WO2024131937A1 - Compound serving as eif4e inhibitor and use thereof - Google Patents

Compound serving as eif4e inhibitor and use thereof Download PDF

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WO2024131937A1
WO2024131937A1 PCT/CN2023/140972 CN2023140972W WO2024131937A1 WO 2024131937 A1 WO2024131937 A1 WO 2024131937A1 CN 2023140972 W CN2023140972 W CN 2023140972W WO 2024131937 A1 WO2024131937 A1 WO 2024131937A1
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group
alkoxy
alkyl
cyano
hydroxy
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PCT/CN2023/140972
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French (fr)
Chinese (zh)
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郁壮壮
王小伟
张小猛
刘琪
于澍嘉
李晴晴
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南京圣和药业股份有限公司
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Publication of WO2024131937A1 publication Critical patent/WO2024131937A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to tricyclic compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as eIF4E inhibitors, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating eIF4E-mediated diseases.
  • eIF4F contains three members: eIF4E, eIF4A and eIF4G. Among them, eIF4E can bind to the 7-Me-GpppN cap structure at the 5' end of mRNA during the initiation of translation, and then bind to the scaffold protein eIF4G and recruit eIF4A to assemble into the eIF4F complex to initiate the translation process. There are certain differences in the binding ability of different mRNAs in cells to eIF4E.
  • eukaryotic cell mRNAs can be divided into two groups according to their structural characteristics and inherent “translatability": one is strong mRNA with a relatively short, unstructured 5'UTR (less C and G content); the other is weak mRNA with a lengthy and highly structured 5'UTR (rich in G and C).
  • strong and weak mRNA The main difference between “strong” and “weak” mRNA is that weak mRNA is more dependent on eIF4E and exhibits poor translation levels under normal conditions.
  • Most of the RNAs transcribed from tumor-related genes, such as MYC and CCND1, are weak mRNAs. When eIF4E is overexpressed or overactive, the translation of these tumor-related weak mRNAs is selectively enhanced, leading to cell deterioration and cancer.
  • eIF4E is highly expressed in a variety of tumors, including prostate cancer, breast cancer, head and neck cancer, gastric cancer, colon cancer, lung cancer, skin cancer, esophageal cancer, bladder cancer, cervical cancer and hematopoietic system tumors, and is associated with poor prognosis in a variety of tumors.
  • Reducing the expression of eIF4E by 50% greatly reduces the probability of normal cells transforming into tumor cells, and has no effect on the normal growth and development of mice (Truitt et al., 2015, Cell).
  • the present invention provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.
  • Ring A is selected from heteroaryl and heterocyclic groups, and the heteroaryl and heterocyclic groups may be substituted by one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, hydroxycycloalkyl, heterocyclic, aryl, heteroaryl and oxo;
  • X is selected from N and C( R5 ), wherein R5 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
  • R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
  • R is selected from the group consisting of alkylaminoalkoxy, heterocyclylalkoxy, heterocyclylamino, aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo; and
  • n are each independently 0, 1, 2 or 3.
  • the present invention provides a compound of general formula (II) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
  • Ring A is selected from heteroaryl and heterocyclic groups, and the heteroaryl and heterocyclic groups may be substituted by one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, hydroxycycloalkyl, heterocyclic, aryl, heteroaryl and oxo;
  • X is selected from N and C( R5 ), wherein R5 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
  • Y1 and Y2 are each independently CH or N;
  • R is selected from the group consisting of alkylaminoalkoxy, heterocyclylalkoxy, heterocyclylamino, heterocyclyloxy, aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl,
  • R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
  • R 8 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, -C(O)-R 9 , wherein R 9 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aminosulfonylamino, alkylaminosulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino, and the C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl and R 9 may be selected from one or more halogen, hydroxy, C 1-3 al
  • n are each independently 0, 1, 2 or 3.
  • the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring A is selected from 5-12 membered heteroaryl and 3-12 membered heterocyclyl, and the 5-12 membered heteroaryl and 3-12 membered heterocyclyl may be substituted by one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, hydroxy C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered ary
  • ring A is selected from 5-10 membered heteroaryl and 3-10 membered heterocyclyl, and the 5-10 membered heteroaryl and 3-10 membered heterocyclyl may be substituted by one or more groups selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl , di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxy C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6
  • ring A is selected from 5-6 membered heteroaryl and 3-6 membered nitrogen heterocyclic group, and the 5-6 membered heteroaryl and 3-6 membered nitrogen heterocyclic group may be substituted by one or more groups selected from halogen, hydroxyl, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxyl C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxyl C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl , aminoacyl, C 1-3 alkylaminoacyl, di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl C 3-8 cycloalkyl, 3-8 membered hetero
  • ring A is selected from aziridine, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyrazolidinyl, dihydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, imidazolyl, oxazolidinyl, dihydrooxazolyl, thiazolidinyl, dihydrothiazolyl, isoxazolidinyl, dihydroisoxazolyl, isothiazolidinyl, dihydroisothiazolyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, di
  • the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R2 is selected from C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, 6-membered heterocyclyloxy, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl, and the C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl may be selected from one or more of halogen, hydroxy, C1-6 alkyl , halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C3-12 cycloalkylC1-6 alkyl, C1-6 alkoxy , halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono-C1-6 al
  • R2 is selected from C1-3 alkylaminoC2-3 alkoxy, heterocyclylC1-3 alkoxy, 6-membered heterocyclylamino, 6-membered heterocyclyloxy, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered heterocyclyl, and the group can be selected from one or more halogen, hydroxyl, C1-3 alkyl, halogenated C1-3 alkyl, hydroxyC1-3 alkyl, C3-10 cycloalkylC1-3 alkyl, C1-3 alkoxy , halogenated C1-3 alkoxy , hydroxyC1-3 alkoxy, nitro, carboxyl, cyano, amino, monoC1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, C1-3 alkylsulfonyl, aminoacyl, C1-3 alkylaminoacyl, diC1-3 alkylamino, C2-6 alkenyl
  • R 2 is selected from the following groups:
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and bis C 1-6 alkylamino;
  • R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino;
  • R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, cyclopropylsulfonylamino, N,N-dimethylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino.
  • the compound of the present invention is a compound of general formula (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and bis-C 1-6 alkylamino;
  • R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino;
  • R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 alkylamino, C 1-3 alkylsulfonylamino, cyclopropylsulfonylamino, N,N-dimethylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino.
  • the compound of the present invention is a compound of formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein L is -(CH 2 ) 2 -O- or -CH 2 C ⁇ C-.
  • the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino.
  • the present invention provides a compound of formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
  • ring A, R 1 , R 2 , R 3 , L and m have the same definitions as described above for the general formula (I).
  • the present invention provides a compound of formula (Ib) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
  • ring A, R 1 , R 2 , R 3 , L and m have the same definitions as described above for the general formula (I).
  • the present invention provides a compound of formula (Ic) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
  • R 7 is selected from hydrogen, halogen, hydroxy, C 3-10 cycloalkyl, hydroxy C 3-10 cycloalkyl, C 1-6 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino; and p is 0, 1, 2 or 3.
  • the compound of the present invention is a compound of the general formula (Ic) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein R7 is selected from hydrogen, halogen, hydroxy , cyclopropyl, methyl, ethyl, propyl, isopropyl, hydroxyC3-6cycloalkyl , halogenated C1-3alkyl , hydroxyC1-3alkyl , C1-3alkoxy , halogenated C1-3alkoxy , hydroxyC1-3alkoxy , nitro, carboxyl, cyano, amino, monoC1-3alkylamino, C1-3alkylsulfonylamino , C1-3alkylacyl , aminoacyl, C1-3alkylaminoacyl and diC1-3alkylamino, and p is 0, 1 , 2 or 3.
  • R7 is selected from hydrogen, halogen, hydroxy , cyclopropyl,
  • the present invention provides the following specific compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.
  • the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the compound or pharmaceutical composition is used to treat a disease associated with eIF4E.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.
  • the compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, suitable for oral or parenteral administration.
  • a pharmaceutically acceptable carrier diluent or excipient
  • the method of administration includes, but is not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
  • the preparation can be administered by any route, such as by infusion or push injection, by the route of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). Administration can be systemic or local.
  • oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc.
  • the preparation can be prepared by methods known in the art, and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.
  • the present invention provides a method for treating diseases associated with eIF4E using compounds represented by formula (I), (Ia), (Ib), (Ic) and (II) of the present invention or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, or pharmaceutical compositions containing the same, as well as their use in the preparation of drugs for treating diseases associated with eIF4E.
  • the present invention provides a method for treating a disease associated with eIF4E and a use of a compound represented by formula (I), (Ia), (Ib), (Ic) and (II) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same for preparing a drug for treating a disease associated with eIF4E, wherein the disease mediated by the disease associated with eIF4E includes but is not limited to: proliferative disease, metabolic disease or blood disease.
  • the disease associated with eIF4E described in the present invention is cancer.
  • the diseases associated with eIF4E described herein include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, angiosarcoma), adnexal cancer, benign monoclonal gammopathy, bile cancer (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer, triple-negative breast cancer), brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chord
  • GEP-NET carcinoid tumor
  • osteosarcoma ovarian cancer
  • cystadenocarcinoma ovarian embryonal carcinoma, ovarian adenocarcinoma, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma
  • papillary adenocarcinoma pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor)
  • penile cancer e.g., Paget’s disease of the penis and scrotum
  • pineal tumor primary neuroectodermal tumor (PNT)
  • prostate cancer e.g., prostate adenocarcinoma
  • rectal cancer rhabdomyosarcoma, salivary duct carcinoma, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma ( KA), melanoma,
  • the present invention provides compounds represented by general formula I, (Ia), (Ib), (Ic) and (II) or their isoforms.
  • the invention relates to a method for treating eIF4E-mediated diseases and a use of a construct, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, or a pharmaceutical composition comprising the same for treating eIF4E-mediated diseases and a use of the construct, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, or a pharmaceutical composition comprising the same for treating eIF4E-mediated diseases and in preparing a medicament for treating eIF4E-mediated diseases, wherein the eIF4E-mediated diseases include but are not limited to: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic system cancer, lymphoma, medulloblastoma, medulloblastoma, rectal adenocarcinom
  • Haldrogen in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium and deuterium, isotopes of carbon include 12 C, 13 C and 14 C, isotopes of oxygen include 16 O and 18 O, etc.
  • the “isomer” of the present invention refers to a molecule with the same atomic composition and connection mode, but different three-dimensional spatial arrangement, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures.
  • Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light.
  • the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefix D, L or (+), (-) is used to name the sign of rotation of plane polarized light of the compound, (-) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed.
  • the chemical structure of these stereoisomers is the same, but their stereostructures are different.
  • Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • halogenated refers to substitution with fluorine, chlorine, bromine, or iodine.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group containing 1 to 6 carbon atoms, and more preferably a straight or branched group containing 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1- Ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • carbonyl group and acyl group of the present invention both refer to -C(O)-.
  • the "sulfonyl group" of the present invention refers to -S(O) 2 -.
  • the "sulfonylamino group" of the present invention refers to -S(O) 2 NH-.
  • haloalkyl group refers to an alkyl group substituted with at least one halogen.
  • hydroxyalkyl group refers to an alkyl group substituted with at least one hydroxy group.
  • Alkoxy of the present invention refers to -O-alkyl.
  • alkoxy include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
  • cycloalkyl refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heterocyclyl refers to a group of a 3- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as long as the valence permits.
  • the heterocyclyl group can be either monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiral ring system (e.g., a bicyclic system (also known as a "bicyclic heterocyclyl”)) and can be saturated or partially unsaturated.
  • Suitable heterocyclyls include, but are not limited to, piperidinyl, azetidinyl, aziridine, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc.
  • Each example of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable point of attachment.
  • aryl refers to an aromatic system that may contain a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic ring, containing 6 to 12 carbon atoms, preferably containing about 6 to about 10 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl.
  • Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any usable point of attachment.
  • heteroaryl refers to an aromatic group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-12 atoms (5-12-membered heteroaryl), and more preferably composed of 5-10 atoms (5-10-membered heteroaryl), wherein the heteroatom is O, S, or N.
  • heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl,
  • the “pharmaceutically acceptable salt” of the present invention refers to the salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity.
  • the "solvate” of the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense.
  • the solvent refers to a solvent known to or easily determined by a person skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative thereof.
  • the in vivo effects of the compounds of formula (I) may be partially exerted by one or more metabolites formed in the human or animal body after the compound of formula (I) is administered. As described above, the in vivo effects of the compounds of formula (I) may also be exerted via the metabolism of precursor compounds ("prodrugs").
  • Prodrugs of the present invention refer to compounds that are converted into compounds of the present invention under physiological conditions in an organism due to reactions with enzymes, gastric acid, etc., i.e., compounds that are converted into compounds of the present invention by oxidation, reduction, hydrolysis, etc. of enzymes and/or compounds that are converted into compounds of the present invention by hydrolysis reactions of gastric acid, etc.
  • crystalline in the present invention refers to a solid whose internal structure is formed by regularly repeating constituent atoms (or groups thereof) in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure.
  • the "pharmaceutical composition” of the present invention refers to a mixture comprising any one of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
  • the composition is generally used to prepare a drug for the treatment and/or prevention of a disease mediated by one or more kinases.
  • the "pharmaceutically acceptable carrier” of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
  • Cuprous bromide (120 g, 0.84 mol) and tert-butyl nitrite (110 mL, 0.84 mol) were added to acetonitrile (500 mL) and heated at 65°C for 15 min.
  • a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (144.0 g, 0.56 mol) in acetonitrile was added to the reaction solution, and the reaction mixture was heated at 65°C for 1 h. After completion, the reaction was quenched with water and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography gave 114.0 g of a transparent solid.
  • n-butyl lithium (2M, 13.0mL, 0.033mol) was slowly added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (7.09mL, 0.043mol) in anhydrous tetrahydrofuran (100mL) at -78°C.
  • the reaction mixture was heated to 0°C and stirred for 30 minutes. It was cooled to -78°C again, and a tetrahydrofuran solution of 1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene was added at -100°C, and the reaction mixture was stirred at -100°C for 45 minutes.
  • 2,3-Dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid (11.0 g, 0.030 mol) was added to the solution in thionyl chloride (30 mL) and heated and stirred at 80° C. for 2 h. After completion, the solution was concentrated to remove thionyl chloride and directly used in the next step.
  • Step 5 Preparation of tert-butyl 3-(2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzamide)-1H-pyrazole-1-carboxylate
  • Step 7 Preparation of 6,7-dibromo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
  • Step 8 Preparation of 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile
  • Cuprous cyanide (7.0 g, 0.078 mol) was added to 6,7-dibromo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one (16.0 g, 0.039 mol) in N,N-dimethylformamide (100 mL) at room temperature and heated and stirred at 90°C for 3 h. After completion, the reactant was cooled at room temperature, diluted with ethyl acetate, and washed with water and 1N hydrochloric acid solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo.
  • the preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester.
  • the preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tert-butyl ester.
  • Intermediate 4 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydroimidazo[1,2-a]quinazoline-6-carbonitrile
  • the preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 2-amino-1H-imidazole-1-carboxylic acid tert-butyl ester.
  • the preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced with 3-amino-4-fluoro-1H-pyrazole-1-carboxylic acid tert-butyl ester.
  • Step 3 Preparation of tert-butyl 5-(3-bromo-2-chloro-5-fluoroisonicotinylamino)-3-methyl-1H-pyrazole-1-carboxylate
  • tert-butyl 5-(3-bromo-2-chloro-5-fluoroisonicotinamide)-3-methyl-1H-pyrazole-1-carboxylate (6.0 g, 0.014 mol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added under stirring, and stirred at room temperature overnight. After the reaction was completed, it was directly concentrated and directly used for the next step.
  • Step 6 Preparation of 7-chloro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • Step 7 Preparation of 7-fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • synthesis method is the same as that of intermediate 6, except that tert-butyl 3-amino-1H-pyrazole-1-carboxylate is used to replace tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate.
  • ESI-MS m/z: 230.1 [MH] - .
  • Step 2 Preparation of methyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Zinc chloride (114 mL, 114 mmol) was added to a 500 mL three-necked flask. Methylmagnesium bromide (38 mL, 114 mmol) was slowly added dropwise under nitrogen protection and ice-water bath. After 45 min of reaction, methyl 5,7-dichlorothieno[3,2-b]pyridine-3-carboxylate (15 g, 57.25 mmol), trisdibenzylideneacetone dipalladium (500 mg, 0.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (550 mg, 1.0 mol) were added. The reaction was carried out at 60°C.
  • Step 4 Preparation of tert-butyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 5 Preparation of tert-butyl 7-(5-chloro-2-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 6 Preparation of tert-butyl 7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 4 Preparation of tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate
  • Step 5 Preparation of tert-butyl 7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carboxylate
  • tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate 5.1 g, 0.02 mol
  • 5-chloro-2-hydroxyphenylboronic acid 3.4 g, 0.02 mol
  • cesium carbonate (19.6 g, 0.06 mol)
  • tetrakis(triphenylphosphine)palladium 1.2 g, 1.0 mmol
  • Step 6 Preparation of 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Step 7 Preparation of 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
  • Step 8 Preparation of 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
  • Step 9 Preparation of 7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
  • synthesis method is the same as that of intermediate 9, except that tert-butyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate is used to replace tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate.
  • Step 1 Preparation of tert-butyl 7-(5-chloro-2-((trifluoromethanesulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate
  • Step 2 Preparation of tert-butyl 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
  • Cuprous iodide (1.3 g, 7.0 mmol) and bis(triphenylphosphine)palladium dichloride (7.3 g, 10.4 mmol) were added to the reaction flask, followed by tert-butyl 7-(5-chloro-2-((trifluoromethanesulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate (86 g, 174 mmol) and trimethyl(prop-2-yn-1-yloxy)silane (45 g, 348 mmol) and N,N-dimethylformamide (600 mL), and finally triethylamine (96 mL, 696 mmol), argon replacement, and reaction at 80 °C for 16 h.
  • Step 3 Preparation of tert-butyl 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
  • Triphenylphosphine (56.1 g, 214 mmol) was added to the reaction flask, replaced with argon, and tert-butyl 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate (57 g, 143 mmol) and carbon tetrabromide (57.0 g, 172 mmol) in dichloromethane (800 mL) were added in sequence at 0°C. After addition, the mixture was moved to room temperature and reacted for 4 h.
  • Example 1 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
  • Step 1 Preparation of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 2 Preparation of tert-butyl 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 3 Preparation of 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
  • Example 1 Referring to the synthesis method of Example 1, the compounds of Examples 2-21 in Table 1 were prepared.
  • Example 22 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
  • Step 2 Preparation of 6,7-dibromo-2-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one
  • Step 3 Preparation of 7-bromo-2-methyl-5-oxo-8-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinazoline-6-carbonitrile
  • Cuprous cyanide (0.29 g, 0.0034 mol) was added to 6,7-dibromo-2-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (0.70 g, 0.0017 mol) in N,N-dimethylformamide (10.0 mL) at room temperature and heated with stirring at 90 °C. 3h. After completion, the reaction was cooled at room temperature, diluted with ethyl acetate, and washed with water and 1N hydrochloric acid solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. 1.2 g of the target product was obtained as a yellow solid.
  • Step 4 Preparation of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-2-methyl-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazoline-4(5H)-ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 5 Preparation of tert-butyl 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
  • Step 6 Preparation of 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
  • Step 1 Preparation of 7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
  • Step 2 7-(5-chloro-2-(3-(6-cyano-7-(4-cyclopropylpiperazin-1-yl)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidine
  • Example 31 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Step 1 7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl
  • Step 2 Preparation of tert-butyl 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
  • Step 3 Preparation of 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Example 23 Referring to the synthetic methods of Example 23 and Example 31, the compounds of Examples 32-54 in Table 3 were prepared.
  • Example 69 4-(3-(2-(3-(2H-tetrazolyl-5-yl)thieno[3,2-b]pyridin-7-yl)-4-chlorophenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • Step 1 Preparation of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboxamide
  • Step 2 Preparation of (Z)-7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboximidoyl chloride
  • Phosphorus pentachloride (0.04 g, 0.19 mmol) was added to a reaction flask, and a dichloromethane (4 mL) solution of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboxamide (0.10 g, 0.13 mmol) and pyridine (0.06 g, 0.75 mmol) was added, and the mixture was heated to 40°C for 3 h and then at 45°C for 2 h. The title compound was obtained.
  • Step 3 Preparation of 4-(3-(4-chloro-2-(3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)phenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • Step 4 Preparation of 4-(3-(2-(3-(2H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)-4-chlorophenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • Example 70 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(cyclopropylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
  • Example 71 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(N,N-dimethylaminosulfonyl)thieno[3,2-b]pyridine -3-Formamide
  • Example 72 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Step 3 Preparation of 7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
  • Step 4 Preparation of tert-butyl 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
  • Step 5 Preparation of 6-(5-chloro-2-(3-(6-cyano-7-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Example 73 7-(5-chloro-2-(3-(6-cyano-7-((1-cyclopropylpiperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • Example 70 The synthesis method is the same as that of Example 70. The difference is that 1-cyclopropylpiperidin-4-ol is used instead of 1-(3,3-difluorocyclobutyl)piperidin-4-ol. The title compound is obtained. ESI-MS m/z: 690.2 [M+H] + .
  • Example 74 4-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid
  • Step 1 Preparation of 7-bromo-4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine
  • Step 2 Preparation of methyl 4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
  • Step 3 Preparation of methyl 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
  • Step 5 Preparation of tert-butyl 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
  • Step 6 Preparation of tert-butyl 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-d]pyrimidine-3-carboxylate
  • Step 7 Preparation of 4-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid
  • Example 75 7-(2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)-5-fluorophenyl)thieno[3,2-b]pyridine-3-carboxylic acid
  • the synthesis method is the same as that of Example 31, except that tert-butyl 7-(5-fluoro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate is used instead of tert-butyl 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate.
  • the title compound is obtained.
  • Example 76 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)benzo[b]thiophene-3-carboxylic acid
  • Step 4 Preparation of tert-butyl 7-bromobenzo[b]thiophene-3-carboxylate
  • Step 5 Preparation of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)benzo[b]thiophene-3-carboxylic acid
  • the compound was prepared into a 20 mM concentration stock solution in DMSO and diluted to the required working concentration. As concentration.
  • %Inhibition [1-(eIF4E Pull-down in drug-treated group/GAPDH Input in drug-treated group)/(eIF4E Pull-down in DMSO-treated group/GAPDH Input in DMSO-treated group)] ⁇ 100
  • Test compounds the compounds of the present invention prepared in the above examples, each compound was prepared with DMSO to 20 mM, and then diluted 3-fold in sequence to 5000.00 nM, 1250.00 nM, 312.50 nM, 78.13 nM, 19.53 nM, 4.88 nM, 1.22 nM, 0.31 nM and 0.08 nM.
  • the colon cancer cell line COLO205 was purchased from the American Type Culture Collection (ATCC).
  • Reagents RPMI-1640Medium (Gibco, 11875-093); Fetal Bovine Serum (Gibco, 10099-141); Penicillin-Streptomycin (Gibco, 15140-122); CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7571).
  • Cell recovery Dissolve the cells in a 37°C water bath, then transfer to 15 mL of pre-warmed culture medium (RPMI-1640 Medium + 10% FBS + 1% penicillin-streptomycin), centrifuge at 1000 rpm for 5 minutes, discard the culture medium, resuspend the cells with 10 mL of fresh culture medium, transfer to a culture dish, and culture in a 37°C, 5% CO2 incubator. Replace the cells with fresh culture medium after 24 hours.
  • pre-warmed culture medium RPMI-1640 Medium + 10% FBS + 1% penicillin-streptomycin
  • Cell passaging Transfer the above revived cells to a 15 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes, discard the culture medium, count the evenly dispersed cells, adjust the appropriate cell concentration to 10 mL of fresh culture medium, add it to the culture dish, and culture it in an incubator at 37°C, 5% CO2 . Depending on the cell growth, change the culture medium or pass the cells every 2-3 days.
  • COLO205 cells were resuspended in complete culture medium at the corresponding density, 5000 cells/well, and inoculated into a 96-well culture plate: the edge wells were filled with 200 ⁇ L PBS to prevent the edge culture medium from evaporating quickly, resulting in excessive differences in culture conditions in the inner wells; 75 ⁇ L complete culture medium was added to each of the 60 inner wells, and the plates were placed in a 5% CO2 incubator at 37°C for 24 h.
  • COLO205 cells were cultured in the original medium (75 ⁇ L) and 75 ⁇ L of (2 ⁇ ) drug was added. Two replicate wells were set for each concentration group and cultured in a 5% CO 2 incubator for 7 days.
  • the compound solution was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 20 mM stock solution using DMSO. The drug was diluted with complete medium. The final drug concentration was 5000 nM as the starting maximum concentration and was diluted to 9 concentration gradients in a 1:3 gradient: 5000.00 nM, 1250.00 nM, 312.50 nM, 78.13 nM, 19.53 nM, 4.88 nM, 1.22 nM, 0.31 nM and 0.08 nM.

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Abstract

The present invention relates to the field of medicinal chemistry, and relates to a tricyclic compound serving as an eIF4E inhibitor and a use thereof. Specifically, the present invention provides a compound represented by formula (I), or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, preparation methods therefor, a pharmaceutical composition containing these compounds, and a use of these compounds or the composition in treatment of eIF4E-mediated diseases.

Description

作为eIF4E抑制剂的化合物及其应用Compounds as eIF4E inhibitors and their use 技术领域Technical Field
本发明属于医药化学领域，具体涉及作为eIF4E抑制剂的三环类化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗eIF4E介导的疾病的用途。The present invention belongs to the field of medicinal chemistry, and specifically relates to tricyclic compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as eIF4E inhibitors, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating eIF4E-mediated diseases.
背景技术Background technique
在真核细胞翻译起始阶段，40S核糖体小亚基会通过翻译起始复合体eIF4F招募到mRNA的5’末端行使蛋白质翻译的功能。eIF4F包含eIF4E、eIF4A和eIF4G三个成员，其中eIF4E可在翻译起始阶段与mRNA5’端的7-Me-GpppN帽式结构结合，然后与支架蛋白eIF4G结合并招募eIF4A，组装成eIF4F复合体起始翻译过程。细胞中不同的mRNA与eIF4E的结合能力存在一定差异。一般来说，真核细胞mRNA可根据其结构特性和固有的“可译性”分为两组：一是具有相对短的，非结构化5’UTR(C和G含量较少)的强mRNA；二是具有冗长且高度结构化5’UTR(富含G和C)的弱mRNA。“强”与“弱”mRNA之间的主要差别在于，弱mRNA更依赖于eIF4E，并在正常条件下体现出较差的翻译水平。肿瘤形成有关的基因，如MYC和CCND1等原癌基因转录而成的RNA大多数是弱mRNA。当eIF4E过表达或过度活跃时，这些肿瘤相关的弱mRNA的翻译被选择性地增强，进而导致细胞的恶化和癌变。During the initiation of translation in eukaryotic cells, the 40S ribosome small subunit is recruited to the 5' end of mRNA through the translation initiation complex eIF4F to perform the function of protein translation. eIF4F contains three members: eIF4E, eIF4A and eIF4G. Among them, eIF4E can bind to the 7-Me-GpppN cap structure at the 5' end of mRNA during the initiation of translation, and then bind to the scaffold protein eIF4G and recruit eIF4A to assemble into the eIF4F complex to initiate the translation process. There are certain differences in the binding ability of different mRNAs in cells to eIF4E. In general, eukaryotic cell mRNAs can be divided into two groups according to their structural characteristics and inherent "translatability": one is strong mRNA with a relatively short, unstructured 5'UTR (less C and G content); the other is weak mRNA with a lengthy and highly structured 5'UTR (rich in G and C). The main difference between "strong" and "weak" mRNA is that weak mRNA is more dependent on eIF4E and exhibits poor translation levels under normal conditions. Most of the RNAs transcribed from tumor-related genes, such as MYC and CCND1, are weak mRNAs. When eIF4E is overexpressed or overactive, the translation of these tumor-related weak mRNAs is selectively enhanced, leading to cell deterioration and cancer.
截至目前，大量文献证明eIF4E在多种肿瘤中处于高表达水平，包括前列腺癌，乳腺癌，头颈癌，胃癌，结肠癌，肺癌，皮肤癌，食道癌，膀胱癌，子宫颈癌和造血系统肿瘤等，并与多种肿瘤的不良预后有关。将eIF4E的表达量降低50％后，会大大降低正常细胞向肿瘤细胞转化的概率，且对小鼠的正常生长发育没有影响(Truitt et al.,2015,Cell)。通过全基因组范围内的CRISPRi筛选与eIF4E合成致死的基因，结果发现了包括BCL-XL在内的600多个与eIF4E合成致死的基因(Kuzuoglu-Ozturk et al.,2021,Cell Reports)，进一步证明了eIF4E作为一个药物靶点在肿瘤治疗方面具有巨大潜力。To date, a large number of literatures have shown that eIF4E is highly expressed in a variety of tumors, including prostate cancer, breast cancer, head and neck cancer, gastric cancer, colon cancer, lung cancer, skin cancer, esophageal cancer, bladder cancer, cervical cancer and hematopoietic system tumors, and is associated with poor prognosis in a variety of tumors. Reducing the expression of eIF4E by 50% greatly reduces the probability of normal cells transforming into tumor cells, and has no effect on the normal growth and development of mice (Truitt et al., 2015, Cell). Through genome-wide CRISPRi screening of genes synthetically lethal to eIF4E, more than 600 genes synthetically lethal to eIF4E, including BCL-XL, were found (Kuzuoglu-Ozturk et al., 2021, Cell Reports), further proving that eIF4E has great potential as a drug target in tumor treatment.
还需要开发更多更好的eIF4E靶点小分子抑制剂，用于治疗eIF4E介导的疾病，为相应患者带来更大的临床益处。There is also a need to develop more and better small molecule inhibitors of the eIF4E target for the treatment of eIF4E-mediated diseases and to bring greater clinical benefits to the corresponding patients.
发明内容Summary of the invention
本发明提供通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
The present invention provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.
其中，in,
环A选自杂芳基和杂环基，所述杂芳基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、羟基环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代；Ring A is selected from heteroaryl and heterocyclic groups, and the heteroaryl and heterocyclic groups may be substituted by one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, hydroxycycloalkyl, heterocyclic, aryl, heteroaryl and oxo;
L为-(CH2)-、-(CH2)2-、-(CH2)3-、-CH((C1-C8)烷基)(CH2)-、-CH((C1-C8)烷基)(CH2)2-、-(CH2)2-O-、-CH2CH＝CH-、-CH2C≡C-或-CH2(环丙基)-；L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH((C 1 -C 8 )alkyl)(CH 2 )-, -CH((C 1 -C 8 )alkyl)(CH 2 ) 2 -, -(CH 2 ) 2 -O-, -CH 2 CH＝CH-, -CH 2 C≡C- or -CH 2 (cyclopropyl)-;
X选自N和C(R5)，其中R5选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；X is selected from N and C( R5 ), wherein R5 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
R1、R3、R4和R6各自独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基磺酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基和双烷基氨基；R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
R2选自烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、芳基、杂芳基、环烷基和杂环基，所述烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、芳基、杂芳基、环烷基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、卤代烷基酰基、羟基烷基酰基、环烷基酰基、杂环基酰基、环烷基、卤代环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代；和 R is selected from the group consisting of alkylaminoalkoxy, heterocyclylalkoxy, heterocyclylamino, aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo; and
m和n各自独立地为0、1、2或3。m and n are each independently 0, 1, 2 or 3.
本发明提供通式(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
The present invention provides a compound of general formula (II) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
其中，in,
环A选自杂芳基和杂环基，所述杂芳基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、羟基环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代；Ring A is selected from heteroaryl and heterocyclic groups, and the heteroaryl and heterocyclic groups may be substituted by one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, hydroxycycloalkyl, heterocyclic, aryl, heteroaryl and oxo;
L为-(CH2)-、-(CH2)2-、-(CH2)3-、-CH((C1-C8)烷基)(CH2)-、-CH((C1-C8)烷基)(CH2)2-、-(CH2)2-O-、-CH2CH＝CH-、-CH2C≡C-或-CH2(环丙基)-；L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH((C 1 -C 8 )alkyl)(CH 2 )-, -CH((C 1 -C 8 )alkyl)(CH 2 ) 2 -, -(CH 2 ) 2 -O-, -CH 2 CH＝CH-, -CH 2 C≡C- or -CH 2 (cyclopropyl)-;
X选自N和C(R5)，其中R5选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；X is selected from N and C( R5 ), wherein R5 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
Y1和Y2各自独立地为CH或N； Y1 and Y2 are each independently CH or N;
R2选自烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、杂环基氧基、芳基、杂芳基、环烷基和杂环基，所述烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、杂环基氧基、芳基、杂芳基、环烷基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、环烷基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、卤代烷基酰基、羟基烷基酰基、环烷基酰基、杂环基酰基、环烷基、卤代环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代； R is selected from the group consisting of alkylaminoalkoxy, heterocyclylalkoxy, heterocyclylamino, heterocyclyloxy, aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo;
R3、R4和R6各自独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基磺酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基和双烷基氨基；R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
R8选自C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环基、-C(O)-R9，其中R9可选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基磺酰基氨基、环烷基磺酰基氨基、氨基磺酰基氨基、烷基氨基磺酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基和双烷基氨基，所述C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环基和R9可被一个或多个选自卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3 烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、C1-3烷基磺酰基、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C2-6烯基、C2-6炔基、C3-8环烷基、卤代C3-8环烷基、3-8元杂环基、C6-8芳基、5-8元杂芳基和氧代基团的基团取代；和R 8 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, -C(O)-R 9 , wherein R 9 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aminosulfonylamino, alkylaminosulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino, and the C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl and R 9 may be selected from one or more halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and oxo; and
m和n各自独立地为0、1、2或3。m and n are each independently 0, 1, 2 or 3.
在一些优选的实施方案中，本发明的化合物为通式(I)、(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中：In some preferred embodiments, the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
环A选自5-12元杂芳基和3-12元杂环基，所述5-12元杂芳基和3-12元杂环基可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基、双C1-6烷基氨基、C2-10烯基、C2-10炔基、C3-12环烷基、羟基C3-12环烷基、3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团的基团取代；Ring A is selected from 5-12 membered heteroaryl and 3-12 membered heterocyclyl, and the 5-12 membered heteroaryl and 3-12 membered heterocyclyl may be substituted by one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, hydroxy C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl and oxo;
进一步优选地，环A选自5-10元杂芳基和3-10元杂环基，所述5-10元杂芳基和3-10元杂环基可被一个或多个选自卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、C1-3烷基磺酰基、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C2-6烯基、C2-6炔基、C3-8环烷基、羟基C3-8环烷基、3-8元杂环基、C6-8芳基、5-8元杂芳基和氧代基团的基团取代；Further preferably, ring A is selected from 5-10 membered heteroaryl and 3-10 membered heterocyclyl, and the 5-10 membered heteroaryl and 3-10 membered heterocyclyl may be substituted by one or more groups selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl , di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxy C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and oxo;
更进一步优选地，环A选自5-6元杂芳基和3-6元氮杂环基，所述5-6元杂芳基和3-6元氮杂环基可被一个或多个选自卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、C1-3烷基磺酰基、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C2-6烯基、C2-6炔基、C3-8环烷基、羟基C3-8环烷基、3-8元杂环基、C6-8芳基、5-8元杂芳基和氧代基团的基团取代；More preferably, ring A is selected from 5-6 membered heteroaryl and 3-6 membered nitrogen heterocyclic group, and the 5-6 membered heteroaryl and 3-6 membered nitrogen heterocyclic group may be substituted by one or more groups selected from halogen, hydroxyl, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxyl C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxyl C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl , aminoacyl, C 1-3 alkylaminoacyl, di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl and oxo group;
再进一步优选地，环A选自氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、二氢吡咯基、吡咯基、哌啶基、四氢吡啶基、二氢吡啶基、吡唑烷基、二氢吡唑基、吡唑基、咪唑烷基、二氢咪唑基、咪唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基、牛磺氨基、氮杂螺[2.3]已烷基，所述基团可被一个或多个选自卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、C1-3烷基磺酰基、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C2-6烯基、C2-6炔基、C3-8环烷基、羟基C3-8环烷基、3-8元杂环基、C6-8芳基、5-8元杂芳基和氧代基团的基团取代。 Still further preferably, ring A is selected from aziridine, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyrazolidinyl, dihydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, imidazolyl, oxazolidinyl, dihydrooxazolyl, thiazolidinyl, dihydrothiazolyl, isoxazolidinyl, dihydroisoxazolyl, isothiazolidinyl, dihydroisothiazolyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, dihydropyridazinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, morpholinyl, thiomorpholinyl, taurine amino, azaspiro [2.3] hexane, and the group may be selected from one or more halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 The alkyl radicals may be substituted with a C 1-3 alkoxy group, a hydroxy C 1-3 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-3 alkylamino group, a C 1-3 alkylacylamino group, a C 1-3 alkylacyl group, a C 1-3 alkylsulfonyl group, an aminoacyl group, a C 1-3 alkylaminoacyl group, a di-C 1-3 alkylamino group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a hydroxy C 3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a C 6-8 aryl group, a 5-8 membered heteroaryl group and an oxo group.
在一些优选的实施方案中，本发明的化合物为通式(I)、(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中：In some preferred embodiments, the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R2选自C1-6烷基氨基C1-6烷氧基、杂环基C1-6烷氧基、6元杂环基氨基、6元杂环基氧基、C6-12芳基、5-12元杂芳基、C3-12环烷基和3-12元杂环基，所述C1-6烷基氨基C1-6烷氧基、杂环基C1-6烷氧基、6元杂环基氨基、C6-12芳基、5-12元杂芳基、C3-12环烷基和3-12元杂环基可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-12环烷基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基、双C1-6烷基氨基、C2-10烯基、C2-10炔基、卤代C1-6烷基酰基、羟基C1-6烷基酰基、C3-12环烷基酰基、3-12元杂环基酰基、C3-12环烷基、卤代C3-12环烷基、3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团的基团取代； R2 is selected from C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, 6-membered heterocyclyloxy, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl, and the C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl may be selected from one or more of halogen, hydroxy, C1-6 alkyl , halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C3-12 cycloalkylC1-6 alkyl, C1-6 alkoxy , halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono-C1-6 alkylamino , C C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, bis-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halogenated C 1-6 alkylacyl, hydroxy C 1-6 alkylacyl, C 3-12 cycloalkylacyl, 3-12 membered heterocyclylacyl, C 3-12 cycloalkyl, halogenated C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl and oxo;
进一步优选地，R2选自C1-3烷基氨基C2-3烷氧基、杂环基C1-3烷氧基、6元杂环基氨基、6元杂环基氧基、C6-10芳基、5-10元杂芳基、C3-10环烷基和3-10元杂环基，所述基团可被一个或多个选自卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C3-10环烷基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、C1-3烷基磺酰基、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C2-6烯基、C2-6炔基、C3-8环烷基、卤代C3-8环烷基、3-8元杂环基、C6-8芳基、5-8元杂芳基和氧代基团的基团取代；Further preferably, R2 is selected from C1-3 alkylaminoC2-3 alkoxy, heterocyclylC1-3 alkoxy, 6-membered heterocyclylamino, 6-membered heterocyclyloxy, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered heterocyclyl, and the group can be selected from one or more halogen, hydroxyl, C1-3 alkyl, halogenated C1-3 alkyl, hydroxyC1-3 alkyl, C3-10 cycloalkylC1-3 alkyl, C1-3 alkoxy , halogenated C1-3 alkoxy , hydroxyC1-3 alkoxy, nitro, carboxyl, cyano, amino, monoC1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, C1-3 alkylsulfonyl, aminoacyl, C1-3 alkylaminoacyl, diC1-3 alkylamino, C2-6 alkenyl, C substituted with C2-6 alkynyl, C3-8 cycloalkyl, halogenated C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-8 aryl, 5-8 membered heteroaryl and oxo;
更进一步优选地，R2选自如下基团：

More preferably, R 2 is selected from the following groups:

在一些优选的实施方案中，本发明的化合物为通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中：In some preferred embodiments, the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R1、R3、R4和R6各自独立地选自氢、卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基磺酰基氨基、C3-10环烷基磺酰基氨基、氨基磺酰基氨基、C1-6烷基氨基磺酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基；R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and bis C 1-6 alkylamino;
进一步优选地，R1、R3、R4和R6各自独立地选自氢、卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、C3-10环烷基磺酰基氨基、氨基磺酰基氨基、C1-3烷基氨基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基；Further preferably, R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino;
更进一步优选地，R1、R3、R4和R6各自独立地选自氢、卤素、羟基、甲基、乙基、丙基、异丙基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、环丙基磺酰基氨基、N,N-二甲基氨基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基。Still further preferably, R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, cyclopropylsulfonylamino, N,N-dimethylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino.
在一些优选的实施方案中，本发明的化合物为通式(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中：In some preferred embodiments, the compound of the present invention is a compound of general formula (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R3、R4、R6和R9各自独立地选自氢、卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基磺酰基氨基、C3-10环烷基磺酰基氨基、氨基磺酰基氨基、C1-6烷基氨基磺酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基；R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and bis-C 1-6 alkylamino;
进一步优选地，R3、R4、R6和R9各自独立地选自氢、卤素、羟基、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、C3-10环烷基磺酰基氨基、氨基磺酰基氨基、C1-3烷基氨基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基；Further preferably, R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 3-10 cycloalkylsulfonylamino, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino;
更进一步优选地，R3、R4、R6和R9各自独立地选自氢、卤素、羟基、甲基、乙基、丙基、异丙基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、 氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、环丙基磺酰基氨基、N,N-二甲基氨基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基。More preferably, R 3 , R 4 , R 6 and R 9 are each independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 alkylamino, C 1-3 alkylsulfonylamino, cyclopropylsulfonylamino, N,N-dimethylaminosulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino.
在一些优选的实施方案中，本发明的化合物为通式(I)、(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中L为-(CH2)2-O-或-CH2C≡C-。In some preferred embodiments, the compound of the present invention is a compound of formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein L is -(CH 2 ) 2 -O- or -CH 2 C≡C-.
在一些优选的实施方案中，本发明的化合物为通式(I)、(Ⅱ)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中：In some preferred embodiments, the compound of the present invention is a compound of general formula (I), (II) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
X选自N和C(R5)，其中R5选自氢、卤素、羟基、甲基、乙基、丙基、异丙基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基。在一些实施方案中，本发明提供通式(Ia)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
X is selected from N and C(R 5 ), wherein R 5 is selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 alkylamino, C 1-3 alkylsulfonylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino. In some embodiments, the present invention provides a compound of formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
其中，环A、R1、R2、R3、L和m具有以上通式(I)所述的定义。Wherein, ring A, R 1 , R 2 , R 3 , L and m have the same definitions as described above for the general formula (I).
在一些实施方案中，本发明提供通式(Ib)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
In some embodiments, the present invention provides a compound of formula (Ib) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
其中，环A、R1、R2、R3、L和m具有以上通式(I)所述的定义。Wherein, ring A, R 1 , R 2 , R 3 , L and m have the same definitions as described above for the general formula (I).
在一些实施方案中，本发明提供通式(Ic)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
In some embodiments, the present invention provides a compound of formula (Ic) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
其中，R1、R2、R3、L和m具有以上通式(I)所述的定义，R7选自氢、卤素、羟基、C3-10环烷基、羟基C3-10环烷基、C1-6烷基、卤代C1-3烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基磺酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基，p为0、1、2或3。wherein R 1 , R 2 , R 3 , L and m have the definitions described above for the general formula (I); R 7 is selected from hydrogen, halogen, hydroxy, C 3-10 cycloalkyl, hydroxy C 3-10 cycloalkyl, C 1-6 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino; and p is 0, 1, 2 or 3.
在一些优选的实施方案中，本发明的化合物为通式(Ic)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中，R7选自氢、卤素、羟基、环丙基、甲基、乙基、丙基、异丙基、羟基C3-6环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、硝基、羧基、氰基、氨基、单C1-3烷基氨基、C1-3烷基磺酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基，p为0、1、2或3。In some preferred embodiments, the compound of the present invention is a compound of the general formula (Ic) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein R7 is selected from hydrogen, halogen, hydroxy , cyclopropyl, methyl, ethyl, propyl, isopropyl, hydroxyC3-6cycloalkyl , halogenated C1-3alkyl , hydroxyC1-3alkyl , C1-3alkoxy , halogenated C1-3alkoxy , hydroxyC1-3alkoxy , nitro, carboxyl, cyano, amino, monoC1-3alkylamino, C1-3alkylsulfonylamino , C1-3alkylacyl , aminoacyl, C1-3alkylaminoacyl and diC1-3alkylamino, and p is 0, 1 , 2 or 3.
本发明提供以下具体化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药：









The present invention provides the following specific compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs:









另一方面，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药。 In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.
在一些实施方案中，本发明提供本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药及包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药的药物组合物，所述化合物或药物组合物用于治疗与eIF4E相关的疾病。In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the compound or pharmaceutical composition is used to treat a disease associated with eIF4E.
在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.
可以将本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药与可药用载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, suitable for oral or parenteral administration. The method of administration includes, but is not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The preparation can be administered by any route, such as by infusion or push injection, by the route of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art, and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.
第三方面，本发明提供本发明式(I)、(Ia)、(Ib)、(Ic)和(Ⅱ)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，或包含其的药物组合物用于治疗与eIF4E相关的疾病的方法以及在制备治疗与eIF4E相关的疾病的药物中的用途。In the third aspect, the present invention provides a method for treating diseases associated with eIF4E using compounds represented by formula (I), (Ia), (Ib), (Ic) and (II) of the present invention or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, or pharmaceutical compositions containing the same, as well as their use in the preparation of drugs for treating diseases associated with eIF4E.
在一些优选的实施方案中，本发明提供本发明式(I)、(Ia)、(Ib)、(Ic)和(Ⅱ)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，或包含其的药物组合物用于治疗与eIF4E相关的疾病的方法以及在制备治疗与eIF4E相关的疾病的药物中的用途，其中所述的与eIF4E相关的疾病介导的疾病包括但不限于：增殖性疾病、代谢疾病或血液疾病。在一些实施方案中，本发明所述的与eIF4E相关的疾病为癌症。In some preferred embodiments, the present invention provides a method for treating a disease associated with eIF4E and a use of a compound represented by formula (I), (Ia), (Ib), (Ic) and (II) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same for preparing a drug for treating a disease associated with eIF4E, wherein the disease mediated by the disease associated with eIF4E includes but is not limited to: proliferative disease, metabolic disease or blood disease. In some embodiments, the disease associated with eIF4E described in the present invention is cancer.
在一些实施方案中，本发明所述的与eIF4E相关的疾病包括但不限于：听神经瘤、腺癌、肾上腺癌、肛门癌、血管肉瘤(例如，淋巴管肉瘤、淋巴管内皮肉瘤、血管肉瘤)、附件癌、良性单克隆性丙种球蛋白病、胆癌(例如，胆管癌)、膀胱癌、乳癌(例如，乳房腺癌、乳房乳头状癌、乳腺癌、乳房髓样癌、三阴性乳腺癌)、脑癌(例如，脑膜瘤；神经胶质瘤，例如星形细胞瘤、少突神经胶质瘤；成神经管细胞瘤)、支气管癌、类癌瘤、宫颈癌(例如宫颈腺癌)、绒毛膜癌、脊索瘤、颅咽管瘤、结肠直肠癌(例如，结肠癌、直肠癌、结肠直肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如，卡波西氏肉瘤(Kaposi's sarcoma)、多发性特发性出血性肉瘤)、子宫内膜癌(例如，子宫癌、子宫肉瘤)、食道癌(例如，食道腺癌、巴瑞特氏腺癌(Barrett’s adenocarinoma))、尤因肉瘤(Ewing sarcoma)、眼癌(例如，眼内黑素瘤、成视网膜细胞瘤)、家族性嗜酸性粒细胞增多症、胆囊癌、胃癌(例如，胃腺癌)、胃肠道间质瘤(GIST)、头颈部癌(例如，头颈部鳞状细胞癌、口腔癌(例如，口腔鳞状细胞癌(OSCC)、咽喉癌(例如，喉癌、咽癌、鼻咽癌、口咽癌))、造血系统癌(例如，白血病如急性淋巴细胞性白血病(ALL)(例如，B-细胞 ALL、T-细胞ALL)、急性髓细胞性白血病(AML)(例如，B-细胞AML、T-细胞AML)、慢性粒细胞性白血病(CML)(例如，B-细胞CML、T-细胞CML)以及慢性淋巴细胞性白血病(CLL)(例如，B-细胞CLL、T-细胞CLL)；淋巴瘤如霍奇金淋巴瘤(HL)(例如，B-细胞HL、T-细胞HL)以及非霍奇金淋巴瘤(NHL)(例如，B-细胞NHL如弥漫性大细胞淋巴瘤(DLCL)(例如，弥漫性大B-细胞淋巴瘤(DLBCL))、滤泡性淋巴瘤、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、边缘带B-细胞淋巴瘤(例如，粘膜相关淋巴样组织(MALT)淋巴瘤、结节边缘带B-细胞淋巴瘤、脾边缘带B-细胞淋巴瘤)、原发性纵隔B-细胞淋巴瘤、伯基特淋巴瘤(Burkittlymphoma)、淋巴浆细胞淋巴瘤(即，“沃尔丹斯特伦巨球蛋白血症(macroglobulinemia)”)、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B-成淋巴细胞性淋巴瘤以及原发性中枢神经系统(CNS)淋巴瘤；以及T-细胞NHL如前体T-成淋巴细胞性淋巴瘤/白血病、外周T-细胞淋巴瘤(PTCL)(例如，皮肤T-细胞淋巴瘤(CTCL)(例如，蕈样真菌病(mycosis fungiodes)、西泽里综合征(Sezary syndrome))、血管免疫母细胞性T-细胞淋巴瘤、结节外天然杀伤T-细胞淋巴瘤、肠病类型T-细胞淋巴瘤、皮下脂膜炎样T-细胞淋巴瘤、间变性大细胞淋巴瘤)；如上所描述的一种或多种白血病/淋巴瘤的混合物；以及多发性骨髓瘤(MM))、重链病(例如，α链病、γ链病、μ链病)、成血管细胞瘤、炎性肌纤维母细胞瘤、免疫细胞淀粉样变性、肾癌(例如，肾母细胞瘤又称韦尔姆斯氏瘤(Wilms’tumor)、肾细胞癌)、肝癌(例如，肝细胞癌(HCC)、恶性肝细胞瘤)、肺癌(例如，支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌)、平滑肌肉瘤(LMS)、肥大细胞增多症(例如，全身性肥大细胞增多症)、骨髓发育不良综合征(MDS)、间皮瘤、骨髓增殖性疾病(MPD)(例如，真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓外化生(AMM)又称为骨髓纤维变性(MF)、慢性特发性骨髓纤维变性、慢性骨髓性白血病(CML)、慢性嗜中性白血病(CNL)、嗜酸性白细胞增多综合征(HES))、成神经细胞瘤、神经纤维瘤(例如，1型或2型多发性神经纤维瘤(NF)、施旺细胞瘤病(schwannomatosis))、神经内分泌癌(例如，胃肠胰腺神经内分泌肿瘤In some embodiments, the diseases associated with eIF4E described herein include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, angiosarcoma), adnexal cancer, benign monoclonal gammopathy, bile cancer (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer, triple-negative breast cancer), brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma (Kaposi's sarcoma), multiple idiopathic hemorrhagic sarcomas), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemias such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrom’s macroglobulinemia” macroglobulinemia)”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemias/lymphomas as described above; and multiple myeloma (MM), heavy chain disease (e.g., α chain disease, γ chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic leukemia syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumors),
(GEP-NET)、类癌瘤)、骨肉瘤、卵巢癌(例如，囊腺癌、卵巢胚胎性癌、卵巢腺癌、卵巢透明细胞癌、卵巢浆液性囊腺癌、)、乳头状腺癌、胰腺癌(例如，胰腺腺癌、管内乳头状粘液瘤(IPMN)、胰岛细胞肿瘤)、阴茎癌(例如，阴茎和阴囊佩吉特氏病(Paget’s disease))、松果体瘤、原发性神经外胚层瘤(PNT)、前列腺癌(例如，前列腺腺癌)、直肠癌、横纹肌肉瘤、唾液管癌、皮肤癌(例如，鳞状细胞癌(SCC)、角化棘皮瘤(KA)、黑素瘤、基底细胞癌(BCC))、小肠癌(例如，附件癌)、软组织肉瘤(例如，恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性外周神经鞘瘤(MPNST)、软骨肉瘤、纤维肉瘤、粘液肉瘤)、皮脂腺癌、汗腺癌、滑膜瘤、睾丸癌(例如，精原细胞瘤、睾丸胚胎性癌)、甲状腺癌(例如，甲状腺乳头状癌、乳头状甲状腺癌(PTC)、髓样甲状腺癌)、尿道癌、阴道癌以及外阴癌(例如，外阴佩吉特氏病)、髓母细胞瘤、腺样囊性癌、黑色素瘤、胶质母细胞癌。(GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g., Paget’s disease of the penis and scrotum), pineal tumor, primary neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary duct carcinoma, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma ( KA), melanoma, basal cell carcinoma (BCC)), small intestinal cancer (e.g., adnexal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva), medulloblastoma, adenoid cystic carcinoma, melanoma, glioblastoma.
在一些优选的实施方案中，本发明提供本发明通式I、(Ia)、(Ib)、(Ic)和(Ⅱ)所示的化合物或其异 构体、药学上可接受的盐、溶剂化物、结晶或前药，或包含其的药物组合物用于治疗eIF4E介导的疾病的方法以及在制备治疗eIF4E介导的疾病的药物中的用途，其中所述的eIF4E介导的疾病包括但不限于：乳腺癌、食道癌、膀胱癌、肺癌、造血系统癌、淋巴瘤、髓母细胞瘤、成神经管细胞瘤、直肠腺癌、结肠癌、胃癌、胰腺癌、肝癌、腺样囊性癌、前列腺癌、肺癌、头颈部鳞状细胞癌、脑癌、肝细胞癌、黑色素瘤、少突神经胶质瘤、胶质母细胞癌、睾丸癌、卵巢透明细胞癌、卵巢浆液性囊腺癌、甲状腺癌、多发性骨髓瘤(AML)、肾细胞癌、套细胞淋巴瘤、三阴性乳腺癌、非小细胞肺癌、血红蛋白病、糖尿病和肥胖症。In some preferred embodiments, the present invention provides compounds represented by general formula I, (Ia), (Ib), (Ic) and (II) or their isoforms. The invention relates to a method for treating eIF4E-mediated diseases and a use of a construct, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, or a pharmaceutical composition comprising the same for treating eIF4E-mediated diseases and a use of the construct, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, or a pharmaceutical composition comprising the same for treating eIF4E-mediated diseases and in preparing a medicament for treating eIF4E-mediated diseases, wherein the eIF4E-mediated diseases include but are not limited to: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic system cancer, lymphoma, medulloblastoma, medulloblastoma, rectal adenocarcinoma, colon cancer, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, lung cancer, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple-negative breast cancer, non-small cell lung cancer, hemoglobinopathy, diabetes and obesity.
术语定义Definition of Terms
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.
本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说，氢的同位素包括氕、氚和氘，碳的同位素包括12C、13C和14C，氧的同位素包括16O和18O等。"Hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium and deuterium, isotopes of carbon include 12 C, 13 C and 14 C, isotopes of oxygen include 16 O and 18 O, etc.
本发明的“异构体”是指原子组成及连接方式相同，而其三维空间排列不同的分子，包括但不限于非对映体，对映异构体，顺反异构体，和它们的混合物，如外消旋混合物。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀D、L或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或L是指化合物是左旋的，前缀(+)或D是指化合物是右旋的。这些立体异构体的化学结构是相同的，但其立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。The "isomer" of the present invention refers to a molecule with the same atomic composition and connection mode, but different three-dimensional spatial arrangement, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefix D, L or (+), (-) is used to name the sign of rotation of plane polarized light of the compound, (-) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed. The chemical structure of these stereoisomers is the same, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
本发明的“卤素”是指氟、氯、溴、碘。本发明的“卤代”是指被氟、氯、溴或碘取代。The "halogen" of the present invention refers to fluorine, chlorine, bromine, and iodine. The "halogenated" of the present invention refers to substitution with fluorine, chlorine, bromine, or iodine.
本发明的“烷基”指直链或支链的饱和脂肪烃基团，优选含1至6个碳原子的直链或支链基团，进一步优选含有1至3个碳原子的直链或支链基团，非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1- 乙基丙基、2-甲基丁基、3-甲基丁基、正己基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。The "alkyl" of the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group containing 1 to 6 carbon atoms, and more preferably a straight or branched group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1- Ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
本发明的“羰基”、“酰基”均指-C(O)-。The "carbonyl group" and "acyl group" of the present invention both refer to -C(O)-.
本发明的“磺酰基”是指-S(O)2-。The "sulfonyl group" of the present invention refers to -S(O) 2 -.
本发明的“磺酰氨基”是指-S(O)2NH-。The "sulfonylamino group" of the present invention refers to -S(O) 2 NH-.
本发明的“卤代烷基”是指至少被一个卤素取代的烷基。The "haloalkyl group" of the present invention refers to an alkyl group substituted with at least one halogen.
本发明的“羟基烷基”是指至少被一个羟基取代的烷基。The "hydroxyalkyl group" of the present invention refers to an alkyl group substituted with at least one hydroxy group.
本发明的“烷氧基”是指-O-烷基。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、正丙氧基、异丙氧基、异丁氧基、仲丁氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。"Alkoxy" of the present invention refers to -O-alkyl. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
本发明的“环烷基”是指环状的饱和烃基。合适的环烷基可以为取代或未取代的具有3-12个碳原子的单环、二环或三环饱和烃基，例如环丙基、环丁基、环戊基、环己基。The "cycloalkyl" of the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
本发明的“杂环基”是指具有1至4个环杂原子(其中每个杂原子独立地选自氮、氧、硫、硼、磷以及硅)的3-至12-元非芳香族环系统的基团(“3-12元杂环基”)。在包含一个或多个氮原子的杂环基基团中，连接点可以是碳或氮原子，只要化合价许可。杂环基基团或者可以是单环的(“单环杂环基”)或者是融合的、桥联的或螺的环系统(例如二环系统(又称“二环杂环基”))并且可以是饱和的或可以是部分不饱和的。合适的杂环基包括但不限于哌啶基、氮杂环丁烷基、氮杂环丙烷基、四氢吡咯基、哌嗪基、二氢喹唑啉基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基等。杂环基的每个实例可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。The "heterocyclyl" of the present invention refers to a group of a 3- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as the valence permits. The heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiral ring system (e.g., a bicyclic system (also known as a "bicyclic heterocyclyl")) and can be saturated or partially unsaturated. Suitable heterocyclyls include, but are not limited to, piperidinyl, azetidinyl, aziridine, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc. Each example of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable point of attachment.
本发明的“芳基”是指可以包含单环或稠合多环的芳香体系，优选包含单环或稠合双环的芳香体系，其含有6个至12个碳原子，优选含有约6至约10个碳原子。合适的芳基包括但不限于苯基、萘基、蒽基、芴基、茚满基。芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。The "aryl" of the present invention refers to an aromatic system that may contain a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic ring, containing 6 to 12 carbon atoms, preferably containing about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any usable point of attachment.
本发明的“杂芳基”是指至少有一个碳原子被杂原子替代的芳基，优选由5-12个原子构成(5-12元杂芳基)，进一步优选由5-10个原子组成(5-10元杂芳基)，所述的杂原子为O、S、N。所述杂芳基包括但不限于咪唑基、吡咯基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、四唑基、吲哚基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、异吲哚基、苯并吡唑基、苯并咪唑基、苯并呋喃基、苯并吡喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并异噁唑基、苯并异噻唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、喹喔啉基、苯并噁嗪基、苯并噻嗪基、咪唑并吡啶基、嘧啶并吡唑基、嘧啶并咪唑基等。杂芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。 The "heteroaryl" of the present invention refers to an aromatic group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-12 atoms (5-12-membered heteroaryl), and more preferably composed of 5-10 atoms (5-10-membered heteroaryl), wherein the heteroatom is O, S, or N. The heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, etc. The heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
本发明的“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。The "pharmaceutically acceptable salt" of the present invention refers to the salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity.
本发明的“溶剂化物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂化物通常被称作水合物，例如半水合物、一水合物、二水合物、三水合物或其替代量等。The "solvate" of the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense. The solvent refers to a solvent known to or easily determined by a person skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative thereof.
具有化学式(I)的化合物的体内作用可以部分地由在给予具有化学式(I)的化合物之后在人体或动物体内形成的一种或多种代谢物来发挥。如上所述，具有化学式(I)的化合物的体内作用也可以经由前体化合物(“前药”)代谢来发挥。本发明的“前药”是指在生物体中的生理条件下，由于与酶、胃酸等反应而转化成本发明化合物的化合物，即通过酶的氧化、还原、水解等转化成本发明化合物的化合物和/或通过胃酸等的水解反应等转化成本发明化合物的化合物等。The in vivo effects of the compounds of formula (I) may be partially exerted by one or more metabolites formed in the human or animal body after the compound of formula (I) is administered. As described above, the in vivo effects of the compounds of formula (I) may also be exerted via the metabolism of precursor compounds ("prodrugs"). "Prodrugs" of the present invention refer to compounds that are converted into compounds of the present invention under physiological conditions in an organism due to reactions with enzymes, gastric acid, etc., i.e., compounds that are converted into compounds of the present invention by oxidation, reduction, hydrolysis, etc. of enzymes and/or compounds that are converted into compounds of the present invention by hydrolysis reactions of gastric acid, etc.
本发明的“结晶”是指其内部结构是在三维上规律地重复构成原子(或其集团)而形成的固体，有别于不具有这种规律的内部结构的无定形固体。The term "crystalline" in the present invention refers to a solid whose internal structure is formed by regularly repeating constituent atoms (or groups thereof) in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure.
本发明的“药物组合物”是指包含任何一种本发明所述的化合物，包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式，和一种或多种可药用载体和/或另一种或多种药物的混合物。药用组合物的目的是促进化合物对生物体的给药。所述组合物通常用于制备治疗和/或预防由一种或多种激酶介导的疾病的药物。The "pharmaceutical composition" of the present invention refers to a mixture comprising any one of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used to prepare a drug for the treatment and/or prevention of a disease mediated by one or more kinases.
本发明的“可药用载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
具体实施方式Detailed ways
下面结合实施例对本发明作进一步详细阐述，但本发明不限于这些实施例。以下实施例中使用的材料如无特殊说明均为商购获得。The present invention is further described in detail below in conjunction with the examples, but the present invention is not limited to these examples. The materials used in the following examples are all commercially available unless otherwise specified.
中间体1：7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈
Intermediate 1: 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile
步骤1：2-溴-4-氟-6-(三氟甲基)苯胺的制备
Step 1: Preparation of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline
将原料2-氨基-5-氟三氟甲苯(100g，0.56mol)溶于乙腈，在冰浴条件下加入N-溴代琥珀酰亚胺(109g，0.61mol)，随后在室温下搅拌3h。TLC(EA：PE 1:10)监测，待反应结束后，将反应液倒入冰水中，并用乙酸乙酯萃取，收集有机相，无水Na2SO4干燥，减压浓缩，得164.2g橘黄色粗品。The raw material 2-amino-5-fluorobenzotrifluoride (100 g, 0.56 mol) was dissolved in acetonitrile, and N-bromosuccinimide (109 g, 0.61 mol) was added under ice bath conditions, followed by stirring at room temperature for 3 h. TLC (EA:PE 1:10) was used for monitoring. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain 164.2 g of an orange-yellow crude product.
步骤2：1,2-二溴-5-氟-3-(三氟甲基)苯的制备
Step 2: Preparation of 1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene
将溴化亚铜(120g，0.84mol)和亚硝酸叔丁酯(110mL，0.84mol)加入到乙腈(500mL)中，65℃下加热15min。在反应液中添加2-溴-4-氟-6-(三氟甲基)苯胺(144.0g，0.56mol)在乙腈中的溶液，并在65℃下加热反应混合物1h。待完成后，用水淬火反应物并用乙酸乙酯萃取，收集有机相，无水Na2SO4干燥，真空浓缩。柱层析得透明固体114.0g。Cuprous bromide (120 g, 0.84 mol) and tert-butyl nitrite (110 mL, 0.84 mol) were added to acetonitrile (500 mL) and heated at 65°C for 15 min. A solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (144.0 g, 0.56 mol) in acetonitrile was added to the reaction solution, and the reaction mixture was heated at 65°C for 1 h. After completion, the reaction was quenched with water and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography gave 114.0 g of a transparent solid.
步骤3：2,3-二溴-6-氟-4-(三氟甲基)苯甲酸的制备
Step 3: Preparation of 2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid
在氩气气氛下，向-78℃的无水四氢呋喃(100mL)中的2,2,6,6-四甲基哌啶(7.09mL，0.043mol)溶液中缓慢滴加添加正丁基锂(2.5M，13.0mL，0.033mol)。将反应混合物加热至0℃并搅拌30分钟。再次将其冷却至-78℃，并在-100℃下添加1,2-二溴-5-氟-3-(三氟甲基)苯的四氢呋喃溶液，并在-100℃下搅拌反应混合物45分钟。在该温度下，将二氧化碳气体鼓泡通过反应物15min，并在2h内逐渐加热至室温。反应完成后，用水淬火反应，用稀盐酸将水层酸化至pH 3-2并用乙酸乙酯萃取，收集有机相，无水Na2SO4干燥，真空浓缩，得到棕色固体14.27g。ESI-MS m/z:362.8[M-H]-。Under an argon atmosphere, n-butyl lithium (2.5M, 13.0mL, 0.033mol) was slowly added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (7.09mL, 0.043mol) in anhydrous tetrahydrofuran (100mL) at -78°C. The reaction mixture was heated to 0°C and stirred for 30 minutes. It was cooled to -78°C again, and a tetrahydrofuran solution of 1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene was added at -100°C, and the reaction mixture was stirred at -100°C for 45 minutes. At this temperature, carbon dioxide gas was bubbled through the reactant for 15min and gradually heated to room temperature within 2h. After the reaction was completed, the reaction was quenched with water, the aqueous layer was acidified to pH 3-2 with dilute hydrochloric acid and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous Na2SO4 , and concentrated in vacuo to give 14.27g of brown solid. ESI-MS m/z:362.8[MH] - .
步骤4:2,3-二溴-6-氟-4-(三氟甲基)苯甲酰氯的制备
Step 4: Preparation of 2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzoyl chloride
在二氯亚砜(30mL)中的溶液中加入2,3-二溴-6-氟-4-(三氟甲基)苯甲酸(11.0g，0.030mol)在80℃下加热搅拌2h。完成后，浓缩除去二氯亚砜，直接投于下一步。2,3-Dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid (11.0 g, 0.030 mol) was added to the solution in thionyl chloride (30 mL) and heated and stirred at 80° C. for 2 h. After completion, the solution was concentrated to remove thionyl chloride and directly used in the next step.
步骤5:3-(2,3-二溴-6-氟-4-(三氟甲基)苯甲酰胺)-1H-吡唑-1-甲酸叔丁酯的制备
Step 5: Preparation of tert-butyl 3-(2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzamide)-1H-pyrazole-1-carboxylate
在室温下，向2,3-二溴-6-氟-4-(三氟甲基)苯甲酰氯的烧瓶中加入无水二氯甲烷(20mL)，加入吡啶(7.9g,100mmol)，将3-氨基-1H-吡唑-1-羧酸叔丁酯(5.4g,30mmol)加入到反应中，室温下搅拌3h。反应结束后，加水100mL，二氯甲烷萃取，有机层经浓缩后硅胶柱层析，得标题化合物。ESI-MS m/z:529.9[M+H]+。At room temperature, add anhydrous dichloromethane (20 mL) to the flask of 2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzoyl chloride, add pyridine (7.9 g, 100 mmol), add tert-butyl 3-amino-1H-pyrazole-1-carboxylate (5.4 g, 30 mmol) to the reaction, and stir at room temperature for 3 hours. After the reaction, add 100 mL of water, extract with dichloromethane, concentrate the organic layer and chromatograph on a silica gel column to obtain the title compound. ESI-MS m/z: 529.9 [M+H] + .
步骤6:2,3-二溴-6-氟-N-(1H-吡唑-3-基)-4-(三氟甲基)苯甲酰胺的制备
Step 6: Preparation of 2,3-dibromo-6-fluoro-N-(1H-pyrazol-3-yl)-4-(trifluoromethyl)benzamide
3-(2,3-二溴-6-氟-4-(三氟甲基)苯甲酰胺)-1H-吡唑-1-甲酸叔丁酯(2g,3.78mmol)置于50mL单颈瓶中，加入二氯甲烷(10mL)和三氟乙酸(3mL)，室温下搅拌过夜。反应结束后浓缩，加入二氯甲烷多次浓缩，直接投于下一步。ESI-MS m/z:429.9[M+H]+。3-(2,3-Dibromo-6-fluoro-4-(trifluoromethyl)benzamide)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2g, 3.78mmol) was placed in a 50mL single-necked bottle, and dichloromethane (10mL) and trifluoroacetic acid (3mL) were added and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated, and dichloromethane was added to concentrate the mixture several times, and the mixture was directly used in the next step. ESI-MS m/z: 429.9[M+H] + .
步骤7:6,7-二溴-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-5(4H)-酮的制备
Step 7: Preparation of 6,7-dibromo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
在N,N-二甲基甲酰胺(5.0mL)溶液中，室温下加入2,3-二溴-6-氟-N-(1H-吡唑-3-基)-4-(三氟甲基)苯甲酰胺(10.0g，0.023mol)和碳酸钾(9.6g，0.07mol)，并将混合物在140℃搅拌1h。反应结束后，用水稀释混合物，并用乙酸乙酯萃取，收集有机相，用无水Na2SO4干燥，真空浓缩收集到黄色固体16.0g。直接投于下一步。ESI-MS m/z:409.9[M+H]+。In N,N-dimethylformamide (5.0 mL) solution, 2,3-dibromo-6-fluoro-N-(1H-pyrazol-3-yl)-4-(trifluoromethyl)benzamide (10.0 g, 0.023 mol) and potassium carbonate (9.6 g, 0.07 mol) were added at room temperature, and the mixture was stirred at 140°C for 1 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to collect 16.0 g of yellow solid. Directly used in the next step. ESI-MS m/z: 409.9 [M+H] + .
步骤8:7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈的制备
Step 8: Preparation of 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile
在室温下将氰化亚铜(7.0g，0.078mol)加入到6,7-二溴-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-5(4H)-酮(16.0g，0.039mol)的N,N-二甲基甲酰胺(100mL)中，并在90℃下加热搅拌3h。完成后，在室温下冷却反应物，用乙酸乙酯稀释，并用水和1N盐酸溶液洗涤。分离有机层，用无水Na2SO4干燥，真空浓缩。柱层析(25％乙酸乙酯/石油醚)得到目标产物黄色固体4.8g。收率：34％。ESI-MS m/z:356.9[M+H]+。Cuprous cyanide (7.0 g, 0.078 mol) was added to 6,7-dibromo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one (16.0 g, 0.039 mol) in N,N-dimethylformamide (100 mL) at room temperature and heated and stirred at 90°C for 3 h. After completion, the reactant was cooled at room temperature, diluted with ethyl acetate, and washed with water and 1N hydrochloric acid solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography (25% ethyl acetate/petroleum ether) gave 4.8 g of the target product as a yellow solid. Yield: 34%. ESI-MS m/z: 356.9[M+H] + .
中间体2:7-溴-2-甲基-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈
Intermediate 2: 7-Bromo-2-methyl-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile
制备方法同7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈，不同是将3-氨基-1H-吡唑-1-甲酸叔丁酯替换成5-氨基-3-甲基-1H-吡唑-1-甲酸叔丁酯。ESI-MS m/z:370.9[M+H]+。The preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester. ESI-MS m/z: 370.9 [M+H] + .
中间体3:7-溴-2-环丙基-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈
Intermediate 3: 7-bromo-2-cyclopropyl-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile
制备方法同7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈，不同是将3-氨基-1H-吡唑-1-甲酸叔丁酯替换成5-氨基-3-环丙基-1H-吡唑-1-甲酸叔丁酯。ESI-MS m/z:396.9[M+H]+。中间体4:7-溴-5-氧代-8-(三氟甲基)-4,5-二氢咪唑并[1,2-a]喹唑啉-6-甲腈
The preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tert-butyl ester. ESI-MS m/z: 396.9 [M+H] + . Intermediate 4: 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydroimidazo[1,2-a]quinazoline-6-carbonitrile
制备方法同7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈，不同是将3-氨基-1H-吡唑-1-甲酸叔丁酯替换成2-氨基-1H-咪唑-1-甲酸叔丁酯。ESI-MS m/z:356.9[M+H]+。The preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced by 2-amino-1H-imidazole-1-carboxylic acid tert-butyl ester. ESI-MS m/z: 356.9 [M+H] + .
中间体5:7-溴-3-氟-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,2-a]喹唑啉-6-甲腈
Intermediate 5: 7-bromo-3-fluoro-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,2-a]quinazoline-6-carbonitrile
制备方法同7-溴-5-氧代-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈，不同是将3-氨基-1H-吡唑-1-甲酸叔丁酯替换成3-氨基-4-氟-1H-吡唑-1-甲酸叔丁酯。ESI-MS m/z:374.9[M+H]+。The preparation method is the same as 7-bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile, except that 3-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester is replaced with 3-amino-4-fluoro-1H-pyrazole-1-carboxylic acid tert-butyl ester. ESI-MS m/z: 374.9 [M+H] + .
中间体6:7-氟-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈
Intermediate 6: 7-Fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
步骤1:2-溴3-溴-5-氟异烟酸的制备
Step 1: Preparation of 2-bromo-3-bromo-5-fluoroisonicotinic acid
将原料2–氯-3-溴-5-氟吡啶(15.0g,0.04mol)溶于四氢呋喃(120mL)，抽换气，氩气保护，在-78℃条件下缓慢滴加二异丙基氨基锂(54mL,0.06mol)，1h后，以鼓泡的方式通入二氧化碳。反应结束后，反应缓慢升至室温，加水淬灭，用盐酸水溶液调节水相pH 3-2，用乙酸乙酯萃取，无水Na2SO4干燥，真空浓缩。柱层析(1％甲醇：二氯甲烷)得16.0g白色固体。ESI-MS m/z:251.9[M-H]-。The raw material 2-chloro-3-bromo-5-fluoropyridine (15.0 g, 0.04 mol) was dissolved in tetrahydrofuran (120 mL), purged, and protected by argon. Diisopropylamide lithium (54 mL, 0.06 mol) was slowly added dropwise at -78 °C. After 1 h, carbon dioxide was introduced by bubbling. After the reaction was completed, the reaction was slowly warmed to room temperature, quenched with water, and the pH of the aqueous phase was adjusted to 3-2 with aqueous hydrochloric acid solution. It was extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography (1% methanol: dichloromethane) gave 16.0 g of a white solid. ESI-MS m/z: 251.9 [MH] - .
步骤2:2-氯-3-溴-5-氟异烟酰氯的制备
Step 2: Preparation of 2-chloro-3-bromo-5-fluoroisonicotinyl chloride
在N,N-二甲基甲酰胺(2mL)中的溶液中加入2-氯3-溴-5-氟异烟酸(4.0g，0.014mol)，并在搅拌下缓慢加入二氯亚砜。完成后，于70℃条件回流反应，反应2h后结束，冷却，直接真空浓缩，得到棕色固体粗品直接投下一步。2-Chloro-3-bromo-5-fluoroisonicotinic acid (4.0 g, 0.014 mol) was added to the solution in N,N-dimethylformamide (2 mL), and dichlorothionyl was slowly added under stirring. After completion, the reaction was refluxed at 70°C for 2 hours, cooled, and directly concentrated in vacuo to obtain a brown solid crude product, which was directly used for the next step.
步骤3:5-(3-溴-2-氯-5-氟异烟酰氨基)-3-甲基-1H-吡唑-1-甲酸叔丁酯的制备
Step 3: Preparation of tert-butyl 5-(3-bromo-2-chloro-5-fluoroisonicotinylamino)-3-methyl-1H-pyrazole-1-carboxylate
在室温条件下，将5-氨基-3-甲基-1H-吡唑-1-甲酸叔丁酯(4.0g，0.014mol)二氯甲烷(20mL)溶液中添加吡啶(4mL)，并在室温下搅拌20min。然后将溶于二氯甲烷(10mL)的2-氯-3-溴-5-氟异烟酰氯溶液缓慢滴加至反应体系，反应30分钟后LCMS监测，反应结束后先浓缩二氯甲烷，再加水稀释反应混合物，并用乙酸乙酯萃取，收集有机相，无水Na2SO4干燥，真空浓缩，柱层析(10％-20％EA：PE)得到黄色固体6g。ESI-MS m/z:433.1[M+H]+。At room temperature, pyridine (4 mL) was added to a solution of tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (4.0 g, 0.014 mol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 20 min. Then, a solution of 2-chloro-3-bromo-5-fluoroisonicotinyl chloride dissolved in dichloromethane (10 mL) was slowly added dropwise to the reaction system, and the reaction was monitored by LCMS after 30 minutes of reaction. After the reaction, the dichloromethane was concentrated first, and then the reaction mixture was diluted with water, and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and subjected to column chromatography (10%-20% EA:PE) to obtain 6 g of a yellow solid. ESI-MS m/z: 433.1 [M+H] + .
步骤4:3-溴-2-氯-5-氟-N-(3-甲基-1H-吡唑-5-基)异烟酰胺制备
Step 4: Preparation of 3-bromo-2-chloro-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)isonicotinamide
在室温条件下，将5-(3-溴-2-氯-5-氟异烟酰胺)-3-甲基-1H-吡唑-1-甲酸叔丁酯(6.0g，0.014mol)溶于二氯甲烷(30mL)溶液中，并于搅拌条件下添加三氟乙酸(10mL)，并在室温下搅拌过夜。反应结束后直接浓缩，直接投下一步。ESI-MS m/z:332.9[M+H]+。At room temperature, tert-butyl 5-(3-bromo-2-chloro-5-fluoroisonicotinamide)-3-methyl-1H-pyrazole-1-carboxylate (6.0 g, 0.014 mol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added under stirring, and stirred at room temperature overnight. After the reaction was completed, it was directly concentrated and directly used for the next step. ESI-MS m/z: 332.9 [M+H] + .
步骤5:6-溴-7-氯-2-甲基吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-5(4H)-酮的制备
Step 5: Preparation of 6-bromo-7-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-5(4H)-one
在室温条件下，将3-溴-2-氯-5-氟-N-(3-甲基-1H-吡唑-5-基)异烟酰胺(6.0g，0.014mol)溶于N,N-二甲基甲酰胺(30mL)溶液中，并于搅拌条件下添加碳酸钾(9g，0.028mol)，并在90℃回流条件下搅 拌过夜。反应结束后加水稀释，用稀盐酸调节水相pH至中性，用乙酸乙酯萃取，饱和食盐水洗涤，无水Na2SO4干燥，真空浓缩。ESI-MS m/z:310.9[M-H]-。At room temperature, 3-bromo-2-chloro-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)isonicotinamide (6.0 g, 0.014 mol) was dissolved in N,N-dimethylformamide (30 mL) solution, and potassium carbonate (9 g, 0.028 mol) was added under stirring, and stirred at 90 ° C under reflux. Stir overnight. After the reaction is completed, dilute with water, adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid, extract with ethyl acetate, wash with saturated brine, dry over anhydrous Na 2 SO 4 , and concentrate in vacuo. ESI-MS m/z: 310.9 [MH] - .
步骤6:7-氯-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈的制备
Step 6: Preparation of 7-chloro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
在室温下将氰化亚铜(0.76g，0.0114mol)加入到6-溴-7-氯-2-甲基吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-5(4H)-酮(1.8g，0.0057mol)的N,N-二甲基甲酰胺(20mL)中，并在90℃下加热搅拌2h。反应完成后，在趁热用乙酸乙酯稀释，室温下搅拌数小时，并用水和1N盐酸溶液洗涤。取有机层，用无水Na2SO4干燥，真空浓缩。柱层析(30％EA：PE)得到目标产物黄色固体1.2g。ESI-MS m/z:258.1[M-H]-.Cuprous cyanide (0.76 g, 0.0114 mol) was added to 6-bromo-7-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-5(4H)-one (1.8 g, 0.0057 mol) in N,N-dimethylformamide (20 mL) at room temperature, and heated and stirred at 90°C for 2 h. After the reaction was completed, it was diluted with ethyl acetate while hot, stirred at room temperature for several hours, and washed with water and 1N hydrochloric acid solution. The organic layer was taken, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography (30% EA:PE) gave 1.2 g of the target product as a yellow solid. ESI-MS m/z: 258.1[MH] - .
步骤7:7-氟-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈的制备
Step 7: Preparation of 7-fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
在室温下将18-冠-6-醚(435.6mg，1.65mmol)加入到7-氯-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈(200mg，1.1mmol)的二甲基亚砜(20mL)中，缓慢加入氟化钾(319mg，5.5mmol)并在130℃下加热搅拌4h。完成后，在室温下冷却反应物，用乙酸乙酯稀释，并用饱和氯化钠溶液洗涤。分离有机层，用无水Na2SO4干燥，真空浓缩。得到目标产物黄色固体200mg。ESI-MS m/z:242.1[M-H]-。18-Crown-6-ether (435.6 mg, 1.65 mmol) was added to 7-chloro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (200 mg, 1.1 mmol) in dimethyl sulfoxide (20 mL) at room temperature, potassium fluoride (319 mg, 5.5 mmol) was slowly added and heated and stirred at 130°C for 4 h. After completion, the reactant was cooled at room temperature, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The target product was obtained as a yellow solid (200 mg). ESI-MS m/z: 242.1[MH] - .
中间体7:7-氟-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈
Intermediate 7: 7-Fluoro-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
合成方法同中间体6，不同的是用3-氨基-1H-吡唑-1-甲酸叔丁酯替换5-氨基-3-甲基-1H-吡唑-1-甲酸叔丁酯。ESI-MS m/z:230.1[M-H]-。The synthesis method is the same as that of intermediate 6, except that tert-butyl 3-amino-1H-pyrazole-1-carboxylate is used to replace tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate. ESI-MS m/z: 230.1 [MH] - .
中间体8:7-(2-(2-溴乙氧基)-5-氯苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯
Intermediate 8: tert-Butyl 7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
步骤1:5,7-二氯噻吩并[3,2-b]吡啶-3-甲酸甲酯的制备
Step 1: Preparation of methyl 5,7-dichlorothieno[3,2-b]pyridine-3-carboxylate
4-氨基噻吩-3-甲酸甲酯(25g,0.129mol),丙二酸(13.43g，0.129mol)加入到三氯氧磷(250mL)中，90℃下过夜反应，反应完全后加入冰水和饱和碳酸氢钠淬灭，二氯甲烷萃取，浓缩，硅胶柱层析(二氯甲烷洗脱)，得标题化合物。ESI-MS m/z:261.8[M+H]+。4-Aminothiophene-3-carboxylic acid methyl ester (25g, 0.129mol) and malonic acid (13.43g, 0.129mol) were added to phosphorus oxychloride (250mL) and reacted at 90°C overnight. After the reaction was complete, ice water and saturated sodium bicarbonate were added to quench the reaction. The mixture was extracted with dichloromethane, concentrated, and chromatographed on a silica gel column (eluted with dichloromethane) to obtain the title compound. ESI-MS m/z: 261.8 [M+H] + .
步骤2:7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸甲酯的制备
Step 2: Preparation of methyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate
氯化锌(114mL，114mmol)加入到500mL三颈瓶中，氮气保护，冰水浴下缓慢滴加甲基溴化镁(38mL，114mmol)，反应45min后，加入5,7-二氯噻吩并[3,2-b]吡啶-3-甲酸甲酯(15g,57.25mmol)、三二亚苄基丙酮二钯(500mg，0.5mmol)，1,1'-双二苯基膦二茂铁(550mg,1.0mol)，60℃反应，反应完全后用饱和氯化铵淬灭，加水，乙酸乙酯萃取，浓缩。柱层析得目标化合物。ESI-MS m/z:241.9[M+H]+。Zinc chloride (114 mL, 114 mmol) was added to a 500 mL three-necked flask. Methylmagnesium bromide (38 mL, 114 mmol) was slowly added dropwise under nitrogen protection and ice-water bath. After 45 min of reaction, methyl 5,7-dichlorothieno[3,2-b]pyridine-3-carboxylate (15 g, 57.25 mmol), trisdibenzylideneacetone dipalladium (500 mg, 0.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (550 mg, 1.0 mol) were added. The reaction was carried out at 60°C. After the reaction was complete, saturated ammonium chloride was used to quench the reaction, water was added, and the mixture was extracted with ethyl acetate and concentrated. The target compound was obtained by column chromatography. ESI-MS m/z: 241.9 [M+H] + .
步骤3:7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 3: Preparation of 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸甲酯溶于甲醇(50mL)中，加入氢氧化锂水溶液(2.88g固体氢氧化锂溶于20mL水)。室温条件下过夜反应，反应完全后用2N盐酸将PH调至酸性，浓缩后二氯甲烷萃取，浓缩。ESI-MS m/z:228.0[M+H]+。7-Chloro-5-methylthieno[3,2-b]pyridine-3-carboxylic acid methyl ester was dissolved in methanol (50 mL), and lithium hydroxide aqueous solution (2.88 g solid lithium hydroxide was dissolved in 20 mL water) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the pH was adjusted to acidic with 2N hydrochloric acid, concentrated, extracted with dichloromethane, and concentrated. ESI-MS m/z: 228.0 [M+H] + .
步骤4:7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate
7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸(6g,21.2mmol)溶于二碳酸二叔丁酯(40mL)中，加入三乙胺10mL。80℃条件下过夜反应，反应完全后用二乙胺淬灭，浓缩后二氯甲烷萃取，浓缩，硅胶柱层析，得目标分子。ESI-MS m/z:284.0[M+H]+。7-Chloro-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (6g, 21.2mmol) was dissolved in di-tert-butyl dicarbonate (40mL), and 10mL of triethylamine was added. The reaction was allowed to proceed overnight at 80°C. After the reaction was complete, the mixture was quenched with diethylamine, concentrated, extracted with dichloromethane, concentrated, and subjected to silica gel column chromatography to obtain the target molecule. ESI-MS m/z: 284.0[M+H] + .
步骤5:7-(5-氯-2-羟基苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 5: Preparation of tert-butyl 7-(5-chloro-2-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(3.8g，0.013mol)，(5-氯-2-羟基苯基)硼酸(3.46g，0.02mol)，四三苯基膦钯(0.75g，0.5mmol)，碳酸钾(3.6g，0.026mol)溶于1,4-二氧六环：水＝10：1的溶剂(共55mL)中。100℃条件下过夜反应，反应完全后抽滤、乙酸乙酯萃取，浓缩，柱层析得目标产物。ESI-MS m/z:376.0[M+H]+。Tert-butyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate (3.8 g, 0.013 mol), (5-chloro-2-hydroxyphenyl)boronic acid (3.46 g, 0.02 mol), tetrakistriphenylphosphine palladium (0.75 g, 0.5 mmol), potassium carbonate (3.6 g, 0.026 mol) were dissolved in a solvent (1,4-dioxane: water = 10:1) (55 mL in total). The reaction was carried out overnight at 100°C. After the reaction was complete, the product was filtered, extracted with ethyl acetate, concentrated, and column chromatography was performed to obtain the target product. ESI-MS m/z: 376.0 [M+H] + .
步骤6:7-(2-(2-溴乙氧基)-5-氯苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 6: Preparation of tert-butyl 7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
7-(5-氯-2-羟基苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(4.7g，12.5mmol)，1,2-二溴乙烷(5.4mL，62.5mmol)，碳酸钾(5.18g，37.5mmol)溶于丙酮30mL中。85℃条件下过夜反应，循环水冷凝。反应完全后乙酸乙酯萃取，浓缩，柱层析得目标产物。ESI-MS m/z:482.0[M+H]+。Tert-butyl 7-(5-chloro-2-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (4.7 g, 12.5 mmol), 1,2-dibromoethane (5.4 mL, 62.5 mmol), potassium carbonate (5.18 g, 37.5 mmol) were dissolved in 30 mL of acetone. The reaction was carried out overnight at 85°C and condensed with circulating water. After the reaction was complete, the mixture was extracted with ethyl acetate, concentrated, and the target product was obtained by column chromatography. ESI-MS m/z: 482.0 [M+H] + .
中间体9:7-(2-(3-溴丙-1-炔-1-基)-5-氯苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺
Intermediate 9: 7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
步骤1:7-氯噻吩并[3,2-b]吡啶-3-溴的制备
Step 1: Preparation of 7-chlorothieno[3,2-b]pyridine-3-bromide
7-氯噻吩并[3,2-b]吡啶(10g，58.8mmol)溶于醋酸(50mL)中，冷却条件下加入液溴(9.4g，0.70588mol)。与搅拌条件下60℃回流反应过夜，反应过半即可结束，冷却后用饱和亚硫酸氢钠淬灭过量液溴，至体系颜色消失，饱和氢氧化钠水溶液调节PH至中性，水和乙酸乙酯萃取，有机相浓缩后的油状物，静置放置，加入乙腈析出固体抽滤，取滤饼得到标题化合物。ESI-MS m/z:247.9[M+H]+。7-Chlorothieno[3,2-b]pyridine (10 g, 58.8 mmol) was dissolved in acetic acid (50 mL), and liquid bromine (9.4 g, 0.70588 mol) was added under cooling conditions. The reaction was refluxed at 60 ° C with stirring overnight, and the reaction was completed when half of the reaction was completed. After cooling, the excess liquid bromine was quenched with saturated sodium bisulfite until the color of the system disappeared. The pH was adjusted to neutral with saturated sodium hydroxide aqueous solution, and extracted with water and ethyl acetate. The oily product after organic phase concentration was allowed to stand, and acetonitrile was added to precipitate the solid and filtered, and the filter cake was taken to obtain the title compound. ESI-MS m/z: 247.9 [M + H] + .
步骤2:7-氯噻吩并[3,2-b]吡啶-3-甲酸甲酯的制备
Step 2: Preparation of methyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate
7-氯噻吩并[3,2-b]吡啶-3-溴(5g，0.02mol)溶于二甲基亚砜(30mL)中，冷却条件下加入1,4-双(二苯基膦)丁烷(1.71g，4.016mmol)，醋酸钯(899mg，4.0mmol)，并加入甲醇(30mL)。一氧化碳气球换气保护并在搅拌条件缓慢加入三乙胺(10.14g，0.1004mol)，70℃回流反应8h。反应结束，旋蒸除去甲醇，加水稀释，水和乙酸乙酯萃取，有机相浓缩后的油状物，柱层析，30％乙酸乙酯/石油醚洗脱得到标题化合物。ESI-MS m/z:228.1[M+H]+。7-Chlorothieno[3,2-b]pyridine-3-bromide (5g, 0.02mol) was dissolved in dimethyl sulfoxide (30mL), and 1,4-bis(diphenylphosphino)butane (1.71g, 4.016mmol), palladium acetate (899mg, 4.0mmol) and methanol (30mL) were added under cooling. Triethylamine (10.14g, 0.1004mol) was slowly added under stirring under carbon monoxide balloon ventilation protection, and the mixture was refluxed at 70°C for 8h. After the reaction was completed, methanol was removed by rotary evaporation, diluted with water, extracted with water and ethyl acetate, and the oily product after organic phase concentration was subjected to column chromatography, eluted with 30% ethyl acetate/petroleum ether to obtain the title compound. ESI-MS m/z: 228.1[M+H] + .
步骤3:7-氯噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 3: Preparation of 7-chlorothieno[3,2-b]pyridine-3-carboxylic acid
7-氯噻吩并[3,2-b]吡啶-3-甲酸甲酯(2.28g,10mmol)溶于甲醇(50mL)中和水(20mL)，加入氢氧化锂水溶液(2.4g,100mmol)。室温条件下过夜反应，反应完全后用2N盐酸将PH调至3，浓缩后二氯甲烷萃取，浓缩得到标题化合物。ESI-MS m/z:213.9[M+H]+。7-Chlorothieno[3,2-b]pyridine-3-carboxylic acid methyl ester (2.28 g, 10 mmol) was dissolved in methanol (50 mL) and water (20 mL), and lithium hydroxide aqueous solution (2.4 g, 100 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the pH was adjusted to 3 with 2N hydrochloric acid, and the mixture was concentrated and extracted with dichloromethane, and concentrated to obtain the title compound. ESI-MS m/z: 213.9 [M+H] + .
步骤4:7-氯噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate
7-氯噻吩并[3,2-b]吡啶-3-甲酸(2.14g，10mmol)溶于二碳酸二叔丁酯(40mL)中，加入三乙胺20mL。80℃条件下过夜反应，反应完全后用乙二胺淬灭，浓缩后二氯甲烷萃取，浓缩得到标题化合物。ESI-MS m/z:270.0[M+H]+。7-Chlorothieno[3,2-b]pyridine-3-carboxylic acid (2.14 g, 10 mmol) was dissolved in di-tert-butyl dicarbonate (40 mL), and 20 mL of triethylamine was added. The reaction was allowed to proceed overnight at 80°C, and after the reaction was complete, the mixture was quenched with ethylenediamine, concentrated, extracted with dichloromethane, and concentrated to obtain the title compound. ESI-MS m/z: 270.0 [M+H] + .
步骤5:7-(5-氯-2-羟基苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 5: Preparation of tert-butyl 7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carboxylate
氩气保护下，向装有磁力搅拌子的双颈瓶中加入7-氯噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(5.1g,0.02mol),5-氯-2-羟基苯基硼酸(3.4g，0.02mol)，碳酸铯(19.6g,0.06mol)和四(三苯基膦)钯(1.2g，1.0mmol),随后加入1,4-二氧六环/水(100mL/10mL)，氩气置换气体3次。反应在90℃下回流搅拌24h。TLC(PE：EA＝2：1)监测。待反应结束后，将反应体系乙酸乙酯(3×100mL)萃取，收集有机相，无水Na2SO4干燥，真空浓缩，硅胶柱层析，得到标题化合物。ESI-MS m/z:362.0[M+H]+。Under argon protection, tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate (5.1 g, 0.02 mol), 5-chloro-2-hydroxyphenylboronic acid (3.4 g, 0.02 mol), cesium carbonate (19.6 g, 0.06 mol) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) were added to a double-necked flask equipped with a magnetic stirrer, followed by the addition of 1,4-dioxane/water (100 mL/10 mL), and the gas was replaced with argon three times. The reaction was stirred under reflux at 90°C for 24 h. TLC (PE:EA=2:1) was used for monitoring. After the reaction was completed, the reaction system was extracted with ethyl acetate (3×100 mL), the organic phase was collected, dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and chromatographed on a silica gel column to obtain the title compound. ESI-MS m/z: 362.0[M+H] + .
步骤6:7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 6: Preparation of 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
向装有磁力搅拌子的单颈瓶中加入7-(5-氯-2-羟基苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(7.6g,22.4mmol)，二氯甲烷(60mL)，冰浴下向反应溶液中加入吡啶(5.4mL,67.2mmol)，缓慢滴加入三氟甲磺酸酐(30mL,179mmol)。待反应结束后，将反应体系二氯甲烷(3×100mL)萃取收集有机相，无水Na2SO4干燥，真空浓缩，经硅胶柱层析纯化得到标题化合物。ESI-MS m/z:437.9[M+H]+。Add tert-butyl 7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carboxylate (7.6 g, 22.4 mmol) and dichloromethane (60 mL) to a single-necked bottle equipped with a magnetic stirrer. Add pyridine (5.4 mL, 67.2 mmol) to the reaction solution under ice bath, and slowly dropwise add trifluoromethanesulfonic anhydride (30 mL, 179 mmol). After the reaction is completed, extract the reaction system with dichloromethane (3×100 mL) to collect the organic phase, dry it over anhydrous Na 2 SO 4 , concentrate it in vacuo, and purify it by silica gel column chromatography to obtain the title compound. ESI-MS m/z: 437.9[M+H] + .
步骤7:7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 7: Preparation of 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
向装有磁力搅拌子的单颈瓶中加入7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)噻吩并[3,2-b]吡啶-3-甲酸(7.4g,17mmol)，二氯甲烷(40mL)，向反应溶液中加入甲磺酰胺(3.2g,34mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(6.5g,34mmol)，4-二甲氨基吡啶(4.1g,34mmol)，待反应结束后，将反应体系用二氯甲烷(3×100mL)萃取，收集有机相，无水Na2SO4干燥，真空浓缩，经硅胶柱层析纯化得到标题化合物。ESI-MS m/z:514.9[M+H]+。7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid (7.4 g, 17 mmol) and dichloromethane (40 mL) were added to a single-necked bottle equipped with a magnetic stirrer. Methanesulfonamide (3.2 g, 34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol) and 4-dimethylaminopyridine (4.1 g, 34 mmol) were added to the reaction solution. After the reaction was completed, the reaction system was extracted with dichloromethane (3×100 mL). The organic phase was collected, dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and purified by silica gel column chromatography to obtain the title compound. ESI-MS m/z: 514.9[M+H] + .
步骤8：7-(5-氯-2-(3-羟基丙-1-炔-1-基))苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 8: Preparation of 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
氩气保护下，向装有磁力搅拌子的双颈瓶中加入7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺(4.8g,9.5mmol),加入N,N-二甲基甲酰胺(20mL),丙炔氧基三甲基硅烷(3mL,19mmol)，碘化铜(0.072g，0.38mmol),三乙胺(5mL,38mmol)和双三苯基磷二氯化钯(0.4g，0.57mmol),氩气置换气体3次。反应在80℃下回流搅拌24h。待反应结束后，将反应体系PH调至2-3左右，乙酸乙酯(3×100mL)萃取，收集有机相，无水Na2SO4干燥，真空浓缩，经硅胶柱层析纯化得到标题化合物。ESI-MS m/z:421.0[M+H]+。Under argon protection, 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide (4.8 g, 9.5 mmol) was added to a double-necked flask equipped with a magnetic stirrer, and N,N-dimethylformamide (20 mL), propynyloxytrimethylsilane (3 mL, 19 mmol), copper iodide (0.072 g, 0.38 mmol), triethylamine (5 mL, 38 mmol) and bistriphenylphosphine palladium dichloride (0.4 g, 0.57 mmol) were added, and the gas was replaced by argon three times. The reaction was refluxed and stirred at 80°C for 24 h. After the reaction was completed, the pH of the reaction system was adjusted to about 2-3, extracted with ethyl acetate (3×100 mL), and the organic phase was collected, dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and purified by silica gel column chromatography to obtain the title compound. ESI-MS m/z: 421.0 [M+H] + .
步骤9：7-(2-(3-溴丙-1-炔-1-基)-5-氯苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 9: Preparation of 7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
向装有磁力搅拌子的单颈瓶中加入7-(5-氯-2-(3-羟基丙-1-炔-1-基))苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺(0.60g,1.4mmol)，二氯甲烷(10mL)，冰浴下向反应溶液中加入三苯基膦(0.58g,2.2mmol)，分批加入四溴化碳(0.73g,2.2mmol)，待反应结束后，将反应体系的二氯甲烷，真空浓缩，经硅胶柱层析纯化得到标题化合物。ESI-MS m/z:482.9[M+H]+。7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide (0.60 g, 1.4 mmol) and dichloromethane (10 mL) were added to a single-necked bottle equipped with a magnetic stirrer. Triphenylphosphine (0.58 g, 2.2 mmol) was added to the reaction solution under ice bath, and carbon tetrabromide (0.73 g, 2.2 mmol) was added in batches. After the reaction was completed, the dichloromethane in the reaction system was concentrated in vacuo and purified by silica gel column chromatography to obtain the title compound. ESI-MS m/z: 482.9 [M+H] + .
中间体10：7-(2-(3-溴丙-1-炔-1-基)-5-氯苯基)-5-甲基-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺
Intermediate 10: 7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)-5-methyl-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
合成方法同中间体9，不同的是用7-氯-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯替换7-氯噻吩并[3,2-b]吡啶-3-甲酸叔丁酯。ESI-MS m/z:496.9[M+H]+。The synthesis method is the same as that of intermediate 9, except that tert-butyl 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate is used to replace tert-butyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate. ESI-MS m/z: 496.9[M+H] + .
中间体11：7-(5-氯-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯
Intermediate 11: tert-butyl 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
步骤1：7-(5-氯-2-((三氟甲磺酰基)氧基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 1: Preparation of tert-butyl 7-(5-chloro-2-((trifluoromethanesulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate
将7-(5-氯-2-羟基苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(75g,208mmol)溶于二氯甲烷(1000mL)中，加入吡啶(51mL,624mmol)。于0℃下缓慢加入三氟甲磺酸酐(53mL,312mmol)，加毕移置室温反应2h。反应完毕后，加水，二氯甲烷萃取，水反洗，无水硫酸钠干燥，乙酸乙酯打浆得产物86g。收率：84.3％。ESI-MS m/z:493.7[M+H]+.Dissolve tert-butyl 7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carboxylate (75g, 208mmol) in dichloromethane (1000mL) and add pyridine (51mL, 624mmol). Slowly add trifluoromethanesulfonic anhydride (53mL, 312mmol) at 0℃, and leave to react at room temperature for 2h. After the reaction is completed, add water, extract with dichloromethane, backwash with water, dry with anhydrous sodium sulfate, and beat with ethyl acetate to obtain 86g of product. Yield: 84.3%. ESI-MS m/z: 493.7[M+H] + .
步骤2：7-(5-氯-2-(3-羟基丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
将碘化亚铜(1.3g,7.0mmol)和双(三苯基膦)二氯化钯(7.3g,10.4mmol)加入反应瓶中，加入7-(5-氯-2-((三氟甲磺酰基)氧基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(86g,174mmol)和三甲基(丙-2-炔-1-基氧基)硅烷(45g,348mmol)和N,N-二甲基甲酰胺(600mL)，最后加入三乙胺(96mL,696mmol)，氩气置换，置于80℃反应16h。反应完毕，加水，乙酸乙酯萃取，水反洗，无水硫酸钠干燥，硅胶柱层析得产物57g。收率：82.6％。ESI-MS m/z:399.9[M+H]+.Cuprous iodide (1.3 g, 7.0 mmol) and bis(triphenylphosphine)palladium dichloride (7.3 g, 10.4 mmol) were added to the reaction flask, followed by tert-butyl 7-(5-chloro-2-((trifluoromethanesulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate (86 g, 174 mmol) and trimethyl(prop-2-yn-1-yloxy)silane (45 g, 348 mmol) and N,N-dimethylformamide (600 mL), and finally triethylamine (96 mL, 696 mmol), argon replacement, and reaction at 80 °C for 16 h. After the reaction was completed, water was added, extracted with ethyl acetate, backwashed with water, dried over anhydrous sodium sulfate, and chromatographed on a silica gel column to obtain 57 g of the product. Yield: 82.6%. ESI-MS m/z: 399.9[M+H] + .
步骤3:7-(5-氯-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 3: Preparation of tert-butyl 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
将三苯基膦(56.1g,214mmol)加入反应瓶中，氩气置换，于0℃下依次加入7-(5-氯-2-(3-羟基丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(57g,143mmol)和四溴化碳(57.0g,172mmol)的二氯甲烷溶液(800mL)。加毕移至室温反应4h。反应完毕，过滤除去部分三苯氧膦，硅胶柱层析得产物44g。收率：66.8％。ESI-MS m/z:461.8[M+H]+. Triphenylphosphine (56.1 g, 214 mmol) was added to the reaction flask, replaced with argon, and tert-butyl 7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate (57 g, 143 mmol) and carbon tetrabromide (57.0 g, 172 mmol) in dichloromethane (800 mL) were added in sequence at 0°C. After addition, the mixture was moved to room temperature and reacted for 4 h. After the reaction was completed, part of triphenylphosphine oxide was removed by filtration, and 44 g of the product was obtained by silica gel column chromatography. Yield: 66.8%. ESI-MS m/z: 461.8 [M+H] + .
中间体12：7-(5-氟-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯
Intermediate 12: tert-butyl 7-(5-fluoro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
合成方法同中间体11，不同的是用5-氟-2-羟基苯基硼酸替换5-氯-2-羟基苯基硼酸ESI-MS m/z:446.06[M+H]+。The synthesis method is the same as that of intermediate 11, except that 5-fluoro-2-hydroxyphenylboronic acid is used instead of 5-chloro-2-hydroxyphenylboronic acid. ESI-MS m/z: 446.06 [M+H] + .
中间体13：1-(3,3-二氟环丁基)-N-甲基哌啶-4-胺
Intermediate 13: 1-(3,3-difluorocyclobutyl)-N-methylpiperidin-4-amine
步骤1:1-(3,3-二氟环丁基)哌啶-4-酮的制备
Step 1: Preparation of 1-(3,3-difluorocyclobutyl)piperidin-4-one
将无水碳酸钠(7.18g,67.7mmol)加入反应瓶中氩气置换，依次加入3,3-二氟环丁烷-1-胺(2.08g,19.4mmol)和1,5-二氯-3-戊酮(3.00g,19.4mmol)的甲醇溶液(30mL)，加毕移置75℃反应3h。反应完毕，过滤，滤液旋干，硅胶柱层析得产物1.95g。ESI-MS m/z:190.0[M+H]+。Anhydrous sodium carbonate (7.18 g, 67.7 mmol) was added to the reaction flask for argon replacement, and a methanol solution (30 mL) of 3,3-difluorocyclobutane-1-amine (2.08 g, 19.4 mmol) and 1,5-dichloro-3-pentanone (3.00 g, 19.4 mmol) was added in sequence. After addition, the mixture was placed at 75°C for reaction for 3 h. After the reaction was completed, the mixture was filtered, the filtrate was dried by rotary evaporation, and 1.95 g of the product was obtained by silica gel column chromatography. ESI-MS m/z: 190.0 [M+H] + .
步骤2:1-(3,3-二氟环丁基)-N-甲基哌啶-4-胺的制备
Step 2: Preparation of 1-(3,3-difluorocyclobutyl)-N-methylpiperidin-4-amine
将甲胺盐酸盐(2.10g,31.2mmol)加入反应瓶中，加入三乙胺(4.74g,46.9mmol)和二氯甲烷(30mL)搅拌至溶解，然后依次加入1-(3,3-二氟环丁基)哌啶-4-酮(1.97g,10.4mmol)的二氯甲烷溶液(30mL)、冰醋酸(3.76g,62.5mmol)和三乙酰氧基硼氢化钠(6.60g,31.2mmol)。加毕室温 反应3h。反应完毕后，加入10％氢氧化钠水溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，旋干得产物2.45g，未纯化直接投下一步。ESI-MS m/z:205.1[M+H]+。Add methylamine hydrochloride (2.10 g, 31.2 mmol) to the reaction flask, add triethylamine (4.74 g, 46.9 mmol) and dichloromethane (30 mL) and stir until dissolved, then add dichloromethane solution (30 mL) of 1-(3,3-difluorocyclobutyl)piperidin-4-one (1.97 g, 10.4 mmol), glacial acetic acid (3.76 g, 62.5 mmol) and sodium triacetoxyborohydride (6.60 g, 31.2 mmol) in turn. The reaction was continued for 3 h. After the reaction was completed, 10% sodium hydroxide aqueous solution was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.45 g of the product, which was directly used in the next step without purification. ESI-MS m/z: 205.1 [M+H] + .
实施例1：7-(5-氯-2-(2-(6-氰基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸
Example 1: 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
步骤1：7-(5-氯-2-(2-(7-溴-6-氰基-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 1: Preparation of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
在N,N-二甲基甲酰胺(15.0mL)溶液中，室温下加入7-溴-5-氧-8-(三氟甲基)-4,5-二氢吡唑并[1,5-a]喹唑啉-6-甲腈(1.0g，0.0028mol)和碳酸钾(1.16g，0.0084mol)，并将混合物搅拌20分钟。然后将7-(2-(2-溴乙氧基)-5-氯苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(1.6g，0.0034mol)添加到反应混合物中，并继续搅拌48小时。完成后，用水稀释反应混合物并用乙酸乙酯萃取，收集有机相，用水和饱和盐水洗涤有机相，用无水Na2SO4干燥，真空浓缩。柱层析(30％乙酸乙酯/石油醚)得到目标分子1.2g。ESI-MS m/z:758.0[M+H]+。7-Bromo-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-6-carbonitrile (1.0 g, 0.0028 mol) and potassium carbonate (1.16 g, 0.0084 mol) were added to a solution of N,N-dimethylformamide (15.0 mL) at room temperature, and the mixture was stirred for 20 minutes. Then tert-butyl 7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (1.6 g, 0.0034 mol) was added to the reaction mixture, and stirring was continued for 48 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was collected, washed with water and saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography (30% ethyl acetate/petroleum ether) gave 1.2 g of the target molecule. ESI-MS m/z:758.0[M+H] + .
步骤2：7-(5-氯-2-(2-(6-氰基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
将7-(5-氯-2-(2-(7-溴-6-氰基-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.4g，0.0005mol)加入到N-甲基吡咯烷酮(10.0mL)中的溶液中添加1-甲基哌嗪(0.12mL，0.0010mol)，然后添加碘化铜(0.01g，0.00016mol)和1,10-菲罗啉(0.02g，0.0002mol)，并在150℃下加热反应混合物4小时。反应完成后，用水稀释混合物，并用乙酸乙酯萃取,收集有机相，用无水Na2SO4干燥，真空浓缩，得到目标产物0.2g粗品。ESI-MS m/z:778.2[M+H]+。 To a solution of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (0.4 g, 0.0005 mol) in N-methylpyrrolidone (10.0 mL), 1-methylpiperazine (0.12 mL, 0.0010 mol) was added, followed by copper iodide (0.01 g, 0.00016 mol) and 1,10-phenanthroline (0.02 g, 0.0002 mol), and the reaction mixture was heated at 150°C for 4 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to obtain 0.2 g of the target product as a crude product. ESI-MS m/z:778.2[M+H] + .
步骤3：7-(5-氯-2-(2-(6-氰基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 3: Preparation of 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
将7-(5-氯-2-(2-(6-氰基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)吡唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.2g，0.25mmol)加入到二氯甲烷(3.0mL)中，在0℃下添加2,2,2-三氟乙酸(3.0mL)，并在室温下搅拌反应混合物12h。完成后，反应混合物在减压下浓缩得到粗化合物，制备HPLC制备得0.030g纯品。1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.03(s,1H),7.60(dd,J＝8.8,2.2Hz,1H),7.46(s,1H),7.37(dd,J＝11.1,5.3Hz,3H),5.69(s,1H),4.47(s,2H),4.25(s,2H),3.67(s,4H),3.17–2.95(m,6H),2.75-2.60(m,4H).ESI-MS m/z:722.1[M+H]+。Tert-butyl 7-(5-chloro-2-(2-(6-cyano-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (0.2 g, 0.25 mmol) was added to dichloromethane (3.0 mL), 2,2,2-trifluoroacetic acid (3.0 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude compound, and 0.030 g of pure product was obtained by preparative HPLC. 1 H NMR (400MHz, DMSO-d 6 )δ8.37(s,1H),8.03(s,1H),7.60(dd,J＝8.8,2.2Hz,1H),7.46(s,1H),7.37(dd,J＝11.1,5.3Hz,3H) ,5.69(s,1H),4.47(s,2H),4.25(s,2H),3.67(s,4H),3.17–2.95(m,6H),2.75-2.60(m,4H).ESI-MS m/z:722.1[M+H] + .
参考实施例1的合成方法，制备得到表1中实施例2-21的化合物。Referring to the synthesis method of Example 1, the compounds of Examples 2-21 in Table 1 were prepared.
表1





Table 1





实施例22：7-(5-氯-2-(2-(6-氰基-2-甲基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸
Example 22: 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
步骤1：2,3-二溴-6-肼基-4-(三氟甲基)苯甲酸的制备
Step 1: Preparation of 2,3-dibromo-6-hydrazino-4-(trifluoromethyl)benzoic acid
在乙醇(50mL)中的溶液中加入2,3-二溴-6-氟-4-(三氟甲基)苯甲酸(16.0g，0.044mol)和水合肼(44.7mL，0.092mol)，在60℃下搅拌过夜。完成后，真空浓缩，除去溶剂和水合肼，柱层析(13％甲醇/二氯甲烷)得到黄色固体2.0g。ESI-MS m/z:376.9[M+H]+。2,3-Dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid (16.0 g, 0.044 mol) and hydrazine hydrate (44.7 mL, 0.092 mol) were added to the solution in ethanol (50 mL), and stirred at 60°C overnight. After completion, the mixture was concentrated in vacuo to remove the solvent and hydrazine hydrate, and column chromatography (13% methanol/dichloromethane) was performed to obtain 2.0 g of a yellow solid. ESI-MS m/z: 376.9 [M+H] + .
步骤2：6,7-二溴-2-甲基-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-5(4H)-酮的制备
Step 2: Preparation of 6,7-dibromo-2-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one
在冰水浴下，向2,3-二溴-6-肼基-4-(三氟甲基)苯甲酸(2.8g，0.0074mol)乙醇(10mL)溶液中添加乙醇钠(0.51g，0.0074mol)，(E)-N-氰基乙酸乙酯(0.92mL，0.0074mol)，然后加热至78℃，反应过夜后，在反应中加入少许盐酸水溶液，将反应液pH调至4-5。完成后，抽滤，滤饼分别用乙醇和水洗涤，得到白色固体0.7g。ESI-MS m/z:424.8[M+H]+。Under an ice-water bath, sodium ethoxide (0.51 g, 0.0074 mol) and ethyl (E)-N-cyanoacetate (0.92 mL, 0.0074 mol) were added to a solution of 2,3-dibromo-6-hydrazinyl-4-(trifluoromethyl)benzoic acid (2.8 g, 0.0074 mol) in ethanol (10 mL), and then heated to 78°C. After reacting overnight, a small amount of aqueous hydrochloric acid was added to the reaction to adjust the pH of the reaction solution to 4-5. After completion, the reaction was filtered and the filter cake was washed with ethanol and water respectively to obtain 0.7 g of a white solid. ESI-MS m/z: 424.8 [M+H] + .
步骤3：7-溴-2-甲基-5-氧-8-(三氟甲基)-4,5-二氢-[1,2,4]三氮唑并[1,5-a]喹唑啉-6-甲腈的制备
Step 3: Preparation of 7-bromo-2-methyl-5-oxo-8-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinazoline-6-carbonitrile
在室温下将氰化亚铜(0.29g，0.0034mol)加入到6,7-二溴-2-甲基-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-5(4H)-酮(0.70g，0.0017mol)的N,N-二甲基甲酰胺(10.0mL)中，并在90℃下加热搅拌 3h。完成后，在室温下冷却反应物，用乙酸乙酯稀释，并用水和1N盐酸溶液洗涤。分离有机层，用无水Na2SO4干燥，真空浓缩。得到目标产物黄色固体1.2g。ESI-MS m/z:371.9[M+H]+。Cuprous cyanide (0.29 g, 0.0034 mol) was added to 6,7-dibromo-2-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (0.70 g, 0.0017 mol) in N,N-dimethylformamide (10.0 mL) at room temperature and heated with stirring at 90 °C. 3h. After completion, the reaction was cooled at room temperature, diluted with ethyl acetate, and washed with water and 1N hydrochloric acid solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. 1.2 g of the target product was obtained as a yellow solid. ESI-MS m/z: 371.9 [M+H] + .
步骤4：7-(5-氯-2-(2-(7-溴-6-氰基-2-甲基-5-氧代-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-4(5H)-乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-2-methyl-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazoline-4(5H)-ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
在N,N-二甲基甲酰胺(5.0mL)溶液中，室温下加入7-溴-2-甲基-5-氧代-8-(三氟甲基)-4,5-二氢-[1,2,4]三氮唑并[1,5-a]喹唑啉-6-甲腈(0.12g，0.00030mol)和碳酸钾(0.13g，0.00090mol)，并将混合物搅拌20分钟。然后将7-(2-(2-溴乙氧基)-5-氯苯基)-5-甲基噻吩并[3,2-b]吡啶-3-羧酸叔丁酯(0.17g，0.00035mol)添加到反应混合物中，并继续搅拌96小时。完成后，用水稀释混合物反应并用乙酸乙酯萃取，收集有机相，用水和饱和盐水洗涤有机相，用无水Na2SO4干燥，真空浓缩。柱层析得到目标分子0.20g。ESI-MS m/z:773.4[M+H]+。In N,N-dimethylformamide (5.0mL) solution, 7-bromo-2-methyl-5-oxo-8-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinazoline-6-carbonitrile (0.12g, 0.00030mol) and potassium carbonate (0.13g, 0.00090mol) were added at room temperature, and the mixture was stirred for 20 minutes. Then tert-butyl 7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (0.17g, 0.00035mol) was added to the reaction mixture, and stirring was continued for 96 hours. After completion, the mixture was diluted with water and extracted with ethyl acetate, the organic phase was collected, washed with water and saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. Column chromatography gave 0.20g of the target molecule. ESI-MS m/z:773.4[M+H] + .
步骤5：7-(5-氯-2-(2-(6-氰基-2-甲基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 5: Preparation of tert-butyl 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate
将7-(5-氯-2-(2-(7-溴-6-氰基-2-甲基-5-氧代-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-4(5H)-乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.2g，0.00026mol)加入到N-甲基吡咯烷酮(5.0mL)中的溶液中添加1-甲基哌嗪(0.14mL，0.0013mol)，然后添加碘化铜(0.005g，0.000030mol)和1,10-菲罗啉(0.009g，0.000050mol)，并在150℃下加热反应混合物4小时。反应完成后，用水稀释混合物，并用乙酸乙酯萃取，收集有机相，用无水Na2SO4干燥，真空浓缩，得到目标产物0.15g粗品。ESI-MS m/z:793.2[M+H]+。To a solution of tert-butyl 7-(5-chloro-2-(2-(7-bromo-6-cyano-2-methyl-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazoline-4(5H)-ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (0.2 g, 0.00026 mol) in N-methylpyrrolidone (5.0 mL) was added 1-methylpiperazine (0.14 mL, 0.0013 mol), followed by copper iodide (0.005 g, 0.000030 mol) and 1,10-phenanthroline (0.009 g, 0.000050 mol), and the reaction mixture was heated at 150°C for 4 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate, the organic phase was collected and washed with anhydrous Na 2 SO 4 and dried, and concentrated in vacuo to obtain 0.15 g crude product of the target product. ESI-MS m/z: 793.2 [M+H] + .
步骤6：7-(5-氯-2-(2-(6-氰基-2-甲基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)-[1,2,4]三唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 6: Preparation of 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid
将7-(5-氯-2-(2-(6-氰基-2-甲基-7-(4-甲基哌嗪-1-基)-5-氧代-8-(三氟甲基)-[1,2,4]三氮唑并[1,5-a]喹唑啉-4(5H)-基)乙氧基)苯基)-5-甲基噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.15g，0.00019mol)加入到二氯甲烷(3.0mL)中，在0℃下添加2,2,2-三氟乙酸(3.0mL)，并在室温下搅拌反应混合物8h。完成后，反应混合物在减压下浓缩得到粗化合物，制备得0.030g纯品。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.99(s,1H),7.59(d,J＝7.9Hz,1H),7.43–7.31(m,3H),4.48(s,2H),4.35(s,2H),3.57(s,4H),2.69(s,4H),2.50(s,3H),2.26(s,3H),2.13(s,3H).ESI-MS m/z:737.2[M+H]+。Tert-butyl 7-(5-chloro-2-(2-(6-cyano-2-methyl-7-(4-methylpiperazin-1-yl)-5-oxo-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazolin-4(5H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (0.15 g, 0.00019 mol) was added to dichloromethane (3.0 mL), 2,2,2-trifluoroacetic acid (3.0 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 8 h. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude compound, and 0.030 g of pure product was prepared. 1 H NMR (400MHz, DMSO-d 6 )δ8.24(s,1H),7.99(s,1H),7.59(d,J＝7.9Hz,1H),7.43–7.31(m,3H),4.48(s,2H),4 .35(s,2H),3.57(s,4H),2.69(s,4H),2.50(s,3H),2.26(s,3H),2.13(s,3H).ESI-MS m/z:737.2[M+H] + .
实施例23：7-(5-氯-2-(3-(6-氰基-7-(4-环丙基哌嗪-1-基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(甲基磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺
Example 23: 7-(5-chloro-2-(3-(6-cyano-7-(4-cyclopropylpiperazin-1-yl)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
步骤1：7-(5-氯-2-(3-(6-氰基-7-氟-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(甲基磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 1: Preparation of 7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
7-(2-(3-溴丙-1-炔-1-基)-5-氯苯基)-N-(甲磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺(240mg，0.5mmol)和7-氟-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈(120mg,0.5mmol)置于50mL单颈瓶中。加入溶剂N,N-二甲基甲酰胺(5mL)和碳酸钾(138mg，1mmol),30℃搅拌3小时。反应结束后，直接硅胶柱层析，得目标分子。ESI-MS m/z:646.1[M+H]+。7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide (240 mg, 0.5 mmol) and 7-fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (120 mg, 0.5 mmol) were placed in a 50 mL single-necked bottle. Solvent N,N-dimethylformamide (5 mL) and potassium carbonate (138 mg, 1 mmol) were added and stirred at 30°C for 3 hours. After the reaction was completed, the target molecule was obtained by direct silica gel column chromatography. ESI-MS m/z: 646.1[M+H] + .
步骤2：7-(5-氯-2-(3-(6-氰基-7-(4-环丙基哌嗪-1-基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶 -4(5H)-基)-1-丙炔基)苯基)-N-(甲基磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 2: 7-(5-chloro-2-(3-(6-cyano-7-(4-cyclopropylpiperazin-1-yl)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidine Preparation of 4-(5H)-1-propynyl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
7-(5-氯-2-(3-(6-氰基-7-氟-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(甲基磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺(150mg，0.23mmol)和环丙基哌嗪(38mg,0.3mmol)置于50mL单颈瓶中。加入溶剂N-甲基吡咯烷酮(2mL)和N,N-二异丙基乙胺(138mg，1mmol),30℃搅拌过夜。反应结束后，制备色谱纯化，得标题分子。7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide (150 mg, 0.23 mmol) and cyclopropylpiperazine (38 mg, 0.3 mmol) were placed in a 50 mL single-necked bottle. Solvent N-methylpyrrolidone (2 mL) and N,N-diisopropylethylamine (138 mg, 1 mmol) were added and stirred at 30°C overnight. After the reaction was completed, the title molecule was obtained by preparative chromatography purification.
1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.82–8.59(m,2H),7.90–7.54(m,4H),5.46(s,1H),4.87(s,2H),3.66(s,5H),2.92–2.71(m,6H),2.25(s,2H),1.79(s,1H),1.30(s,1H),0.59–0.40(m,4H).ESI-MS m/z:752.1[M+H]+。 1 H NMR (400MHz, DMSO-d 6 )δ9.22(s,1H),8.82–8.59(m,2H),7.90–7.54(m,4H),5.46(s,1H),4.87(s,2H),3.66(s, 5H),2.92–2.71(m,6H),2.25(s,2H),1.79(s,1H),1.30(s,1H),0.59–0.40(m,4H).ESI-MS m/z:752.1[M+H] + .
参考实施例23的合成方法，制备得到表2中实施例24-30的化合物。Referring to the synthetic method of Example 23, the compounds of Examples 24-30 in Table 2 were prepared.
表2


Table 2


实施例31：7-(5-氯-2-(3-(6-氰基-2-甲基-7-((1-(3,3-二氟环丁烷基)哌啶-4-基)(N-甲基)氨基)-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸
Example 31: 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
步骤1：7-(5-氯-2-(3-(6-氰基-7-氟-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1- 基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 1: 7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl Preparation of tert-butyl (1,2-dimethyl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
将7-氟-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈(15.1g,0.062mol)和碳酸钾(11.3g,0.082mol)加入反应瓶中，加入N,N-二甲基甲酰胺(60mL)室温搅拌10min，加入7-(5-氯-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(19.1g,0.041mol)升温至30℃反应3h。反应完毕，加饱和氯化钠，乙酸乙酯萃取，水反洗，无水硫酸钠干燥，硅胶柱层析得产物15g和乙酸乙酯加少量二氯甲烷打浆得产物9g。收率：94.1％。ESI-MS m/z:625.1[M+H]+。7-Fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (15.1 g, 0.062 mol) and potassium carbonate (11.3 g, 0.082 mol) were added to a reaction flask, N,N-dimethylformamide (60 mL) was added and stirred at room temperature for 10 min, 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid tert-butyl ester (19.1 g, 0.041 mol) was added and the temperature was raised to 30°C for 3 h. After the reaction was completed, saturated sodium chloride was added, ethyl acetate was extracted, backwashed with water, dried over anhydrous sodium sulfate, and silica gel column chromatography was performed to obtain 15 g of the product and ethyl acetate was added with a small amount of dichloromethane to obtain 9 g of the product. Yield: 94.1%. ESI-MS m/z: 625.1 [M+H] + .
步骤2：7-(5-氯-2-(3-(6-氰基-2-甲基-7-((1-(3,3-二氟环丁烷基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
将7-(5-氯-2-(3-(6-氰基-7-氟-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(15g,0.024mol)溶于N-甲基吡咯烷酮(100mL)，依次加入1-(3,3-二氟环丁基)-N-甲基哌啶-4-胺(9.8g,0.048mol)和N,N-二异丙基乙胺(14mL,0.072mol)。加毕置于50℃反应12h。反应完毕后，加水，乙酸乙酯萃取，水反洗，无水硫酸钠干燥，硅胶柱层析得产物10g。收率：52.6％。ESI-MS m/z:809.3[M+H]+。Dissolve tert-butyl 7-(5-chloro-2-(3-(6-cyano-7-fluoro-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate (15g, 0.024mol) in N-methylpyrrolidone (100mL), and add 1-(3,3-difluorocyclobutyl)-N-methylpiperidin-4-amine (9.8g, 0.048mol) and N,N-diisopropylethylamine (14mL, 0.072mol) in sequence. After addition, place at 50℃ to react for 12h. After the reaction is completed, add water, extract with ethyl acetate, backwash with water, dry over anhydrous sodium sulfate, and chromatograph on a silica gel column to obtain 10g of the product. Yield: 52.6%. ESI-MS m/z: 809.3 [M+H] + .
步骤3：7-(5-氯-2-(3-(6-氰基-2-甲基-7-((1-(3,3-二氟环丁烷基)哌啶-4-基)(N-甲基)氨基)-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 3: Preparation of 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
7-(5-氯-2-(3-(6-氰基-2-甲基-7-((1-(3,3-二氟环丁烷基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(100mg，0.00012mol)置于50mL单颈瓶中，加入二氯甲烷5mL和三氟乙酸2mL，室温搅拌过夜。反应结束后，减压浓缩，碳酸氢钠水溶液调节PH至中性，乙酸乙酯萃取，有机相浓缩后，经制备色谱纯化，得到标题化合物。1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.58(d,J＝4.6Hz,1H),8.50(s,1H),7.59(d,J＝8.3Hz,1H),7.49(dd,J＝8.3,1.3Hz,1H),7.41(s,1H),7.36(d,J＝4.6Hz,1H),5.33(s,1H),4.76(s,2H),4.41(s,1H),3.21(s,3H),2.99(s,2H),2.71(s,3H),2.46(s,2H),2.30(s,3H),2.08(s,2H),1.98(s,4H).ESI-MS m/z:753.2[M+H]+。Tert-butyl 7-(5-chloro-2-(3-(6-cyano-2-methyl-7-((1-(3,3-difluorocyclobutane)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate (100 mg, 0.00012 mol) was placed in a 50 mL single-necked bottle, 5 mL of dichloromethane and 2 mL of trifluoroacetic acid were added, and stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, the pH was adjusted to neutral with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparative chromatography to obtain the title compound. 1 H NMR (400MHz, CDCl 3 )δ9.26(s,1H),8.58(d,J＝4.6Hz,1H),8.50(s,1H),7.59(d,J＝8.3Hz,1H),7.49(dd,J＝8.3,1.3Hz,1H),7.41(s,1H),7.36(d,J＝4.6Hz,1H), 5.33(s,1H),4.76(s,2H),4.41(s,1H),3.21(s,3H),2.99(s,2H),2.71(s,3H),2.46(s,2H),2.30(s,3H),2.08(s,2H),1.98(s,4H).ESI-MS m/z:753.2[M+H] + .
参考实施例23和实施例31的合成方法，制备得到表3中实施例32-54的化合物。Referring to the synthetic methods of Example 23 and Example 31, the compounds of Examples 32-54 in Table 3 were prepared.
表3











table 3











实施例69：4-(3-(2-(3-(2H-四氮唑-5-基)噻吩并[3,2-b]吡啶-7-基)-4-氯苯基)丙-2-炔-1-基)-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈
Example 69: 4-(3-(2-(3-(2H-tetrazolyl-5-yl)thieno[3,2-b]pyridin-7-yl)-4-chlorophenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
步骤1：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(2-氰乙基)噻吩并[3,2-b]吡啶-3-甲酰胺的制备
Step 1: Preparation of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboxamide
将7-(5-氯-2-(3-(6-氰基-7-(1-(3,3-二氟环丁基)哌啶-4-基甲基氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸(0.10g,0.13mmol)溶于二氯甲烷(1.5mL)中，然后依次加入3-氨基丙腈(0.01g,0.20mmol)、N,N-二异丙基乙胺(0.05g,0.40mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.06g,0.16mmol)。加毕，室温反应2h。 反应完毕，用水洗涤有机相，无水硫酸钠干燥，旋干得产物，未纯化直接投下一步。ESI-MS m/z:805.2[M+H]+。7-(5-chloro-2-(3-(6-cyano-7-(1-(3,3-difluorocyclobutyl)piperidin-4-ylmethylamino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid (0.10 g, 0.13 mmol) was dissolved in dichloromethane (1.5 mL), and then 3-aminopropionitrile (0.01 g, 0.20 mmol), N,N-diisopropylethylamine (0.05 g, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.06 g, 0.16 mmol) were added in sequence. After addition, the reaction was carried out at room temperature for 2 h. After the reaction was completed, the organic phase was washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain the product, which was directly used for the next step without purification. ESI-MS m/z: 805.2 [M+H] + .
步骤2：(Z)-7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(2-氰基乙基)噻吩并[3,2-b]吡啶-3-碳酰亚胺酰氯的制备
Step 2: Preparation of (Z)-7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboximidoyl chloride
将五氯化磷(0.04g,0.19mmol)加入反应瓶中，加入7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(2-氰乙基)噻吩并[3,2-b]吡啶-3-甲酰胺(0.10g,0.13mmol)和吡啶(0.06g,0.75mmol)的二氯甲烷(4mL)溶液，升温至40℃反应3h，45℃反应2h。即得标题化合物。Phosphorus pentachloride (0.04 g, 0.19 mmol) was added to a reaction flask, and a dichloromethane (4 mL) solution of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboxamide (0.10 g, 0.13 mmol) and pyridine (0.06 g, 0.75 mmol) was added, and the mixture was heated to 40°C for 3 h and then at 45°C for 2 h. The title compound was obtained.
步骤3：4-(3-(4-氯-2-(3-(1-(2-氰基乙基)-1H-四氮唑-5-基)噻吩并[3,2-b]吡啶-7-基)苯基)丙-2-炔-1-基)-7-((1-(3,3-二氟环丁基)哌啶-4-基(N-甲基)氨基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈的制备
Step 3: Preparation of 4-(3-(4-chloro-2-(3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)phenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
将(Z)-7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(2-氰基乙基)噻吩并[3,2-b]吡啶-3-碳酰亚胺酰氯(0.10g,0.13mmol)的反应液恢复至室温，加入叠氮基三甲基硅烷(0.06g,0.50mmol)，加毕室温反应3h。反应完毕，加入饱和碳酸钠淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，旋干得产物，未纯化直投下一步。The reaction solution of (Z)-7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(2-cyanoethyl)thieno[3,2-b]pyridine-3-carboximidoyl chloride (0.10 g, 0.13 mmol) was restored to room temperature, and trimethylsilyl azide (0.06 g, 0.50 mmol) was added, and the reaction was continued at room temperature for 3 h. After the reaction was completed, saturated sodium carbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the product was dried by spin drying and directly used for the next step without purification.
步骤4：4-(3-(2-(3-(2H-四氮唑-5-基)噻吩并[3,2-b]吡啶-7-基)-4-氯苯基)丙-2-炔-1-基)-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈的制备
Step 4: Preparation of 4-(3-(2-(3-(2H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)-4-chlorophenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
将4-(3-(4-氯-2-(3-(1-(2-氰乙基)-1H-四氮唑-5-基)噻吩并[3,2-b]吡啶-7-基)苯基)丙-2-炔-1-基)-7-((1-(3,3-二氟环丁基)哌啶-4-基(甲基)氨基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-甲腈(0.10g,0.10mmol)溶于四氢呋喃(2mL)中，加入2M氢氧化钠(0.16g,2mL)水溶液，加毕室温反应1h。反应完毕，加入4M盐酸调pH至2，二氯甲烷萃取，无水硫酸钠干燥，旋干送分离平台纯化，得产物2mg，纯度97％。ESI-MS m/z:777.3[M+H]+。1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.69(d,J＝4.0Hz,1H),8.51(s,1H),7.59(d,J＝8.3Hz,1H),7.50(d,J＝8.2Hz,1H),7.42(s,1H),7.34(d,J＝4.2Hz,1H),5.34(s,1H),4.73(s,2H),4.37(s,1H),3.20(s,3H),3.00(d,J＝8.7Hz,2H),2.71(s,4H),2.46(s,2H),2.25(s,3H),2.13–2.06(m,2H),1.99(s,4H).4-(3-(4-chloro-2-(3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)phenyl)prop-2-yn-1-yl)-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl(methyl)amino)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (0.10 g, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and a 2M aqueous solution of sodium hydroxide (0.16 g, 2 mL) was added. The mixture was reacted at room temperature for 1 h. After the reaction was completed, 4M hydrochloric acid was added to adjust the pH to 2, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then spin-dried and sent to a separation platform for purification to obtain 2 mg of the product with a purity of 97%. ESI-MS m/z:777.3[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ8.94(s,1H),8.69(d,J＝4.0Hz,1H),8.51(s,1H),7.59(d,J＝8.3Hz,1H),7.50(d,J＝8.2Hz,1H),7.42(s,1H),7.34(d,J＝4.2Hz,1H),5.34(s ,1H),4.73(s,2H),4.37(s,1H),3.20(s,3H),3.00(d,J＝8.7Hz,2H),2 .71(s,4H),2.46(s,2H),2.25(s,3H),2.13–2.06(m,2H),1.99(s,4H).
实施例70：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(环丙基磺酰基)噻吩并[3,2-b]吡啶-3-甲酰胺
Example 70: 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(cyclopropylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide
将7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸(80mg,0.106mmol)置于0℃冰浴下加入2mL二氯甲烷溶解，依次加入环丙基磺酰胺(26mg，0.212mmol)，EDCI(40.7mg，0.212mmol)，dmap(25mg，0.212mmol)，置于室温下搅拌过夜。得标题化合物。ESI-MS m/z:856.3[M+H]+。1H NMR(400MHz,CDCl3)δ12.57(s,1H),9.27(s,1H),8.63(d,J＝4.7Hz,1H),8.55(s,1H),7.58(d,J＝8.3Hz,1H),7.48(d,J＝8.3Hz,1H),7.41(s,1H),7.35(d,J＝4.7Hz,1H),5.21(s,1H),4.78(s,2H),4.39(s,1H),3.20(s,3H),2.98(d,J＝9.7Hz,2H),2.80–2.55(m,5H),2.50-2.35(m,2H),2.28(s,3H),2.14–1.79(m,6H),1.25–1.14(m,3H).7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid (80 mg, 0.106 mmol) was placed in an ice bath at 0°C, 2 mL of dichloromethane was added to dissolve, cyclopropylsulfonamide (26 mg, 0.212 mmol), EDCI (40.7 mg, 0.212 mmol), dmap (25 mg, 0.212 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. The title compound was obtained. ESI-MS m/z: 856.3[M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ12.57(s,1H),9.27(s,1H),8.63(d,J＝4.7Hz,1H),8.55(s,1H),7.58(d,J＝8 .3Hz,1H),7.48(d,J＝8.3Hz,1H),7.41(s,1H),7.35(d,J＝4.7Hz,1H),5.21(s, 1H),4.78(s,2H),4.39(s,1H),3.20(s,3H),2.98(d,J＝9.7Hz,2H),2.80–2.55 (m,5H),2.50-2.35(m,2H),2.28(s,3H),2.14–1.79(m,6H),1.25–1.14(m,3H).
实施例71：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)-N-(N，N-二甲基氨基磺酰基)噻吩并[3,2-b]吡啶 -3-甲酰胺
Example 71: 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)-N-(N,N-dimethylaminosulfonyl)thieno[3,2-b]pyridine -3-Formamide
合成方法同实施例70。不同的是N,N-二甲基磺酰胺代替环丙基磺酰胺。得标题化合物。ESI-MS m/z:859.3[M+H]+。1H NMR(400MHz,CDCl3)δ12.42(s,1H),9.27(s,1H),8.64(d,J＝4.7Hz,1H),8.56(s,1H),7.58(d,J＝8.3Hz,1H),7.47(d,J＝8.3Hz,1H),7.42(s,1H),7.36(d,J＝4.7Hz,1H),5.24(s,1H),4.79(s,2H),4.38(s,1H),3.19(s,3H),3.12(s,6H),3.03(s,1H),2.97(d,J＝10.3Hz,2H),2.69(s,3H),2.44(s,3H),2.28(s,3H),2.02(d,J＝10.2Hz,4H).The synthesis method is the same as that of Example 70. The difference is that N,N-dimethylsulfonamide replaces cyclopropylsulfonamide. The title compound is obtained. ESI-MS m/z: 859.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ12.42(s,1H),9.27(s,1H),8.64(d,J＝4.7Hz,1H),8.56(s,1H),7.58(d,J＝8 .3Hz,1H),7.47(d,J＝8.3Hz,1H),7.42(s,1H),7.36(d,J＝4.7Hz,1H),5.24(s,1 H),4.79(s,2H),4.38(s,1H),3.19(s,3H),3.12(s,6H),3.03(s,1H),2.97(d, J＝10.3Hz,2H),2.69(s,3H),2.44(s,3H),2.28(s,3H),2.02(d,J＝10.2Hz,4H).
实施例72：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸
Example 72: 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
步骤1：1-(3,3-二氟环丁基)哌啶-4-酮的制备
Step 1: Preparation of 1-(3,3-difluorocyclobutyl)piperidin-4-one
称取碳酸钠(12g,0.113mol)于三颈瓶中，通入氩气保护，一次加入1,5-二氯戊-3-酮(5g，0.0322mol)，3,3-二氟环丁烷-1-胺(3.45g,0.0322mol)，加入甲醇50mL，75℃加热搅拌回流。反应完毕，制砂，过硅胶层析柱，得到产物1.3g。ESI-MS m/z:190.1[M+H]+。Weigh sodium carbonate (12g, 0.113mol) in a three-necked flask, pass argon gas into it, add 1,5-dichloropentan-3-one (5g, 0.0322mol), 3,3-difluorocyclobutane-1-amine (3.45g, 0.0322mol) at a time, add 50mL of methanol, heat and stir under reflux at 75℃. After the reaction is completed, sand is made and passed through a silica gel chromatography column to obtain 1.3g of the product. ESI-MS m/z: 190.1[M+H] + .
步骤2：1-(3,3-二氟环丁基)哌啶-4-醇的制备
Step 2: Preparation of 1-(3,3-difluorocyclobutyl)piperidin-4-ol
称取硼氢化钠(0.9g,24mmol)于反应瓶中，加入甲醇(10mL)溶解，将步骤1的产物(1.3g,6.87mmol)加入反应瓶中，再次加入甲醇(10mL)溶解，0℃冰浴下反应。反应完毕后，加入水(10mL)淬灭，加入等体积的乙酸乙酯萃取三次，合并有机相，加入无水硫酸钠干燥，抽滤，旋干后抽油泵得产物3.8g。ESI-MS m/z:192.1[M+H]+。Weigh sodium borohydride (0.9 g, 24 mmol) in a reaction flask, add methanol (10 mL) to dissolve, add the product of step 1 (1.3 g, 6.87 mmol) to the reaction flask, add methanol (10 mL) again to dissolve, and react in an ice bath at 0°C. After the reaction is completed, add water (10 mL) to quench, add an equal volume of ethyl acetate to extract three times, combine the organic phases, add anhydrous sodium sulfate to dry, filter, spin dry, and pump to obtain 3.8 g of product. ESI-MS m/z: 192.1 [M+H] + .
步骤3：7-((1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-腈的制备
Step 3: Preparation of 7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile
称取1-(3,3-二氟环丁基)哌啶-4-醇(0.5g,2.6mmol)于反应瓶中，加入N,N-二甲基甲酰胺(10mL)溶解，通入氩气保护，加入钠氢(0.1g,2.6mmol)，反应5min，加入7-氟-2-甲基-5-氧代-4,5-二氢吡唑[1,5-a]吡啶并[4,3-e]嘧啶-6-腈(0.3g,1.3mmol)，室温下反应。反应结束后，加入等体积水淬灭，加入氯化铵固体调节pH值＝7，加入等体积的乙酸乙酯萃取三次，合并有机相，加入无水硫酸钠干燥，旋蒸，得产物0.81g。ESI-MS m/z:415.2[M+H]+。Weigh 1-(3,3-difluorocyclobutyl)piperidin-4-ol (0.5 g, 2.6 mmol) into a reaction bottle, add N,N-dimethylformamide (10 mL) to dissolve, pass argon protection, add sodium hydrogen (0.1 g, 2.6 mmol), react for 5 min, add 7-fluoro-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (0.3 g, 1.3 mmol), and react at room temperature. After the reaction is completed, add an equal volume of water to quench, add ammonium chloride solid to adjust the pH value to 7, add an equal volume of ethyl acetate to extract three times, combine the organic phases, add anhydrous sodium sulfate to dry, and rotary evaporate to obtain 0.81 g of the product. ESI-MS m/z: 415.2[M+H] + .
步骤4：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate
称取7-((1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代-4,5-二氢吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-6-腈(0.5g,1.2mmol)，于反应瓶中，加入N,N-二甲基甲酰胺(10mL)溶解，加入6-(2-(溴乙炔基)-5-氯苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.26g,0.56mmol)，和碳酸钾(0.166g,1.2mmol)，25℃下反应。反应完毕后，加入氯化铵固体，调节pH值＝7，加入等体积的乙酸乙酯萃取三次，合并有机相，加入无水硫酸钠干燥。制砂装柱，过硅胶层析柱，旋蒸，得产物0.1g。ESI-MS m/z:796.2[M+H]+。Weigh 7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[4,3-e]pyrimidine-6-carbonitrile (0.5 g, 1.2 mmol) in a reaction bottle, add N,N-dimethylformamide (10 mL) to dissolve, add 6-(2-(bromoethynyl)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylic acid tert-butyl ester (0.26 g, 0.56 mmol), and potassium carbonate (0.166 g, 1.2 mmol), and react at 25°C. After the reaction is complete, add solid ammonium chloride to adjust the pH value to 7, add an equal volume of ethyl acetate to extract three times, combine the organic phases, add anhydrous sodium sulfate to dry. Load the column with sand making, pass through a silica gel chromatography column, and rotary evaporate to obtain 0.1 g of the product. ESI-MS m/z:796.2[M+H] + .
步骤5：6-(5-氯-2-(3-(6-氰基-7-(1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸的制备
Step 5: Preparation of 6-(5-chloro-2-(3-(6-cyano-7-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
将7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)氧基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯(0.1g,0.1mmol)，用DCM(6mL)溶解，加入三氟乙酸(3mL)，室温下反应。反应完毕，制备HPLC纯化，得淡黄色固体20mg。ESI-MS m/z:740.2[M+H]+。1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.61(s,1H),8.45(s,1H),7.59(d,J＝8.2Hz,1H),7.50(d,J＝8.1Hz,1H),7.40(s,1H),7.36(s,1H),5.46(s,1H),5.36(s,1H),4.75(s,2H),2.71(s,4H),2.47(s,4H),2.31(s,3H),2.11(s,4H),1.25(s,1H).7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid tert-butyl ester (0.1 g, 0.1 mmol) was dissolved in DCM (6 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature. After the reaction was completed, the mixture was purified by preparative HPLC to obtain 20 mg of a light yellow solid. ESI-MS m/z: 740.2[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ9.28(s,1H),8.61(s,1H),8.45(s,1H),7.59(d,J＝8.2Hz,1H),7.50(d,J＝8.1Hz,1H),7.40(s,1H),7.36(s, 1H),5.46(s,1H),5.36(s,1H),4.75(s,2H),2.71(s,4H),2.47(s,4H),2.31(s,3H),2.11(s,4H),1.25(s,1H).
实施例73：7-(5-氯-2-(3-(6-氰基-7-((1-环丙基哌啶-4-基)氧基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸
Example 73: 7-(5-chloro-2-(3-(6-cyano-7-((1-cyclopropylpiperidin-4-yl)oxy)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid
合成方法同实施例70。不同是用1-环丙基哌啶-4-醇代替1-(3,3-二氟环丁基)哌啶-4-醇。得标题化合物。ESI-MS m/z:690.2[M+H]+。1H NMR(400MHz,CDCl3)δ12.20(s,1H),9.30(s,1H),8.57(s,1H),8.47(s,1H),7.59(d,J＝8.3Hz,1H),7.52(d,J＝7.8Hz,1H),7.38(s,1H),7.28(d,J＝4.5Hz,1H),5.50(s, 1H),4.72(s,2H),3.67(s,1H),3.58(s,2H),2.61(d,J＝11.5Hz,2H),2.44(m,4H),2.34(s,3H),1.37(s,2H),0.87(d,J＝6.0Hz,2H).The synthesis method is the same as that of Example 70. The difference is that 1-cyclopropylpiperidin-4-ol is used instead of 1-(3,3-difluorocyclobutyl)piperidin-4-ol. The title compound is obtained. ESI-MS m/z: 690.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 12.20 (s, 1H), 9.30 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J = 4.5 Hz, 1H), 5.50 (s, 1H),4.72(s,2H),3.67(s,1H),3.58(s,2H),2.61(d,J＝11.5Hz,2H),2.44(m,4H),2.34(s,3H),1.37(s,2H),0.87(d,J＝6.0Hz,2H).
实施例74：4-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-d]嘧啶-7-甲酸
Example 74: 4-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid
步骤1:7-溴-4-(5-氯-2-甲氧基苯基)噻吩并[3,2-d]嘧啶的制备
Step 1: Preparation of 7-bromo-4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine
氩气保护下，向装有磁力搅拌子的双颈瓶中加入7-溴-4-氯噻吩[3,2-d]嘧啶(10g,1mmol),5-氯-2-甲氧基苯基硼酸(9g，1.2mmol),碳酸铯(33g,2.5mmol)和四三苯基膦钯(932mg，0.02mmol),随后加入二氧六环/水(100mL/10mL),置换气体3次。反应在40℃下搅拌4h。TLC(PE：EA＝4：1)监测。待反应结束后，将反应体系乙酸乙酯(3×100mL)萃取，收集有机相，无水Na2SO4干燥，真空浓缩，二氯甲烷打浆，得到白色目标化合物12g。ESI-MS m/z:354.9[M+H]+。Under argon protection, 7-bromo-4-chlorothiophene[3,2-d]pyrimidine (10 g, 1 mmol), 5-chloro-2-methoxyphenylboronic acid (9 g, 1.2 mmol), cesium carbonate (33 g, 2.5 mmol) and tetrakistriphenylphosphine palladium (932 mg, 0.02 mmol) were added to a double-necked flask equipped with a magnetic stirrer, followed by the addition of dioxane/water (100 mL/10 mL) and replacement of the gas three times. The reaction was stirred at 40°C for 4 h. TLC (PE:EA=4:1) was used for monitoring. After the reaction was completed, the reaction system was extracted with ethyl acetate (3×100 mL), the organic phase was collected, dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and slurried with dichloromethane to obtain 12 g of the white target compound. ESI-MS m/z: 354.9[M+H] + .
步骤2:4-(5-氯-2-甲氧基苯基)噻吩并[3,2-d]嘧啶-7-甲酸甲酯的制备
Step 2: Preparation of methyl 4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
化合物7-溴-4-(5-氯-2-甲氧基苯基)噻吩并[3,2-d]嘧啶(12g，0.02008mol)溶于二甲基亚砜(100mL)中，冷却条件下加入1,4-双(二苯基膦)丁烷(3.2g，0.004016mol),醋酸钯(1.45g，0.004016mol)。并加入甲醇(100mL)一氧化碳气球换气保护与搅拌条件缓慢加入三乙胺(15.16g，0.1004mol)，80℃回流反应8h，反应结束，旋蒸除去甲醇，加水稀释，水和乙酸乙酯萃取，有机相浓缩后的油状物，柱层析，20％EA/PE得到目标化合物80g。ESI-MS m/z:335.2[M+H]+。 The compound 7-bromo-4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine (12 g, 0.02008 mol) was dissolved in dimethyl sulfoxide (100 mL), and 1,4-bis(diphenylphosphino)butane (3.2 g, 0.004016 mol) and palladium acetate (1.45 g, 0.004016 mol) were added under cooling conditions. Methanol (100 mL) was added, and triethylamine (15.16 g, 0.1004 mol) was slowly added under the protection of carbon monoxide balloon ventilation and stirring conditions. The mixture was refluxed at 80°C for 8 h. After the reaction was completed, methanol was removed by rotary evaporation, diluted with water, extracted with water and ethyl acetate, and the oily substance after organic phase concentration was subjected to column chromatography and 20% EA/PE to obtain 80 g of the target compound. ESI-MS m/z: 335.2[M+H] + .
步骤3:4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸甲酯的制备
Step 3: Preparation of methyl 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
称取4-(5-氯-2-甲氧基苯基)噻吩并[3,2-d]嘧啶-7-甲酸甲酯(10g，29.85mmol)溶于二氯甲烷(100mL)中，加入三溴化硼二氯甲烷溶液(10g三溴化硼溶于10mL二氯甲烷中)。冰浴条件下缓慢滴加，反应完全后用冰水淬灭体系，浓缩后乙酸乙酯萃取，浓缩得到目标化合物6g。ESI-MS m/z:321.1[M+H]+。Weigh 4-(5-chloro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester (10 g, 29.85 mmol) and dissolve it in dichloromethane (100 mL). Add boron tribromide dichloromethane solution (10 g boron tribromide dissolved in 10 mL dichloromethane). Slowly add dropwise under ice bath conditions. After the reaction is complete, quench the system with ice water, concentrate and extract with ethyl acetate. Concentrate to obtain 6 g of the target compound. ESI-MS m/z: 321.1 [M+H] + .
步骤4:4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸的制备
Step 4: Preparation of 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid
化合物4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸甲酯(5g，15.6mmol)溶于甲醇(60mL)中，加入氢氧化锂饱和水溶液6mL。室温条件下搅拌反应，反应完全后用水稀释，盐酸溶液调节PH至3-4，二氯甲烷萃取，浓缩得到标题化合物4g。ESI-MS m/z:306.9[M+H]+。Compound 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester (5g, 15.6mmol) was dissolved in methanol (60mL), and 6mL of saturated aqueous lithium hydroxide solution was added. The reaction was stirred at room temperature, and after the reaction was complete, it was diluted with water, the pH was adjusted to 3-4 with hydrochloric acid solution, extracted with dichloromethane, and concentrated to obtain 4g of the title compound. ESI-MS m/z: 306.9[M+H] + .
步骤5:4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸叔丁酯的制备
Step 5: Preparation of tert-butyl 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate
将4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸(2.9g,9.5mmol)溶于二碳酸二叔丁酯(10mL)中，加入三乙胺(1.33g,13.1mmol)，置于80℃反应48h。反应完毕，加入乙酸乙酯，水洗，有机相浓缩，无水硫酸钠干燥，硅胶柱层析得产物1.5g。ESI-MS m/z:363.1[M+H]+。Dissolve 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid (2.9 g, 9.5 mmol) in di-tert-butyl dicarbonate (10 mL), add triethylamine (1.33 g, 13.1 mmol), and react at 80°C for 48 h. After the reaction is complete, add ethyl acetate, wash with water, concentrate the organic phase, dry over anhydrous sodium sulfate, and chromatograph on a silica gel column to obtain 1.5 g of the product. ESI-MS m/z: 363.1[M+H] + .
步骤6:7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)噻吩并[3,2-d]嘧啶-3-甲酸叔丁酯的制备
Step 6: Preparation of tert-butyl 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-d]pyrimidine-3-carboxylate
将4-(5-氯-2-羟基苯基)噻吩并[3,2-d]嘧啶-7-甲酸叔丁酯(1.00g,2.77mmol)溶于二氯甲烷(20mL)中，加入吡啶(0.44g,5.54mmol)。于0℃下缓慢加入三氟甲磺酸酐(1.18g,4.16mmol)，加毕移置室温反应2h。反应完毕后，加水，二氯甲烷萃取，水反洗，无水硫酸钠干燥，硅胶柱层析得产物0.96g。ESI-MS m/z:495.0[M+H]+。Dissolve tert-butyl 4-(5-chloro-2-hydroxyphenyl)thieno[3,2-d]pyrimidine-7-carboxylate (1.00 g, 2.77 mmol) in dichloromethane (20 mL), add pyridine (0.44 g, 5.54 mmol). Slowly add trifluoromethanesulfonic anhydride (1.18 g, 4.16 mmol) at 0°C, and react at room temperature for 2 h. After the reaction is completed, add water, extract with dichloromethane, backwash with water, dry with anhydrous sodium sulfate, and chromatograph on a silica gel column to obtain 0.96 g of the product. ESI-MS m/z: 495.0[M+H] + .
步骤7:4-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)噻吩并[3,2-d]嘧啶-7-甲酸的制备
Step 7: Preparation of 4-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-d]pyrimidine-7-carboxylic acid
后续反应参照实施例31的合成，不同的是用7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)噻吩并[3,2-d]嘧啶-3-甲酸叔丁酯替换7-(5-氯-2-(((三氟甲基)磺酰基)氧基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯。得标题化合物。ESI-MS m/z:753.8[M+H]+.1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.57(d,J＝4.4Hz,1H),8.50(s,1H),7.58(d,J＝8.2Hz,1H),7.53–7.46(m,1H),7.33(d,J＝3.9Hz,1H),5.38(s,1H),4.74(s,2H),4.44(d,J＝9.3Hz,1H),3.19(s,3H),2.86–2.54(m,4H),2.31(s,3H),2.20–1.97(m,4H),1.72(m,4H),1.26(s,1H).The subsequent reaction was carried out in accordance with the synthesis of Example 31, except that tert-butyl 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-d]pyrimidine-3-carboxylate was used to replace tert-butyl 7-(5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate. The title compound was obtained. ESI-MS m/z:753.8[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ9.26(s,1H),8.57(d,J＝4.4Hz,1H),8.50(s,1H),7.58(d,J＝8.2Hz,1H),7.53–7.46(m,1H),7.33(d,J＝3.9Hz,1H),5.38(s,1H) ,4.74(s,2H),4.44(d,J=9.3Hz,1H),3.19(s,3H),2.86–2.54(m,4H),2.31(s,3H),2.20–1.97(m,4H),1.72(m,4H),1.26(s,1H).
实施例75：7-(2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)-5-氟苯基)噻吩并[3,2-b]吡啶-3-甲酸
Example 75: 7-(2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)-5-fluorophenyl)thieno[3,2-b]pyridine-3-carboxylic acid
合成方法同实施例31。不同是用7-(5-氟-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯代替7-(5-氯-2-(3-溴丙-1-炔-1-基)苯基)噻吩并[3,2-b]吡啶-3-甲酸叔丁酯。得标题化合物。ESI-MS m/z:737.2[M+H]+。1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.58(d,J＝4.6Hz,1H),8.51(s,1H),7.71–7.58(m,1H),7.35(s,1H),7.23(s,1H),7.14(d,J＝7.9Hz,1H),5.37(s,1H),4.75(s,2H),4.43(s,1H),3.19(s,3H),3.10(s,2H),2.74(s,3H),2.31(s,3H),2.04(s,4H),1.72(s,4H).The synthesis method is the same as that of Example 31, except that tert-butyl 7-(5-fluoro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate is used instead of tert-butyl 7-(5-chloro-2-(3-bromoprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate. The title compound is obtained. ESI-MS m/z: 737.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ9.26(s,1H),8.58(d,J＝4.6Hz,1H),8.51(s,1H),7.71–7.58(m,1H),7.35(s,1H),7.23(s,1H),7.14(d,J＝7.9Hz,1H) ,5.37(s,1H),4.75(s,2H),4.43(s,1H),3.19(s,3H),3.10(s,2H),2.74(s,3H),2.31(s,3H),2.04(s,4H),1.72(s,4H).
实施例76：7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)苯并[b]噻吩-3-甲酸
Example 76: 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)benzo[b]thiophene-3-carboxylic acid
步骤1:7-溴苯并[b]噻吩-3-甲酰氯的制备
Step 1: Preparation of 7-bromobenzo[b]thiophene-3-carbonyl chloride
将无水三氯化铝(20.8g,156mmol)加入反应瓶中，氩气置换，加入二氯甲烷(80mL)，于0℃下预冷10min，缓慢加入2M草酰氯(78.0mL,156mmol)继续搅拌30min，降温至-25℃缓慢加入7-溴苯并[b]噻吩(9.50g,44.6mmol)的二氯甲烷(40mL)溶液。加毕反应30min，移至室温反应1.5h。反应完毕，过滤，滤液浓缩得产物，未纯化直投下一步。Add anhydrous aluminum chloride (20.8g, 156mmol) to the reaction bottle, replace with argon, add dichloromethane (80mL), precool at 0℃ for 10min, slowly add 2M oxalyl chloride (78.0mL, 156mmol) and continue stirring for 30min, cool to -25℃ and slowly add 7-bromobenzo[b]thiophene (9.50g, 44.6mmol) in dichloromethane (40mL). After the addition, react for 30min, move to room temperature and react for 1.5h. After the reaction is completed, filter and concentrate the filtrate to obtain the product, which is directly used for the next step without purification.
步骤2:7-溴苯并[b]噻吩-3-甲酸甲酯的制备
Step 2: Preparation of methyl 7-bromobenzo[b]thiophene-3-carboxylate
将7-溴苯并[b]噻吩-3-甲酰氯用二氯甲烷(20mL)溶解，于0℃下加入甲醇(60mL)，加毕升温至70℃反应2h。反应完毕，旋干反应液，硅胶柱层析得产物12.0g。ESI-MS m/z:270.9[M+H]+。Dissolve 7-bromobenzo[b]thiophene-3-carbonyl chloride in dichloromethane (20 mL), add methanol (60 mL) at 0°C, and heat to 70°C for 2 h. After the reaction is complete, spin dry the reaction solution, and obtain 12.0 g of the product by silica gel column chromatography. ESI-MS m/z: 270.9 [M+H] + .
步骤3:7-溴苯并[b]噻吩-3-甲酸的制备
Step 3: Preparation of 7-bromobenzo[b]thiophene-3-carboxylic acid
将7-溴苯并[b]噻吩-3-羧酸甲酯(3.0g,11.1mmol)溶于甲醇(30mL)和四氢呋喃(10mL)中，加入氢氧化锂(0.53g,22.2mmol)和水(8mL)，加毕室温反应4h。反应完毕，旋干反应液，调pH值至4-5，抽滤，滤饼干燥得产物2.4g。ESI-MS m/z:254.9[M-H]- Dissolve 7-bromobenzo[b]thiophene-3-carboxylic acid methyl ester (3.0 g, 11.1 mmol) in methanol (30 mL) and tetrahydrofuran (10 mL), add lithium hydroxide (0.53 g, 22.2 mmol) and water (8 mL), and react at room temperature for 4 h. After the reaction is completed, spin dry the reaction solution, adjust the pH value to 4-5, filter, and dry the filter cake to obtain 2.4 g of the product. ESI-MS m/z: 254.9 [MH] -
步骤4:7-溴苯并[b]噻吩-3-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-bromobenzo[b]thiophene-3-carboxylate
将7-溴苯并[b]噻吩-3-羧酸(2.4g,9.34mmol)溶于二碳酸二叔丁酯(9mL)中，加入三乙胺(1.33g,13.1mmol)，置于80℃反应48h。反应完毕，加入乙酸乙酯，水洗，有机相浓缩，无水硫酸钠干燥，硅胶柱层析得产物1.6g。Dissolve 7-bromobenzo[b]thiophene-3-carboxylic acid (2.4 g, 9.34 mmol) in di-tert-butyl dicarbonate (9 mL), add triethylamine (1.33 g, 13.1 mmol), and react at 80°C for 48 h. After the reaction is complete, add ethyl acetate, wash with water, concentrate the organic phase, dry over anhydrous sodium sulfate, and chromatograph on a silica gel column to obtain 1.6 g of the product.
步骤5:7-(5-氯-2-(3-(6-氰基-7-((1-(3,3-二氟环丁基)哌啶-4-基)(N-甲基)氨基)-2-甲基-5-氧代吡唑并[1,5-a]吡啶并[4,3-e]嘧啶-4(5H)-基)丙-1-炔-1-基)苯基)苯并[b]噻吩-3-甲酸的制备
Step 5: Preparation of 7-(5-chloro-2-(3-(6-cyano-7-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(N-methyl)amino)-2-methyl-5-oxopyrazolo[1,5-a]pyrido[4,3-e]pyrimidin-4(5H)-yl)prop-1-yn-1-yl)phenyl)benzo[b]thiophene-3-carboxylic acid
后续合成方法同实施例31。不同是用7-溴苯并[b]噻吩-3-甲酸叔丁酯代替7-溴噻吩并[3,2-b]吡啶-7-甲酸叔丁酯。得标题化合物。ESI-MS m/z:752.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.22(s,1H),8.15–8.11(m,1H),7.67(d,J＝8.4Hz,1H),7.58(d,J＝8.3Hz,1H),7.52(s,1H),7.26(s,2H),5.48(s,1H),4.74(s,2H),4.14(s,1H),3.05(s,4H),2.94(s,3H),2.70(s,3H),2.20(s,4H),1.93–1.81(m,5H).The subsequent synthesis method is the same as that of Example 31, except that tert-butyl 7-bromobenzo[b]thiophene-3-carboxylate is used instead of tert-butyl 7-bromothieno[3,2-b]pyridine-7-carboxylate. The title compound is obtained. ESI-MS m/z: 752.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.09(s,1H),8.22(s,1H),8.15–8.11(m,1H),7.67(d,J＝8.4Hz,1H),7.58(d,J＝8.3Hz,1H),7.52(s,1H),7.26(s, 2H),5.48(s,1H),4.74(s,2H),4.14(s,1H),3.05(s,4H),2.94(s,3H),2.70(s,3H),2.20(s,4H),1.93–1.81(m,5H).
实验例1：化合物生化活性评价Experimental Example 1: Evaluation of biochemical activity of compounds
1.实验方法1. Experimental Methods
1.1药物配制1.1 Drug preparation
根据分子量、纯度及质量，将化合物以DMSO配制成20mM浓度的储存液，用时稀释至所需工 作浓度。According to the molecular weight, purity and quality, the compound was prepared into a 20 mM concentration stock solution in DMSO and diluted to the required working concentration. As concentration.
1.2细胞的复苏1.2 Cell recovery
从液氮罐中取出COLO205细胞冻存管置于37℃水浴锅中，轻轻摇动使其尽快解冻。解冻后取出冻存管，用酒精棉球消毒后旋开盖子，吸出细胞液注入离心管，并加入1mL含血清的完全培养基(1640培养基+10％FBS+1％青链霉素)，混匀后置于离心机中，1000rpm，离心5min。之后弃上清液，加入完全培养基反复吹打至细胞完全吹散、重悬。以适宜浓度接种于培养皿中。置于37℃，5％CO2培养箱内37℃培养。Take out the COLO205 cell cryopreservation tube from the liquid nitrogen tank and place it in a 37°C water bath, gently shake it to thaw as soon as possible. After thawing, take out the cryopreservation tube, disinfect it with an alcohol cotton ball, unscrew the lid, aspirate the cell fluid and inject it into the centrifuge tube, and add 1mL of complete culture medium containing serum (1640 culture medium + 10% FBS + 1% penicillin and streptomycin), mix well and place it in a centrifuge, 1000rpm, centrifuge for 5min. Then discard the supernatant, add complete culture medium and blow repeatedly until the cells are completely blown away and resuspended. Inoculate in a culture dish at an appropriate concentration. Place it in a 37°C, 5% CO2 incubator and culture at 37°C.
1.3细胞的培养和传代1.3 Cell culture and passaging
细胞生长至约80-90％融合，吸弃培养液，加入1mL PBS洗去残余培养基后吸弃，加入1mL胰蛋白酶消化液，37℃消化3-5min，镜下观察细胞伪足回缩变圆但细胞还未大片脱落时，吸弃胰酶并加入2mL完全培养基终止消化，轻轻吹打并收集细胞悬液，1000rpm，离心5min。去除上清，用完全培养基重悬细胞，按所需密度接种于培养皿中，置于37℃、5％CO2培养箱中培养，根据细胞生长情况每2-3天换一次培养液或传代。When the cells grow to about 80-90% confluence, discard the culture medium, add 1mL PBS to wash away the residual culture medium, then discard it, add 1mL trypsin digestion solution, digest at 37℃ for 3-5min, and when the pseudopodia of the cells shrink and become round under the microscope but the cells have not fallen off in large pieces, discard the trypsin and add 2mL complete culture medium to terminate the digestion, gently blow and collect the cell suspension, centrifuge at 1000rpm for 5min. Remove the supernatant, resuspend the cells with complete culture medium, inoculate them in a culture dish at the required density, and culture them in a 37℃, 5% CO2 incubator. Change the culture medium or subculture every 2-3 days according to the growth of the cells.
1.4细胞铺板1.4 Cell plating
(1)Day0：COLO205细胞传代后以每孔6×105个的细胞密度接种于6孔培养板内，每孔含1mL完全培养基，5％CO2培养箱内37℃培养24h。(1) Day 0: After passage, COLO205 cells were seeded in a 6-well culture plate at a cell density of 6×10 5 cells per well, with 1 mL of complete medium per well, and cultured in a 5% CO 2 incubator at 37° C. for 24 h.
1.5给药1.5 Administration
(2)Day 1：24h后，在原来每孔1mL培养基的基础上依次加入1mL含0.5％对照溶剂(DMSO)或300nM药物的培养基，使得最终浓度达到既定浓度，继续放入培养箱孵育4h。药物处理4h后收集细胞于15mL离心管中，离心后弃上清，进行总蛋白提取。(2) Day 1: 24 hours later, 1 mL of culture medium containing 0.5% control solvent (DMSO) or 300 nM drug was added to the original 1 mL culture medium in each well to make the final concentration reach the predetermined concentration, and the cells were placed in the incubator for another 4 hours. After 4 hours of drug treatment, the cells were collected in a 15 mL centrifuge tube, the supernatant was discarded after centrifugation, and total protein was extracted.
1.6总蛋白抽提1.6 Total protein extraction
将细胞收集离心后，于每个离心管内加入100μL含有1％的蛋白酶抑制剂的预冷RIPA裂解液，吸取细胞裂解液于提前预冷的1.5mL EP内，冰上孵育10min，期间振荡数次，4℃，14000rpm离心5min，小心吸取上清加入至新的提前预冷1.5mL EP管中，通过BCA方法对蛋白浓度进行检测。(7)取30μg蛋白，根据蛋白定量的结果计算体积依次加入到对应的1.5mL EP中，取等量蛋白加入5×loading buffer，用PBS来补足体系体积，混匀后放置金属浴加热10min，取15μL作为Input组进行后续Western Blot实验。After collecting the cells and centrifuging them, add 100 μL of pre-cooled RIPA lysis buffer containing 1% protease inhibitors to each centrifuge tube, aspirate the cell lysate into a pre-cooled 1.5 mL EP, incubate on ice for 10 min, shake several times, centrifuge at 4°C, 14,000 rpm for 5 min, carefully aspirate the supernatant and add it to a new pre-cooled 1.5 mL EP tube, and detect the protein concentration using the BCA method. (7) Take 30 μg of protein, calculate the volume based on the protein quantification results, and add it to the corresponding 1.5 mL EP in sequence. Take an equal amount of protein and add 5× loading buffer, use PBS to make up the system volume, mix well, place in a metal bath and heat for 10 min, take 15 μL as the input group for subsequent Western Blot experiments.
1.7 eIF4E Pull-down实验1.7 eIF4E Pull-down Experiment
(1)将提取后的蛋白从-80℃超低温冰箱中取出，冰上融化。(1) Take the extracted protein out of the -80°C ultra-low temperature freezer and thaw it on ice.
(2)提前30min把装有m7GTP beads(AC-155L，Jena Bioscience)置于实验台静置，使beads自然沉降于瓶子底部。吸取20μL m7GTP beads至1.5mL离心管，用500μL PBS清洗，离心600g，5min， 重复3次。(2) 30 minutes in advance, place the bottle containing m7 GTP beads (AC-155L, Jena Bioscience) on the laboratory bench and let it settle naturally at the bottom of the bottle. Pipette 20 μL of m7 GTP beads into a 1.5 mL centrifuge tube, wash with 500 μL of PBS, and centrifuge at 600g for 5 minutes. Repeat 3 times.
(3)根据蛋白定量的结果向1.5mL离心管中加入200μg细胞裂解后的总蛋白，加入1mL含有1％的蛋白酶抑制剂的预冷RIPA裂解buffer，4℃旋转摇床上过夜孵育，使得m7GTP beads与eIF4E蛋白结合。第二天将离心管放入预冷的离心机中600g，离心5min。过夜孵育的beads离心后，尽量弃完上清液，使用500μL含有1％的蛋白酶抑制剂的预冷RIPA裂解buffer清洗与m7GTP结合的eIF4E蛋白2次。(3) According to the results of protein quantification, add 200 μg of total protein after cell lysis to a 1.5 mL centrifuge tube, add 1 mL of pre-cooled RIPA lysis buffer containing 1% protease inhibitors, and incubate overnight on a rotating shaker at 4°C to allow the m7GTP beads to bind to the eIF4E protein. The next day, place the centrifuge tube in a pre-cooled centrifuge at 600g and centrifuge for 5 minutes. After the overnight incubation beads are centrifuged, discard the supernatant as much as possible, and use 500 μL of pre-cooled RIPA lysis buffer containing 1% protease inhibitors to wash the eIF4E protein bound to m7GTP twice.
(4)将上一步离心后的裂解buffer尽量吸弃干净，每个离心管中加入40μL裂解液buffer，加10μL 5×Loading buffer混匀，金属浴煮10min后取15μL上清作为Pull-down组进行后续Western Blot实验。(4) Aspirate and discard the lysis buffer after centrifugation in the previous step as much as possible, add 40 μL lysis buffer to each centrifuge tube, add 10 μL 5× Loading buffer and mix well. Boil in a metal bath for 10 min, then take 15 μL of supernatant as the pull-down group for subsequent Western Blot experiments.
1.8 Western blot实验1.8 Western blot experiment
将前面的Input和Pull-down样品上样进行SDS-PAGE电泳，随后进行转膜、封闭。随后，依次进行孵育eIF4E一抗(R&D，MAB3228)和GAPDH一抗(CST，D16H11)、孵育二抗和显影等常规Western Blot实验操作。The input and pull-down samples were loaded for SDS-PAGE electrophoresis, followed by transfer and blocking. Subsequently, routine Western Blot experimental operations such as incubation with eIF4E primary antibody (R&D, MAB3228) and GAPDH primary antibody (CST, D16H11), incubation with secondary antibody and development were performed in sequence.
1.9数据处理1.9 Data Processing
获得Western blot显影图片后，使用Image Lab对条带进行分析及量化。最终各药物对eIF4E-m7GTP结合的抑制能力通过以下公式进行计算：After obtaining the Western blot images, the bands were analyzed and quantified using Image Lab. Finally, the inhibitory ability of each drug on eIF4E-m 7 GTP binding was calculated using the following formula:
％Inhibition＝[1-(药物处理组eIF4E Pull-down/药物处理组GAPDH Input)/(DMSO处理组eIF4E Pull-down/DMSO处理组GAPDH Input)]×100%Inhibition＝[1-(eIF4E Pull-down in drug-treated group/GAPDH Input in drug-treated group)/(eIF4E Pull-down in DMSO-treated group/GAPDH Input in DMSO-treated group)]×100
2.实验结果2. Experimental results
实验结果见表4。The experimental results are shown in Table 4.
表4 eIF4E-m7GTP结合的相对抑制率

Table 4 Relative inhibition rate of eIF4E-m 7 GTP binding

实验结果表明，本发明的化合物对eIF4E具有非常好的抑制作用。The experimental results show that the compounds of the present invention have a very good inhibitory effect on eIF4E.
实验例2：化合物体外细胞活性评价Experimental Example 2: Evaluation of in vitro cell activity of compounds
1.实验材料1. Experimental Materials
受试化合物：以上实施例制备的本发明的化合物，每个化合物用DMSO配制成20mM，然后依次3倍稀释为5000.00nM、1250.00nM、312.50nM、78.13nM、19.53nM、4.88nM、1.22nM、0.31nM和0.08nM。Test compounds: the compounds of the present invention prepared in the above examples, each compound was prepared with DMSO to 20 mM, and then diluted 3-fold in sequence to 5000.00 nM, 1250.00 nM, 312.50 nM, 78.13 nM, 19.53 nM, 4.88 nM, 1.22 nM, 0.31 nM and 0.08 nM.
结肠癌细胞株COLO205购于美国典型培养物保藏中心(ATCC)。The colon cancer cell line COLO205 was purchased from the American Type Culture Collection (ATCC).
试剂：RPMI-1640Medium(Gibco,11875-093)；Fetal Bovine Serum(Gibco,10099-141)；青链霉素(Gibco,15140-122)；CellTiter-Glo Luminescent Cell Viability Assay(Promega,G7571)。Reagents: RPMI-1640Medium (Gibco, 11875-093); Fetal Bovine Serum (Gibco, 10099-141); Penicillin-Streptomycin (Gibco, 15140-122); CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7571).
2.实验方法2. Experimental Methods
2.1细胞培养：2.1 Cell culture:
细胞复苏：将细胞置于37℃水浴中溶解，然后转移到15mL已预热的培养基(RPMI-1640 Medium+10％FBS+1％青链霉素)中，1000rpm离心5分钟，弃去培养基，用10mL新鲜培养基重悬细胞，转移至培养皿中，置于37℃，5％CO2的培养箱中培养，24小时后细胞更换新鲜培养基。Cell recovery: Dissolve the cells in a 37°C water bath, then transfer to 15 mL of pre-warmed culture medium (RPMI-1640 Medium + 10% FBS + 1% penicillin-streptomycin), centrifuge at 1000 rpm for 5 minutes, discard the culture medium, resuspend the cells with 10 mL of fresh culture medium, transfer to a culture dish, and culture in a 37°C, 5% CO2 incubator. Replace the cells with fresh culture medium after 24 hours.
细胞传代：将上述复苏的细胞转移到15mL无菌离心管中，1000rpm离心5分钟，弃去培养基，取分散均匀的细胞计数，调整合适的细胞浓度到10mL新鲜培养基，加入到培养皿中，置于37℃，5％CO2的培养箱中培养，视细胞生长情况每2-3天换一次培养液或进行传代。Cell passaging: Transfer the above revived cells to a 15 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes, discard the culture medium, count the evenly dispersed cells, adjust the appropriate cell concentration to 10 mL of fresh culture medium, add it to the culture dish, and culture it in an incubator at 37°C, 5% CO2 . Depending on the cell growth, change the culture medium or pass the cells every 2-3 days.
2.2实验步骤：2.2 Experimental steps:
实验第1天：Experimental day 1:
COLO205细胞传代后以对应的密度重悬于完全培养基中，5000个/孔，接种于96孔培养板内：边缘孔内以200μL PBS填充，以防边缘培养基蒸发较快导致内部板孔的培养条件差异过大；内部60个孔每孔加入75μL完全培养基，放入5％CO2的培养箱内37℃培养24h。After passaging, COLO205 cells were resuspended in complete culture medium at the corresponding density, 5000 cells/well, and inoculated into a 96-well culture plate: the edge wells were filled with 200 μL PBS to prevent the edge culture medium from evaporating quickly, resulting in excessive differences in culture conditions in the inner wells; 75 μL complete culture medium was added to each of the 60 inner wells, and the plates were placed in a 5% CO2 incubator at 37°C for 24 h.
实验第2天：Experimental day 2:
COLO205细胞在原培养基(75μL)的基础上，加入75μL的(2×)药物，每个浓度组设置两个复孔，继续放入5％CO2培养箱培养7天。化合物溶液配制如下：提前称取化合物1-2mg，使用DMSO配置成20mM母液。使用完全培养基稀释药物，药物终浓度以5000nM为起始最高浓度，按1:3梯度依次稀释至9个浓度梯度：5000.00nM、1250.00nM、312.50nM、78.13nM、19.53nM、4.88nM、1.22nM、0.31nM和0.08nM。COLO205 cells were cultured in the original medium (75 μL) and 75 μL of (2×) drug was added. Two replicate wells were set for each concentration group and cultured in a 5% CO 2 incubator for 7 days. The compound solution was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 20 mM stock solution using DMSO. The drug was diluted with complete medium. The final drug concentration was 5000 nM as the starting maximum concentration and was diluted to 9 concentration gradients in a 1:3 gradient: 5000.00 nM, 1250.00 nM, 312.50 nM, 78.13 nM, 19.53 nM, 4.88 nM, 1.22 nM, 0.31 nM and 0.08 nM.
实验第5天：Experimental day 5:
COLO205细胞处理3天后，提前30min将CellTiter-Glo Luminescent Cell Viabillity Assay取出， 平衡至室温。加入75μL Celltiter-Glo reagent工作液。室温震荡2min。继续室温孵育10min后，吸取180μL细胞液转移至白板中，检测化学发光信号，震荡，Read进样检测条件为500ms。。根据酶标仪导出的A.U.值，计算每个孔相对于溶剂对照孔的抑制率：Inhibition(％)＝100-(A.U.实验孔–A.U.空白孔)/(A.U.溶剂对照孔-A.U.空白孔)*100。根据不同药物浓度及其所对应的抑制率，使用GraghPad5.0软件拟合四参数逻辑S型曲线，分析数据并得出IC50值，实验结果见表5。After COLO205 cells were treated for 3 days, the CellTiter-Glo Luminescent Cell Viabillity Assay was taken out 30 minutes in advance. Equilibrate to room temperature. Add 75 μL Celltiter-Glo reagent working solution. Oscillate at room temperature for 2 minutes. After continuing to incubate at room temperature for 10 minutes, aspirate 180 μL of cell solution and transfer it to the white plate, detect the chemiluminescent signal, oscillate, and read the detection conditions for 500ms. . According to the AU value derived from the microplate reader, calculate the inhibition rate of each well relative to the solvent control well: Inhibition (%) = 100-(AU experimental well-AU blank well)/(AU solvent control well-AU blank well)*100. According to different drug concentrations and their corresponding inhibition rates, use GraghPad5.0 software to fit the four-parameter logistic S-type curve, analyze the data and obtain the IC 50 value. The experimental results are shown in Table 5.
表5化合物对结肠癌细胞的抑制活性


Table 5 Inhibitory activity of compounds on colon cancer cells


从以上实验结果可以看出，本发明的化合物对结肠癌细胞具有较好的抑制活性。It can be seen from the above experimental results that the compounds of the present invention have good inhibitory activity on colon cancer cells.
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。 Although the present invention has been described in detail above, it is understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but should be attributed to the claims.

Claims (10)

  1. 一种通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
    A compound represented by general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug,
    其中，in,
    环A选自杂芳基和杂环基，所述杂芳基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代；Ring A is selected from heteroaryl and heterocyclic groups, and the heteroaryl and heterocyclic groups may be substituted by one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl and oxo;
    L为-(CH2)-、-(CH2)2-、-(CH2)3-、-CH((C1-C8)烷基)(CH2)-、-CH((C1-C8)烷基)(CH2)2-、-(CH2)2-O-、-CH2CH＝CH-、-CH2C≡C-或-CH2(环丙基)-；L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH((C 1 -C 8 )alkyl)(CH 2 )-, -CH((C 1 -C 8 )alkyl)(CH 2 ) 2 -, -(CH 2 ) 2 -O-, -CH 2 CH＝CH-, -CH 2 C≡C- or -CH 2 (cyclopropyl)-;
    X选自N和C(R5)，其中R5选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；X is selected from N and C( R5 ), wherein R5 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
    R1、R3、R4和R6各自独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基磺酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基和双烷基氨基；R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylsulfonylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
    R2选自烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、芳基、杂芳基、环烷基和杂环基，所述烷基氨基烷氧基、杂环基烷氧基、杂环基氨基、芳基、杂芳基、环烷基和杂环基可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、卤代烷基酰基、羟基烷基酰基、环烷基酰基、杂环基酰基、环烷基、卤代环烷基、杂环基、芳基、杂芳基和氧代基团的基团取代；和 R is selected from the group consisting of alkylaminoalkoxy, heterocyclylalkoxy, heterocyclylamino, aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo; and
    m和n各自独立地为0、1、2或3。m and n are each independently 0, 1, 2 or 3.
  2. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，The compound according to claim 1 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug,
    其中环A选自5-12元杂芳基和3-12元杂环基，所述5-12元杂芳基和3-12元杂环基可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟 基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基、双C1-6烷基氨基、C2-10烯基、C2-10炔基、C3-12环烷基、羟基C3-12环烷基、3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团的基团取代。wherein Ring A is selected from 5-12 membered heteroaryl and 3-12 membered heterocyclic group, and the 5-12 membered heteroaryl and 3-12 membered heterocyclic group may be selected from one or more of halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy The alkyl group may be substituted with a C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkylacylamino group, a C 1-6 alkylacyl group, a C 1-6 alkylsulfonyl group, an aminoacyl group, a C 1-6 alkylaminoacyl group, a di-C 1-6 alkylamino group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 3-12 cycloalkyl group, a hydroxy C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group and an oxo group.
  3. 根据权利要求1或2所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R2选自C1-6烷基氨基C1-6烷氧基、杂环基C1-6烷氧基、6元杂环基氨基、C6-12芳基、5-12元杂芳基、C3-12环烷基和3-12元杂环基，所述C1-6烷基氨基C1-6烷氧基、杂环基C1-6烷氧基、6元杂环基氨基、C6-12芳基、5-12元杂芳基、C3-12环烷基和3-12元杂环基可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基、双C1-6烷基氨基、C2-10烯基、C2-10炔基、卤代C1-6烷基酰基、羟基C1-6烷基酰基、C3-12环烷基酰基、3-12元杂环基酰基、C3-12环烷基、卤代C3-12环烷基、3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团的基团取代。The compound according to claim 1 or 2, or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein R2 is selected from C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl, and the C1-6 alkylaminoC1-6 alkoxy, heterocyclylC1-6 alkoxy, 6-membered heterocyclylamino, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered heterocyclyl can be selected from one or more halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono -C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono-C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono -C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkoxy, hydroxyC1-6 alkoxy , nitro, carboxyl, cyano, amino, mono- C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkoxy, hydroxyC1-6 alkoxy, nitro The present invention may be substituted by a C 1-6 alkylamino, a C 1-6 alkylacylamino, a C 1-6 alkylacyl group, a C 1-6 alkylacyl group, a C 1-6 alkylsulfonyl group, an aminoacyl group, a C 1-6 alkylaminoacyl group, a bis-C 1-6 alkylamino group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a halogenated C 1-6 alkylacyl group, a hydroxyC 1-6 alkylacyl group, a C 3-12 cycloalkylacyl group, a 3-12 membered heterocyclylacyl group, a C 3-12 cycloalkyl group, a halogenated C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group and an oxo group.
  4. 根据权利要求1-3之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R1、R3、R4和R6各自独立地选自氢、卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、C1-6烷基磺酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基。The compound according to any one of claims 1 to 3 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein R 1 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino.
  5. 根据权利要求1-4之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中L为-(CH2)2-O-或-CH2C≡C-。The compound according to any one of claims 1 to 4, or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein L is -(CH 2 ) 2 -O- or -CH 2 C≡C-.
  6. 根据权利要求1-5之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中通式(I)具有以下通式(Ia)的结构，
    The compound according to any one of claims 1 to 5, or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein the general formula (I) has the following general formula (Ia):
    其中，环A、R1、R2、R3、L和m具有权利要求1-5中所述的定义。wherein ring A, R 1 , R 2 , R 3 , L and m have the meanings as described in claims 1-5.
  7. 根据权利要求1-6之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R2选自
    The compound according to any one of claims 1 to 6 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein R 2 is selected from
  8. 一种化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中所述化合物为选自以下的化合物：









    A compound or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein the compound is selected from the following compounds:









  9. 一种药物组合物，其包含权利要求1至8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier.
  10. 权利要求1-8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药或权利要求9所述的药物组合物在制备用于治疗eIF4E介导的疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 8 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating eIF4E-mediated diseases.
PCT/CN2023/140972 2022-12-23 2023-12-22 Compound serving as eif4e inhibitor and use thereof WO2024131937A1 (en)

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