06-21 2021-11-09 成都海博为药业有限公司 一种作为蛋白质激酶抑制剂的化合物及其制备方法和用途
CN111875620A (zh) * 2020-09-28 2020-11-03 上海美迪西生物医药股份有限公司 吡唑并嘧啶类大环衍生物及其应用
WO2023284058A1 (zh) * 2021-07-10 2023-01-19 深圳市真味生物科技有限公司 一种手性合成尼古丁的制备方法
US12145919B2 (en) 2021-07-10 2024-11-19 Shenzhen Zinwi Bio-Tech Co., Ltd Method for preparing chiral synthetic nicotine
WO2023025141A1 (zh) * 2021-08-23 2023-03-02 正大天晴药业集团股份有限公司 含有氨基的大环化合物在治疗trk激酶介导的肿瘤中的用途

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