WO2022037643A1 - 作为ret激酶抑制剂的杂芳环化合物及其制备和应用 - Google Patents

作为ret激酶抑制剂的杂芳环化合物及其制备和应用 Download PDF

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WO2022037643A1
WO2022037643A1 PCT/CN2021/113514 CN2021113514W WO2022037643A1 WO 2022037643 A1 WO2022037643 A1 WO 2022037643A1 CN 2021113514 W CN2021113514 W CN 2021113514W WO 2022037643 A1 WO2022037643 A1 WO 2022037643A1
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alkyl
compound
pharmaceutically acceptable
membered
substituted
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PCT/CN2021/113514
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English (en)
French (fr)
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朱永强
刘兆刚
冯超
陈浩
徐锴锴
王佳
石晶淼
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江苏正大丰海制药有限公司
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Priority to US18/022,413 priority Critical patent/US20230322769A1/en
Priority to CN202180051059.1A priority patent/CN115968288A/zh
Priority to JP2023512248A priority patent/JP2023538096A/ja
Priority to KR1020237009506A priority patent/KR20230054425A/ko
Priority to CA3191183A priority patent/CA3191183A1/en
Priority to AU2021326917A priority patent/AU2021326917A1/en
Priority to EP21857735.1A priority patent/EP4201936A4/en
Publication of WO2022037643A1 publication Critical patent/WO2022037643A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a series of derivative compounds of heteroaromatic ring structures and their application as RET kinase inhibitors. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • RET is a one-way transmembrane protein with a typical intracellular tyrosine kinase domain.
  • RTKs receptor tyrosine kinases
  • RET receptor tyrosine kinases
  • ligands glial cell-derived neurotrophic factor family ligands, GFLS
  • GFLS family receptor-alpha Interactions between coreceptors
  • the GFL-GFR ⁇ complex binds to the extracellular domain of Ret, resulting in phosphorylation of the intracellular tyrosine kinase domain, which activates several pathways, including MAPK, PI3K, JAK-STAT, PKA, and PKC.
  • RET is associated with kidney development and gastrointestinal nervous system development in normal physiology, however, mutations in the RET gene lead to aberrant activation of ligand-independent, constitutive RET kinases, leading to tumorigenesis.
  • RET in medullary thyroid carcinoma are very common, present in approximately 50% of sporadic MTCs and nearly all familial MTCs.
  • the RET gene is recombined by itself breaking and fused with other genes to become a new fusion gene, which enables the activation of the RET tyrosine kinase to escape the regulation of the ligand and further autophosphorylate, thereby enhancing the signal transduction function and promoting the activation of the kinase. , triggering tumorigenesis.
  • RET fusions are present in approximately 20% of papillary thyroid carcinomas (PTCs), 1-2% of non-small cell lung cancers (NSCLC) and other cancers such as colon and breast cancers.
  • the object of the present invention is to provide a class of RET kinase inhibitors heteroaromatic compounds.
  • the object of the present invention can be achieved by the following measures:
  • HetAr 1 is a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, S or O;
  • HetCyc 1 is a 4-8-membered heterocyclic ring having 1-3 heteroatoms selected from N or O, an 8-10-membered spirocyclic ring having 1-3 heteroatoms selected from N or O, or a spirocyclic ring having 1-3 heteroatoms selected from N or O 7-11-membered condensed heterocycle of 1-3 heteroatoms of O;
  • C is a 5- to 6-membered heteroaromatic ring having 1 to 3 heteroatoms independently selected from N, S or O; wherein the heteroaromatic ring is unsubstituted or optionally substituted by one or more identical or different substituents Substituted, the substituents are independently selected from halogen, hydroxyl, -CN, nitro, C1-C3 alkyl or halogenated C1-C3 alkyl;
  • D is a C1-C6 alkyl group having 1-3 heteroatoms selected from N or O, a 4-8 membered heterocycle having 1-3 heteroatoms selected from N and O, a 1-membered heterocyclic ring having 1-3 heteroatoms selected from N and O 7-8-membered bridged ring with ⁇ 3 heteroatoms, 7-11-membered spiro ring with 1-3 heteroatoms selected from N and O, 7-10-membered condensed ring with 1-3 heteroatoms selected from N and O heterocycle,
  • M is selected from C1-C3 alkyl or C3-C8 cycloalkyl
  • K is a 4-8 membered heterocycle with 1-3 heteroatoms selected from N or O;
  • E is HetAr 2 substituted or unsubstituted with one or more identical or different substituents independently selected from halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, Deuterated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C1-C6 haloalkyl, cyano C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl, C3-C6 cycloalkyl , (C1-C6 alkoxy SO 2 ) C1-C6 alkyl;
  • HetAr 2 is a 5-6 membered heteroaromatic ring having 1-3 ring heteroatoms independently selected from N, S and O.
  • HetCyc 1 is a 4-8-membered heterocyclic ring having 1-2 heteroatoms selected from N or O, a 7-11-membered spirocyclic ring having 1-2 heteroatoms selected from N or O, or a 7-11-membered spirocyclic ring having 1-2 heteroatoms selected from N or O 8-10-membered condensed heterocyclic ring of 1-2 heteroatoms of O.
  • a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof, B is selected from the group consisting of one or two identical or different Substituents substituted or unsubstituted following groups: R 1 -C ⁇ CH, R 1 is selected from C1-C4 alkyl, hydroxy C1-C4 alkyl; R 2 or R 3 is independently selected from H, C1-C4 alkyl, deuterated C1-C4 alkyl, hydroxy C1-C4 alkyl; The substituents are independently selected from hydroxyl, cyano, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl.
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof, B is substituted with one or two identically or differently substituted or unsubstituted
  • C is a 5- to 6-membered heteroaromatic ring having 1-2 ring heteroatoms independently selected from N or S;
  • D is Wherein, M is selected
  • a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof, C is substituted with one or two identically or differently
  • the following groups are substituted or unsubstituted:
  • the substituents are independently selected from fluoro, chloro, bromo.
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof, D is Wherein, M is selected from C1-C3 alkane or C3-C6 cycloalkyl; K is a 4-8 membered heterocycle with 1-3 heteroatoms selected from N or O; more preferably, D is -N(CH 3 ) CH 2 CH 2 N(CH 3 )-,
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof, L is or -CH 2 -.
  • a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, E is substituted with one or two identical or different substituents or unsubstituted
  • the substituents are independently selected from C1-C3 alkoxy or deuterated C1-C3 alkoxy.
  • the present invention also provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof,
  • B is selected from HetCyc 1 substituted or unsubstituted by one or two identical or different substituents; HetCyc 1 is a 4-5 membered heterocyclic ring with 1 N atom or
  • the substituents are independently selected from H, halogen, hydroxyl, -CN, carbonyl, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluoro C1- C3 alkyl, cyano C1-C3 alkyl; in some embodiments, the substituents of B in formula (II) are independently selected from halogen, hydroxyl, -CN, carbonyl, methyl, ethyl, deuterated methyl, Methoxy.
  • the present invention also provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof,
  • B is selected from substituted or unsubstituted HetCyc 2 , or B is a substituted or unsubstituted 7- to 8-membered bridged ring with 1 to 3 heteroatoms selected from N, S, O or P;
  • HetCyc 2 is a A 4- to 6-membered heterocycle of P atom or a 4- to 6-membered heterocycle of P atom and N atom; the substituents are independently selected from H, halogen, hydroxyl, -CN, carbonyl, C1-C3 alkyl, deuterated C1- C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluoro C1-C3 alkyl, cyano C1-C3 alkyl; in some embodiments, B is substituted or unsubstituted HetCyc 2 , Or B is a substituted or unsubstituted 7-8 membered bridged ring with 1-2 heteroatoms containing
  • the present invention also provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, oxide or prodrug thereof,
  • B is selected from HetCyc 1 substituted or unsubstituted by one or two identical or different substituents; HetCyc 1 is a 6-membered heterocycle with 1-2 N atoms; the substituents are independently selected from H, C1- C3 alkyl, deuterated C1-C3 alkyl, fluoro C1-C3 alkyl; in some more preferred embodiments, HetCyc 1 is substituted or unsubstituted by a substituent
  • the substituents of B are independently selected from halogen, methyl, ethyl, deuterated methyl, -CF3 .
  • the oxide described in the present invention can be any position that is easy to form oxidation.
  • the oxide is formed at the N atom of a 4-8 membered heterocycle or bridged ring with N heteroatom, for example, in In some instances, in oxides are formed at the nitrogen atoms.
  • the present invention also provides a compound preparation route of the general formula (I):
  • A, B, C, D, L, E are defined as above.
  • Step 1 Using dioxane as solvent, compound I is coupled with boronic acid reagent C to obtain II;
  • Step 2 Intermediate II is nucleophilically substituted with an amine compound to obtain III;
  • Step 3 Using 1,2-dichloroethane as a solvent, intermediate III and L-E are subjected to reductive amination or acylation to obtain intermediate IV;
  • Step 4 The final product (I) is obtained by C-N coupling using dioxane and N,N-dimethylformamide as solvents.
  • the present invention also provides a preparation method of a compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof:
  • the preparation of the oxides described in the present invention can be obtained by oxidation of compound IV before obtaining the compound of formula (I), or by oxidation after obtaining the compound of formula (I).
  • the oxidation method can adopt a conventional method in the art, for example, in some specific embodiments, a common oxidant such as m-chloroperoxybenzoic acid (m-CPBA) is used for oxidation to obtain the oxide of the corresponding compound.
  • m-CPBA m-chloroperoxybenzoic acid
  • salts that the compounds of the present invention may form are also within the scope of the present invention.
  • compounds in the present invention are understood to include their salts.
  • a compound of formula (I) is reacted with a certain amount, such as an equivalent amount, of an acid or base, salted out in a medium, or lyophilized in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of formula I include monohydrochloride, dihydrochloride, trifluoroacetate, and ditrifluoroacetate.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising subjecting the cells to an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical combination thereof object contact.
  • Also provided herein is a method of treating a RET-related disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable form thereof A salt or solvate or a pharmaceutical composition thereof.
  • RET kinase inhibitor a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, as a RET kinase inhibitor.
  • the RET-related disease or disorder is cancer.
  • Also provided herein is a method of treating cancer and/or inhibiting cancer metastasis associated with a particular cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula I as defined herein The compound or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof.
  • Also provided herein is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.
  • Also provided herein is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer and/or the inhibition of cancer metastasis associated with a particular cancer.
  • Also provided herein is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of a RET-related disease or disorder.
  • Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer and/or the inhibition of cancer metastasis associated with a particular cancer .
  • Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting RET kinase activity.
  • Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a RET-related disease or disorder.
  • the patient is then administered a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • a pharmaceutical combination for treating a cancer comprising: (a) formula A compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein said compound of formula I or a pharmaceutically acceptable
  • the received salt or solvate and the additional treatment are formulated as separate compositions or doses for simultaneous, separate or sequential use in the treatment of cancer, wherein a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is The amount and the amount of the additional therapeutic agent together are effective to treat cancer.
  • a pharmaceutical composition comprising such a combination.
  • a use of such a combination in the manufacture of a medicament for the treatment of cancer is also provided herein.
  • a commercial package or product comprising the combination, as a combined preparation for simultaneous, separate or sequential use; and a method of treating cancer in a patient in need thereof.
  • Also provided herein is a method of reversing or preventing acquired resistance to an anticancer drug, comprising administering to a patient at risk of developing or having acquired resistance to an anticancer drug, a therapeutically effective amount of a compound of formula I or A pharmaceutically acceptable salt or solvate thereof.
  • a dose of an anticancer drug is administered to a patient (eg, substantially at the same time as a dose of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered to the patient).
  • Also provided herein is a method of delaying and/or preventing the development of cancer resistance to an anticancer drug in an individual, comprising administering to the individual an effective amount of Formula I before, during or after administration of the effective amount of the anticancer drug A compound or a pharmaceutically acceptable salt or solvate thereof.
  • Also provided herein is a method of treating an individual suffering from cancer having an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual before, during or after administering (b) an effective amount of the anticancer drug (a) An effective amount of a compound of formula I is administered.
  • Also provided are methods of treating an individual with a RET-related cancer having one or more RET inhibitor resistance mutations e.g., a substitution at amino acid position 804, eg V804M, V804L or V804E
  • the method comprising administering a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during or after administration of another anticancer drug (eg, a second RET kinase inhibitor) .
  • a compound of Formula I or a pharmaceutically acceptable form thereof, before, during, or after administration of another anticancer drug (eg, a first RET kinase inhibitor). salt or solvate.
  • the cancer eg, a RET-associated cancer
  • the cancer is a blood cancer.
  • the cancer eg, a RET-associated cancer
  • the cancer is a solid tumor.
  • the cancer is lung cancer (eg, small cell lung cancer or non-small cell lung cancer), thyroid cancer (eg, papillary thyroid cancer, medullary thyroid cancer) carcinoma, differentiated thyroid cancer, recurrent thyroid cancer or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (respectively (MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, mammary carcinoma, breast neoplasms, colorectal cancer (e.g. metastatic colorectal cancer) carcinoma), papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, inflammatory myofibroblastoma, or cervical cancer.
  • lung cancer eg, small cell lung cancer or non-small cell lung cancer
  • thyroid cancer eg, papillary thyroid cancer, medull
  • the patient is a human.
  • Also provided herein is a method for treating a patient diagnosed with or identified as having a RET-related cancer (eg, any of the exemplary RET-related cancers disclosed herein), comprising administering to the patient a therapeutically effective amount of a RET-related cancer as defined herein
  • a RET-related cancer as defined herein
  • the compound of formula I or a pharmaceutically acceptable salt or solvate or a pharmaceutical composition thereof comprising administering to the patient a therapeutically effective amount of a RET-related cancer as defined herein.
  • the FGFR family described in the present invention includes but does not Limited to FGFR1, FGFR1 V561M, FGFR2, FGFR2 V564F, FGFR2 N549H, FGFR2 V564I, FGFR2 K641R, FGFR3, FGFR3 V555M, FGFR3 K650E, FGFR4; in some more specific examples, the FGFR family includes FGFR2 V564F, FGFR2 N549H, FGFR2 V564I and FGFR3 V555M.
  • halogen means -F (sometimes referred to herein as “fluoro"), -Cl, -Br and -I.
  • C1-C3 alkyl refers to groups having one to three, one to six, two to six, respectively A saturated linear or branched monovalent hydrocarbon radical of one or three to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl base, neopentyl and hexyl.
  • C1-C6 alkoxy refers to a saturated straight or branched monovalent alkoxy group having one to six carbon atoms, wherein the bond is on an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • (C1-C6alkoxy)C1-C6alkyl-" and “(C1-C6alkoxy)C2-C6alkyl-” mean from one to six carbon atoms or two to six carbon atoms, respectively A saturated straight or branched monovalent group of carbon atoms wherein one carbon atom is substituted with a (C1-C6alkoxy) group as defined herein. Examples include methoxymethyl ( CH3OCH2- ) and methoxyethyl ( CH3OCH2CH2- ) .
  • hydroxy C1-C6 alkyl- and "hydroxy C2-C6 alkyl-” refer to a saturated straight or branched monovalent alkyl group having one to six or two to six carbon atoms, respectively, of which one Carbon atoms are replaced by hydroxyl groups.
  • deuterated C1-C6 alkyl- refers to a saturated straight or branched chain monovalent alkane of one to six carbon atoms, respectively group in which one of the carbon atoms is replaced by deuterium, halogen or cyano.
  • C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • alkenyl refers to a straight chain, branched chain or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond.
  • C2-C6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Examples include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, cyclohexenyl, and the like.
  • alkynyl refers to a straight chain, branched chain or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon triple bond.
  • C2-C6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Examples include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like.
  • heterocycle refers to a monocyclic or bicyclic non-aromatic heterocycle containing, in addition to carbon atoms, 1-4 heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms, as Specific examples include azetidine, pyrrolidine, pyrazolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, dihydroimidazole, imidazolidine ( imidazolidine), tetrahydropyrazine, piperazine, morpholine, etc.
  • Non-aromatic heterocycles of the formula azabicyclo[3.1.0]hexane, etc. 6-8 containing 1-4 heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms
  • heteromatic ring represents a stable monocyclic ring of up to 3-10 atoms in the ring or a bicyclic carbocyclic ring of up to 3-10 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 A heteroatom selected from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxolinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzene thienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
  • spirocycle refers to a group of two rings joined by a spiro link of carbon atoms, wherein each ring has 4 to 6 ring atoms (wherein one ring carbon atom is common to both rings).
  • heterospirocycle refers to a group containing two rings of one or more identical or different heteroatoms joined by a spirocyclic linkage of carbon atoms, wherein each ring has 4 to 6 ring atoms (wherein One ring carbon atom is common to both rings), the heteroatoms are selected from nitrogen atoms, oxygen atoms.
  • fused heterocycle refers to a cyclic hydrocarbon in which 2-3 rings share two adjacent (ortho) atoms; at least one ring is an aromatic ring containing 1 to 3 heteroatoms selected from O, N and S , in some instances, is a cyclic hydrocarbon in which 2 rings share two adjacent (ortho) atoms; one ring is an aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S, and the other ring is a saturated heterocycle.
  • bridged ring refers to polycyclic hydrocarbons that share two or more carbon atoms (bridgehead carbons), and are classified into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, and the like according to the number of constituent rings.
  • treating or “treatment” as referred to throughout this document is conventional, eg, managing for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder such as cancer or nursing individuals.
  • the term "individual” or “patient” includes organisms, such as humans and non-human animals, that can suffer from a cell proliferative disorder or that can benefit from administration of the compounds of the present invention.
  • Preferred humans include human patients having or susceptible to having a cell proliferative disorder or related condition as described herein.
  • non-human animal includes vertebrates, such as mammals, such as non-human primates, sheep, cows, dogs, cats, and rodents (eg, mice), as well as non-mammals, such as chickens, amphibians , reptiles, etc.
  • cell proliferation includes the involvement of undesired or uncontrolled proliferation of cells.
  • the compounds of the present invention can be used to prevent, inhibit, block, reduce, reduce, control, etc. cell proliferation and/or cell division, and/or produce apoptosis.
  • the method comprises administering to an individual (including mammals, including humans) in need thereof, an amount of a compound of the invention, or a pharmaceutically acceptable salt, isomer, polymorph thereof, in an amount effective to treat or prevent the disorder , metabolites, hydrates or solvates.
  • the RET kinase inhibitor compound of the present invention has better biological activity at the enzyme and cell levels than the listed drug Selpercatinib (LOXO-292) and has lower cardiotoxicity.
  • the compounds of the present invention provide more choices for new antitumor drugs and have good drug application prospects.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • RET WT RET wild type
  • V804M RET
  • M918T point mutant CCDC6-RET fusion mutation
  • KDR VEGFR2 kinase activity IC50 test.
  • the above kinases were purchased from Thermo Fisher Scientific and ProQinase GmbH.
  • HTRF Homogeneous time-resolved fluorescence
  • TK antibody-cryptate 4 ⁇ L of streptavidin-XL665 (reaction concentration of 62.5 nM) were added to the reaction solution, and the incubation was continued at 25° C. for 60 minutes. After incubation, HTRF fluorescence value was detected on CLARIOstar (BMG LABTECH), and IC 50 was calculated using GraphPad Prism 5.0 software.
  • LC-MS/MS liquid chromatography-mass spectrometry
  • Ba/F3 KIF5B-RET, Ba/F3KIF5B-RET-V804M, Ba/F3 RET-M918T, Ba/F3 KIF5B-RET-G810R cells in logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%. Adjust the cell concentration and add 90 ⁇ L of the cell suspension to the 96-well plate. Cells in 96-well plates were incubated overnight at 37°C, 5% CO 2 , and 95% humidity.
  • the corresponding 10 ⁇ L gradient concentration of drug solution (the highest concentration is 1000 nM) was added to each well, three duplicate wells were set for each drug concentration, and the final concentration of DMSO was 0.1%.
  • the cells in the medicated 96-well plate were further cultured for 72 hours at 37°C, 5% CO 2 , and 95% humidity. After the effect of the drug, 100 ⁇ L of CellTiter-Glo reagent was added to each well, and the cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plate was placed at room temperature for 20 minutes to stabilize the luminescence signal, and then the luminescence value was read. The data were analyzed using GraphPad Prism 5.0 software, and a dose-response curve was obtained by fitting the data using nonlinear S-curve regression, and IC50 values were calculated therefrom. The results are shown in Table 4.
  • test compounds were prepared on the same day and redissolved in extracellular fluid.
  • Extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl2 , 1.8; MgCl2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • HEK293 cells stably expressing hERG ion channel were transferred to a perfusion tank and perfused with extracellular fluid. The intracellular fluid was stored in a -80 degree refrigerator in batches and thawed on the day of the experiment.
  • Intracellular fluid was: K Aspartate, 130; MgCl2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). Electrodes were drawn with PC-10 (Narishige, Japan). Whole-cell patch-clamp recordings, with noise filtered at one-fifth of the sampling frequency.
  • hERG tail currents are pure hERG currents.
  • the maximum current induced by the second square wave was detected.
  • the test compound was perfused.
  • the blocking intensity was calculated.
  • the IC50 of the compound for hERG channel inhibition was calculated according to the blocking strength, and the results are shown in Table 5.
  • SD male rats (body weight 220 ⁇ 20 g) were given compound 94 and Loxo-292 by tail vein injection at a dose of 1.0 mg/kg and oral dose of 5.0 mg/kg, 3 animals in each group.
  • the administration solvent was 5% DMSO+5% polyoxyethylene castor oil (Cremophor EL) in physiological saline solution. Fasting for about 12 hours before administration, free food for 4 hours after administration; water is not allowed. Before administration and at 5, 15, 30 min, 1, 2 , 4, 6, 8, 10, and 24 h after administration, about 0.2 mL of blood was collected from the orbit and placed in an EDTA-K2 anticoagulated EP tube for ice bath.
  • mice Male NVSG mice (body weight 20-25 g) were orally administered compound 94 and Loxo-292 at a dose of 30 mg/kg, respectively. Plasma, liver, brain, lung and other tissue samples of animals were collected 4 h after administration. Plasma collection: 80-100 ⁇ L of whole blood was collected in an EP tube containing EDTA. After centrifugation at 4000g for 5 minutes, the upper plasma was collected and stored at -80°C.
  • Tissue collection After the animals were euthanized, the tissues were taken and snap-frozen in liquid nitrogen, 5 mL of homogenate (50% acetonitrile) was added per 1 g of tissue, and the tissue was processed into a homogenate in a tissue homogenizer, and transferred to -80 Store at °C. Compound concentrations in plasma and tissue samples were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • BA/F3 KIF5B-RET cells were cultured in RPMI-1640 medium supplemented with 10% FBS in a 37°C incubator with 5% CO 2 .
  • the cells were inoculated subcutaneously on the right shoulder of NVSG mice by subcutaneous injection, and each mouse was inoculated with about 1 ⁇ 10 6 cells, and the inoculation volume was 100 ⁇ L.
  • mice with appropriate transplanted tumor size were selected and randomly divided into groups according to body weight and transplanted tumor size. Administer by gavage at a volume of 10 ⁇ L/g body weight.
  • the dosage of Loxo-292 is 30 mg/kg, administered twice a day (bid); the dosage of compound 94 is 30 mg/kg, administered twice a day (bid) and 30 and 60 mg/kg are administered once a day ( qd); the solvent control group was given 2% DMSO+2% polyoxyethylene castor oil in physiological saline solution. The patients were administered for 15 consecutive days, and the volume of the transplanted tumor was measured twice a week. Day 0 was the first day of grouping and administration.
  • Test compounds are IC50 for FGFR family kinase activity. Related kinases were purchased from Carna and Signalchem.
  • the homogeneous time-resolved fluorescence (HTRF) method was used to establish the activity detection method of related kinases, and the inhibitory activity of the compounds was determined.
  • Prepare 5 ⁇ L of reaction solution including 1 ⁇ enzymatic buffer (Cisbio, HTRF KinEASE TM -TK), 5 mM MgCl 2 , 1 mM DTT, 1 ⁇ M TK substrate-biotin (Cisbio, HTRF KinEASE TM-TK) corresponding concentrations of ATP and related kinases, and Gradient concentrations of compounds.
  • 1 ⁇ enzymatic buffer Cisbio, HTRF KinEASE TM -TK
  • 5 mM MgCl 2 5 mM DTT
  • 1 ⁇ M TK substrate-biotin Cisbio, HTRF KinEASE TM-TK
  • Gradient concentrations of compounds The relevant kinase concentrations and corresponding ATP concentrations are shown in Table 9:

Abstract

公开了作为RET激酶抑制剂的杂芳环化合物及其制备和应用，化合物为具有式(I)结构的化合物或其药学上可接受的盐，这些化合物或其盐可通过靶向RET基因融合及突变形式的受体，而用于疾病或病况的治疗或预防，可以有效抑制多种肿瘤细胞的生长，并对RET基因融合突变及其它蛋白酶产生抑制作用，可用于制备抗肿瘤药物。

Description

作为RET激酶抑制剂的杂芳环化合物及其制备和应用 技术领域
本发明涉及一系列杂芳环结构的衍生化合物，及其作为RET激酶抑制剂的应用。具体涉及式(I)所示化合物或其药学上可接受的盐。
背景技术
1985年，将人T细胞淋巴瘤的高分子量DNA转染NIH3T3细胞，发现RET是一种新的转化基因。该基因是通过DNA重排激活的，在DNA重排中，人类DNA的两个未连接的片段重新组合，产生一个新的转录单位。随后，研究将RET定位在染色体10q11.2上，在那里它编码一种受体酪氨酸激酶。RET是一种单程跨膜蛋白，具有典型的细胞内酪氨酸激酶结构域。虽然受体酪氨酸激酶(RTK)的“经典”激活是由于配体-受体的相互作用，但RET的激活需要其配体(胶质细胞源性神经营养因子家族配体，GFLS)和辅助受体(GFLS家族受体-α)之间的相互作用。GFL-GFRα复合物与Ret的胞外结构域结合，导致细胞内酪氨酸激酶结构域的磷酸化，从而激活几条通路，包括MAPK、PI3K、JAK-STAT、PKA及PKC。
RET在正常生理状态下与肾脏的发育和胃肠神经系统发育有关，但是，RET基因的突变导致不依赖配体的，组成型的RET激酶异常激活，将导致肿瘤发生。RET激酶的激活主要有两种机制：1.RET基因点突变；2.RET基因重排。RET的错义突变可能发生在胞外的Cys残基上，引起异常的激酶激活。突变也可能发生在胞内激酶活性域，这种突变将促进不依赖配体的RET激酶激活。甲状腺髓样癌(MTC)中RET的点突变非常常见，存在于大约50％的散发性MTC及几乎所有的家族性MTC中。RET基因通过本身断裂与其它基因融合的方式发生重组，成为一个新的融合基因，使得RET酪氨酸激酶的活化逃脱配体的调控，进一步自我磷酸化，从而增强信号转导功能，促使激酶活化，引发肿瘤生成。在约20％的甲状腺乳头状癌(PTC)中，1～2％的非小细胞肺癌(NSCLC)和其它癌症，如结肠癌和乳腺癌中都存在RET融合。以上结果表明RET信号通路的失调是很多肿瘤疾病的重要驱动原因。
目前就活性和耐受性而言，各种多激酶抑制剂对RET有活性但非特异性，患者长期暴露于RET TKI中，因为对VEGFR激酶的抑制作用，产生3～4级毒性发生率较高。所以，研发活性强、选择性高的RET特异性抑制剂，满足临床需求，有望成为治疗甲状腺癌和非小细胞等多种癌症的新方法。
发明内容
本发明的目的是提供一类RET激酶抑制剂的杂芳环化合物。
本发明的目的可以通过以下措施达到：
具有式I结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，
Figure PCTCN2021113514-appb-000001
其中，
A选自H、-CN、卤素、-C＝ONH 2、-C＝C-CN或-C≡CH；
B选自被一个或多个相同或不同取代基取代或未取代的以下基团：C1-C6烷基、C1-C6烷胺基、C2-C6炔基、C2-C6烯基、HetAr 1或HetCyc 1；取代基独立选自卤素、羟基、-CN、＝O(羰基)、C1-C6烷基，氘代C1-C6烷基、C1-C6烷氧基、羟基C1-C6烷基、卤代C1-C6烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、C3-C6环烷基、(C1-C6烷氧基SO 2)C1-C6烷基；
HetAr 1是具有独立地选自N、S或O的1～3个杂原子的5～6元杂芳环；
HetCyc 1是具有选自N或O的1～3个杂原子的4～8元杂环、具有选自N或O的1～3个杂原子的8～10元螺环或具有选自N或O的1～3个杂原子的7～11元稠杂环；
C是具有独立地选自N、S或O的1～3个杂原子的5～6元杂芳环；其中所述杂芳环未被取代或者任选被一个或多个相同或不同取代基取代，所述取代基独立选自卤素、羟基、-CN、硝基、C1-C3烷基或卤代C1-C3烷基；
D是具有选自N或O的1～3个杂原子的C1-C6烷基、具有选自N和O的1～3杂原子的4～8元杂环、具有选自N和O的1～3杂原子的7～8元桥环、具有选自N和O的1～3杂原子的7～11元螺环、具有选自N和O的1～3杂原子的7～10元稠杂环、
Figure PCTCN2021113514-appb-000002
Figure PCTCN2021113514-appb-000003
其中，M选自C1-C3烷基或C3-C8环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；
L是
Figure PCTCN2021113514-appb-000004
-C(＝O)-C1-C3烷基或C1-C3烷基；
E是被一个或多个相同或不同取代基取代或未取代的HetAr 2，所述取代基独立选自卤素、C1-C6烷基、氘代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、羟基C1-C6烷基、C1-C6卤代烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、C3-C6环烷基、(C1-C6烷氧基SO 2)C1-C6烷基；
HetAr 2是具有独立地选自N、S和O的1～3个环杂原子的5～6元杂芳环。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，A选自-CN、-C＝C-CN或-C≡CH；在一种具体的实施例中，A为-CN。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，B选自被一个或两个相同或不同取代基取代或未取代的以下基团：
Figure PCTCN2021113514-appb-000005
R 1-C≡CH或HetCyc 1；R 1选自H、C1-C6烷基、氘代C1-C6氘代烷基、C1-C6羟基烷基；R 2或R 3独立地选自H、C1-C6烷基、氘代C1-C6烷基、羟基C1-C6烷基；所述取代基独立选自卤素、羟基、-CN、＝O(羰基)、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基、(C1-C3烷氧基)C1-C3烷基、C3-C6环烷基、(C1-C3烷氧基SO 2)C1-C3烷基；
HetCyc 1是具有选自N或O的1～2个杂原子的4～8元杂环、具有选自N或O的1～2个杂原子的7～11元螺环或具有选自N或O的1～2个杂原子的8～10元稠杂环。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，B选自被一个或两个相同或不同取代基取代或未取代的以下基团：R 1-C≡CH、
Figure PCTCN2021113514-appb-000006
Figure PCTCN2021113514-appb-000007
R 1选自C1-C4烷基、羟基C1-C4烷基；R 2或R 3独立的选自H、C1-C4烷基、氘代C1-C4烷基、羟基C1-C4烷基；所述取代基独立选自羟基、氰基、卤素、C1-C3烷基、氘代C1-C3烷基、 C1-C3烷氧基、C3-C6环烷基。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，B为被一个或两个相同或不同取代基取代或未取代的
Figure PCTCN2021113514-appb-000008
所述取代基独立选自卤素、羟基、-CN、＝O(羰基)、C1-C3烷基，氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基、(C1-C3烷氧基)C1-C3烷基、C3-C6环烷基、(C1-C3烷氧基SO 2)C1-C3烷基C1-C3烷基；C是具有独立地选自N或S的1～2个环杂原子的5～6元杂芳环；D是
Figure PCTCN2021113514-appb-000009
Figure PCTCN2021113514-appb-000010
其中，M选自C3-C6环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；L为-CH 2-；E为
Figure PCTCN2021113514-appb-000011
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，C是被一个或两个相同或不同取代基取代或未取代的以下基团：
Figure PCTCN2021113514-appb-000012
取代基独立地选自氟、氯、溴。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，D是
Figure PCTCN2021113514-appb-000013
Figure PCTCN2021113514-appb-000014
其中，M选自C1-C3烷烃或C3-C6环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；进一步优选地，D是-N(CH 3)CH 2CH 2N(CH 3)-、
Figure PCTCN2021113514-appb-000015
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构 体、溶剂化合物、氧化物或前药，L是
Figure PCTCN2021113514-appb-000016
或-CH 2-。
在一些实施例中，具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药，E是被一个或两个相同或不同取代基取代或未取代的
Figure PCTCN2021113514-appb-000017
取代基独立地选自C1-C3烷氧基或氘代C1-C3烷氧基。
在一些实施例中，本发明还提供一种具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，
Figure PCTCN2021113514-appb-000018
其中，B选自被一个或两个相同或不同取代基取代或未取代的HetCyc 1；HetCyc 1是具有1个N原子的4～5元杂环或
Figure PCTCN2021113514-appb-000019
所述取代基独立选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；在一些实施例中，式(II)中B的取代基独立选自卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基。
在一些实施例中，本发明还提供的具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药，
Figure PCTCN2021113514-appb-000020
其中，B选自取代或未取代的HetCyc 2，或者B是取代或未取代的具有选自N、S、O或P的1～3个杂原子的7～8元桥环；HetCyc 2是具有P原子的4～6元杂环或具有P原子和N原子的4～6元杂环；取代基独立选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；在 一些实施例中，B是取代或未取代的HetCyc 2，或者B是取代或未取代的具有含N的1～2个杂原子的7～8元桥环；HetCyc 2是具有P原子和N原子的4～6元杂环；在一些更具体的实例中，B是取代或未取代的
Figure PCTCN2021113514-appb-000021
其中R 4选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；优选的R 4选自H、卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基或三氟甲基；在一些实施例中，取代基独立选自卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基或三氟甲基。
在一些实施例中，本发明还提供的具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，
Figure PCTCN2021113514-appb-000022
其中，B选自被一个或两个相同或不同取代基取代或未取代的HetCyc 1；HetCyc 1是具有1～2个N原子的6元杂环；所述取代基独立选自H、C1-C3烷基、氘代C1-C3烷基、氟代C1-C3烷基；在一些更优选的实施例中，HetCyc 1是被取代基取代或未取代的
Figure PCTCN2021113514-appb-000023
B的取代基独立选自卤素、甲基、乙基、氘代甲基、-CF 3。
本发明所述的氧化物可以为易形成氧化的任意位置，在一些具体的实施例中，是在具有N杂原子的4～8元杂环或桥环的N原子处形成氧化物，例如在一些实例中，是在
Figure PCTCN2021113514-appb-000024
的氮原子处形成氧化物。
本发明的化合物或其药学上可接受的盐，其中一些具体化合物选自：
Figure PCTCN2021113514-appb-000025
Figure PCTCN2021113514-appb-000026
Figure PCTCN2021113514-appb-000027
Figure PCTCN2021113514-appb-000028
Figure PCTCN2021113514-appb-000029
本发明还提供一种通式(I)的化合物制备路线：
Figure PCTCN2021113514-appb-000030
其中，A、B、C、D、L、E定义如前所述。
在一些实施例中，上述制备路线的具体步骤如下：
步骤1：以二氧六环为溶剂，化合物I通过和硼酸试剂C偶联得到II；
步骤2：中间体II与胺类化合物亲核取代得到III；
步骤3：以1,2-二氯乙烷为溶剂，中间体III和L-E通过还原胺化或酰化反应得到中间体IV；
步骤4：以二氧六环和N,N-二甲基甲酰胺作为溶剂，通过C-N偶联，获得终产物(I)。
本发明还提供具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药的制备方法：
Figure PCTCN2021113514-appb-000031
其中，B的定义如前所述。
本发明所述的氧化物的制备可以在获得式(I)的化合物之前由化合物IV氧化获得，或者获得式(I)的化合物之后氧化获得。氧化方法可以采用本领域的常规方法，例如在一些具体的实施例中采用常用氧化剂如间氯过氧苯甲酸(m-CPBA)进行氧化获得相应化合物的氧化物。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。例如，式(I)化合物与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。式I化合物的药学上可接受的盐的非限制性实例包含单盐酸盐、二盐酸盐、三氟乙酸盐和二三氟乙酸盐。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。 此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本文还提供一种药物组合物，其包括式I化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药，以及药学上可接受的载体。
本文还提供一种活体外或活体内抑制细胞增殖的方法，所述方法包括使细胞与有效量的如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物接触。
本文还提供一种治疗需要这类治疗的患者的RET相关疾病或病症的方法，所述方法包括向所述患者施用治疗有效量的如本文所定义的式I的化合物或其药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药作为RET激酶抑制剂的应用。
本文还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备治疗RET相关疾病药物中的应用。
在本发明的一些实例中，RET相关疾病或病症为癌症。
本文还提供一种治疗需要这类治疗的患者的癌症和/或抑制与特定癌症相关联的癌转移的方法，所述方法包括向所述患者施用治疗有效量的如本文所定义的式I的化合物或或其药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物，其用于疗法中。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物，其用于治疗癌症和/或抑制与特定癌症相关的癌转移中。
本文还提供一种式I化合物或其药学上可接受的盐或溶剂合物，其用于抑制RET激酶活性。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物，其用于治疗RET相关疾病或病症。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物的用途，其用于制造用于治疗癌症和/或抑制与特定癌症相关的癌转移的药物中。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物的用途，其用于制造用于抑制RET激酶活性的药物。
本文还提供一种如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物的用途，其用于制造用于治疗RET相关疾病或病症的药物。
本文还提供一种用于治疗有需要的患者的癌症的方法，所述方法包括：(a)确定所述癌症是否与RET基因、RET激酶或其中的任一个的表达或活性或水平的调节异常相关联(例如，RET相关癌症)；和(b)如果确定所述癌症是与RET基因、RET激酶或其中的任一个的表达或活性或水平的调节异常相关联(例如，RET相关癌症)，那么向所述患者施用治疗有效量的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供一种用于治疗有需要的患者的癌症(例如，RET相关癌症，如具有一个或多个RET抑制剂抗性的突变的RET相关癌症)的药物组合，其包括：(a)式I化合物或其药学上可接受的盐或溶剂合物，(b)额外治疗剂，和(c)任选的至少一种药学上可接受的载体，其中所述式I化合物或其药学上可接受的盐或溶剂合物和所述额外治疗被配制成单独组合物或剂量，以同时、单独或依序用于治疗癌症，其中式I化合物或其药学上可接受的盐或溶剂合物的量和额外治疗剂的量一起有效治疗癌症。本文还提供一种药物组合物，其包括这种组合。本文还提供一种这种组合的用途，其用于制备用于治疗癌症的药物。本文还提供一种商业包装或产品，其包括这种组合，呈用于同时、单独或依序使用的组合制剂；和一种治疗有需要的患者的癌症的方法。
本文还提供一种逆转或预防对抗癌药物的获得性抗性的方法，其包括向处于发展或具有对抗癌药物的获得性抗性风险下的患者，施用治疗有效量的式I化合物或其药学上可接受的盐或溶剂合物。在一些实施例中，向患者施用一定剂量的抗癌药物(例如，基本上在向所述患者施用一定剂量的式I化合物或其药学上可接受的盐或溶剂合物同时)。
本文还提供一种延迟和/或预防个体中发展对抗癌药物的癌症抗性的方法，其包括在施用有效量的抗癌药物之前、期间或之后，向所述个体施用有效量的式I化合物或其药学上可接受的盐或溶剂合物。
本文还提供一种治疗患有癌症、具有对抗癌药物发展抗性的增加可能性的个体的方法，其包括在施用(b)有效量的抗癌药物之前、期间或之后，向所述个体施用(a)有效量的式I化合物。
还提供治疗患有RET相关癌症的个体的方法，所述个体具有增加癌症对第一RET抑制剂的抗性的一个或多个RET抑制剂抗性突变(例如，在氨基酸位置804处的取代，例如V804M、V804L或V804E)，所述方法包括在施用另一抗癌药物(例如第二RET激酶抑制剂)之前、期间或之后，施用式I化合物或其药学上可接受的盐或溶剂合物。
还提供治疗患有RET相关癌症的个体的方法，其包含在施用另一种抗癌药物(例如，第一RET激酶抑制剂)之前、期间或之后，施用式I化合物或其药学上可接受的盐或溶剂 合物。
在本文所描述的任一方法或用途的一些实施例中，癌症(例如，RET相关癌症)是血液癌。在本文所描述的任一方法或用途的一些实施例中，癌症(例如，RET相关癌症)是实体肿瘤。在本文所描述的任一方法或用途的一些实施例中，癌症(例如RET相关癌症)是肺癌(例如，小细胞肺癌或非小细胞肺癌)、甲状腺癌(例如乳头状甲状腺癌、甲状腺髓样癌、分化型甲状腺癌、复发性甲状腺癌或难治性分化型甲状腺癌)、甲状腺腺瘤、内分泌腺肿瘤、肺腺癌、细支气管肺细胞癌、多发性内分泌瘤形成2A或2B型(分别地MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳癌(breast cancer)、乳腺癌(mammary cancer)、乳腺癌瘤(mammary carcinoma)、乳腺赘瘤、结肠直肠癌(例如转移性结肠直肠癌)、乳头状肾细胞癌、胃肠粘膜神经节细胞瘤、发炎性成肌纤维细胞瘤或宫颈癌。
在一些实施例中，患者是人类。
式I化合物和其药学上可接受的盐和溶剂合物也适用于治疗RET相关癌症。
本文还提供一种用于治疗诊断患有或鉴定为患有RET相关癌症(例如，本文公开的任一示范性RET相关癌症)的患者的方法，其包括向患者施用治疗有效量的如本文所定义的式I化合物或其药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备FGFR家族激酶抑制剂药物中的应用；本发明所述的FGFR家族包括但不限于FGFR1、FGFR1 V561M、FGFR2、FGFR2 V564F、FGFR2 N549H、FGFR2 V564I、FGFR2 K641R、FGFR3、FGFR3 V555M、FGFR3 K650E、FGFR4；在一些更具体的实例中，所述的FGFR家族包括FGFR2 V564F、FGFR2 N549H、FGFR2 V564I以及FGFR3 V555M。
本发明术语若无特别说明定义如下：
术语“卤素”意指-F(在本文中有时被称作“氟”)、-Cl、-Br和-I。
术语“C1-C3烷基”、“C1-C6烷基”、“C2-C6烷基”和“C3-C6烷基”是指分别具有一个到三个、一个到六个、两个到六个或三个到六个碳原子的饱和的直链或分支链一价烃基。实例包含(但不限于)甲基、乙基、1-丙基、异丙基、1-丁基、异丁基、仲丁基、叔丁基、2-甲基-2-丙基、戊基、新戊基和己基。
术语“C1-C6烷氧基”是指具有一到六个碳原子的饱和直链或分支链一价烷氧基，其中键是在氧原子上。实例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和叔丁氧基。
术语“(C1-C6烷氧基)C1-C6烷基-”和“(C1-C6烷氧基)C2-C6烷基-”是指分别具有一到六个碳原子或两个到六个碳原子的饱和直链或分支链一价基团，其中一个碳原子被如 本文所定义的(C1-C6烷氧基)基团取代。实例包含甲氧基甲基(CH 3OCH 2-)和甲氧基乙基(CH 3OCH 2CH 2-)。
术语“羟基C1-C6烷基-”和“羟基C2-C6烷基-”分别是指具有一个到六个或两个到六个碳原子的饱和直链或分支链一价烷基，其中一个碳原子被羟基取代。
术语“氘代C1-C6烷基-”、“卤代C1-C6烷基”、“氰基C1-C6烷基”分别是指一个到六个碳原子的饱和直链或分支链一价烷基，其中一个碳原子被氘、卤素或氰基取代。
术语“C3-C6环烷基”是指环丙基、环丁基、环戊基或环己基。
术语“烯基”指直链、支链或环状的，含有至少一个碳-碳双键的非芳香烃基。因此，“C2-C6烯基”指具有2～6个碳原子的烯基。例如包括但不限于乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基等。
术语“炔基”指直链、支链或环状的，含有至少一个碳碳三键的非芳香烃基。因此，“C2-C6炔基”指具有2～6个碳原子的炔基。例如包括但不限于乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。
术语“杂环”是指除了含有碳原子以外还含有1-4个选自由氧原子、硫原子及氮原子组成的组中的杂原子的单环式或双环式的非芳香族杂环，作为具体例，可以举出：氮杂环丁烷、吡咯烷、吡唑烷(pyrazolidine)、哌啶、氧杂环丁烷、四氢呋喃、四氢吡喃、四氢噻吩、二氢咪唑、咪唑烷(imidazolidine)、四氢吡嗪、哌嗪、吗啉等除了含有碳原子以外还含有1个或2个选自由氧原子、硫原子及氮原子组成的组中的杂原子的4-7元单环式非芳香族杂环；氮杂双环[3.1.0]己烷等除了含有碳原子以外还含有1-4个选自由氧原子、硫原子及氮原子组成的组中的杂原子的6-8元双环式非芳香族杂环。
术语“杂芳环”代表环中多达3-10个原子的稳定的单环或每个环中多达3-10个原子双环碳环，其中至少一个环为芳香环且含有1-4个选自O、N和S的杂原子。本定义范围内的杂芳基包括但不限于吖啶基、咔唑基、噌啉基、喹噁啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基。
术语“螺环”是指通过碳原子进行螺环连接而连接的两个环的基团，其中每个环具有4到6个环原子(其中一个环碳原子对于两个环是共同的)。
术语“杂螺环”是指含有一个或多个相同或不同的杂原子且通过碳原子进行螺环连接而连接的两个环的基团，其中每个环具有4到6个环原子(其中一个环碳原子对于两个环是共同的)，杂原子选自氮原子、氧原子。
术语“稠杂环”是指2-3个环共用两个相邻(邻位)原子的环烃；其中至少一个环为含有1到3个选自O、N和S的杂原子的芳香环，在一些实例中，为2个环共用两个相邻(邻位)原子的环烃；其中一个环为含有1到3个选自O、N和S的杂原子的芳香环，另一个环为饱和杂环。
术语“桥环”是指共用两个以上碳原子(桥头碳)的多环烃，根据组成环的数目分为二环烃、三环烃、四环烃等。
本文件通篇提及的术语“治疗(treating)”或“治疗(treatment)”的使用是常规的，例如为了抵抗、减轻、减少、缓解、改善诸如癌的疾病或病症的病况的目的来管理或护理个体。
术语“个体”或“患者”包括能够患细胞增殖性病症或者能够受益于给药本发明的化合物的有机体，例如人和非人的动物。优选的人包括患有或易于患有如本文所述的细胞增殖性病症或相关的状态的人患者。术语“非人的动物”包括脊椎动物，例如哺乳动物，如非人灵长类动物、绵羊、母牛、狗、猫和啮齿动物(例如小鼠)，以及非哺乳动物，例如鸡、两栖动物、爬行动物等。
术语“细胞增殖”包括涉及细胞的不期望的或不受控制的增殖。本发明的化合物可以用于防止、抑制、阻断、降低、减少、控制等细胞增殖和/或细胞分裂，和/或产生细胞凋亡。该方法包括向需要其的个体(包括哺乳动物，包括人)给药可有效治疗或预防所述病症的量的本发明的化合物或其药学上可接受的盐、异构体、多晶型物、代谢物、水合物或溶剂合物。
与现有技术相比，本发明的有益效果为：
本发明的RET激酶抑制剂化合物，具有优于上市药物Selpercatinib(LOXO-292)的酶和细胞水平生物活性且具有更低的心脏毒性。本发明的化合物为新型抗肿瘤药物提供了更多的选择，具有良好的药物应用前景。
具体实施方式
下面有代表性的例子旨在帮助阐述本发明，而不是有意也不应该被解释为限制本发明的范围。事实上，除了那些出现和描述于此的以外，本发明中文件的全部内容，包括依据此处引用的科技文献和专利的例子，以及由此产生的各种修饰和许多进一步变化对本专业内一般技术人员都是清晰明白的。还应当明白，这些参考文献的引用有助于陈述本文内容。下面的例子包含了重要的补充信息、范例和指导，可适应于本发明中各种变化及类似情况。
实施例1
合成路线如下：
Figure PCTCN2021113514-appb-000032
化合物1
Figure PCTCN2021113514-appb-000033
取2L三口烧瓶，低温温度计，氩气保护装置，三口瓶中分别加入2,4,6-三甲基苯磺酰氯(80g，367mmol)，N-羟基氨基甲酸叔丁酯(62.4g，468mmol)和THF(1.2L)，温度降至0℃,该温度下缓慢滴加TEA(64ml)，并在室温下继续搅拌1h，TLC监测无原料剩余，减压蒸馏除去溶剂，加入EA(1.2L)溶解，H 2O(1.2L*3)洗涤，10％NaHCO 3溶液(1.2L)洗涤，无水Na 2SO 4干燥，减压蒸馏得到110g淡黄色固体即产物1，收率95％。
化合物2
Figure PCTCN2021113514-appb-000034
取500ml三口烧瓶，低温温度计，氩气保护装置，三口瓶中加入TFA(150ml)，温 度降至0℃,该温度下分批加入1(110g，348.8mmol)，并在该温度下继续搅拌3h，TLC监测无原料剩余，将反应液缓慢倒入剧烈搅拌的冰水中，搅拌10mins有白色固体析出，过滤，滤饼用冰水洗涤，干燥得到60.1g白色固体即产物2，收率80％。
化合物3
Figure PCTCN2021113514-appb-000035
取500ml三口烧瓶，低温温度计，氩气保护装置，三口瓶中分别加入2(60g，278.5mmol)，3-溴-5-甲氧基吡啶(52.37g，278.6mmol)和DCM(1L)，温度降至0℃，搅拌1h后补加3-溴-5-甲氧基吡啶(523mg，2.8mmol)0℃下继续搅拌2h，该温度下加入PE(1L)搅拌10mins有白色固体析出，过滤，滤液浓缩加入DCM(300ml)溶解降至0℃后加入PE(300ml)继续搅拌10mins析出白色固体，过滤，合并两次得到的固体，干燥得到87.6g白色固体即产物3，收率78％。
化合物4
Figure PCTCN2021113514-appb-000036
取500ml单口烧瓶，分别加入3(87.6g，217.2mmol)，丙炔酸乙酯(42.6g，434.4mmol)和DMF(200ml)，室温下缓慢滴加TEA(60.4ml，434.4mmol)滴加完毕后，在室温下继续搅拌2ds，TLC监测无原料剩余，加入H 2O(600ml)稀释淬灭，EA(200ml*3)萃取，合并浓缩，柱层析纯化得到48.7g橙色固体即产物4，收率75％。
化合物5
Figure PCTCN2021113514-appb-000037
取1L单口茄形瓶，加入40％HBr(400ml)，搅拌下分批加入4(48.7g，162.8mmol)，升温至100℃，继续搅拌1h，TLC监测无原料剩余，冷却至室温后，倒入碎冰中搅拌， 2M NaOH溶液调节pH﹥8，有固体析出，过滤干燥得到34.38g粉色固体即产物5，收率为93％。
化合物6
Figure PCTCN2021113514-appb-000038
取500ml单口烧瓶，分别加入5(34.38g，151.4mmol)和DMF(200ml)，0℃下缓慢滴加POCl 3(76ml)，滴加完毕后升至室温继续搅拌4h，TLC监测无原料剩余，倒入200mlH 2O稀释，3MNaOH溶液调pH﹥8，室温下搅拌20mins有固体析出，过滤干燥得到34.7g灰色固体即产物6，收率90％。
化合物7
Figure PCTCN2021113514-appb-000039
取500ml单口烧瓶，分别加入6(34.38g，151.4mmol)，盐酸羟胺(13.7g，196.82mmol)，EtOH(250ml)和H 2O(80ml)，50℃下搅拌4h。TLC监测无原料剩余，减压蒸馏除去EtOH，加入250mlH 2O，饱和NaHCO 3溶液调pH＝9，固体析出，过滤干燥得到38g灰色固体即产物7，收率为93％。
化合物8
Figure PCTCN2021113514-appb-000040
取500ml单口烧瓶，分别加入7(38g，140.8mmol)，Cu(OAc) 2(25.6g，140.8mmol)和乙腈(200ml)，85℃下反应过夜。TLC监测已无原料剩余，冷却至室温，NH 3·H 2O调节pH＝8固体析出，过滤，滤饼用甲叔醚打浆洗涤，过滤烘干得到19.4g棕黄色固体即产物8，收率为55％。
化合物9
Figure PCTCN2021113514-appb-000041
取45ml封管，分别加入8(5g，19.8mmol)，1,2-二氯乙烷(100ml)，室温下分批加入AlCl 3(9.34mg，70mmol)，80℃下搅拌过夜，TLC监测无原料8剩余，冷却至室温，加入Na 2SO 4·10H 2O淬灭，搅拌1h，过滤MeOH洗涤，浓缩除去溶剂，柱层析纯化得到3g灰色固体即产物9，收率为55％。
化合物10
Figure PCTCN2021113514-appb-000042
取50ml单口烧瓶，分别加入化合物9(3g，12.6mmol)，N-苯基双(三氟甲烷磺酰)亚胺(4.5g，12.6mmol)，DIEA(3.26g，25.2mmol)和DMA(20ml)，于室温下搅拌过夜。TLC监测反应完全。将反应液倒入搅拌的60ml H 2O中，棕色固体析出。过滤烘干得到4.4g棕色固体即产物10，收率为95％。
化合物11
Figure PCTCN2021113514-appb-000043
取12ml封管，分别加入10(4.4g，11.9mmol)，Pd(dppf)Cl 2二氯甲烷络合物(490mg，0.6mmol)，2-氟-5-硼酸吡啶(1.68g，11.9mmol)，KOAc(2.92g，29.75mmol)，dioxane(50ml)，Ar保护，85℃下搅拌过夜，TLC监测反应完全，冷却至室温，加入100ml水搅拌10min棕黄色固体析出，过滤烘干得到3g即为产物11，收率为80％。
化合物12
Figure PCTCN2021113514-appb-000044
取45ml封管，分别加入11(3g，9.46mmol)，6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(2.25g，11.3mmol)，K 2CO 3(3.9g，28.35mmol)，DMSO(20ml)，110℃下搅拌过夜，TLC监测反应完全，冷却至室温，加入50ml水搅拌10min黄色固体析出，过滤烘干得到3.2g即为产物12，收率为69％。
化合物13
Figure PCTCN2021113514-appb-000045
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入12(94.5mg，0.2mmol)的EA溶液，滴加完毕后室温下继续搅拌1h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到68mg棕黄色固体即产物13，收率为90％。
化合物14
Figure PCTCN2021113514-appb-000046
取50ml单口烧瓶，分别加入13(68mg，0.18mmol)，6-甲氧基-3-吡啶甲醛(30.2mg，0.22mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(190.8mg，0.9mmol)，室温下继续搅拌过夜，TLC监测无原料13剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到55mg黄色固体即产物14，收率为61％。
化合物15
Figure PCTCN2021113514-appb-000047
取25ml封管，分别加入14(500mg，0.97mmol)，Pd 2(dba) 3(106.4mg，0.12mmol)，t-BuXPhos(152.9mg,0.36mmol),6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(384.12mg，1.94mmol)，Cs 2CO 3(632.1mg，1.94mmol)，dioxane(6ml)和DMF(3ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料15剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到450mg即为产物97，收率为73％。
1H NMR(400MHz,CDCl 3)δ8.43(d,J＝2.2Hz,1H),8.17(s,1H),8.11(d,J＝2.1Hz,1H),7.95(d,J＝2.1Hz,1H),7.83(dd,J＝8.8,2.5Hz,1H),7.64(dd,J＝8.5,2.4Hz,1H),7.10(d,J＝2.1Hz,1H),6.72(dd,J＝8.6,6.0Hz,2H),4.00(d,J＝5.9Hz,2H),3.92(d,J＝7.4Hz,3H),3.85(d,J＝12.0Hz,2H),3.77(t,J＝9.9Hz,2H),3.60(d,J＝13.1Hz,8H),2.86(dt,J＝8.8,6.2Hz,1H),2.70(dd,J＝14.2,6.2Hz,1H),1.69(dd,J＝20.8,8.8Hz,2H),1.42(s,9H)
化合物16
Figure PCTCN2021113514-appb-000048
取25ml单口茄形瓶，加入盐酸乙酸乙酯溶液(10ml)，缓慢加入15(450mg，0.71mmol)，室温下搅拌3小时，TLC监测无原料剩余，浓缩，加入氨水调节pH＝9，DCM(3ml*3)萃取，合并有机相浓缩，柱层析纯化得到350mg黄色固体即为目标产物16，收率为92％。
1H NMR(400MHz,CDCl 3)δ8.43(d,J＝2.2Hz,1H),8.17(s,1H),8.11(d,J＝2.1Hz,1H),7.95(d,J＝2.1Hz,1H),7.83(dd,J＝8.8,2.5Hz,1H),7.64(dd,J＝8.5,2.4Hz,1H),7.10(d,J＝2.1Hz,1H),6.72(dd,J＝8.6,6.0Hz,2H),4.00(d,J＝5.9Hz,2H),3.92(d,J＝7.4Hz,3H),3.85(d,J＝12.0Hz,2H),3.77(t,J＝9.9Hz,2H),3.60(d,J＝13.1Hz,8H),2.86(dt,J＝8.8,6.2Hz,1H),2.70(dd,J＝14.2,6.2Hz,1H),1.69(dd,J＝20.8,8.8Hz,2H).
实施例2
Figure PCTCN2021113514-appb-000049
化合物17
取25ml单口茄形瓶，加入16(200mg，0.37mmol)，多聚甲醛(333mg，3.7mmol)和DCM(15ml)，室温下搅拌30分钟，加入醋酸硼氢化钠(392.2mg，1.85mmol)，室温下继续搅拌过夜，TLC监测无原料剩余，加入氨水调节pH＝9，DCM(3ml*3)萃取，合并有机相浓缩，柱层析纯化得到150mg黄色固体即为目标产物17，收率为74.2％。
1H NMR(400MHz,CDCl 3)δ8.45(d,J＝2.2Hz,1H),8.18(s,1H),8.12(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.84(dd,J＝8.8,2.5Hz,1H),7.67(dd,J＝8.5,2.4Hz,1H),7.13(d,J＝2.1Hz,1H),6.77–6.68(m,2H),4.74(s,3H),3.94(s,3H),3.90–3.78(m,6H),3.69–3.55(m,6H),3.41(d,J＝10.7Hz,2H),2.83–2.67(m,2H),1.70(dt,J＝14.4,7.2Hz,2H).
实施例3
Figure PCTCN2021113514-appb-000050
化合物18
Figure PCTCN2021113514-appb-000051
取250ml三口烧瓶，氩气保护，低温温度计，加入100ml THF，甲基膦酞二氯(5g，37.6mmol)，降温至-78℃，30min内缓慢滴加乙烯基溴化镁(38ml，38mmol)，升温至0℃，搅拌1小时，滴加苄胺(4.8g，44.8mmol)的甲醇溶液，温度升至68℃，回流过夜，TLC监测无原料剩余，柱层析纯化得到目标产物3.1g，为白色固体18，收率36.9％。
化合物19
Figure PCTCN2021113514-appb-000052
取100ml单口烧瓶，分别加入18(3g，13.4mmol)，钯碳(500mg)和甲醇(30ml)，H2下，室温搅拌过夜，TLC监测无原料剩余，过滤除去废钯碳，浓缩得到1.5g目标产物19，收率为83.85％。未纯化直接用于下一步。
化合物20
Figure PCTCN2021113514-appb-000053
取25ml封管，分别加入14(300mg，0.58mmol)，Pd 2(dba) 3(64.1mg，0.07mmol)，t-BuXPhos(89.2mg,0.21mmol),19(231.6mg，1.74mmol)，Cs 2CO 3(378mg，1.16mmol)，dioxane(6ml)和DMF(3ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料14剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到230mg即为产物20，收率为70％。
1H NMR(400MHz,CDCl 3)δ8.45(d,J＝2.2Hz,1H),8.18(s,1H),8.12(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.84(dd,J＝8.8,2.5Hz,1H),7.67(dd,J＝8.5,2.4Hz,1H),7.13(d,J＝2.1Hz,1H),6.77–6.68(m,2H),δ3.92(s,3H),3.84(m,4H),3.62(m,4H),3.51(m,5H),2.75(m,1H),2.08(m,4H),1.64(m,3H).
实施例4
合成路线如下：
Figure PCTCN2021113514-appb-000054
化合物8的合成同实施例1。
化合物9-a
Figure PCTCN2021113514-appb-000055
取25ml封管，分别加入8(1g，3.97mmol)，Pd(PPh 3) 4(229.3mg，0.2mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(991mg，4.76mmol)，2M Na 2CO 3(1.26g，11.9mmol)，1,4-二氧六环(8ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料8剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干得到850mg即为产物9-a，收率为85％。
化合物10-a
Figure PCTCN2021113514-appb-000056
取45ml封管，分别加入9-a(850mg，3.36mmol)，1,2-二氯乙烷(15ml)，室温下分批加入AlCl 3(1.57g，11.76mmol)，80℃下搅拌过夜，TLC监测无原料9-a剩余，冷却至室温，加入Na 2SO 4·10H 2O淬灭，搅拌1h，过滤MeOH洗涤，浓缩除去溶剂，柱层析纯化得到450mg灰色固体即产物10-a，收率为56％。
化合物11-a
Figure PCTCN2021113514-appb-000057
取50ml单口烧瓶，分别加入化合物10-a(450mg，1.88mmol)，N-苯基双(三氟甲烷磺酰)亚胺(806mg，2.26mmol)，DIEA(486mg，3.76mmol)和DMA(5ml)，于室温下搅拌过夜。TLC监测无原料10-a剩余。将反应液倒入搅拌的10ml H 2O中，棕色固体析出。过滤烘干得到628mg棕色固体即产物11-a，收率为90％。
化合物12-a
Figure PCTCN2021113514-appb-000058
取12ml封管，分别加入11-a(628mg，1.69mmol)，Pd(PPh 3) 4(97.6mg，0.08mmol)，2-氟-5-硼酸吡啶(238.3mg，1.69mmol)，2M Na 2CO 3(358.3mg，3.38mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料11-a剩余，冷却至室温，加入10ml水搅拌10min棕黄色固体析出，过滤烘干得到430mg即为产物12-a，收率为80％。
化合物16-a
Figure PCTCN2021113514-appb-000059
取12ml封管，分别加入12-a(70mg，0.22mmol)，N,N’-二甲基乙二胺(23.2mg，0.26mmol)，K 2CO 3(61mg，0.44mmol)，DMSO(1ml)，120℃下搅拌过夜，TLC监测无原料12-a剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干得到51mg即为产物16-a，收率为60％。
LC-MS[M+H] +387.2。
化合物17-a
Figure PCTCN2021113514-appb-000060
取50ml单口烧瓶，分别加入16-a(51mg，0.13mmol)，6-甲氧基-3-吡啶甲醛(26.7mg，0.19mmol)和DCM(15ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(137.8mg，0.65mmol)，室温下继续搅拌过夜，TLC监测无原料16-a剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到30mg黄色固体即产物17-a，收率为46％。
1H NMR(400MHz,CDCl 3)δ8.62(s,1H),8.31(s,1H),8.25(s,1H),8.02(s,1H),7.80(s,1H),7.70(s,1H),7.68(s,1H),7.54(d,J＝6.6Hz,1H),7.39(s,1H),6.64(dd,J＝36.1,8.7Hz,2H),3.99(s,3H),3.89(s,3H),3.79(t,J＝6.7Hz,2H),3.53(s,2H),3.11(s,3H),2.67(t,J＝6.6Hz,2H),2.30(s,3H).LC-MS[M+H] +507.6。
实施例5
Figure PCTCN2021113514-appb-000061
Figure PCTCN2021113514-appb-000062
合成路线如下：
Figure PCTCN2021113514-appb-000063
化合物18-a
Figure PCTCN2021113514-appb-000064
取12ml封管，分别加入12-a(80mg，0.25mmol)，1-Boc-4-氨基哌啶(60.5mg，0.3mmol)，K 2CO 3(69mg，0.5mmol)，DMSO(1ml)，120℃下搅拌过夜，TLC监测无原料12-a剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干得到70mg即为产物18-a，收率为56％。
LC-MS[M+H] +499.25。
化合物19-a
Figure PCTCN2021113514-appb-000065
取50ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入18-a(70mg， 0.14mmol)的EA溶液，滴加完毕后室温下继续搅拌3h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，得到55mg黄色固体即产物19-a，收率为98％。
LC-MS[M+H] +399.25。
化合物21
Figure PCTCN2021113514-appb-000066
取50ml单口烧瓶，分别加入19-a(55mg，0.138mmol)，6-甲氧基-3-吡啶甲醛(22.7mg，0.166mmol)和DCM(15ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(146.28mg，0.69mmol)，室温下继续搅拌过夜，TLC监测无原料19-a剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到30mg黄色固体即产物21，收率为41.8％。
1H NMR(400MHz,CDCl 3)δ8.63(s,1H),8.29–8.20(m,2H),8.06(s,1H),7.79(s,1H),7.64(ddd,J＝19.4,7.1,2.8Hz,3H),7.38(s,1H),6.74(d,J＝8.4Hz,1H),6.52(d,J＝8.6Hz,1H),4.78(d,J＝7.7Hz,1H),4.00(s,3H),3.94(s,3H),3.77(s,1H),3.54(s,2H),2.90(s,2H),2.29(d,J＝10.2Hz,2H),2.10(d,J＝15.2Hz,2H),1.61(d,J＝10.2Hz,2H).LC-MS[M+H]+519.6。
实施例6
Figure PCTCN2021113514-appb-000067
合成路线如下：
Figure PCTCN2021113514-appb-000068
化合物30
Figure PCTCN2021113514-appb-000069
取12ml封管，分别加入12-a(70mg，0.22mmol)，1,4-二氮杂环庚烷-1-甲酸叔丁酯(52.1mg，0.26mmol)，K 2CO 3(60.8mg，0.44mmol)，DMSO(3ml)，120℃下搅拌过夜，TLC监测无原料12-a剩余，冷却至室温，加入5ml水搅拌10min黄色固体析出，过滤烘干得到55mg即为产物30，收率为50％。
LC-MS[M+H] +499.25。
化合物31
Figure PCTCN2021113514-appb-000070
取50ml单口烧瓶，加入3.5M HCl的EA溶液(5ml)，搅拌下缓慢滴入30(55mg，0.11mmol)的EA溶液，滴加完毕后室温下继续搅拌3h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，得到44.6mg黄色固体即产物31，收率为100％。
LC-MS[M+H] +399.25。
化合物32
Figure PCTCN2021113514-appb-000071
取50ml单口烧瓶，分别加入31(44.6mg，0.11mmol)，6-甲氧基-3-吡啶甲醛(18.1mg，0.13mmol)和DCM(5ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(93.3mg，0.44mmol)，室温下继续搅拌过夜，TLC监测无原料31剩余，加入氨水淬灭，分液，水 相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到32mg黄色固体即产物32，收率为55％。
1H NMR(400MHz,CDCl 3)δ8.62(d,J＝1.4Hz,1H),8.34(d,J＝2.4Hz,1H),8.25(s,1H),8.05(d,J＝1.8Hz,1H),7.79(s,1H),7.71(dd,J＝8.9,2.5Hz,1H),7.68(s,1H),7.63–7.57(m,1H),7.39(d,J＝1.4Hz,1H),6.72(d,J＝8.5Hz,1H),6.63(d,J＝8.9Hz,1H),3.99(s,3H),3.93(s,3H),3.85(m,2H),3.73(t,J＝6.1Hz,2H),3.58(s,2H),2.79(s,2H),2.64(d,J＝5.1Hz,2H),1.98(s,2H),1.68(s,2H).LC-MS[M+H] +519.6。
实施例7
Figure PCTCN2021113514-appb-000072
合成路线如下：
Figure PCTCN2021113514-appb-000073
化合物33
Figure PCTCN2021113514-appb-000074
取12ml封管，分别加入12-a(70mg，0.22mmol)，(1S,2S)-(+)-N,N'-二甲基-1,2-环己二胺(31.3mg，0.22mmol)，K 2CO 3(60.8mg，0.44mmol)，DMSO(3ml)，120℃下搅拌过夜，TLC监测无原料12-a剩余，冷却至室温，加入5ml水搅拌10min黄色固体析出，柱层析纯化得到43.6mg即为产物33，收率为45％。
LC-MS[M+H] +441.24。
化合物34
Figure PCTCN2021113514-appb-000075
取50ml单口烧瓶，分别加入33(43.6mg，0.1mmol)，6-甲氧基-3-吡啶甲醛(16.7mg，0.12mmol)和DCM(5ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(84.8mg，0.4mmol)，室温下继续搅拌过夜，TLC监测无原料33剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到30mg黄色固体即产物34，收率为53％。
1H NMR(400MHz,CDCl 3)δ8.59(s,1H),8.24(s,1H),8.21(s,1H),7.84(s,1H),7.78(s,1H),7.73(d,J＝9.2Hz,1H),7.67(s,1H),7.25–7.21(m,1H),7.15(s,1H),6.64(d,J＝8.6Hz,1H),6.58(d,J＝8.2Hz,1H),3.99(s,3H),3.83(s,3H),3.73(d,J＝12.9Hz,1H),3.25(d,J＝13.0Hz,1H),2.89(s,3H),2.70(s,1H),2.10(s,3H),2.04(s,1H),1.92–1.76(m,3H),1.44(dd,J＝38.9,14.7Hz,3H).LC-MS[M+H] +561.7。
实施例8
Figure PCTCN2021113514-appb-000076
合成路线如下：
Figure PCTCN2021113514-appb-000077
化合物35
Figure PCTCN2021113514-appb-000078
取50ml单口烧瓶，分别加入化合物2,4-二溴噻唑(1.5g，6.17mmol)，1-N-BOC-哌嗪(1.7g，9.26mmol)，Cs 2CO 3(4.0g，12.3mmol)和乙腈(20ml)，升温至回流过夜。TLC监测无原料剩余。加入H2O(50ml)稀释，EA(20ml*3)萃取，合并有机相，浓缩柱层析纯化得到1.6g白色固体即产物35，收率为74.5％。
LC-MS[M+H] +348.03。
化合物36
Figure PCTCN2021113514-appb-000079
取45ml封管，分别加入35(1.2g，3.45mmol)，联硼酸频那醇酯(918.7mg，3.62mmol)，Pd(dppf)Cl 2·DCM(140.9mg，0.17mmol)，KOAc(1.02g，10.35mmol)，1,4-二氧六环 (15ml)，Ar保护，100℃下搅拌3h，TLC监测无原料35剩余，冷却至室温，加入10ml水搅拌10min红棕色固体析出，过滤烘干得到1.26g即为产物36，收率为92.38％。
LC-MS[M+H] +396.21。化合物37
Figure PCTCN2021113514-appb-000080
取45ml封管，分别加入化合物36(1.25g，3.18mmol)，11-a(1.0g，2.69mmol)，Pd(PPh 3) 4(155mg，0.13mmol)，4ml 2M Na 2CO 3(855.4mg，8.07mmol)，1,4-二氧六环(20ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料11剩余，冷却至室温，加入10ml水搅拌10min固体析出，过滤烘干得到1.2g灰色固体即为产物37，收率为91％。
LC-MS[M+H] +491.19。
化合物38
Figure PCTCN2021113514-appb-000081
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入37(1.2g，2.45mmol)的EA溶液，滴加完毕后室温下继续搅拌3h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到680mg棕黄色固体即产物38，收率为71.1％。
LC-MS[M+H] +492.19。
化合物39
Figure PCTCN2021113514-appb-000082
取50ml单口烧瓶，分别加入38(200mg，0.51mmol)，6-甲氧基-3-吡啶甲醛(70.2mg，0.51mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(324.3mg，1.53mmol)，室温下继续搅拌过夜，TLC监测无原料38剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到170mg黄色固体即产物39，收率为65％。
1H NMR(400MHz,CDCl 3)δ8.61(d,J＝1.4Hz,1H),8.26(s,1H),8.07(d,J＝2.0Hz,1H),7.79(s,1H),7.76(d,J＝1.4Hz,1H),7.69(s,1H),7.60(dd,J＝8.5,2.2Hz,1H),6.95(s,1H),6.74(d,J＝8.5Hz,1H),3.98(s,3H),3.94(s,3H),3.66–3.57(m,4H),3.51(s,2H),2.65–2.57(m,4H).LC-MS[M+H] +511.6。
实施例9
Figure PCTCN2021113514-appb-000083
合成路线如下：
Figure PCTCN2021113514-appb-000084
化合物40
Figure PCTCN2021113514-appb-000085
取45ml封管，分别加入化合物11-a(200mg，0.54mmol)，4-吡唑硼酸频哪醇酯(104.5mg，0.54mmol)，Pd(PPh 3) 4(31.2mg，0.,07mmol)，0.54ml 2M Na 2CO 3(114.5mg，1.08mmol)，1,4-二氧六环(2ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料11-a剩余，冷却至室温，加入5ml水搅拌10min固体析出，过滤烘干得到115.7mg灰色固体即为产物40，收率为74％。
LC-MS[M+H] +290.11。
化合物41
Figure PCTCN2021113514-appb-000086
取50ml单口烧瓶，分别加入化合物40(115.7mg，0.4mmol)，1-Boc-4-甲烷磺酰氧基哌啶(167.6mg，0.6mmol)，Cs 2CO 3(260.7mg，0.8mmol)和DMF(2ml)，升温至回流过夜。TLC监测无原料40剩余。加入H2O(6ml)稀释，EA(2ml*3)萃取，合并有机相，浓缩柱层析纯化得到94.5mg黄色固体即产物41，收率为50％。
LC-MS[M+H] +473.23。
化合物42
Figure PCTCN2021113514-appb-000087
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入41(94.5mg， 0.2mmol)的EA溶液，滴加完毕后室温下继续搅拌3h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到68mg棕黄色固体即产物42，收率为90％。
化合物43
Figure PCTCN2021113514-appb-000088
取50ml单口烧瓶，分别加入42(68mg，0.18mmol)，6-甲氧基-3-吡啶甲醛(30.2mg，0.22mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(190.8mg，0.9mmol)，室温下继续搅拌过夜，TLC监测无原料42剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到55mg黄色固体即产物43，收率为61％。
1H NMR(400MHz,CDCl 3)δ8.59(s,1H),8.25(s,1H),8.06(s,1H),7.95(s,1H),7.79(s,2H),7.70(s,1H),7.62(dd,J＝8.4,1.9Hz,1H),7.47(s,1H),6.73(d,J＝8.4Hz,1H),4.24(d,J＝10.7Hz,1H),3.99(s,3H),3.93(s,3H),3.50(s,2H),2.19(dt,J＝22.9,10.5Hz,8H).LC-MS[M+H] +493.56。
实施例10
Figure PCTCN2021113514-appb-000089
合成路线如下：
Figure PCTCN2021113514-appb-000090
化合物44
Figure PCTCN2021113514-appb-000091
取45ml封管，分别加入8(5g，19.8mmol)，1,2-二氯乙烷(100ml)，室温下分批加入AlCl 3(9.34mg，70mmol)，80℃下搅拌过夜，TLC监测无原料8剩余，冷却至室温，加入Na 2SO 4·10H 2O淬灭，搅拌1h，过滤MeOH洗涤，浓缩除去溶剂，柱层析纯化得到3g灰色固体即产物44，收率为55％。
化合物45
Figure PCTCN2021113514-appb-000092
取50ml单口烧瓶，分别加入化合物44(3g，12.6mmol)，N-苯基双(三氟甲烷磺酰)亚胺(4.5g，12.6mmol)，DIEA(3.26g，25.2mmol)和DMA(20ml)，于室温下搅拌过 夜。TLC监测无原料44剩余。将反应液倒入搅拌的60ml H 2O中，棕色固体析出。过滤烘干得到4.4g棕色固体即产物45，收率为95％。
化合物46
Figure PCTCN2021113514-appb-000093
取12ml封管，分别加入45(4.4g，11.9mmol)，Pd(dppf)Cl 2二氯甲烷络合物(490mg，0.6mmol)，2-氟-5-硼酸吡啶(1.68g，11.9mmol)，KOAc(2.92g，29.75mmol)，1,4-二氧六环(50ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料45剩余，冷却至室温，加入100ml水搅拌10min棕黄色固体析出，过滤烘干得到3g即为产物46，收率为80％。
化合物47
Figure PCTCN2021113514-appb-000094
取45ml封管，分别加入46(3g，9.46mmol)，6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(2.25g，11.3mmol)，K 2CO 3(3.9g，28.35mmol)，DMSO(20ml)，110℃下搅拌过夜，TLC监测无原料46剩余，冷却至室温，加入50ml水搅拌10min黄色固体析出，过滤烘干得到3.2g即为产物47，收率为69％。
化合物48
Figure PCTCN2021113514-appb-000095
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入47(94.5mg， 0.2mmol)的EA溶液，滴加完毕后室温下继续搅拌1h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到68mg棕黄色固体即产物48，收率为90％。
化合物49
Figure PCTCN2021113514-appb-000096
取50ml单口烧瓶，分别加入48(68mg，0.18mmol)，6-甲氧基-3-吡啶甲醛(30.2mg，0.22mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(190.8mg，0.9mmol)，室温下继续搅拌过夜，TLC监测无原料48剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到55mg黄色固体即产物49，收率为61％。
化合物50
Figure PCTCN2021113514-appb-000097
取25ml封管，分别加入3-溴-5,6-二氢-4H-吡咯并[1,2-B]吡唑(1.45g，7.8mmol)，联硼酸片呐醇酯(2.1g，8.2mmol)，Pd(dppf)Cl 2DCM(318.2mg，0.4mmol)，1,1'-双(二苯基膦)二茂铁(221.8mg，0.4mmol)KOAc(2.3g，23.4mmol)，1,4-二氧六环(40ml)，Ar保护，70℃下搅拌过夜，TLC监测无原料56-2剩余，冷却至室温，加入60ml水搅拌10min，DCM(20ml*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到1.5g红棕色液体产物，未纯化直接用于下一步，收率为82％。
LC-MS[M+H] +235.15。
化合物51
Figure PCTCN2021113514-appb-000098
取25ml封管，分别加入49(55mg，0.11mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，50(25.74mg，0.11mmol)，2M Na 2CO 3(23.3mg，0.22mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干柱层析纯化得到47.8mg即为产物51，收率为80％。
1H NMR(400MHz,CDCl 3)δ8.56(d,J＝1.3Hz,1H),8.36(d,J＝2.3Hz,1H),8.25(s,1H),8.08(d,J＝1.9Hz,1H),8.04(d,J＝1.9Hz,1H),8.02(s,1H),7.82(s,1H),7.75(dd,J＝8.8,2.5Hz,1H),7.63(dd,J＝8.4,2.2Hz,1H),7.40(d,J＝1.4Hz,1H),4.23(t,J＝7.3Hz,2H),3.92(s,3H),3.84(d,J＝11.9Hz,2H),3.77(d,J＝5.6Hz,2H),3.62(s,2H),3.58(s,2H),2.97(t,J＝7.3Hz,2H),2.67(dd,J＝14.3,7.2Hz,3H),1.67(d,J＝8.6Hz,1H).LC-MS[M+H] +544.6
实施例11
Figure PCTCN2021113514-appb-000099
化合物52
Figure PCTCN2021113514-appb-000100
取45ml封管，分别加入46(500mg，1.58mmol)，N-BOC-哌嗪(352.2mg，1.89mmol)，K 2CO 3(436.1mg，3.16mmol)，DMSO(20ml)，120℃下搅拌过夜，TLC监测无原料46剩余，冷却至室温，加入50ml水搅拌10min黄色固体析出，过滤烘干得到611mg即为产物52，收率为80％。
化合物53
Figure PCTCN2021113514-appb-000101
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入52(611mg，1.26mmol)的EA溶液，滴加完毕后室温下继续搅拌1h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到473.2mg棕黄色固体即产物53，收率为98％。
化合物54
Figure PCTCN2021113514-appb-000102
取50ml单口烧瓶，分别加入53(473.2mg，1.23mmol)，6-甲氧基-3-吡啶甲醛(203.2mg，1.48mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(1.3g，6.15mmol)，室温下继续搅拌过夜，TLC监测无原料53剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到55mg黄色固体即产物54，收率为61％。
化合物55
Figure PCTCN2021113514-appb-000103
取25ml封管，分别加入54(50mg，0.1mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，50(23.41mg，0.1mmol)，2M Na 2CO 3(21.2mg，0.2mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料54剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干柱层析纯化得到60.4mg即为产物55，收率为88％。
1H NMR(400MHz,CDCl 3)δ8.56(d,J＝1.3Hz,1H),8.36(d,J＝2.3Hz,1H),8.25(s,1H),8.08(d,J＝1.9Hz,1H),8.04(d,J＝1.9Hz,1H),8.02(s,1H),7.82(s,1H),7.75(dd,J＝8.8,2.5Hz,1H),7.63(dd,J＝8.4,2.2Hz,1H),7.40(d,J＝1.4Hz,1H),4.23(t,J＝7.3Hz,2H),3.95(s,3H),3.93(s,3H),3.70–3.59(m,4H),3.50(s,2H),3.15–3.08(m,2H),2.79–2.69(m,2H),2.60–2.51(m,4H).LC-MS[M+H] +531.6。
实施例12
Figure PCTCN2021113514-appb-000104
化合物56-1
Figure PCTCN2021113514-appb-000105
取100ml封管，分别加入6-氯-3-氧代己酸乙酯(10g，51.9mmol)，水合肼(33.3ml)，EtOH(20ml)于120℃下搅拌过夜。TLC监测无原料剩余，冷却至室温，浓缩，EA(20ml*3)萃取，合并有机相，浓缩，柱层析纯化得到3.4g黄色固体产物。收率为53％。
LC-MS[M+H] +125.06。
化合物56-2
Figure PCTCN2021113514-appb-000106
取100ml三颈瓶，分别加入56-1(3.4g，27.4mmol)，pyridine(55ml)，温度降到0℃，缓慢滴加三氟甲磺酸酐(8.1g，28.8mmol)，滴加完毕后升至室温，继续搅拌过夜。TLC监测无56-1剩余，将反应液倒入20ml 2MHCl中。EA(10ml*3)萃取，合并有机相，依次用饱和食盐水，饱和碳酸钠溶液洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到1.7g无色油状产物。收率为24％。
LC-MS[M+H] +257.01。
化合物56
Figure PCTCN2021113514-appb-000107
取25ml封管，分别加入56-2(2g，7.8mmol)，联硼酸片呐醇酯(2.1g，8.2mmol)，Pd(dppf)Cl 2DCM(318.2mg，0.4mmol)，1,1'-双(二苯基膦)二茂铁(221.8mg，0.4mmol)KOAc(2.3g，23.4mmol)，1,4-二氧六环(40ml)，Ar保护，70℃下搅拌过夜，TLC监测无原料56-2剩余，冷却至室温，加入60ml水搅拌10min，DCM(20ml*3)萃取，合并 有机相，无水硫酸钠干燥，过滤，浓缩得到1.7g红棕色液体产物，未纯化直接用于下一步，收率为93％。
LC-MS[M+H] +235.15。
化合物57
Figure PCTCN2021113514-appb-000108
取25ml封管，分别加入49(50mg，0.1mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，56(23.41mg，0.1mmol)，2M Na 2CO 3(21.2mg，0.2mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到46.3mg即为产物57，收率为88％。
1H NMR(400MHz,CDCl 3)δ8.90(s,1H),8.47(d,J＝2.3Hz,1H),8.28(s,1H),8.12(d,J＝1.8Hz,1H),7.82(dd,J＝9.9,3.4Hz,2H),7.63(dd,J＝8.5,2.2Hz,1H),6.70(t,J＝8.9Hz,2H),6.31(s,1H),4.22(t,J＝7.2Hz,2H),3.92(s,3H),3.84(d,J＝11.9Hz,2H),3.77(d,J＝5.6Hz,2H),3.62(s,2H),3.58(s,2H),2.97(t,J＝7.3Hz,2H),2.67(dd,J＝14.3,7.2Hz,3H),1.67(d,J＝8.6Hz,1H).LC-MS[M+H] +543.6。
实施例13
Figure PCTCN2021113514-appb-000109
化合物58
取25ml封管，分别加入54(50mg，0.1mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，56(23.41mg，0.1mmol)，2M Na 2CO 3(21.2mg，0.2mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料54剩余，冷却至室温，加入10ml水搅拌10min 黄色固体析出，过滤烘干，柱层析纯化得到46.3mg即为产物58，收率为88％。
1H NMR(400MHz,CDCl 3)δ8.88(d,J＝1.3Hz,1H),8.39(d,J＝2.3Hz,1H),8.26(s,1H),8.08(d,J＝2.0Hz,1H),7.77(d,J＝1.3Hz,1H),7.74(dd,J＝8.9,2.5Hz,1H),7.62(dd,J＝8.5,2.3Hz,1H),6.76(d,J＝2.7Hz,1H),6.74(d,J＝2.2Hz,1H),6.29(s,1H),4.20(t,J＝7.2Hz,2H),3.94(s,3H),3.75–3.59(m,4H),3.50(s,2H),2.96(t,J＝7.3Hz,2H),2.73–2.59(m,2H),2.60–2.48(m,4H).LC-MS[M+H] +531.6。
实施例14
Figure PCTCN2021113514-appb-000110
化合物59
取25ml单口烧瓶，分别加入53(50mg，0.13mmol)，6-甲氧基烟酸(19.9mg，0.13mmol)，EDCI(37.38mg，0.2mmol)，HOBt(35.13mg，0.26mmol)，DIEA(50.4mg，0.39mmol)，DCM(8ml)，Ar保护，室温下搅拌过夜，TLC监测无原料53剩余，加入10ml水搅拌10min分液，浓缩有机相，柱层析纯化得到55.25mg即为产物59，收率为82％。
LC-MS[M+H] +518.09。
化合物60
Figure PCTCN2021113514-appb-000111
取25ml封管，分别加入59(55.2mg，0.1mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，56(23.41mg，0.1mmol)，2M Na 2CO 3(21.2mg，0.2mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料59剩余，冷却至室温，加入10ml水搅拌10min 黄色固体析出，过滤烘干，柱层析纯化得到40mg即为产物60，收率为73％。
1H NMR(400MHz,CDCl 3)δ8.90(s,1H),8.42(d,J＝2.0Hz,1H),8.33(s,1H),8.27(s,1H),7.87–7.77(m,2H),7.73(dd,J＝8.6,2.2Hz,1H),6.81(dd,J＝8.6,5.7Hz,2H),6.31(s,1H),4.21(t,J＝7.2Hz,2H),3.99(d,J＝4.7Hz,3H),3.73(s,8H),3.00–2.91(m,2H),2.72–2.57(m,3H).LC-MS[M+H] +545.6。
实施例15
Figure PCTCN2021113514-appb-000112
化合物61
Figure PCTCN2021113514-appb-000113
取45ml封管，分别加入46(200mg，0.63mmol)，1,4-二氮杂环庚烷-1-甲酸叔丁酯(151.57mg，0.76mmol)，K 2CO 3(173.88mg，1.26mmol)，DMSO(10ml)，120℃下搅拌过夜，TLC监测无原料46剩余，冷却至室温，加入50ml水搅拌10min黄色固体析出，过滤烘干得到250mg即为产物61，收率为80％。
LC-MS[M+H] +497.12。
化合物62
Figure PCTCN2021113514-appb-000114
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入61(250mg，0.5mmol)的EA溶液，滴加完毕后室温下继续搅拌1h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到188.7mg棕黄色固体即产物62，收率为95％。
LC-MS[M+H] +397.07。
化合物63
Figure PCTCN2021113514-appb-000115
取50ml单口烧瓶，分别加入62(188.7mg，0.47mmol)，6-甲氧基-3-吡啶甲醛(78.2mg，0.57mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(498.2mg，2.35mmol)，室温下继续搅拌过夜，TLC监测无原料62剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到158mg黄色固体即产物63，收率为65％。
LC-MS[M+H] +518.12。
化合物64
Figure PCTCN2021113514-appb-000116
取25ml封管，分别加入63(52mg，0.1mmol)，Pd(PPh 3) 4(6.36mg，0.005mmol)，56(23.41mg，0.1mmol)，2M Na 2CO 3(21.2mg，0.2mmol)，1,4-二氧六环(5ml)，Ar保护，85℃下搅拌过夜，TLC监测无原料63剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到39.8mg即为产物64，收率为73％。
1H NMR(400MHz,CDCl 3)δ8.88(d,J＝1.3Hz,1H),8.37(d,J＝2.4Hz,1H),8.26(s,1H),8.05(d,J＝2.0Hz,1H),7.77(d,J＝1.3Hz,1H),7.72(dd,J＝8.8,2.6Hz,1H),7.61(d,J＝6.9Hz,1H),6.72(d,J＝8.5Hz,1H),6.61(d,J＝9.0Hz,1H),6.31(s,1H),4.25–4.17(t,2H),3.93(s,3H),3.86(m,2H),3.72(t,J＝6.1Hz,2H),3.58(s,2H),3.02–2.92(m,2H),2.79(m,2H),2.71,2.63(m,4H),1.99(m,2H).LC-MS[M+H] +545.6。
实施例16
化合物65
Figure PCTCN2021113514-appb-000117
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(7.6mg,0.018mmol),吗啡啉(26mg，0.3mmol)，Cs 2CO 3(65.2mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到47mg即为产物65，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝2.3Hz,1H),8.20(s,1H),8.10(d,J＝2.0Hz,1H),8.02(d,J＝1.9Hz,1H),7.79(dd,J＝8.8,2.5Hz,1H),7.65(dd,J＝8.5,2.2Hz,1H),7.17(d,J＝1.9Hz,1H),6.71(dd,J＝13.3,8.7Hz,2H),3.91(m,J＝8.4Hz,6H),3.82(m,J＝19.6,8.9Hz,4H),3.59(m,4H),3.22–3.09(m,4H),2.71(m,J＝7.0Hz,1H),1.66(d,J＝8.7Hz,2H).LC-MS[M+H] +522.6。
实施例17
化合物66
Figure PCTCN2021113514-appb-000118
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(PPh 3) 2(5.5mg，0.005mmol)，CuI(19mg，0.1mmol)，PPh 3(52mg,0.2mmol),3-甲基丁炔醇-3(25mg，0.3mmol)，TEA(2ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到46.7mg即为产物65，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.61(d,J＝1.3Hz,1H),8.40(d,J＝2.3Hz,1H),8.31(s,1H),8.11(d,J＝2.0Hz,1H),7.76(dd,J＝8.8,2.5Hz,1H),7.67(d,J＝8.3Hz,1H),7.30(d,J＝1.3Hz,1H),6.71(dd,J＝13.8,8.6Hz,2H),3.92(s,3H),3.89–3.74(m,4H),3.61(m,4H),2.73(m,1H),2.22(m,1H),1.66(s,6H).LC-MS[M+H] +519.6。
实施例18
化合物67
Figure PCTCN2021113514-appb-000119
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(7.6mg,0.018mmol),3-羟基吡咯烷(26mg，0.3mmol)，Cs 2CO 3(65.2mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到47mg即为产物67，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.14(s,1H),8.10(d,J＝1.9Hz,1H),7.82(d,J＝2.5Hz,1H),7.79(d,J＝1.8Hz,1H),7.65(dd,J＝8.5,2.3Hz,1H),6.93(d,J＝2.0Hz,1H),6.71(t,J＝9.2Hz,2H),4.69(m,1H),3.92(s,3H),3.88–3.75(m,4H),3.67– 3.50(m,6H),3.40(td,J＝8.7,3.1Hz,1H),3.31(d,J＝10.0Hz,1H),2.70(m,1H),2.25(m,1H),2.15(m,1H),1.67(d,J＝8.6Hz,2H).LC-MS[M+H] +522.6。
实施例19
化合物68
Figure PCTCN2021113514-appb-000120
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(7.6mg,0.018mmol),3-甲氧基吡咯烷(26mg，0.3mmol)，Cs 2CO 3(65.2mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到48.3mg即为产物68，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.14(s,1H),8.10(d,J＝2.0Hz,1H),7.82(d,J＝2.5Hz,1H),7.80(t,J＝2.5Hz,1H),7.66(d,J＝8.3Hz,1H),6.94(d,J＝2.0Hz,1H),6.76-6.65(m,2H),4.20-4.10(m,1H),3.92(s,3H),3.83(m,4H),3.65-3.60(m,4H),3.55-3.42(m,2H),3.39(s,3H),3.37-3.34(m,1H),2.74-2.68(m,1H),2.29–2.09(m,2H),1.67(d,J＝8.6Hz,2H).LC-MS[M+H] +536.6。
实施例20
化合物69
Figure PCTCN2021113514-appb-000121
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(7.6mg,0.018mmol),3-吗啉酮(30mg，0.3mmol)，Cs 2CO 3(65.2mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩 余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到48.3mg即为产物69，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝2.3Hz,1H),8.20(s,1H),8.10(d,J＝2.0Hz,1H),8.02(d,J＝1.9Hz,1H),7.79(dd,J＝8.8,2.5Hz,1H),7.65(dd,J＝8.5,2.2Hz,1H),7.17(d,J＝1.9Hz,1H),6.71(dd,J＝13.3,8.7Hz,2H),3.91(m,J＝8.4Hz,6H),3.82(m,J＝19.6,8.9Hz,4H),3.59(m,2H),3.22–3.09(m,2H),2.92(s,2H)2.71(m,J＝7.0Hz,1H),1.66(d,J＝8.7Hz,2H).LC-MS[M+H] +537.58
实施例21
化合物70
Figure PCTCN2021113514-appb-000122
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(7.6mg,0.018mmol),3-羟基-3-甲基吡咯(30mg，0.3mmol)，Cs 2CO 3(65.2mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到48.3mg即为产物70，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝2.4Hz,1H),8.14(s,1H),8.11(d,J＝2.2Hz,1H),7.80(dd,J＝8.8,2.3Hz,1H),7.76(d,J＝1.3Hz,1H),7.65(dd,J＝8.5,2.4Hz,1H),6.90(d,J＝1.7Hz,1H),6.72(dd,J＝11.9,8.7Hz,2H),3.93(s,3H),3.85(d,J＝11.7Hz,2H),3.80(d,J＝5.8Hz,2H),3.65-3.60(m,2H),3.59(s,3H),3.42(td,J＝8.5,3.0Hz,1H),3.38–3.30(m,2H),2.71(dd,J＝14.1,6.3Hz,1H),2.22–2.05(m,3H),1.67(d,J＝8.7Hz,0H),1.56(s,1H).LC-MS[M+H] +536.6。
实施例22
Figure PCTCN2021113514-appb-000123
化合物71
Figure PCTCN2021113514-appb-000124
取12ml封管，分别加入45(500mg，1.35mmol)，Pd(dppf)Cl 2二氯甲烷络合物(57mg，0.07mmol)，2，3-二氟-5-硼酸吡啶(178.7mg，1.13mmol)，KOAc(265mg，2.7mmol)，THF(10ml)，H 2O(2ml)Ar保护，85℃下搅拌过夜，TLC监测无原料45剩余，冷却至室温，加入20ml水搅拌10min棕黄色固体析出，过滤烘干得到93.8mg即为产物71，收率为80％。
LC-MS[M+H] +334.97。
化合物72
Figure PCTCN2021113514-appb-000125
取45ml封管，分别加入71(93.8mg，1.08mmol)，6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(257mg，1.3mmol)，K 2CO 3(298.5mg，2.16mmol)，DMSO(2ml)，110℃下搅拌 过夜，TLC监测无原料71剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干得到382.5mg即为产物72，收率为69％。
LC-MS[M+H] +513.1。
化合物73
Figure PCTCN2021113514-appb-000126
取25ml单口烧瓶，加入3.5M HCl的EA溶液(10ml)，搅拌下缓慢滴入72(382.5mg，0.74mmol)的EA溶液，滴加完毕后室温下继续搅拌1h，浓缩除去溶剂，滴加NH 3的甲醇溶液中和浓缩，柱层析得到277mg棕黄色固体即产物73，收率为90％。
LC-MS[M+H] +413.04。
化合物74
Figure PCTCN2021113514-appb-000127
取50ml单口烧瓶，分别加入73(100mg，0.24mmol)，6-甲氧基-3-吡啶甲醛(39.8mg，0.29mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(254.4mg，1.2mmol)，室温下继续搅拌过夜，TLC监测无原料73剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到77mg黄色固体即产物74，收率为60％。
LC-MS[M+H] +534.1。
化合物75
Figure PCTCN2021113514-appb-000128
取25ml封管，分别加入74(77mg，0.14mmol)，Pd 2(dba) 3(7.9mg，0.009mmol)，t-BuXPhos(11.5mg,0.027mmol),吗啡啉(36.6mg，0.42mmol)，Cs 2CO 3(91.2mg，0.28mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料74剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到68mg即为产物75，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.21(s,1H),8.18(s,1H),8.15(s,1H),8.04(d,J＝1.9Hz,1H),7.50(s,1H),7.46(s,1H),7.19(d,J＝1.9Hz,1H),6.76(d,J＝8.6Hz,1H),3.95–3.88(m,10H),3.78(s,2H),3.23–3.11(m,5H),2.39–2.18(m,2H),2.01(s,2H).LC-MS[M+H] +540.6。
实施例23
Figure PCTCN2021113514-appb-000129
取50ml单口烧瓶，分别加入48(60mg，0.15mmol)，6-氘代甲氧基-3-吡啶甲醛(25.5mg，0.18mmol)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(159mg，0.75mmol)，室温下继续搅拌过夜，TLC监测无原料73剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到56mg黄色固体即产物76，收率为71.8％。
化合物77
Figure PCTCN2021113514-appb-000130
取25ml封管，分别加入74(56mg，0.11mmol)，Pd 2(dba) 3(6mg，0.007mmol)，t-BuXPhos(8.4mg,0.02mmol),吗啡啉(26mg，0.33mmol)，Cs 2CO 3(71.6mg，0.22mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料74剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到53.7mg即为产物77，收率为93％。
1H NMR(400MHz,CDCl 3)δ8.39(s,1H),8.20(s,1H),8.10(s,1H),8.02(s,1H),7.79(d,J＝8.4Hz,1H),7.17(s,1H),6.99(d,J＝8.9Hz,1H),6.71(dd,J＝15.3,8.5Hz,2H),3.91(d,J＝4.7Hz,4H),3.86-3.81(m,2H),3.63(s,2H),3.20–3.12(m,4H),2.78-2.74(m,1H),2.35(m,1H),2.24(dd,J＝20.5,6.6Hz,2H),2.04-2.00(m,2H).LC-MS[M+H] +525.6。
实施例24
化合物78
Figure PCTCN2021113514-appb-000131
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),1-氨基-2-甲基-2-丙醇(26.7mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料74剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到42.5mg即为产物78，收率为81％。
1HNMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.15(s,1H),8.11(s,1H),7.93(d,J＝1.4Hz,1H),7.82(dd,J＝8.7,2.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.08(d,J＝1.5Hz,1H),6.72(dd,J＝16.0,8.7Hz,2H),3.97(d,J＝21.1Hz,4H),3.91(s,3H),3.76-3.73(m,4H),3.33 (dd,J＝43.0,8.5Hz,2H),2.92-2.86(m,2H),1.76-1.72(m,1H),1.47(s,3H),1.27(s,3H).LC-MS[M+H] +526.6
实施例25
化合物79
Figure PCTCN2021113514-appb-000132
取25ml单口烧瓶，分别加入78(50mg，0.09mmol)，多聚甲醛(50mg)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(95.4mg，0.45mmol)，室温下继续搅拌过夜，TLC监测无原料78剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到33.9mg黄色固体即产物79，收率为70％。
1HNMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.15(s,1H),8.11(s,1H),7.93(d,J＝1.4Hz,1H),7.82(dd,J＝8.7,2.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.08(d,J＝1.5Hz,1H),6.72(dd,J＝16.0,8.7Hz,2H),3.97(d,J＝21.1Hz,4H),3.91(s,3H),3.84(s,3H),3.76-3.73(m,4H),3.33(dd,J＝43.0,8.5Hz,2H),2.92-2.86(m,2H),1.76-1.72(m,1H),1.47(s,3H),1.27(s,3H).LC-MS[M+H] +539.6
实施例26
化合物80
Figure PCTCN2021113514-appb-000133
取25ml单口烧瓶，分别加入78(50mg，0.09mmol)，环丙甲醛(0.5ml)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(95.4mg，0.45mmol)，室温下继续搅拌过夜，TLC监测无原料78剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到30mg黄色固体即产物80，收率为58％。
1HNMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.15(s,1H),8.11(s,1H),7.93(d,J＝1.4Hz,1H),7.82(dd,J＝8.7,2.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.08(d,J＝1.5Hz,1H),6.72(dd,J＝16.0,8.7Hz,2H),4.84(d,J＝5.7Hz,1H),3.97(d,J＝21.1Hz,4H),3.91(s,3H),3.76-3.73(m,4H),3.33(dd,J＝43.0,8.5Hz,2H),2.92-2.86(m,2H),2.05(s,1H),1.76-1.72(m,1H),1.47(s,3H),1.27(d,J＝4.1Hz,3H),1.24(s,3H),1.18-1.11(m,1H),0.7-0.50(m,5H).LC-MS[M+H] +576.7。
实施例27
化合物81
Figure PCTCN2021113514-appb-000134
取25ml单口烧瓶，分别加入78(50mg，0.09mmol)，环丙甲醛(0.5ml)和DCM(10ml)，搅拌10Mins后，室温下分批加入NaBH(OAc) 3(95.4mg，0.45mmol)，室温下继续搅拌过夜，TLC监测无原料78剩余，加入氨水淬灭，分液，水相用DCM(5ml*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩柱层析纯化得到28mg黄色固体即产物81，收率为54％。
1HNMR(400MHz,CDCl 3)δ8.40(d,J＝2.3Hz,1H),8.15(s,1H),8.11(s,1H),7.93(d,J＝1.4Hz,1H),7.82(dd,J＝8.7,2.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.08(d,J＝1.5Hz,1H),6.72(dd,J＝16.0,8.7Hz,2H),3.97(d,J＝21.1Hz,4H),3.91(s,3H),3.84(d,J＝5.7Hz,2H),3.76-3.73(m,4H),3.33(dd,J＝43.0,8.5Hz,2H),2.92-2.86(m,2H),1.76-1.72(m,1H),1.47(s,3H),1.27(s,3H),1.18-1.11(m,1H),0.65-0.50(m,4H).LC-MS[M+H] +579.7
实施例28
化合物82
Figure PCTCN2021113514-appb-000135
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),3-羟基哌啶(30.3mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到40.2mg即为产物82，收率为75％。
1H NMR(400MHz,CDCl 3)δ8.40(s,1H),8.19(s,1H),8.11(s,1H),8.05(s,1H),7.78(d,J＝10.9Hz,1H),7.29(s,1H),7.19(s,1H),6.71(dd,J＝17.2,8.7Hz,2H),4.03-3.99(m,1H),3.92(s,3H),3.88-3.82(m,3H),3.65-3.60(m,3H),3.33(d,J＝9.2Hz,1H),3.16–3.01(m,3H),2.83–2.70(m,2H),1.99-1.94(m,4H).LC-MS[M+H] +536.6。
实施例29
化合物83
Figure PCTCN2021113514-appb-000136
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),2-甲基吗啉(30.3mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到38mg即为产物83，收率为70.8％。
1H NMR(400MHz,CDCl 3)δ8.40(s,1H),8.20(s,1H),8.11(s,1H),8.01(s,1H),7.80(d,J＝8.6Hz,1H),7.69(s,1H),7.18(s,1H),6.75–6.63(m,2H),4.08-4.05(m,1H),3.92(s,3H),3.88-3.84(m,5H),3.64-3.58(m,4H),3.38(dd,J＝23.9,11.6Hz,2H),2.93-2.90(m,1H),2.76-2.72(m,1H),2.59–2.51(m,1H),1.41(d,J＝19.1Hz,2H),1.31–1.24(m,3H).LC-MS [M+H] +536.6。
实施例30
化合物84
Figure PCTCN2021113514-appb-000137
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),3-(S)-3-甲基吗啉(30.3mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到30mg即为产物84，收率为56％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.2Hz,1H),8.20(s,1H),8.11(s,1H),8.02(d,J＝1.8Hz,1H),7.81(dd,J＝8.8,2.5Hz,1H),7.70(s,1H),7.18(d,J＝1.9Hz,1H),6.72(dd,J＝14.1,8.7Hz,2H),4.02(d,J＝11.2Hz,1H),3.92(s,3H),3.90-3.85(m,5H),3.81-3.75(m,2H),3.75-3.63(m,6H),3.27–3.16(m,1H),3.03(d,J＝11.8Hz,1H),2.79-2.75(m,1H),1.14(d,J＝6.5Hz,3H).LC-MS[M+H] +536.6。
实施例31
化合物85
Figure PCTCN2021113514-appb-000138
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),(R)-3-甲基吗啉(30.3mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到32mg 即为产物85，收率为56％。
1H NMR(400MHz,CDCl 3)δ8.41(d,J＝2.1Hz,1H),8.20(s,1H),8.13(s,1H),8.03(d,J＝1.9Hz,1H),7.82(dd,J＝8.7,2.2Hz,1H),7.34(d,J＝7.1Hz,1H),7.18(d,J＝1.8Hz,1H),6.74(dd,J＝21.1,8.7Hz,2H),4.02(d,J＝11.8Hz,2H),3.93(s,3H),3.92-3.89(m,2H),3.85–3.56(m,6H),3.38–2.81(m,4H),2.50-2.39(m,3H),1.14(d,J＝6.5Hz,3H).LC-MS[M+H] +536.6。
实施例32
化合物86
Figure PCTCN2021113514-appb-000139
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),3-甲基-3-吖啶醇(26mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到34mg即为产物86，收率为65％。
1H NMR(400MHz,CDCl 3)δ8.37(d,J＝2.3Hz,1H),8.15(s,1H),8.10(d,J＝2.0Hz,1H),7.78(dd,J＝8.8,2.5Hz,1H),7.72(d,J＝1.9Hz,1H),7.65(dd,J＝8.5,2.2Hz,1H),6.77–6.66(m,3H),4.12–3.98(m,1H),3.92(s,3H),3.91(s,2H),3.87–3.74(m,6H),3.62-3.58(m,4H),2.73-2.67(m,1H),1.67(s,3H).LC-MS[M+H] +522.6。
实施例33
化合物87
Figure PCTCN2021113514-appb-000140
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)， t-BuXPhos(8.4mg,0.02mmol),N-甲基哌嗪(30mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到34mg即为产物87，收率为63.5％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.2Hz,1H),8.21(s,1H),8.12(d,J＝2.0Hz,1H),8.04(d,J＝2.0Hz,1H),7.80(dd,J＝8.8,2.5Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.20(d,J＝2.0Hz,1H),6.72(dd,J＝14.9,8.6Hz,2H),3.94(s,3H),3.85(d,J＝11.9Hz,2H),3.81(d,J＝5.8Hz,2H),3.65-3.61(m,2H),3.60(s,2H),3.29–3.16(m,4H),2.77–2.68(m,1H),2.68–2.63(m,4H),2.41(s,3H),1.68(d,J＝8.7Hz,1H).LC-MS[M+H] +535.6。
实施例34
化合物88
Figure PCTCN2021113514-appb-000141
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),2-氧杂-6-氮杂-螺[3,3]庚烷(29.7mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到35.3mg即为产物88，收率为66％。
1H NMR(400MHz,CDCl 3)δ8.37(d,J＝2.2Hz,1H),8.16(s,1H),8.10(d,J＝1.9Hz,1H),7.78(dd,J＝8.8,2.5Hz,1H),7.71(d,J＝1.9Hz,1H),7.66(d,J＝6.9Hz,1H),6.76–6.66(m,3H),4.88(s,4H),4.10(s,4H),3.92(s,3H),3.83–3.80(m,4H),3.69–3.60(m,2H),3.59(s,2H),2.76-2.72(m,1H),1.96-1.89(m,1H).LC-MS[M+H] +534.6。
实施例35
化合物89
Figure PCTCN2021113514-appb-000142
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),1-甲基哌嗪-2-酮(34.2mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，1,4-二氧六环(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到50mg即为产物89，收率为90％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝2.3Hz,1H),8.21(s,1H),8.10(d,J＝2.0Hz,1H),8.03(d,J＝2.0Hz,1H),7.78(dd,J＝8.8,2.5Hz,1H),7.66(dd,J＝8.5,2.2Hz,1H),7.14(d,J＝2.0Hz,1H),6.71(dd,J＝11.8,8.7Hz,2H),3.92(s,3H),3.87(s,2H),3.85–3.75(m,4H),3.75-3.60(m,4H),3.57–3.47(m,4H),3.07(s,3H),2.72(d,J＝7.1Hz,1H),2.07-2.01(m,1H).LC-MS[M+H] +549.6。
实施例36
Figure PCTCN2021113514-appb-000143
化合物92
Figure PCTCN2021113514-appb-000144
取25ml单口茄形瓶，分别加入D 3-对甲苯磺酰甲酯(500mg，2.64mmol)，1-叔丁氧羰基哌嗪(327.8mg，1.76mmol)，三乙胺(534mg,5.28mmol)，1,4-二氧六环(10ml)室温下搅拌过夜，TLC监测无原料剩余，冷却至室温，加入10ml水搅拌10min分液，水相用DCM(5ml*3)萃取，合并有机相，无水硫酸钠干燥，浓缩得到无色油状液体粗产物， 柱层析纯化得到340mg无色液体产物92，收率为95％。
LC-MS[M+H] +204.17。
化合物93
Figure PCTCN2021113514-appb-000145
取25ml单口茄形瓶，加入盐酸乙酸乙酯溶液(50ml)，缓慢滴入92(340mg，1.68mmol)，室温下搅拌3小时，TLC监测无原料剩余，有白色固体析出，过滤，烘干得到296mg白色固体为目标产物93，收率为100％。
化合物94
Figure PCTCN2021113514-appb-000146
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),93(52.8mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，dioxane(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到42mg即为产物94，收率为78％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.2Hz,1H),8.21(s,1H),8.12(d,J＝2.0Hz,1H),8.04(d,J＝2.0Hz,1H),7.80(dd,J＝8.8,2.5Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.20(d,J＝2.0Hz,1H),6.72(dd,J＝14.9,8.6Hz,2H),3.94(s,3H),3.85(d,J＝11.9Hz,2H),3.81(d,J＝5.8Hz,2H),3.65-3.61(m,2H),3.60(s,2H),3.29–3.16(m,4H),2.77–2.68(m,1H),2.68–2.63(m,4H),1.68(d,J＝8.7Hz,1H).LC-MS[M+H] +539.6。
实施例37
Figure PCTCN2021113514-appb-000147
化合物95
Figure PCTCN2021113514-appb-000148
取25ml封管，分别加入49(52mg，0.1mmol)，Pd 2(dba) 3(5.5mg，0.006mmol)，t-BuXPhos(8.4mg,0.02mmol),1-叔丁氧羰基哌嗪(55.9mg，0.3mmol)，Cs 2CO 3(65mg，0.2mmol)，dioxane(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料49剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到53mg即为产物95，收率为88％。
LC-MS[M+H] +622.32。
化合物96
Figure PCTCN2021113514-appb-000149
取25ml单口茄形瓶，加入盐酸乙酸乙酯溶液(10ml)，缓慢加入95(53mg，0.09mmol)，室温下搅拌3小时，TLC监测无原料剩余，浓缩，加入氨水调节pH＝9，DCM(3ml*3)萃取，合并有机相浓缩，柱层析纯化得到36mg黄色固体即为目标产物96，收率为78％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.2Hz,1H),8.21(s,1H),8.12(d,J＝2.0Hz,1H),8.04(d,J＝2.0Hz,1H),7.80(dd,J＝8.8,2.5Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.20(d,J＝2.0Hz,1H),6.72(dd,J＝14.9,8.6Hz,2H),3.94(s,3H),3.85(d,J＝11.9Hz,2H),3.81(d,J＝5.8Hz,2H),3.65-3.61(m,2H),3.60(s,2H),3.29–3.16(m,4H),2.77–2.68(m,1H),2.68–2.63(m,4H),1.68(d,J＝8.7Hz,1H).LC-MS[M+H] +522.6。
实施例38
Figure PCTCN2021113514-appb-000150
化合物98
Figure PCTCN2021113514-appb-000151
取25ml单口烧瓶，分别加入97(500mg，0.97mmol)，K 2CO 3(402mg，2.91mmol)和DCM(50ml)。0℃下分批加入m-CPBA(200mg，1.16mmol)，升至室温，继续搅拌过夜。TLC监测无原料97剩余，加入50ml水搅拌10min，分液，有机相相继用H 2O，饱和NaCl溶液洗涤，无水Na 2SO 4干燥浓缩，柱层析纯化得到439mg淡黄色固体产物98，收率85％。
化合物99
Figure PCTCN2021113514-appb-000152
取25ml封管，分别加入98(100mg，0.19mmol)，Pd 2(dba) 3(10.4mg，0.01mmol)，t-BuXPhos(12.7mg,0.03mmol),氘代甲基哌嗪(23.7mg，0.23mmol)，Cs 2CO 3(187mg，0.57mmol)，dioxane(3ml)和DMF(1ml)，Ar保护，80℃下搅拌过夜，TLC监测无原料98剩余，冷却至室温，加入10ml水搅拌10min黄色固体析出，过滤烘干，柱层析纯化得到79mg即为产物99，收率为75％。
1H NMR(400MHz,CDCl3)δ8.34–8.28(m,1H),8.17(d,J＝2.0Hz,1H),8.12(d,J＝2.1Hz,1H),8.01(s,1H),7.72–7.63(m,2H),7.16(d,J＝1.5Hz,1H),6.76(dd,J＝8.5,3.2Hz,1H),6.56(dd,J＝41.0, 8.8Hz,1H),4.07–3.88(m,6H),3.84–3.57(m,5H),3.49(d,J＝4.3Hz,1H),3.23(t,4H),2.66(t,4H),2.49(d,J＝7.0Hz,1H).
实施例39
Figure PCTCN2021113514-appb-000153
化合物101
Figure PCTCN2021113514-appb-000154
取25ml单口烧瓶，分别加入94(100mg，0.18mmol)，K 2CO 3(51.2mg，0.36mmol)和DCM(20ml)。0℃下分批加入m-CPBA(37mg，0.22mmol)，升至室温，继续搅拌过夜。TLC监测无原料94剩余，加入20ml水搅拌10min，分液，有机相相继用H 2O，饱和NaCl溶液洗涤，无水Na 2SO 4干燥浓缩，柱层析纯化得到78mg淡黄色固体产物101，收率78％。
1H NMR(400MHz,DMSO)δ8.55(s,1H),8.49–8.34(m,2H),8.07(s,1H),7.85(dd,J＝8.7,2.2Hz,1H),7.68(dd,J＝8.5,2.1Hz,1H),7.55(s,1H),6.78(t,J＝8.2Hz,2H),3.82(s,3H),3.73(d,J＝11.9Hz,2H),3.68(d,J＝5.6Hz,2H),3.64–3.51(m,7H),3.50(s,2H),3.00(s,2H),2.51(s,2H),1.59(d,J＝8.3Hz,1H).
活性实验1：制备的化合物对RET家族激酶活性的抑制
测试此类化合物对RET野生型(RET WT)，RET(V804M)，RET(M918T)点突变型CCDC6-RET融合突变以及KDR(VEGFR2)的激酶活性IC 50测试。上述激酶采购于Thermo Fisher Scientific以及ProQinase GmbH。
采用均相时间分辨荧光(HTRF)的方法建立上述激酶的活性检测方法，测定化合物的抑制活性。配置8uL的反应液，包括1×enzymatic buffer(Cisbio,HTRF KinEASE TM-TK)，5mM MgCl 2，1mM MnCl 2，1mM DTT，1μM TK substrate-biotin(Cisbio,HTRF KinEASETM-TK)10μM ATP(1μM for RET WT,CCDC6-RET；20μM for KDR)，梯度浓度的 化合物以及如下浓度的相关激酶：0.03ng/μL RET WT,0.2ng/μL RET(V804M),0.04ng/μL RET(M918T),0.12ng/μL CCDC6-RET,0.02ng/μL KDR。激酶和化合物预孵育5分钟，然后加入ATP和底物开始反应。所有酶催化反应都在25℃下进行60分钟。酶催化反应结束后，反应液中加入4μL TK antibody-cryptate和4μL streptavidin-XL665(反应浓度为62.5nM)，继续在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism5.0软件计算IC 50。
表1，体外酶学活性测试数据(IC 50，nM)
Compound ID RET WT RET(V804M) RET(M918T) CCDC6-RET KDR
16 8.40 4.78 2.42 3.65 405.70
17 5.50 3.82 1.70 2.61 551.30
20 4.10 3.23 1.45 2.14 339.70
17-a 27.93 127.80 48.40 17.16 122.20
21 45.00 188.00 80.00 60.45 108.90
32 2.11 4.80 1.73 3.13 39.11
34 35.79 209.60 97.76 71.57 311.00
39 98.29 860.50 325.80 N.D. N.D.
43 30.89 241.90 53.15 N.D. N.D.
51 4.61 7.16 3.90 2.15 51.99
55 12.35 39.66 15.32 7.45 222.90
57 2.24 4.33 4.06 4.44 7.40
58 4.98 19.35 9.52 8.07 134.10
60 12.56 26.34 10.73 6.01 185.6
64 26.55 110.80 42.80 30.74 386.60
65 1.09 3.37 0.92 0.52 92.84
66 1.66 7.69 2.05 1.13 123.50
67 0.79 1.09 0.75 0.34 24.63
68 1.30 5.37 8.47 2.54 16.60
69 18.60 38.54 22.30 11.99 754.50
70 1.17 1.01 1.62 1.02 23.88
78 1.28 8.23 5.47 4.60 51.91
79 11.81 45.20 4.77 N.D. N.D.
80 21.60 N.D. N.D. N.D. 565.96
81 193.10 N.D. N.D. N.D. 612.50
82 10.73 N.D. N.D. N.D. 280.40
83 15.81 N.D. N.D. N.D. N.D.
84 24.81 N.D. N.D. N.D. N.D.
85 19.04 N.D. N.D. N.D. N.D.
86 4.56 N.D. N.D. N.D. 71.26
87 2.26 7.40 2.78 3.00 154.20
88 7.22 N.D. N.D. N.D. 96.93
89 0.674 4.719 1.471 3.045 156.90
94 4.625 N.D. N.D. N.D. 169.10
96 5.238 N.D. N.D. N.D. 239.60
99 56.6 N.D. N.D. N.D. N.D.
101 2.5 N.D. N.D. N.D. 215.2
Selpercatinib 1.98 5.09 2.17 2.07 172.00
N.D.-未测试
活性实验2：制备的化合物在人肝微粒体中的代谢稳定性研究报告
通过液质联用(LC-MS/MS)方法考察化合物在NADPH还原辅酶的作用下在肝微粒体中代谢的速度和程度。分别取445μL 0.562mg/mL人肝微粒体工作溶液于对应的96孔板中，于37℃水浴中预孵育10.0min。然后加入5.00μL 100μM化合物和50.0μL 10.0mM NADPH启动反应。于0、2、5、10、20、30、60min后，取出50.0μL反应液加入到400μL含50.0ng/mL内标(甲苯磺丁脲)的冰乙腈中终止反应。对于不添加辅助因子的样品(NCF)，取445μL各个物种的微粒体工作溶液，50.0μL 10mM MgCl 2混匀，最后加入5.00μL待测物工作溶液，混匀，于37℃孵育10min。到时间后，取50.0μL反应液于400μL冰的I02中终止反应。涡旋混匀，1700×g，4℃条件下离心15min，取上清150μL，加入150μL超纯水稀释，进行LC-MS/MS分析，结果如表2和表3所示。
表2，化合物在人肝微粒体中的半衰期及内在清除率
Figure PCTCN2021113514-appb-000155
表3，化合物在人肝微粒体中的半衰期及内在清除率
Figure PCTCN2021113514-appb-000156
活性实验3：制备的化合物对Ba/F3KIF5B-RET细胞生长的抑制作用
收获处于对数生长期的Ba/F3 KIF5B-RET、Ba/F3KIF5B-RET-V804M、Ba/F3 RET-M918T、Ba/F3 KIF5B-RET-G810R细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整细胞浓度，分别添加90μL细胞悬液至96孔板中。将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。在接种有细胞的96孔板中每孔加入相应的10μL梯度浓度的药物溶液(最高浓度为1000nM)，每个药物浓度设置三个复孔，DMSO终浓度为0.1％。将已加药的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下继续培养72小时。药物作用结束后，每孔加入100μL CellTiter-Glo试剂，在定轨摇床上振动5分钟使细胞裂解，并将细胞板放置于室温20分钟以稳定冷光信号，然后读取冷光值。使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值，结果如表4所示。
表4，体外细胞水平活性测试数据(IC 50，nM)
Figure PCTCN2021113514-appb-000157
BLU-667的结构式如下：
Figure PCTCN2021113514-appb-000158
Selpercatinib(Loxo-292)的结构式如下：
Figure PCTCN2021113514-appb-000159
活性实验4：制备的化合物对hERG钾离子通道的抑制作用
测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。将hERG离子通道稳定表达的HEK293细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液分批少量储存于-80度冰箱，实验当天融化。细胞内液(mM)为：K Aspartate,130；MgCl 2,5；EGTA 5；HEPES,10；Tris-ATP 4；pH 7.2(KOH滴定)。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。
将细胞钳制在–80mV，然后用持续4秒方波去极化到40mV，再用持续2秒方波超极化到-40mV，以得到hERG尾电流。这一程序每20秒重复一次。hERG尾电流是纯hERG电流。检测第二个方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。根据阻断强度计算化合物对hERG通道抑制的IC 50，结果如表5所示。
表5，化合物在细胞水平对hERG钾离子通道抑制的IC 50(μM)
Compound ID IC 50
16 2.06
17 1.31
20 22.2
65 2.72
70 4.74
87 2.13
89 7.17
Selpercatinib 2.75
活性实验5：大鼠药代动力学测试
SD雄性大鼠(体重220±20g)，按1.0mg/kg剂量尾静脉注射以及5.0mg/kg剂量口服给予化合物94、Loxo-292，每组3只动物。给药溶剂为5％DMSO+5％聚氧乙烯蓖麻油(Cremophor EL)的生理盐水溶液。给药前禁食约12小时，给药后4h自由进食；不禁 水。于给药前及给药后5、15、30min，1、2、4、6、8、10、24h，由眼眶采血约0.2mL，置于EDTA-K 2抗凝的EP管中冰浴，4℃，8000rpm离心5分钟分离血浆，于-20℃保存直至分析。使用液相色谱-串联质谱联用方法(LC-MS/MS)对血浆中化合物浓度进行定量分析。样品分析结果采用WinNonlin5.2对药动学参数进行计算。
表6.药代动力学参数
Figure PCTCN2021113514-appb-000160
由表6中数据可见，口服给药后，与Loxo-292相比，化合物94在大鼠体内消除时间更长，生物利用度更高。
活性实验6：小鼠体内组织分布试验
雄性NVSG小鼠(体重20-25g)，以30mg/kg剂量分别口服给予化合物94、Loxo-292。于给药后4h采集动物的血浆及肝、脑、肺等组织样本。血浆的采集：用含有EDTA的EP管收集全血80-100μL左右，4000g离心5分钟后，收集上层血浆于-80℃保存。组织的采集：于动物安乐死后取组织并于液氮速冻后，按每1g组织加入5mL匀浆液(50％乙腈)比例，于组织匀浆机中将组织处理为匀浆液，并转移至-80℃保存。使用液相色谱-串联质谱联用方法(LC-MS/MS)对血浆及组织样本中化合物浓度进行定量分析。
表7.化合物在小鼠血浆及器官组织中的分布浓度
Figure PCTCN2021113514-appb-000161
Figure PCTCN2021113514-appb-000162
由表7中数据可见，口服给药后，化合物94在小鼠靶器官组织中具有更高的分布浓度，更有利于在靶器官药效的发挥。
活性实验7：小鼠皮下BA/F3 KIF5B-RET移植瘤模型测试
BA/F3 KIF5B-RET细胞，以RPMI-1640培养基添加10％FBS培养于含5％CO 2的37℃培养箱。细胞通过皮下注射接种于NVSG小鼠右侧肩部皮下，每只小鼠接种约1×10 6个细胞，接种体积为100μL。当移植瘤的体积达到约100mm 3，选取移植瘤大小合适的小鼠，根据体重和移植瘤大小进行随机分组。以10μL/g体重体积灌胃给药。Loxo-292给药剂量为30mg/kg，每天给药2次(b.i.d.)；化合物94给药剂量为30mg/kg，每天给药2次(b.i.d.)及30、60mg/kg每天给药1次(q.d.)；溶剂对照组给予2％DMSO+2％聚氧乙烯蓖麻油的生理盐水溶液。连续给药15天，每周测量两次移植瘤体积，Day 0为分组及给药第1天。
表8，化合物对BA/F3 KIF5B-RET小鼠移植瘤模型的抑制作用
Figure PCTCN2021113514-appb-000163
*第15天溶剂对照组动物全部死亡，无测量数据
由表8中数据可见，给药15天后，化合物94各剂量组小鼠移植瘤体积均小于Loxo-292组，体现更优的肿瘤抑制活性；并且化合物94每日给药一次仍具有优良的肿瘤抑制活性。
活性实验8：制备的化合物对FGFR家族激酶活性的抑制
测试化合物对FGFR家族激酶活性IC 50。相关激酶采购于Carna以及Signalchem。
采用均相时间分辨荧光(HTRF)的方法建立相关激酶的活性检测方法，测定化合物的抑制活性。配置5μL的反应液，包括1×enzymatic buffer(Cisbio,HTRF KinEASE TM-TK)，5mM MgCl 2，1mM DTT，1μM TK substrate-biotin(Cisbio,HTRF KinEASETM-TK)相应浓 度的ATP和相关激酶，以及梯度浓度的化合物。相关激酶浓度及相应ATP浓度如下表9：
表9激酶浓度及相应ATP浓度
激酶名称 激酶反应浓度 ATP反应浓度
FGFR1 0.02ng/ul 50
FGFR1 V561M 0.04ng/ul 5
FGFR2 0.005ng/ul 50
FGFR2 V564F 0.02ng/ul 10
FGFR2 N549H 0.02ng/ul 5
FGFR2 V564I 0.04ng/ul 5
FGFR2 K641R 0.02ng/ul 1
FGFR3 0.02ng/ul 50
FGFR3 V555M 0.02ng/ul 20
FGFR3 K650E 0.04ng/ul 50
FGFR4 5nM 50
激酶和化合物预孵育10分钟，然后加入ATP和底物开始反应。所有酶催化反应都在25℃下进行40分钟。酶催化反应结束后，反应液中加入5μL TK antibody-cryptate和streptavidin-XL665(streptavidin-XL665反应浓度为62.5nM)，继续在25℃孵育60分钟。孵育结束后在用Biotek读615nm(Cryptate)和665nm(XL665)的荧光信号，并使用GraphPad Prism5.0软件计算IC 50。
表10，化合物对FGFR家族激酶活性的测试(IC 50，nM)
  化合物94 Loxo-292
FGFR1 300.6 303.9
FGFR1 V561M 1397 1954
FGFR2 26.49 20.6
FGFR2 V564F 3.576 12.94
FGFR2 N549H 2.188 9.262
FGFR2 V564I 45.63 97.56
FGFR2 K641R 7.393 11.25
FGFR3 308.6 348.8
FGFR3 V555M 74.29 188.3
FGFR3 K650E 36.47 45.89
FGFR4 595.4 474.9
以上表10数据显示，化合物94对FGFR家族激酶的活性具有抑制作用，其中化合物94对FGFR2 V564F、FGFR2 N549H、FGFR2 V564I以及FGFR3 V555M激酶抑制活性优于LOXO-292(IC 50低于2倍及以上)。

Claims (18)

  1. 具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，
    Figure PCTCN2021113514-appb-100001
    其中，
    A选自H、-CN、卤素、-C＝ONH 2、-C＝C-CN或-C≡CH；
    B选自被一个或多个相同或不同取代基取代或未取代的以下基团：C1-C6烷基、C1-C6烷胺基、C2-C6炔基、C2-C6烯基、HetAr 1或HetCyc 1；取代基独立选自卤素、羟基、-CN、＝O(羰基)、C1-C6烷基，氘代C1-C6烷基、C1-C6烷氧基、羟基C1-C6烷基、卤代C1-C6烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、C3-C6环烷基、(C1-C6烷氧基SO 2)C1-C6烷基；
    HetAr 1是具有独立地选自N、S或O的1～3个杂原子的5～6元杂芳环；
    HetCyc 1是具有选自N或O的1～3个杂原子的4～8元杂环、具有选自N或O的1～3个杂原子的8～10元螺环或具有选自N或O的1～3个杂原子的7～11元稠杂环；
    C是具有独立地选自N、S或O的1～3个杂原子的5～6元杂芳环；其中所述杂芳环未被取代或者任选被一个或多个相同或不同取代基取代，所述取代基独立选自卤素、羟基、-CN、硝基、C1-C3烷基或卤代C1-C3烷基；
    D是具有选自N或O的1～3个杂原子的C1-C6烷基、具有选自N和O的1～3杂原子的4～8元杂环、具有选自N和O的1～3杂原子的7～8元桥环、具有选自N和O的1～3杂原子的7～11元螺环、具有选自N和O的1～3杂原子的7～10元稠杂环、
    Figure PCTCN2021113514-appb-100002
    Figure PCTCN2021113514-appb-100003
    其中，M选自C1-C3烷基或C3-C8环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；
    L是
    Figure PCTCN2021113514-appb-100004
    -C(＝O)-C1-C3烷基或C1-C3烷基；
    E是被一个或多个相同或不同取代基取代或未取代的HetAr 2，所述取代基独立选自卤 素、C1-C6烷基、氘代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、羟基C1-C6烷基、C1-C6卤代烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、C3-C6环烷基、(C1-C6烷氧基SO 2)C1-C6烷基；
    HetAr 2是具有独立地选自N、S和O的1～3个环杂原子的5～6元杂芳环。
  2. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，A选自-CN、-C＝C-CN或-C≡CH；优选的，A为-CN。
  3. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，B选自被一个或两个相同或不同取代基取代或未取代的以下基团：
    Figure PCTCN2021113514-appb-100005
    R 1-C≡CH或HetCyc 1；R 1选自H、C1-C6烷基、氘代C1-C6烷基、C1-C6羟基烷基；R 2或R 3独立地选自H、C1-C6烷基、氘代C1-C6烷基、C1-C6羟基烷基；所述取代基独立选自卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基、(C1-C3烷氧基)C1-C3烷基、C3-C6环烷基、(C1-C3烷氧基SO 2)C1-C3烷基；
    HetCyc 1是具有选自N或O的1～2个杂原子的4～8元杂环、具有选自N或O的1～2个杂原子的7～11元螺环或具有选自N或O的1～2个杂原子的8～10元稠杂环；
    优选的，B选自被一个或两个相同或不同取代基取代或未取代的以下基团：R 1-C≡CH、
    Figure PCTCN2021113514-appb-100006
    Figure PCTCN2021113514-appb-100007
    R 1选自C1-C4烷基、C1-C4羟基烷基；R 2或R 3独立的选自H、C1-C4烷基、氘代C1-C4烷基、C1-C4羟基烷基；所述取代基独立选自羟基、氰基、卤素、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、C3-C6环烷基。
  4. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，B为被一个或两个相同或不同取 代基取代或未取代的
    Figure PCTCN2021113514-appb-100008
    所述取代基独立选自卤素、羟基、-CN、羰基、C1-C3烷基，氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基、(C1-C3烷氧基)C1-C3烷基、C3-C6环烷基、(C1-C3烷氧基SO 2)C1-C3烷基C1-C3烷基；C是具有独立地选自N或S的1～2个环杂原子的5～6元杂芳环；D是
    Figure PCTCN2021113514-appb-100009
    其中，M选自C3-C6环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；L为-CH 2-；E为
    Figure PCTCN2021113514-appb-100010
  5. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，C是被一个或两个相同或不同取代基取代或未取代的以下基团：
    Figure PCTCN2021113514-appb-100011
    取代基独立地选自氟、氯、溴。
  6. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，D是
    Figure PCTCN2021113514-appb-100012
    Figure PCTCN2021113514-appb-100013
    其中，M选自C1-C3烷烃或C3-C6环烷基；K是具有选自N或O的1～3个杂原子的4～8元杂环；优选的，D是-N(CH 3)CH 2CH 2N(CH 3)-、
    Figure PCTCN2021113514-appb-100014
    Figure PCTCN2021113514-appb-100015
  7. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，L是
    Figure PCTCN2021113514-appb-100016
    或-CH 2-。
  8. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，E是被一个或两个相同或不同取代基取代或未取代的
    Figure PCTCN2021113514-appb-100017
    取代基独立地选自C1-C3烷氧基或氘代C1-C3烷氧基。
  9. 具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，
    Figure PCTCN2021113514-appb-100018
    其中，B选自被一个或两个相同或不同取代基取代或未取代的HetCyc 1；HetCyc 1是具有1个N原子的4～5元杂环或
    Figure PCTCN2021113514-appb-100019
    所述取代基独立选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；优选的，所述取代基独立选自卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基；
    或者，B选自被一个或两个相同或不同取代基取代或未取代的HetCyc 1；HetCyc 1是具有1～2个N原子的6元杂环；所述取代基独立选自H、C1-C3烷基、氘代C1-C3烷基、氟代C1-C3烷基；优选的，HetCyc 1是被取代基取代或未取代的
    Figure PCTCN2021113514-appb-100020
    B的取代基独立选自卤素、甲基、乙基、氘代甲基、-CF 3；
    或者，B是取代或未取代的HetCyc 2，或者B是取代或未取代的具有选自N、S、O或P的1～3个杂原子的7～8元桥环；HetCyc 2是具有P原子的4～6元杂环或具有P原子和N原子的4～6元杂环；取代基独立选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；优选的，B是取代或未取代的HetCyc 2，或者B是取代或未取代的具有含N的1～2个杂原子的7～8元桥环；HetCyc 2是具有P原子和N原子的4～6元杂环；优选的，
    B是取代或未取代的
    Figure PCTCN2021113514-appb-100021
    其中R 4选自H、卤素、羟基、-CN、羰基、C1-C3烷基、氘代C1-C3烷基、C1-C3烷氧基、羟基C1-C3烷基、氟代C1-C3烷基、氰基C1-C3烷基；优选的R 4选自H、卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基或三氟甲基；优选的，取代基独立选自卤素、羟基、-CN、羰基、甲基、乙基、氘代甲基、甲氧基或三氟甲基。
  10. 根据权利要求1～9任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物、氧化物或前药，其特征在于，所述氧化物是在具有N杂原子的4～8元杂环或桥环的N原子处形成氧化物，优选的，是在
    Figure PCTCN2021113514-appb-100022
    的氮原子处形成氧化物。
  11. 化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药，选自：
    Figure PCTCN2021113514-appb-100023
    Figure PCTCN2021113514-appb-100024
    Figure PCTCN2021113514-appb-100025
    Figure PCTCN2021113514-appb-100026
    Figure PCTCN2021113514-appb-100027
  12. 具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药的制备方法：
    Figure PCTCN2021113514-appb-100028
    其中，各基团定义如权利要求1所述。
  13. 根据权利要求11所述的制备方法，其特征在于，包括如下步骤：
    步骤1：以二氧六环为溶剂，化合物I通过和硼酸试剂C偶联得到II；
    步骤2：中间体II与胺类化合物亲核取代得到III；
    步骤3：以1,2-二氯乙烷为溶剂，中间体III和L-E通过还原胺化或酰化反应得到中间体IV；
    步骤4：以二氧六环和N,N-二甲基甲酰胺作为溶剂，通过C-N偶联，获得终产物(I)。
  14. 具有式(II)结构的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药的制备方法：
    Figure PCTCN2021113514-appb-100029
    其中，B的定义如权利要求9所述。
  15. 一种药物组合物，其包括权利要求1～11任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药，以及药学上可接受的载体。
  16. 权利要求1～11任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药作为RET激酶抑制剂的应用。
  17. 权利要求1～11任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备治疗RET相关疾病药物中的应用；优选的，RET相关疾病为癌症；更优选的，所述癌症选自肺癌、甲状腺癌、乳癌或结直肠癌。
  18. 权利要求1～11任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备FGFR家族激酶抑制剂药物中的应用；优选的，所述的FGFR家族包括FGFR1、FGFR1 V561M、FGFR2、FGFR2 V564F、FGFR2 N549H、FGFR2 V564I、FGFR2 K641R、FGFR3、FGFR3 V555M、FGFR3 K650E和FGFR4；更优选包括FGFR2  V564F、FGFR2 N549H、FGFR2 V564I和FGFR3 V555M。
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