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WO2024125437A1 - Gspt1 degradation agent and use thereof - Google Patents

Gspt1 degradation agent and use thereof Download PDF

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Publication number
WO2024125437A1
WO2024125437A1 PCT/CN2023/137785 CN2023137785W WO2024125437A1 WO 2024125437 A1 WO2024125437 A1 WO 2024125437A1 CN 2023137785 W CN2023137785 W CN 2023137785W WO 2024125437 A1 WO2024125437 A1 WO 2024125437A1
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alkyl
alkoxy
hydroxy
halogenated
mmol
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PCT/CN2023/137785
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French (fr)
Chinese (zh)
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王小伟
许龙
田新磊
张小猛
全旭
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南京圣和药业股份有限公司
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Publication of WO2024125437A1 publication Critical patent/WO2024125437A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as GSPT1 degraders, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating diseases such as cancer that are beneficial for degrading GSPT1.
  • Cereblon is a protein encoded by the CRBN gene. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex can ubiquitinate many other proteins.
  • DDB1 DNA binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • Cereblon as a component of the DDB1-CUL4a-Roc1 ubiquitin ligase complex, is a molecular target for immunomodulators such as thalidomide, lenalidomide, and pomalidomide. Inhibition of CRBN ubiquitination by these drugs can lead to CRBN accumulation, resulting in increased degradation of target proteins mediated by cullin-4RING E3 ligase. Cereblon E3 ligase inhibitors have a clear mechanism in the treatment of tumor-related diseases.
  • GSPT1 (G1to S phase transition 1, also known as eRF3a) plays an important role in inhibiting cell proliferation by interacting with the release factor eRF1, mediating stop codon recognition and the release of nascent proteins from ribosomes.
  • eRF3a a new substrate of CRBN
  • GSPT1 is a cause of off-target effects of PTOTAC molecules that recruit CRBN.
  • GSPT1 plays an important role in the protein translation process. Its degradation can lead to abnormal protein synthesis, thereby affecting the proliferation and survival of tumor cells.
  • GSPT1 is difficult to target because the GTP concentration in the cell is very high and the GTP binding pocket binds strongly to the GTPase.
  • One object of the present invention is to provide a class of compounds having GSPT1 degradation activity represented by general formula (I) or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs,
  • Another object of the present invention is to provide a method for preparing the compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvent Methods for producing compounds, crystals or prodrugs.
  • Another object of the present invention is to provide a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, as well as a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another one or more drugs.
  • Another object of the present invention is to provide a method for treating GSPT1-related diseases such as cancer using the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, and the use of the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs in the preparation of drugs for treating GSPT1-related diseases such as cancer.
  • 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,
  • X 1 is selected from -C(O)-, -S(O)- and -S(O) 2 -;
  • X3 and X4 are each independently selected from a bond, -CH- and -S-;
  • X5 and X6 are each independently selected from -CH- and -N-;
  • L 1 is selected from -CH 2 -O- and -C ⁇ C-;
  • L 2 is selected from a bond, -CH 2 -O-, -C ⁇ C- and -S-;
  • Y is selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which is optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl;
  • R 1 and R 2 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino; or two R 1 and the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which is optionally substituted by halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, cycloalkyl, heterocycloalkyl,
  • R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl
  • n and m are each independently selected from 1, 2, 3, 4 and 5.
  • 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:
  • Y is selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo-substituted C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo-substituted 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, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted by halogen, hydroxy, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 al
  • R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo - substituted C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy, hydroxy C1-6 alkoxy, nitro, carboxyl, cyano, amino, mono- C1-6 alkylamino, C1-6 alkylacylamino, C1-6 alkylacyl, aminoacyl, C1-6 alkylaminoacyl and di- C1-6 alkylamino; or two R1 and the atoms to which they are attached form a C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl or C5-12 heteroaryl, which is optionally substituted by halogen, hydroxy, C1-6 alkyl, halo-substituted C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 al
  • R3 is selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl and hydroxy C1-6 alkyl;
  • n and m are each independently selected from 1, 2, 3 and 4.
  • 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:
  • X1 is -C(O)-
  • X2 is -CH2- ;
  • X3 and X4 are each independently -CH-;
  • X5 and X6 are each independently -CH-;
  • L1 is -CH2 -O-;
  • L 2 is selected from a bond, -CH 2 -O- and -C ⁇ C-;
  • Y is selected from halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, C 3-8 cycloalkyl, C 3-8 oxacycloalkyl, C 3-8 azacycloalkyl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted with halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3
  • R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, hydroxy C1-3 alkoxy , nitro , carboxyl, cyano , amino, mono C1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl , aminoacyl, C1-3 alkylaminoacyl and di- C1-3 alkylamino; or two R1 and the atoms to which they are attached form a C3-8 cycloalkyl, C3-8 oxacycloalkyl, C3-8 azacycloalkyl, C6-12 aryl or C5-12 heteroaryl, which is optionally substituted by halogen, hydroxy, C1-3 alkyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C
  • R3 is selected from hydrogen, C1-3 alkyl, halogenated C1-3 alkyl and hydroxy C1-3 alkyl;
  • n and m are each independently selected from 1, 2, 3 and 4.
  • the compound of formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug according to the present invention wherein Selected from It is optionally substituted by one or more fluorine, chlorine, bromine, iodine, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl such as trifluoromethyl, 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, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino.
  • the compound of the present invention is a compound of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Y is selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogenated C 1-3 alkyl, vinyl, ethynyl, 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 alkyl acyl, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclopropyl, oxetanyl, o
  • R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, 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, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino; or two R 1 and the atoms to which they are attached form a C 3-8 cycloalkyl, C 3-8 oxacycloalkyl, C 3-8 azacycloalkyl, C 6-12 aryl or C 5-12 heteroaryl such as which is optionally substituted with hydroxy, hydrogen, flu
  • R3 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, halogenated C1-3 alkyl and hydroxy C1-3 alkyl.
  • the present invention provides a compound represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
  • Ring A is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl and alkylaminoacyl; and
  • R1 and R2 have the same meanings as those described above for the general formula (I).
  • ring A is selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, which is optionally substituted by halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl and C 1-6 alkylaminoacyl substituted;
  • R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono- C1-6 alkylamino, C1-6 alkylacylamino, C1-6 alkylacyl, aminoacyl, C1-6 alkylaminoacyl and di - C1-6 alkylamino, and the heteroatom is selected from carbon, nitrogen and oxygen atoms; and
  • n and m are each independently selected from 1, 2, 3 and 4.
  • R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C1-3 alkyl, hydroxyl C1-3 alkyl, C1-3 alkoxy , halogenated C1-3 alkoxy, hydroxyl C1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, aminoacyl, C1-3 alkylaminoacyl and di C1-3 alkylamino, which are optionally replaced by hydroxyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl,
  • ring A is selected from It is optionally substituted by 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, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl and C 1-6 alkylaminoacyl; further, it is optionally substituted by hydroxy, hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl such as trifluoromethyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogen
  • the present invention provides the following specific compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs:
  • the inventors of the present invention unexpectedly found that the compound of formula (Ia) of the present invention has significantly reduced cardiac toxicity and good drug safety.
  • 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 the pharmaceutical composition is used to treat a GSPT1-related disease such as cancer.
  • 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 GSPT1-related diseases using a compound represented by formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same, as well as use of the compound in the preparation of a drug for treating GSPT1-related diseases.
  • the present invention provides a method for treating GSPT1-related diseases such as cancer using a compound represented by formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same, as well as use in the preparation of a medicament for treating GSPT1-related diseases such as cancer.
  • the present invention provides a method for treating cancer and a use of a compound represented by general formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same in the preparation of a drug for treating cancer, wherein the cancer includes but is not limited to: non-small cell lung cancer, lung adenocarcinoma, lung cancer, large cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, small cell lung cancer, melanoma, desmoplastic melanoma, uveal melanoma, ovarian small cell carcinoma, ovarian rhabdoid tumor, skin squamous cell carcinoma, glioma, uterine cancer, endometrial cancer, ovarian serous cystadenocarcinoma, bladder urothelial carcinoma, primary central nervous system lymphoma, esophageal cancer, bladder cancer, gastric adeno
  • the compound represented by the general formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug is used to treat a disease caused by accumulation of GSPT1 protein, such as non-Hodgkin's lymphoma, leukemia and/or solid tumor.
  • GSPT1 protein such as non-Hodgkin's lymphoma, leukemia and/or solid tumor.
  • the non-Hodgkin's lymphoma is selected from one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma and T-cell lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • follicular lymphoma mucosa-associated lymphoid tissue lymphoma
  • T-cell lymphoma T-
  • the leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia.
  • the solid tumor includes one or more of lung cancer, liver cancer, breast cancer and brain glioma.
  • 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 that lacks 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 diastereoisomer 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 further preferably a straight or branched group containing 1 to 3 carbon atoms, non-limiting examples of which 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.
  • the -C(O)- group of the present invention means a "carbonyl group”.
  • the -S(O) 2 - group of the present invention means a "sulfonyl group”.
  • 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 spiro 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 or “heteroaromatic ring” of the present invention refers to an aryl 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.
  • Step 1 Preparation of 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Step 5 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)carbamate
  • Step 2 Preparation of phenyl (4-chloro-3-((cyclopropyl)ethynyl)phenyl)carbamate
  • Step 3 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(cyclopropylethynyl)phenyl)carbamate
  • step 1 in Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.73 mmol) was weighed and added to a three-necked flask, NaH was added at 0°C, stirred for 10 min, and a solution of phenyl(4-chloro-3-((cyclopropyl)ethynyl)phenyl)carbamate (250 mg, 0.80 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and reacted at room temperature for 1 h.
  • Step 3 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamate
  • step 1 in Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147 mg, 0.54 mmol) was weighed and added to a three-necked flask, and N,N-dimethylformamide (3 mL) and triethylamine (60 mg, 0.59 mmol) were added, and stirred at 0°C for 0. 5h. 4-(2-chloro-5-isocyanophenyl)-2-methylbutyric acid-3-yn-2-ol was added dropwise at 0°C and reacted at room temperature for 1h.
  • Step 3 (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(5-(cyclopropylethynyl)-6-methylpyridin-3-yl)amino
  • step 1 of Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147 mg, 0.54 mmol) and add it to a three-necked flask, add 4 mL of N,N-dimethylformamide and triethylamine (60 mg, 0.59 mmol), and stir at 0°C for 0.5 h. Then, 3-(cyclopropynyl)-5-isocyanate-2-methylpyridine (120 mg, 0.54 mmol) was added dropwise at 0°C and reacted at room temperature for 1 h.
  • Step 4 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(cyclopropylethynyl)-2-fluorophenyl)carbamate
  • step 1 of Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112 mg, 0.41 mmol) was added to a three-necked flask, and 3 mL of N,N-dimethylformamide and triethylamine (50 mg, 0.49 mmol) were added.
  • 1-chloro-2-(cyclopropylethynyl)-5-fluoro-4-isocyanobenzene was added dropwise at 0°C under argon protection, and the mixture was reacted at room temperature for 1 h.
  • Step 5 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)phenyl)carbamate
  • step 1 of Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.44 mmol) was weighed and added to a three-necked flask, N,N-dimethylformamide (2 mL) was added to dissolve, triethylamine (132 mg, 1.30 mmol) was added, and 3-((2-chloro-5-isocyanatophenyl)ethynyl)-3-fluorooxetane (122 mg, 0.49 mmol) was added dropwise under stirring, and the mixture was reacted at room temperature for 2 h.
  • Step 3 Synthesis of phenyl (6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate
  • Step 4 Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate
  • Step 3 Synthesis of phenyl (4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate
  • Step 4 Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate
  • Step 4 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate
  • step 1 of Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was added to a three-necked flask, sodium hydride (30 mg, 0.73 mmol) was added at 0°C, and a solution of (2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate (149 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the mixture was reacted at room temperature for 1 h.
  • Step 1 Preparation of phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
  • Step 2 Preparation of (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
  • Step 3 Preparation of (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
  • Step 4 Preparation of (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
  • Step 5 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
  • step 1 of Example 1 (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (100 mg, 0.17 mmol) was added to a single-necked flask, and acetonitrile (3 mL) and ammonia water (0.02 mL) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and column chromatography was performed to obtain the title product.
  • Step 2 Synthesis of tert-butyl 5-bromo-4-chloro-2-fluorophenyl)carbamate
  • Step 5 Synthesis of phenyl (4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)carbamate
  • Step 6 Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)carbamate
  • step 1 in Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.06 g, 0.2 mmol) and 1.6 mL of N,N-dimethylformamide were added to a 10 mL Schlenk tube.
  • Sodium hydride (0.02 g, 0.4 mmol)
  • phenyl (4- A solution of 2-chloro-5-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)carbamate (0.09 g, 0.23 mmol) in N,N-dimethylformamide (1 mL).
  • Step 1 Preparation of 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]
  • Step 2 Preparation of tert-butyl (7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)carbamate
  • Step 4 Preparation of phenyl 7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)carbamate
  • Step 5 Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)phenyl)carbamate
  • step 1 of Example 1 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87 mg, 0.26 mmol) was added to a three-necked flask, N,N-dimethylformamide (2 mL) was added to dissolve it, sodium hydride (14 mg, 0.58 mmol) and phenyl (7'-fluoro-2'-methylspiro [cyclopentane-1,3'-indole] -5'-yl) carbamate (100 mg, 0.29 mmol) were added at 0°C, and the reaction was carried out at room temperature for 15 minutes.
  • Examples 14-31 were synthesized using different raw materials according to the synthesis method of Examples 1-13 of the present invention.
  • the characterization parameters of Examples 14-31 are shown in Table 1.
  • Test compounds the compounds of the present invention and comparative example compounds A, B and C prepared in the above embodiments, each compound was prepared into a 10 mM stock solution with DMSO and finally diluted to 10 concentrations for detection.
  • the final concentrations of the compounds in the NCI-H1155 cell experiment were 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.051 nM/30000 nM, 7500 nM, 1875 nM, 468.75 nM, 117.19 nM, 29.30 nM, 7.32 nM, 1.83 nM, 0.46 nM and 0.11 nM.
  • Reagents TrypLE TM Express Enzyme (1X), no phenol red, catalog number Gibco 12604-021; Celltiter Glo assay kit (CTG), catalog number Promega G7573.
  • NCI-H1155 cells mulated Leibovitz's L-15 medium, 10% FBS, 1% penicillin-streptomycin.
  • the culture medium should be changed every 2-3 days or the cells should be subcultured.
  • NCI-H1155 cells were cultured in the original medium (40 ⁇ L).
  • the drug group was added with 40 nL of drugs of different concentrations.
  • the DMSO group was Add 40nL DMSO, set up two replicate wells for each concentration group, and continue to culture in a 5% CO2 incubator for 3 days.
  • the compound was prepared as follows: 1-2mg of the compound was weighed in advance and prepared into a 10mM stock solution using DMSO.
  • the drug was diluted with DMSO, with a starting concentration of 10mM, and then diluted to 10 concentration gradients in a 1:4 gradient.
  • the final concentrations of the drugs were: 30000nM, 7500nM, 1875nM, 468.75nM, 117.19nM, 29.30nM, 7.32nM, 1.83nM, 0.46nM, 0.11nM.
  • the experimental results show that the compound of the present invention has a strong inhibitory effect on human lung cancer cell NCI-H1155 cells (highly expressing MYC).
  • Test compounds the compounds of the present invention and comparative example compound A prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to 10 concentrations for detection, with the final concentrations of the compounds being 100000 nM, 25000 nM, 6250 nM, 1562.5 nM, 390.62 nM, 97.65 nM, 24.41 nM, 6.10 nM, 1.52 nM, and 0.38 nM.
  • the HTRF signal (Ratio 665/615 nm) was read using a BMG microplate reader. Based on different drug concentrations and their corresponding inhibition rates, the IC50 curve was drawn using GraphicPad 5.0 software. The data was analyzed to obtain the final IC50 value. The experimental results are shown in Table 3.
  • the IC50 value of the test compound indicates the ability to bind to the CRBN protein, and the lower the value, the stronger the binding ability.
  • Test compounds The compounds of the present invention and comparative example compound A prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to three concentrations for detection, and the final concentrations of the compounds in the NCI-H1155 cell experiment were 1000 nM, 100 nM, and 10 nM. 0.5% DMSO was used as a solvent control.
  • NCI-H1155 cells highly expressing MYC: ATCC.
  • Reagents TrypLE TM Express Enzyme (1X), no phenol red, catalog number Gibco 12604-021; eRF3, catalog number CST 14980S; BCA kit, catalog number Beyotime P0010; color pre-stained protein ladder, Thermo 26619; anti-rabbit secondary antibody, CST 7074.
  • the experimental results show that the compounds of the present invention exhibit excellent protein degradation ability in the GSPT1 (eRF3) protein degradation experiment. After treating NCH-H1155 cells for 6 hours, at concentrations of 10 nM and 100 nM, the compounds of Example 2 and Example 4 have better GSPT1 (eRF3) protein degradation ability than Compound A.

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Abstract

The present invention belongs to the field of medicinal chemistry, and in particular relates to a compound that acts as a GSPT1 degradation agent, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, a preparation method therefor, a pharmaceutical composition comprising the compounds, and the use of the compounds or the composition for treating diseases benefiting from the degradation of GSPT1, such as cancers.

Description

GSPT1降解剂及其应用GSPT1 degraders and their applications 技术领域Technical Field
本发明属于医药化学领域，具体涉及作为GSPT1降解剂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，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降解GSPT1有益的疾病如癌症的用途。The present invention belongs to the field of medicinal chemistry, and specifically relates to compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as GSPT1 degraders, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating diseases such as cancer that are beneficial for degrading GSPT1.
背景技术Background technique
Cereblon(CRBN)是由CRBN基因编码的蛋白质。Cereblon与受损的DNA结合蛋白1(DDB1)、Cullin-4A(CUL4A)和cullins 1调节因子(ROC1)形成E3泛素连接酶复合物。该复合物能将许多其它蛋白泛素化。Cereblon (CRBN) is a protein encoded by the CRBN gene. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex can ubiquitinate many other proteins.
Cereblon作为DDB1-CUL4a-Roc1泛素连接酶复合物的组分是免疫调节剂如沙利度胺、来那度胺和泊马度胺的分子靶标。这些药物对CRBN泛素化的抑制可使得CRBN积累，导致cullin-4RING E3连接酶介导的靶蛋白的降解增加。Cereblon E3连接酶抑制剂在治疗肿瘤相关疾病方面机制较明确。Cereblon, as a component of the DDB1-CUL4a-Roc1 ubiquitin ligase complex, is a molecular target for immunomodulators such as thalidomide, lenalidomide, and pomalidomide. Inhibition of CRBN ubiquitination by these drugs can lead to CRBN accumulation, resulting in increased degradation of target proteins mediated by cullin-4RING E3 ligase. Cereblon E3 ligase inhibitors have a clear mechanism in the treatment of tumor-related diseases.
GSPT1(G1to S phase transition 1，也被称为eRF3a)通过与释放因子eRF1相互作用，介导终止密码子识别和新生蛋白从核糖体释放，对抑制细胞增殖有重要作用。研究显示，GSPT1作为CRBN的新底物，可被CRBN蛋白调节剂有效降解，导致白血病细胞增殖被显著抑制。也有报道称，GSPT1是招募CRBN的PTOTAC分子产生脱靶效应的一种原因。GSPT1作为分子胶的一个靶点，在蛋白翻译过程中发挥重要作用，它的降解可导致蛋白合成异常，进而影响肿瘤细胞的增殖和生存，同时GSPT1作为一种GTP酶，很难靶向，因为细胞内的GTP浓度很高，而且GTP结合口袋与GTP酶结合强烈。GSPT1 (G1to S phase transition 1, also known as eRF3a) plays an important role in inhibiting cell proliferation by interacting with the release factor eRF1, mediating stop codon recognition and the release of nascent proteins from ribosomes. Studies have shown that GSPT1, as a new substrate of CRBN, can be effectively degraded by CRBN protein regulators, resulting in significant inhibition of leukemia cell proliferation. It has also been reported that GSPT1 is a cause of off-target effects of PTOTAC molecules that recruit CRBN. As a target of molecular glue, GSPT1 plays an important role in the protein translation process. Its degradation can lead to abnormal protein synthesis, thereby affecting the proliferation and survival of tumor cells. At the same time, as a GTPase, GSPT1 is difficult to target because the GTP concentration in the cell is very high and the GTP binding pocket binds strongly to the GTPase.
需要开发安全、有效的GSPT1降解剂以满足临床需求。Safe and effective GSPT1 degraders need to be developed to meet clinical needs.
发明内容Summary of the invention
本发明的一个目的是提供通式(I)所示的一类具有GSPT1降解活性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，
One object of the present invention is to provide a class of compounds having GSPT1 degradation activity represented by general formula (I) or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs,
本发明的另一个目的是提供制备本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂 化物、结晶或前药的方法。Another object of the present invention is to provide a method for preparing the compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvent Methods for producing compounds, crystals or prodrugs.
本发明的再一个目的是提供包含本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体的组合物，以及包含本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和另一种或多种药物的组合物。Another object of the present invention is to provide a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, as well as a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another one or more drugs.
本发明的还一个目的是提供本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药治疗GSPT1相关的疾病如癌症的方法，以及本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药在制备用于治疗GSPT1相关的疾病如癌症的药物中的应用。Another object of the present invention is to provide a method for treating GSPT1-related diseases such as cancer using the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, and the use of the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs in the preparation of drugs for treating GSPT1-related diseases such as cancer.
针对上述发明目的，本发明提供以下技术方案：In view of the above-mentioned invention object, the present invention provides the following technical solutions:
第一方面，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，
In a first aspect, 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,
X1选自-C(O)-、-S(O)-和-S(O)2-；X 1 is selected from -C(O)-, -S(O)- and -S(O) 2 -;
X2选自-CH2-、-O-和-N＝CH-； X2 is selected from -CH2- , -O- and -N=CH-;
X3和X4各自独立地选自键、-CH-和-S-； X3 and X4 are each independently selected from a bond, -CH- and -S-;
X5和X6各自独立地选自-CH-和-N-； X5 and X6 are each independently selected from -CH- and -N-;
L1选自-CH2-O-和-C≡C-；L 1 is selected from -CH 2 -O- and -C≡C-;
L2选自键、-CH2-O-、-C≡C-和-S-；L 2 is selected from a bond, -CH 2 -O-, -C≡C- and -S-;
Y选自氢、卤素、羟基、烷基、烯基、炔基、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、环烷基、杂环烷基、芳基和杂芳基，其任选被卤素、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、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基取代；Y is selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which is optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl;
R1和R2各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、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、烷基氨基酰基和双烷基氨基；或者两个R1与它们所连接的原子形成环烷基、杂环烷基、芳基或杂芳基，其任选被卤素、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、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、环烷基、杂环烷基、芳基、 杂芳基、螺环烷基、螺杂环烷基、螺芳基或螺杂芳基取代；R 1 and R 2 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino; or two R 1 and the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which is optionally substituted by halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, cycloalkyl, heterocycloalkyl, aryl, substituted with heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, spiroaryl or spiroheteroaryl;
R3选自氢、烷基、卤代烷基和羟基烷基；和 R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl; and
n和m各自独立地选自1、2、3、4和5。n and m are each independently selected from 1, 2, 3, 4 and 5.
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:
Y选自卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、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、氨基酰基、C1-6烷基氨基酰基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环烷基、C6-12芳基和C5-12杂芳基，其任选被卤素、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、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基取代；Y is selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo-substituted C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo-substituted 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, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted by halogen, hydroxy, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, hydroxy C 1-6 alkoxy, amino, mono-C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl and C 5-12 heteroaryl. C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl substituted;
R1和R2各自独立地选自氢、卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、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、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基；或者两个R1与它们所连接的原子形成C3-8环烷基、C3-8杂环烷基、C6-12芳基或C5-12杂芳基，其任选被卤素、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、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基、C3-8螺环烷基、C3-8螺杂环烷基、C6-12螺芳基或C5-12螺杂芳基取代； R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo - substituted C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy, hydroxy C1-6 alkoxy, nitro, carboxyl, cyano, amino, mono- C1-6 alkylamino, C1-6 alkylacylamino, C1-6 alkylacyl, aminoacyl, C1-6 alkylaminoacyl and di- C1-6 alkylamino; or two R1 and the atoms to which they are attached form a C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl or C5-12 heteroaryl, which is optionally substituted by halogen, hydroxy, C1-6 alkyl, halo-substituted C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy , halo-substituted C1-6 alkoxy, hydroxy C1-6 The alkyl is substituted with C1-6 alkoxy, amino, mono C1-6 alkylamino, C1-6 alkylacylamino, C1-6 alkylacyl, aminoacyl, C1-6 alkylaminoacyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-8 spirocycloalkyl , C3-8 spiroheterocycloalkyl, C6-12 spiroaryl or C5-12 spiroheteroaryl;
R3选自氢、C1-6烷基、卤代C1-6烷基和羟基C1-6烷基；和 R3 is selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl and hydroxy C1-6 alkyl; and
n和m各自独立地选自1、2、3和4。n and m are each independently selected from 1, 2, 3 and 4.
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:
X1为-C(O)-； X1 is -C(O)-;
X2为-CH2-； X2 is -CH2- ;
X3和X4各自独立地为-CH-； X3 and X4 are each independently -CH-;
X5和X6各自独立地为-CH-； X5 and X6 are each independently -CH-;
L1为-CH2-O-； L1 is -CH2 -O-;
L2选自键、-CH2-O-和-C≡C-；L 2 is selected from a bond, -CH 2 -O- and -C≡C-;
Y选自卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、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、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C3-8环烷基、C3-8氧杂环烷基、C3-8氮杂环烷基、C6-12芳基和C5-12杂芳基，其任选被卤素、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基取代；Y is selected from halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, C 3-8 cycloalkyl, C 3-8 oxacycloalkyl, C 3-8 azacycloalkyl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted with halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxyC 1-3 alkoxy, amino, monoC 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl , aminoacyl , C 1-3 alkylaminoacyl;
R1和R2各自独立地选自氢、卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、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、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基；或者两个R1与它们所连接的原子形成C3-8环烷基、C3-8氧杂环烷基、C3-8氮杂环烷基、C6-12芳基或C5-12杂芳基，其任选被卤素、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基、C3-8螺环烷基、C3-8螺杂环烷基、C6-12螺芳基或C5-12螺杂芳基取代； R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, hydroxy C1-3 alkoxy , nitro , carboxyl, cyano , amino, mono C1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl , aminoacyl, C1-3 alkylaminoacyl and di- C1-3 alkylamino; or two R1 and the atoms to which they are attached form a C3-8 cycloalkyl, C3-8 oxacycloalkyl, C3-8 azacycloalkyl, C6-12 aryl or C5-12 heteroaryl, which is optionally substituted by halogen, hydroxy, C1-3 alkyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, The alkyl is substituted with C1-3 alkoxy, hydroxyC1-3 alkoxy, amino, monoC1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, aminoacyl, C1-3 alkylaminoacyl , C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-8 spirocycloalkyl , C3-8 spiroheterocycloalkyl , C6-12 spiroaryl or C5-12 spiroheteroaryl;
R3选自氢、C1-3烷基、卤代C1-3烷基和羟基C1-3烷基；和 R3 is selected from hydrogen, C1-3 alkyl, halogenated C1-3 alkyl and hydroxy C1-3 alkyl; and
n和m各自独立地选自1、2、3和4。n and m are each independently selected from 1, 2, 3 and 4.
在一些具体的实施方案中，根据本发明的通式(I)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，其中选自 其任选被一个或多个氟、氯、溴、碘、羟基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基如三氟甲基、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、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基取代。In some specific embodiments, the compound of formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug according to the present invention, wherein Selected from It is optionally substituted by one or more fluorine, chlorine, bromine, iodine, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl such as trifluoromethyl, 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, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino.
在一些实施方案中，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 embodiments, the compound of the present invention is a compound of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
Y选自卤素、羟基、甲基、乙基、丙基、异丙基、氟、氯、溴、碘、环丙基、环丁基、环戊基、环己基、卤代C1-3烷基、乙烯基、乙炔基、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、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、环丙基、环丁基、环戊基、氧杂环丙基、氧杂环丁基、氧杂环戊基、苯基、吡唑基、吡啶基、C3-8氮氧杂环烷基如7-氧杂-2-氮杂螺[3.5]壬-2-基、C6-12芳基和C5-12杂芳基，其任选被氟、氯、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基取代；Y is selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogenated C 1-3 alkyl, vinyl, ethynyl, 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 alkyl acyl, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, phenyl, pyrazolyl, pyridyl, C 3-8 azacycloalkyl such as 7-oxa-2-azaspiro[3.5]non-2-yl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted with fluorine, chlorine, hydroxy, methyl, ethyl, propyl, isopropyl, halo-substituted C 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, halo-substituted C 1-3 alkoxy, hydroxyC 1-3 alkoxy, amino, mono-C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl;
R1和R2各自独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、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、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基；或者两个R1与它们所连接的原子形成C3-8环烷基、C3-8氧杂环烷基、C3-8氮杂环烷基、C6-12芳基或C5-12杂芳基如其任选被羟基、氢、氟、氯、溴、碘、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基、C3-8螺环烷基、C3-8螺杂环烷基、C6-12螺芳基或C5-12螺杂芳基取代；R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, 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, aminoacyl, C 1-3 alkylaminoacyl and di-C 1-3 alkylamino; or two R 1 and the atoms to which they are attached form a C 3-8 cycloalkyl, C 3-8 oxacycloalkyl, C 3-8 azacycloalkyl, C 6-12 aryl or C 5-12 heteroaryl such as which is optionally substituted with hydroxy, hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, halo-C 1-3 alkyl, hydroxy-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, hydroxy-C 1-3 alkoxy, amino, mono-C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, C 3-8 spirocycloalkyl, C 3-8 spiroheterocycloalkyl, C 6-12 spiroaryl or C 5-12 spiroheteroaryl;
R3选自氢、甲基、乙基、丙基、异丙基、卤代C1-3烷基和羟基C1-3烷基。 R3 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, halogenated C1-3 alkyl and hydroxy C1-3 alkyl.
在一些实施方案中，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，其中通式(I)具有以下通式(Ia)的结构，
In some embodiments, the present invention provides a compound represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
其中，in,
环A选自环烷基、杂环烷基、芳基、杂芳基，其任选被卤素、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、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基取代；和Ring A is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl and alkylaminoacyl; and
R1和R2具有以上通式(I)所述的定义。 R1 and R2 have the same meanings as those described above for the general formula (I).
在一些具体的实施方案中，根据本发明的通式(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，其中环A选自C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基，其任选被卤素、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、 氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基取代；In some specific embodiments, according to the compound of formula (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, which is optionally substituted by halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl and C 1-6 alkylaminoacyl substituted;
R1和R2各自独立地选自氢、卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、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、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基，所述杂原子选自碳、氮、氧原子；和 R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, nitro, carboxyl, cyano, amino, mono- C1-6 alkylamino, C1-6 alkylacylamino, C1-6 alkylacyl, aminoacyl, C1-6 alkylaminoacyl and di - C1-6 alkylamino, and the heteroatom is selected from carbon, nitrogen and oxygen atoms; and
n和m各自独立地选自1、2、3和4。n and m are each independently selected from 1, 2, 3 and 4.
在一些具体的实施方案中，根据本发明以上的通式(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，其中R1和R2各自独立地选自氢、氟、氯、溴、碘、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，其任选被羟基、氢、氟、氯、溴、碘、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基所取代。In some specific embodiments, according to the compound of the above general formula (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C1-3 alkyl, hydroxyl C1-3 alkyl, C1-3 alkoxy , halogenated C1-3 alkoxy, hydroxyl C1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, aminoacyl, C1-3 alkylaminoacyl and di C1-3 alkylamino, which are optionally replaced by hydroxyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C1-3 alkyl, hydroxyl C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, hydroxyl C1-3 The alkylene group may be substituted with C 1-3 alkoxy, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, aminoacyl or C 1-3 alkylaminoacyl.
在一些具体的实施方案中，根据本发明以上的通式(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，其中环A选自其任选被卤素、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、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基取代；进一步地，其任选被羟基、氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、卤代C1-3烷基如三氟甲基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基所取代。In some specific embodiments, according to the compound of the above general formula (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from It is optionally substituted by 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, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl and C 1-6 alkylaminoacyl; further, it is optionally substituted by hydroxy, hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl such as trifluoromethyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy.
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:


本发明的发明人意料不到地发现，本发明的式(Ia)化合物具有明显降低的心脏毒性，用药安全性好。The inventors of the present invention unexpectedly found that the compound of formula (Ia) of the present invention has significantly reduced cardiac toxicity and good drug safety.
第二方面，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 a second 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GSPT1相关的疾病例如癌症。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 the pharmaceutical composition is used to treat a GSPT1-related disease such as cancer.
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)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GSPT1相关的疾病的方法以及在制备治疗GSPT1相关的疾病的药物中的用途。In a third aspect, the present invention provides a method for treating GSPT1-related diseases using a compound represented by formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same, as well as use of the compound in the preparation of a drug for treating GSPT1-related diseases.
在一些优选的实施方案中，本发明提供本发明式(I)、(Ia)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GSPT1相关的疾病如癌症的方法以及在制备治疗GSPT1相关的疾病如癌症的药物中的用途。In some preferred embodiments, the present invention provides a method for treating GSPT1-related diseases such as cancer using a compound represented by formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same, as well as use in the preparation of a medicament for treating GSPT1-related diseases such as cancer.
在一些优选的实施方案中，本发明提供本发明通式(I)、(Ia)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癌症的方法以及在制备治疗癌症的药物中的用途，其中所述的癌症包括但不限于：非小细胞肺癌、肺腺癌、肺癌、大细胞肺癌、非小细胞肺癌、肺鳞状细胞癌、小细胞肺癌、黑色素瘤、促纤维增生性黑色素瘤、葡萄膜黑色素瘤、卵巢小细胞癌、卵巢横纹肌样瘤、皮肤鳞状细胞癌、神经胶质瘤、子宫癌、子宫内膜癌、卵巢浆液性囊腺癌、膀胱尿路上皮癌、原发性中枢神经系统淋巴瘤、食道癌、膀胱癌、胃腺癌、腺样囊性癌、淋巴 样肿瘤弥漫性大B细胞淋巴瘤、胰腺癌、结直肠腺癌、胆管癌、肉瘤、头颈癌、宫颈癌和宫颈管癌、髓母细胞瘤、皮肤T细胞淋巴瘤、肝细胞癌、肾乳头状细胞癌、乳腺癌、套细胞淋巴瘤、胆囊癌、睾丸生殖细胞癌、肾细胞透明细胞癌、前列腺癌、小儿尤因肉瘤、胸腺瘤、肾嫌色细胞癌、肾非透明细胞癌、嗜铬细胞瘤和副神经节瘤、甲状腺癌、恶性周围神经鞘瘤、神经内分泌前列腺癌、头颈鳞状细胞癌、肾上腺皮质癌、宫颈癌和宫颈管癌、皮肤鳞状细胞癌、睾丸生殖细胞癌、成胶质细胞瘤、多形性成胶质细胞瘤、尤因肉瘤、透明细胞肾细胞癌、成神经细胞瘤、弥漫性大B细胞淋巴瘤、急性髓样白血病、慢性淋巴细胞性白血病、多发性骨髓瘤、恶性横纹肌样瘤、上皮样肉瘤、肾髓质癌、滑膜肉瘤、脑膜瘤和软组织肉瘤。In some preferred embodiments, the present invention provides a method for treating cancer and a use of a compound represented by general formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same in the preparation of a drug for treating cancer, wherein the cancer includes but is not limited to: non-small cell lung cancer, lung adenocarcinoma, lung cancer, large cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, small cell lung cancer, melanoma, desmoplastic melanoma, uveal melanoma, ovarian small cell carcinoma, ovarian rhabdoid tumor, skin squamous cell carcinoma, glioma, uterine cancer, endometrial cancer, ovarian serous cystadenocarcinoma, bladder urothelial carcinoma, primary central nervous system lymphoma, esophageal cancer, bladder cancer, gastric adenocarcinoma, adenoid cystic carcinoma, lymphoma diffuse large B-cell lymphoma, pancreatic cancer, colorectal adenocarcinoma, bile duct cancer, sarcoma, head and neck cancer, cervical cancer and endocervical cancer, medulloblastoma, cutaneous T-cell lymphoma, hepatocellular carcinoma, renal papillary cell carcinoma, breast cancer, mantle cell lymphoma, gallbladder cancer, testicular germ cell cancer, renal clear cell carcinoma, prostate cancer, pediatric Ewing sarcoma, thymoma, renal chromophobe cell carcinoma, renal non-clear cell carcinoma, pheochromocytoma and paraganglioma, thyroid cancer, malignant peripheral nerve sheath tumor , neuroendocrine prostate cancer, squamous cell carcinoma of the head and neck, adrenal cortical carcinoma, cervical cancer and endocervical canal cancer, squamous cell carcinoma of the skin, testicular germ cell cancer, glioblastoma, glioblastoma multiforme, Ewing sarcoma, clear cell renal cell carcinoma, neuroblastoma, diffuse large B-cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, malignant rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, synovial sarcoma, meningioma, and soft tissue sarcoma.
在一些具体的实施方案中，本发明的通式(I)、(Ia)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药用于治疗由GSPT1蛋白累积引起的病症，如非霍奇金淋巴瘤、白血病和/或实体瘤。所述非霍奇金淋巴瘤选自弥漫大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤、黏膜相关淋巴组织淋巴瘤和T细胞淋巴瘤的一种或多种。所述白血病包括慢性淋巴细胞白血病、慢性粒细胞性白血病、急性淋巴细胞白血病、急性髓性白血病中的一种或多种。所述实体瘤包括肺癌、肝癌、乳腺癌、脑胶质瘤中的一种或多种。In some specific embodiments, the compound represented by the general formula (I) or (Ia) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug is used to treat a disease caused by accumulation of GSPT1 protein, such as non-Hodgkin's lymphoma, leukemia and/or solid tumor. The non-Hodgkin's lymphoma is selected from one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma and T-cell lymphoma. The leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia. The solid tumor includes one or more of lung cancer, liver cancer, breast cancer and brain glioma.
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 that lacks 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 diastereoisomer 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 further preferably a straight or branched group containing 1 to 3 carbon atoms, non-limiting examples of which 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-C(O)-是指“羰基”。The -C(O)- group of the present invention means a "carbonyl group".
本发明的-S(O)2-是指“磺酰基”。The -S(O) 2 - group of the present invention means a "sulfonyl group".
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 spiro 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”或“杂芳环”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" or "heteroaromatic ring" of the present invention refers to an aryl 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 commercially available unless otherwise specified.
实施例1：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-5-(3,6-二氢-2H-吡喃-4-基)-2-氟苯基)氨基甲酸酯
Example 1: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)carbamate
步骤1：3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
Step 1: Preparation of 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
称取3-(6-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(5g,15.5mmol)、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(690mg,0.8mmol)和三丁基锡甲醇(6.0g,18.6mmol)于250mL三颈烧瓶中，加入N,N-二甲基甲酰胺(150mL)溶解，80℃反应8h。反应结束后，反应液浓缩，抽滤，二氯甲烷洗涤，烘干得标题化合物。ESI-MS m/z:275.1[M+H]+ Weigh 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5 g, 15.5 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (690 mg, 0.8 mmol) and tributyltinmethanol (6.0 g, 18.6 mmol) in a 250 mL three-necked flask, add N,N-dimethylformamide (150 mL) to dissolve, and react at 80°C for 8 h. After the reaction is completed, the reaction solution is concentrated, filtered, washed with dichloromethane, and dried to obtain the title compound. ESI-MS m/z: 275.1[M+H] +
步骤2：5-溴-4-氯-2-氟苯胺的制备
Step 2: Preparation of 5-bromo-4-chloro-2-fluoroaniline
将1-溴-2-氯-4-氟-5-硝基苯(1.00g，3.9mmol)和乙醇(10mL)加入到三颈烧瓶中，室温搅拌下加入铁粉(1.10g，19.7mmol)、氯化铵(1.1g，19.7mmol)和水(2ml)，70℃反应2h。反应结束后，乙酸乙酯萃取，无水硫酸钠干燥后，减压浓缩，得标题化合物，ESI-MS m/z:224.2[M+H]+ 1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (1.00 g, 3.9 mmol) and ethanol (10 mL) were added to a three-necked flask, and iron powder (1.10 g, 19.7 mmol), ammonium chloride (1.1 g, 19.7 mmol) and water (2 ml) were added under stirring at room temperature, and the mixture was reacted at 70°C for 2 h. After the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, ESI-MS m/z: 224.2 [M+H] +
步骤3：4-氯-5-(3,6-二氢-2H-吡喃-4-基)-2-氟苯胺的制备
Step 3: Preparation of 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoroaniline
称取5-溴-4-氯-2-氟苯胺(2.1g,9.1mmol)、3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(2.9g,13.7m ml)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(1.3g,1.8mmol)和碳酸铯(8.9g,27.4mmol)加入到 100mL三颈烧瓶中，加入二氧六环(50mL)和水(2mL)，氩气保护下，80℃反应12h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，得标题化合物，ESI-MS m/z:228.1[M+H]+。Weigh 5-bromo-4-chloro-2-fluoroaniline (2.1 g, 9.1 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (2.9 g, 13.7 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.3 g, 1.8 mmol) and cesium carbonate (8.9 g, 27.4 mmol) and add In a 100 mL three-necked flask, add dioxane (50 mL) and water (2 mL), and react at 80°C for 12 h under argon protection. After the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound, ESI-MS m/z: 228.1 [M+H] + .
步骤4：4-(2-氯-4-氟-5-异氰基苯基)-3,6-二氢-2H-吡喃的制备
Step 4: Preparation of 4-(2-chloro-4-fluoro-5-isocyanophenyl)-3,6-dihydro-2H-pyran
称取4-氯-5-(3,6-二氢-2H-吡喃-4-基)-2-氟苯胺(122mg，0.54mmol)于25mL三口瓶中，3mL甲苯溶解，搅拌下加入三光气(159mg，0.54mmol)，100℃下回流2h小时。反应结束后，反应液浓缩得标题化合物。ESI-MS m/z:254.2[M+H]+。Weigh 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoroaniline (122 mg, 0.54 mmol) in a 25 mL three-necked flask, dissolve in 3 mL of toluene, add triphosgene (159 mg, 0.54 mmol) under stirring, and reflux at 100°C for 2 hours. After the reaction is completed, the reaction solution is concentrated to obtain the title compound. ESI-MS m/z: 254.2 [M+H] + .
步骤5：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-5-(3,6-二氢-2H-吡喃-4-基)-2-氟苯基)氨基甲酸酯的制备
Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)carbamate
称取化合物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147mg，0.54mmol)、三乙胺(60mg，0.59mmol)于三颈烧瓶中，用N,N-二甲基甲酰胺(3mL)溶解，0℃下搅拌0.5h。然后在0℃下滴加4-(2-氯-4-氟-5-异氰基苯基)-3,6-二氢-2H-吡喃，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析纯化得标题产物。ESI-MS m/z:528.2[M+H]+。Weigh the compound 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147 mg, 0.54 mmol) and triethylamine (60 mg, 0.59 mmol) in a three-necked flask, dissolve it with N,N-dimethylformamide (3 mL), and stir it at 0°C for 0.5 h. Then, add 4-(2-chloro-4-fluoro-5-isocyanophenyl)-3,6-dihydro-2H-pyran dropwise at 0°C and react at room temperature for 1 h. After the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with column chromatography to obtain the title product. ESI-MS m/z: 528.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.70(s,1H),7.80(s,1H),7.72-7.55(m,3H),7.46(d,J＝10.5Hz,1H),5.77(s,1H),5.28(s,2H),5.13(dd,1H),4.41(dd,2H),4.18(s,2H),3.79(t,J＝5.0Hz,2H),2.96-2.87(m,1H),2.65-2.56(m,1H),2.44-2.38(m,1H),2.32(s,2H),2.05-1.98(m,1H). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.70 (s, 1H), 7.80 (s, 1H), 7.72-7.55 (m, 3H), 7.46 (d, J = 10.5 Hz, 1H), 5.77 (s, 1H), 5.28 (s, 2H), 5.13 (dd, 1H), 4.41 (dd, 2H), 4.18 (s, 2H), 3.79 (t, J = 5.0 Hz, 2H), 2.96-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.38 (m, 1H), 2.32 (s, 2H), 2.05-1.98 (m, 1H).
实施例2：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-(环丙基乙炔基)苯基)氨基甲酸酯
Example 2: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(cyclopropylethynyl)phenyl)carbamate
步骤1：4-氯-3-(环丙基乙炔基)苯胺的制备
Step 1: Preparation of 4-chloro-3-(cyclopropylethynyl)aniline
将4-氯-3-碘-苯胺(1.5g,5.9mmol)加入到三颈烧瓶中，加入10mL 1,4-二氧六环使其溶解，然后加入环丙基乙炔(783mg,11.8mmol)、双三苯基膦二氯化钯(831mg,1.2mmol)、碘化亚铜(226mg,1.2mmol)和三乙胺(1.2g,11.8mmol)，惰性气体保护，45℃下反应12h。反应结束后，抽滤，滤液用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩得标题产物。ESI-MS m/z:192.1[M+H]+ Add 4-chloro-3-iodo-aniline (1.5 g, 5.9 mmol) to a three-necked flask, add 10 mL of 1,4-dioxane to dissolve it, then add cyclopropylacetylene (783 mg, 11.8 mmol), bistriphenylphosphine palladium dichloride (831 mg, 1.2 mmol), cuprous iodide (226 mg, 1.2 mmol) and triethylamine (1.2 g, 11.8 mmol), protect with inert gas, and react at 45 ° C for 12 h. After the reaction is completed, filter, extract the filtrate with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title product. ESI-MS m/z: 192.1 [M + H] +
步骤2：苯基(4-氯-3-((环丙基)乙炔基)苯基)氨基甲酸酯的制备
Step 2: Preparation of phenyl (4-chloro-3-((cyclopropyl)ethynyl)phenyl)carbamate
将4-氯-3-((环丙基)乙炔基)苯胺(700mg,3.65mmol)加入到三颈烧瓶中，加入二氯甲烷(15mL)和三乙胺(739mg,7.3mmol)，0℃滴加氯甲酸苯酯(686mg,4.4mmol)，室温反应1h。反应结束后，反应液浓缩，柱层析，得到720mg棕色油状物。ESI-MS m/z:312.1[M+H]+ 4-Chloro-3-((cyclopropyl)ethynyl)aniline (700 mg, 3.65 mmol) was added to a three-necked flask, followed by dichloromethane (15 mL) and triethylamine (739 mg, 7.3 mmol), and phenyl chloroformate (686 mg, 4.4 mmol) was added dropwise at 0°C, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and column chromatography was performed to obtain 720 mg of a brown oil. ESI-MS m/z: 312.1 [M+H] +
步骤3：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-(环丙基乙炔基)苯基)氨基甲酸酯的制备
Step 3: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(cyclopropylethynyl)phenyl)carbamate
称取实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(200mg,0.73mmol)加入到三颈烧瓶中，0℃下加入NaH，搅拌10min，滴加苯基(4-氯-3-((环丙基)乙炔基)苯基)氨基甲酸酯(250mg,0.80mmol)的N,N-二甲基甲酰胺(5mL)溶液，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析，得白色标题产物。ESI-MS m/z:492.2[M+H]+ The product of step 1 in Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.73 mmol) was weighed and added to a three-necked flask, NaH was added at 0°C, stirred for 10 min, and a solution of phenyl(4-chloro-3-((cyclopropyl)ethynyl)phenyl)carbamate (250 mg, 0.80 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and reacted at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain a white title product. ESI-MS m/z: 492.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.99(s,1H),7.79(s,1H),7.71-7.57(m,3H),7.40(s,2H),5.28(s,2H),5.13(dd,J＝13.1,4.8Hz,1H),4.47(d,J＝17.4Hz,1H),4.34(d,J＝17.4Hz,1H),2.98-2.86(m,1H),2.60(d,J＝16.6Hz,1H),2.40(d,J＝9.2Hz,1H),2.06-1.98(m,1H),1.64-1.55(m,1H),0.97 -0.89(m,2H),0.80-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.99 (s, 1H), 7.79 (s, 1H), 7.71-7.57 (m, 3H), 7.40 (s, 2H), 5.28 (s, 2H), 5.13 (dd, J = 13.1, 4.8 Hz, 1H), 4.47 (d, J = 17.4 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 2.98-2.86 (m, 1H), 2.60 (d, J = 16.6 Hz, 1H), 2.40 (d, J = 9.2 Hz, 1H), 2.06-1.98 (m, 1H), 1.64-1.55 (m, 1H), 0.97 -0.89(m,2H),0.80-0.72(m,2H).
实施例3：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-(3-羟基-3-甲基丁-1-炔-1-基)苯基)氨基甲酸酯
Example 3: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamate
步骤1：4-(5-氨基-2-氯苯基)-2-甲基丁-3-炔-2-醇的制备
Step 1: Preparation of 4-(5-amino-2-chlorophenyl)-2-methylbut-3-yn-2-ol
将3-碘-4-氯苯胺(500mg,1.97mmol)和1,4-二氧六环(10ml)加入到三颈烧瓶中，搅拌下加入双三苯基膦二氯化钯(554mg,0.39mmol)、碘化亚铜(150mg,0.39mmol)和三乙胺(798mg,3.94mmol)，最后加入2-甲基-3-丁炔-2-醇(522mg,3.94mmol)。惰性气体保护，50℃反应12h。反应结束后，乙酸乙酯萃取，无水硫酸钠干燥后，减压浓缩，得标题产物。ESI-MS m/z:210.1[M+H]+步骤2：4-(2-氯-5-异氰基苯基)-2-甲基丁-3-炔-2-醇的制备
Add 3-iodo-4-chloroaniline (500 mg, 1.97 mmol) and 1,4-dioxane (10 ml) to a three-necked flask, add bistriphenylphosphine palladium dichloride (554 mg, 0.39 mmol), cuprous iodide (150 mg, 0.39 mmol) and triethylamine (798 mg, 3.94 mmol) under stirring, and finally add 2-methyl-3-butyn-2-ol (522 mg, 3.94 mmol). Protect with inert gas and react at 50 ° C for 12 hours. After the reaction is completed, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title product. ESI-MS m/z: 210.1 [M+H] + Step 2: Preparation of 4-(2-chloro-5-isocyanophenyl)-2-methylbut-3-yn-2-ol
将4-(5-氨基-2-氯苯基)-2-甲基丁-3-炔-2-醇(113mg，0.54mmol)和三光气(159mg，0.54mmol)加入到单颈烧瓶中，量取3mL溶解，100℃下回流2h小时。反应结束后，反应液浓缩得标题产物。ESI-MS m/z:236.1[M+H]+ 4-(5-amino-2-chlorophenyl)-2-methylbut-3-yn-2-ol (113 mg, 0.54 mmol) and triphosgene (159 mg, 0.54 mmol) were added to a single-necked flask, 3 mL was dissolved, and refluxed at 100°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title product. ESI-MS m/z: 236.1 [M+H] +
步骤3：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-(3-羟基-3-甲基丁-1-炔-1-基)苯基)氨基甲酸酯的制备
Step 3: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamate
称取实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147mg，0.54mmol)加入到三颈烧瓶中，加入N,N-二甲基甲酰胺(3mL)和三乙胺(60mg，0.59mmol)，0℃下搅拌0. 5h。0℃下滴加4-(2-氯-5-异氰基苯基)-2-甲基丁酸-3-炔-2-醇，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析，制备分离得标题产物。ESI-MS m/z:510.2[M+H]+ The product of step 1 in Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147 mg, 0.54 mmol) was weighed and added to a three-necked flask, and N,N-dimethylformamide (3 mL) and triethylamine (60 mg, 0.59 mmol) were added, and stirred at 0°C for 0. 5h. 4-(2-chloro-5-isocyanophenyl)-2-methylbutyric acid-3-yn-2-ol was added dropwise at 0°C and reacted at room temperature for 1h. After the reaction, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title product. ESI-MS m/z: 510.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.03(s,1H),7.80(s,1H),7.70-7.62(m,3H),7.43(s,2H),5.53(s,1H),5.29(s,2H),5.13(dd,J＝13.2,4.9Hz,1H),4.41(dd,J＝51.3,17.4Hz,2H),2.96-2.87(m,1H),2.61(d,J＝16.1Hz,1H),2.44-2.36(m,1H),2.05-1.98(m,1H),1.48(s,6H). 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.03 (s, 1H), 7.80 (s, 1H), 7.70-7.62 (m, 3H), 7.43 (s, 2H), 5.53 (s, 1H), 5.29 (s, 2H), 5.13 (dd, J = 13.2, 4.9 Hz, 1H), 4.41 (dd, J = 51.3, 17.4 Hz, 2H), 2.96-2.87 (m, 1H), 2.61 (d, J = 16.1 Hz, 1H), 2.44-2.36 (m, 1H), 2.05-1.98 (m, 1H), 1.48 (s, 6H).
实施例4：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(5-(环丙基乙炔基)-6-甲基吡啶-3-基)氨基甲酸酯
Example 4: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(5-(cyclopropylethynyl)-6-methylpyridin-3-yl)carbamate
步骤1：5-(环丙基乙炔基)-6-甲基吡啶-3-胺的制备
Step 1: Preparation of 5-(cyclopropylethynyl)-6-methylpyridin-3-amine
将5-氨基-3-溴-2-甲基吡啶(1.0g,5.3mmol)和1,4-二氧六环(10mL)加入到三颈烧瓶中，加入双三苯基膦二氯化钯(1.5g,1.1mmol)、碘化亚铜(407mg,1.07mmol)、三乙胺(2.2g,10.7mmol)，最后加入环丙乙炔(1.8g,26.7mmol)。惰性气体保护，50℃反应12h。反应结束后，乙酸乙酯萃取，无水硫酸钠干燥后，减压浓缩，得标题产物。ESI-MS m/z:173.1[M+H]+ Add 5-amino-3-bromo-2-methylpyridine (1.0 g, 5.3 mmol) and 1,4-dioxane (10 mL) to a three-necked flask, add bistriphenylphosphine palladium dichloride (1.5 g, 1.1 mmol), cuprous iodide (407 mg, 1.07 mmol), triethylamine (2.2 g, 10.7 mmol), and finally add cyclopropylacetylene (1.8 g, 26.7 mmol). Protect with inert gas and react at 50 °C for 12 h. After the reaction is completed, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title product. ESI-MS m/z: 173.1 [M+H] +
步骤2：3-(环丙基乙炔基)-5-异氰基-2-甲基吡啶的制备
Step 2: Preparation of 3-(cyclopropylethynyl)-5-isocyano-2-methylpyridine
称取5-(环丙基乙炔基)-6-甲基吡啶-3-胺(93mg，0.54mmol)于25mL单颈烧瓶中，3mL甲苯溶解，加入三光气(160mg，0.54mmol)，100℃下回流2h小时。反应结束后，反应液浓缩得标题产物，收率按100％计算。ESI-MS m/z:199.2[M+H]+ Weigh 5-(cyclopropylethynyl)-6-methylpyridin-3-amine (93 mg, 0.54 mmol) in a 25 mL single-necked flask, dissolve in 3 mL toluene, add triphosgene (160 mg, 0.54 mmol), and reflux at 100 ° C for 2 hours. After the reaction is completed, the reaction solution is concentrated to obtain the title product, and the yield is calculated as 100%. ESI-MS m/z: 199.2 [M + H] +
步骤3：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(5-(环丙基乙炔基)-6-甲基吡啶-3-基)氨基 甲酸酯的制备
Step 3: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(5-(cyclopropylethynyl)-6-methylpyridin-3-yl)amino Preparation of formate
称取实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147mg，0.54mmol)加入到三颈烧瓶中，加入4mL N,N-二甲基甲酰胺和三乙胺(60mg，0.59mmol)，0℃下搅拌0.5h。然后在0℃下滴加3-(环丙炔基)-5-异氰酸酯-2-甲基吡啶(120mg，0.54mmol)，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析，制备分离得到30mg白色固体。ESI-MS m/z:473.2[M+H]+ Weigh the product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147 mg, 0.54 mmol) and add it to a three-necked flask, add 4 mL of N,N-dimethylformamide and triethylamine (60 mg, 0.59 mmol), and stir at 0°C for 0.5 h. Then, 3-(cyclopropynyl)-5-isocyanate-2-methylpyridine (120 mg, 0.54 mmol) was added dropwise at 0°C and reacted at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 30 mg of a white solid. ESI-MS m/z:473.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.98(s,1H),8.42(s,1H),7.80(s,2H),7.66(dd,J＝19.7,7.7Hz,2H),5.28(s,2H),5.12(dd,J＝13.2,4.5Hz,1H),4.41(dd,J＝52.0,17.4Hz,2H),2.97-2.86(m,1H),2.60(d,J＝17.5Hz,1H),2.44(s,3H),2.41-2.34(m,1H),2.07-1.98(m,1H),1.65-1.54(m,1H),0.99-0.86(m,2H),0.81-0.70(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.98 (s, 1H), 8.42 (s, 1H), 7.80 (s, 2H), 7.66 (dd, J = 19.7, 7.7 Hz, 2H), 5.28 (s, 2H), 5.12 (dd, J = 13.2, 4.5 Hz, 1H), 4.41 (dd, J = 52.0, 17.4 Hz, 2H), 2.97-2.86 (m, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.44 (s, 3H), 2.41-2.34 (m, 1H), 2.07-1.98 (m, 1H), 1.65-1.54 (m, 1H), 0.99-0.86 (m, 2H), 0.81-0.70 (m, 2H).
实施例5：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-5-(环丙基乙炔基)-2-氟苯基)氨基甲酸酯
Example 5: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(cyclopropylethynyl)-2-fluorophenyl)carbamate
步骤1：5-溴-4-氯-2-氟苯胺的制备
Step 1: Preparation of 5-bromo-4-chloro-2-fluoroaniline
将1-溴-2-氯-4-氟-5-硝基苯(1.8g,7.2mmol)加入到单颈烧瓶中，加入铁粉(2.0g,36.0mmol)、氯化铵(1.92g,36.0mmol)、乙醇(30mL)和水(6mL)，70℃反应2h。反应结束后，抽滤反应液，滤液减压浓缩，用乙酸乙酯溶解，抽滤，滤液减压浓缩，得标题产物。ESI-MS m/z:223.8[M+H]+.1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (1.8 g, 7.2 mmol) was added to a single-necked flask, and iron powder (2.0 g, 36.0 mmol), ammonium chloride (1.92 g, 36.0 mmol), ethanol (30 mL) and water (6 mL) were added, and the mixture was reacted at 70°C for 2 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, dissolved with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product. ESI-MS m/z: 223.8 [M+H] + .
步骤2：4-氯-5-(环丙基乙炔基)-2-氟苯胺的制备
Step 2: Preparation of 4-chloro-5-(cyclopropylethynyl)-2-fluoroaniline
将5-溴-4-氯-2-氟苯胺(1g,4.5mmol)加入到封管中，加入1,4-二氧六环(10mL)，然后加入乙基环丙烷(0.76mL,8.91mmol)、双三苯基磷二氯化钯(313mg,0.45mmol)、碘化亚铜(170mg，0.89mmol)和三乙胺(1.2mL)，氩气保护，80℃反应过夜。反应结束后，过滤除催化剂，滤液减压浓缩，柱层析，得到白色标题产物。ESI-MS m/z:210.1[M+H]+.Add 5-bromo-4-chloro-2-fluoroaniline (1g, 4.5mmol) to a sealed tube, add 1,4-dioxane (10mL), then add ethylcyclopropane (0.76mL, 8.91mmol), bistriphenylphosphine palladium dichloride (313mg, 0.45mmol), cuprous iodide (170mg, 0.89mmol) and triethylamine (1.2mL), protect with argon, and react at 80℃ overnight. After the reaction is completed, filter out the catalyst, concentrate the filtrate under reduced pressure, and column chromatography to obtain the white title product. ESI-MS m/z: 210.1[M+H] + .
步骤3：1-氯-2-(环丙基乙炔基)-5-氟-4-异氰基苯的制备
Step 3: Preparation of 1-chloro-2-(cyclopropylethynyl)-5-fluoro-4-isocyanobenzene
将4-氯-5-(环丙基乙炔基)-2-氟苯胺(103mg,0.49mmol)加入到三颈烧瓶中，加入甲苯(3mL)和三光气(146mg,0.49mmol)，氩气保护，100℃反应2h。反应结束后，反应液浓缩，收率按100％，直接用于下一步反应。ESI-MS m/z:236.1[M+H]+.4-Chloro-5-(cyclopropylethynyl)-2-fluoroaniline (103 mg, 0.49 mmol) was added to a three-necked flask, and toluene (3 mL) and triphosgene (146 mg, 0.49 mmol) were added. The mixture was protected by argon and reacted at 100°C for 2 h. After the reaction, the reaction solution was concentrated and the yield was 100%, which was directly used for the next step. ESI-MS m/z: 236.1 [M+H] + .
步骤4：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-5-(环丙基乙炔基)-2-氟苯基)氨基甲酸酯的制备
Step 4: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-5-(cyclopropylethynyl)-2-fluorophenyl)carbamate
将实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(112mg,0.41mmol)加入到三颈烧瓶中，加入3mL N,N-二甲基甲酰胺和三乙胺(50mg,0.49mmol)，0℃下，氩气保护，滴加1-氯-2-(环丙基乙炔基)-5-氟-4-异氰基苯，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析得标题产物。ESI-MS m/z:509.9[M+H]+。The product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112 mg, 0.41 mmol) was added to a three-necked flask, and 3 mL of N,N-dimethylformamide and triethylamine (50 mg, 0.49 mmol) were added. 1-chloro-2-(cyclopropylethynyl)-5-fluoro-4-isocyanobenzene was added dropwise at 0°C under argon protection, and the mixture was reacted at room temperature for 1 h. After the reaction, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m/z: 509.9 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.77(s,1H),7.87-7.77(m,2H),7.66(dd,J＝18.1,7.2Hz,2H),7.55(d,J＝10.4Hz,1H),5.28(s,2H),5.13(dd,J＝12.9,4.2Hz,1H),4.47(d,J＝17.3Hz,1H),4.34(d,J＝17.3Hz,1H),2.98-2.86(m,1H),2.61(d,J＝17.0Hz,1H),2.45-2.34(m,1H),2.07-1.97(m,1H),1.64-1.54(m,1H),0.98-0.88(m,2H),0.81-0.70(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.77 (s, 1H), 7.87-7.77 (m, 2H), 7.66 (dd, J = 18.1, 7.2 Hz, 2H), 7.55 (d, J = 10.4 Hz, 1H), 5.28 (s, 2H), 5.13 (dd, J = 12.9, 4.2 Hz, 1H), 4.47 (d, J =17.3 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 2.98-2.86 (m, 1H), 2.61 (d, J = 17.0 Hz, 1H), 2.45-2.34 (m, 1H), 2.07 -1.97(m,1H),1.64-1.54(m,1H),0.98-0.88(m,2H),0.81-0.70(m,2H).
实施例6：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-((3-氟氧杂环丁烷-3-基)乙炔基)苯基)氨基甲酸酯
Example 6: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)phenyl)carbamate
步骤1：3-((2-氯-5-硝基苯基)乙炔基)氧杂环丁烷-3-醇的制备
Step 1: Preparation of 3-((2-chloro-5-nitrophenyl)ethynyl)oxetane-3-ol
称取1-氯-2-碘-4-硝基苯(1g,3.53mmol)于单颈烧瓶中，加入10mL 1,4-二氧六环溶解，加入双三苯基膦二氯化钯(246mg,0.35mmol)、碘化亚铜(133mg,0.7mmol)、三乙胺(715mg,7.06mmol)以及3-乙基氧杂环丁烷-3-醇(693mg,7.06mmol)，氩气保护下，45℃反应12h。反应结束后，减压浓缩，柱层析纯化得标题产物。ESI-MS m/z:254.1[M+H]+.Weigh 1-chloro-2-iodo-4-nitrobenzene (1g, 3.53mmol) in a single-necked flask, add 10mL 1,4-dioxane to dissolve, add bistriphenylphosphine palladium dichloride (246mg, 0.35mmol), cuprous iodide (133mg, 0.7mmol), triethylamine (715mg, 7.06mmol) and 3-ethyloxetane-3-ol (693mg, 7.06mmol), and react at 45℃ for 12h under argon protection. After the reaction is completed, concentrate under reduced pressure and purify by column chromatography to obtain the title product. ESI-MS m/z: 254.1[M+H] + .
步骤2：3-((2-氯-5-硝基苯基)乙炔基)-3-氟氧杂环丁烷的制备
Step 2: Preparation of 3-((2-chloro-5-nitrophenyl)ethynyl)-3-fluorooxetane
将3-((2-氯-5-硝基苯基)乙炔基)氧杂环丁烷-3-醇(500mg,1.9mmol)加入到三颈烧瓶中,加入二氯甲烷(5mL)溶解，惰性气体保护，-78℃下加入双(2-甲氧基乙基)氨基三氟化硫(510mg,2.3mmol)，保持此温度反应0.5h。反应结束后，二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析纯化得标题产物。ESI-MS m/z:256.1[M+H]+.3-((2-chloro-5-nitrophenyl)ethynyl)oxetane-3-ol (500mg, 1.9mmol) was added to a three-necked flask, and dichloromethane (5mL) was added to dissolve. Under inert gas protection, bis(2-methoxyethyl)aminosulfur trifluoride (510mg, 2.3mmol) was added at -78°C, and the temperature was maintained for 0.5h. After the reaction, dichloromethane was extracted, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS m/z: 256.1[M+H] + .
步骤3：4-氯-3-((3-氟氧杂环丁烷-3-基)乙炔基)苯胺的制备
Step 3: Preparation of 4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)aniline
将3-((2-氯-5-硝基苯基)乙炔基)-3-氟氧杂环丁烷(340mg,1.3mmol)加入到三颈烧瓶中,加入乙醇(4mL)溶解，加入铁粉(372mg,6.7mmol)、氯化铵(71mg,1.3mmol)、水(1mL)，惰性气体保护，90℃反应5h。反应结束后，抽滤，甲醇溶液洗涤，减压浓缩，得到淡黄色固体(290mg)。ESI-MS m/z:226.1[M+H]+ 3-((2-chloro-5-nitrophenyl)ethynyl)-3-fluorooxetane (340 mg, 1.3 mmol) was added to a three-necked flask, ethanol (4 mL) was added to dissolve, iron powder (372 mg, 6.7 mmol), ammonium chloride (71 mg, 1.3 mmol), and water (1 mL) were added, and the mixture was reacted at 90 °C for 5 h under inert gas protection. After the reaction was completed, the mixture was filtered, washed with methanol solution, and concentrated under reduced pressure to obtain a light yellow solid (290 mg). ESI-MS m/z: 226.1[M+H] +
步骤4：3-((2-氯-5-异氰基苯基)乙炔基)-3-氟氧杂环丁烷的制备
Step 4: Preparation of 3-((2-chloro-5-isocyanophenyl)ethynyl)-3-fluorooxetane
将4-氯-3-((3-氟氧杂环丁烷-3-基)乙炔基)苯胺(110mg，0.48mmol)加入到单颈烧瓶中，加入甲苯(2mL)溶解，加入二(三氯甲基)碳酸酯(143mg，0.48mmol)，惰性气体保护，100℃反应2h。反应结束后，浓缩得标题产物。ESI-MS m/z:252.1[M+H]+ 4-Chloro-3-((3-fluorooxetane-3-yl)ethynyl)aniline (110 mg, 0.48 mmol) was added to a single-necked flask, toluene (2 mL) was added to dissolve, and di(trichloromethyl)carbonate (143 mg, 0.48 mmol) was added. The mixture was protected by inert gas and reacted at 100°C for 2 h. After the reaction was completed, the mixture was concentrated to obtain the title product. ESI-MS m/z: 252.1[M+H] +
步骤5：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-((3-氟氧杂环丁烷-3-基)乙炔基)苯基)氨基甲酸酯的制备
Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)phenyl)carbamate
称取实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(120mg，0.44mmol)加入到三颈烧瓶中，加入N,N-二甲基甲酰胺(2mL)溶解，加入三乙胺(132mg，1.30mmol)，j搅拌下滴加3-((2-氯-5-异氰基苯基)乙炔基)-3-氟氧杂环丁烷(122mg,0.49mmol)，室温反应2h。反应结束后，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩，柱层析纯化得标题产物。ESI-MS m/z:524.2[M-H]+ The product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.44 mmol) was weighed and added to a three-necked flask, N,N-dimethylformamide (2 mL) was added to dissolve, triethylamine (132 mg, 1.30 mmol) was added, and 3-((2-chloro-5-isocyanatophenyl)ethynyl)-3-fluorooxetane (122 mg, 0.49 mmol) was added dropwise under stirring, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by column chromatography to obtain the title product. ESI-MS m/z: 524.2 [MH] +
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.15(s,1H),7.59(d,J＝14.6Hz,6H),5.29(s,2H),5.12(s,1H),4.90(d,4H),4.41(dd,J＝16.8Hz,2H),2.91(s,1H),2.60(s,1H),2.40-2.33(m,1H),2.01(s,1H). 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.15 (s, 1H), 7.59 (d, J = 14.6 Hz, 6H), 5.29 (s, 2H), 5.12 (s, 1H), 4.90 (d, 4H), 4.41 (dd, J = 16.8 Hz, 2H), 2.91 (s, 1H), 2.60 (s, 1H), 2.40-2.33 (m, 1H), 2.01 (s, 1H).
实施例7：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-基)氨基甲酸酯
Example 7: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate
步骤1：6-甲基-5-((三甲基硅烷基)乙炔基)吡啶-3-胺的合成
Step 1: Synthesis of 6-methyl-5-((trimethylsilyl)ethynyl)pyridin-3-amine
向100mL封管中加入双(三苯基膦)氯化钯(1.1g,1.6mmol)、碘化亚铜(0.3g,1.6mmol)、5-溴-6-甲基吡啶-3-胺(1.5g,8.0mmol)、三甲基乙炔硅烷(1.6g,16mmol)、15mL 1,4-二氧六环和三乙胺(2.2mL,16.1mmol)。氩气保护下，80℃反应12h小时。反应结束后，浓缩溶剂，乙酸乙酯萃 取，无水硫酸钠干燥。抽滤，浓缩后柱层析纯化得标题产物，直接用于下一步。ESI-MS m/z:205.1[M+H]+.Add bis(triphenylphosphine)palladium chloride (1.1 g, 1.6 mmol), cuprous iodide (0.3 g, 1.6 mmol), 5-bromo-6-methylpyridin-3-amine (1.5 g, 8.0 mmol), trimethylethynylsilane (1.6 g, 16 mmol), 15 mL 1,4-dioxane and triethylamine (2.2 mL, 16.1 mmol) to a 100 mL sealed tube. React at 80 °C for 12 h under argon protection. After the reaction is complete, concentrate the solvent and extract with ethyl acetate. The product was collected and dried over anhydrous sodium sulfate. After filtration and concentration, it was purified by column chromatography to obtain the title product, which was used directly in the next step. ESI-MS m/z: 205.1 [M + H] + .
步骤2：6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-胺的合成
Step 2: Synthesis of 6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-amine
向50mL二口瓶中加入双(三苯基膦)氯化钯(0.35g,0.5mmol)、碘化亚铜(0.10g,0.5mmol)、4-碘-1-甲基吡唑(1g,5mmol)和氟化铯(1.5g,10mmol)，氩气保护下加入6-甲基-5-((三甲基硅烷基)乙炔基)吡啶-3-胺(1g,5mmol)、10mL N,N-二甲基甲酰胺、二异丙基乙胺(2.6mL,15mmol)，升温至50℃反应。反应完全后，冷却，饱和食盐水淬灭。二氯甲烷:异丙醇＝4:1萃取3次，合并有机相，水洗，无水硫酸钠干燥有机相。柱层析纯化得标题产物。ESI-MS m/z:213.2[M+H]+.Add bis(triphenylphosphine)palladium chloride (0.35g, 0.5mmol), cuprous iodide (0.10g, 0.5mmol), 4-iodo-1-methylpyrazole (1g, 5mmol) and cesium fluoride (1.5g, 10mmol) to a 50mL two-necked flask, add 6-methyl-5-((trimethylsilyl)ethynyl)pyridine-3-amine (1g, 5mmol), 10mL N,N-dimethylformamide, diisopropylethylamine (2.6mL, 15mmol) under argon protection, and heat to 50℃ for reaction. After the reaction is complete, cool and quench with saturated brine. Extract three times with dichloromethane:isopropanol=4:1, combine the organic phases, wash with water, and dry the organic phases with anhydrous sodium sulfate. Purify by column chromatography to obtain the title product. ESI-MS m/z:213.2[M+H] + .
步骤3：苯基(6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-基)氨基甲酸酯的合成
Step 3: Synthesis of phenyl (6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate
向50mL单口瓶中加入6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-胺(0.2g,0.94mmol)、6mL二氯甲烷和吡啶(0.12mL,1.5mmol)，冰浴下搅拌10分钟。滴加氯甲酸苯酯(0.23g,1.5mmol)和0.5mL二氯甲烷的混合液，结束后继续在冰浴下反应。反应完全后，饱和氯化铵溶液淬灭，水相用二氯甲烷萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩后粗产品柱层析纯化得标题产物。ESI-MS m/z:333.2[M+H]+.Add 6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-amine (0.2g, 0.94mmol), 6mL dichloromethane and pyridine (0.12mL, 1.5mmol) to a 50mL single-mouth bottle and stir for 10 minutes under ice bath. Add a mixture of phenyl chloroformate (0.23g, 1.5mmol) and 0.5mL dichloromethane dropwise, and continue to react under ice bath after completion. After the reaction is complete, quench with saturated ammonium chloride solution, extract the aqueous phase with dichloromethane three times, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, the crude product is purified by column chromatography to obtain the title product. ESI-MS m/z:333.2[M+H]+.
步骤4：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-基)氨基甲酸酯的合成
Step 4: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate
向50mL Schlenk管中加入实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(0.096g,0.35mmol)和2mL N,N-二甲基甲酰胺，冰浴下搅拌5分钟。缓慢加入氢化钠(0.028g,0.7mmol)，再滴加苯基(6-甲基-5-((1-甲基-1H-吡唑-4-基)乙炔基)吡啶-3-基)氨基甲酸酯(0.12g,0.38mmol) 和1.5mL N,N-二甲基甲酰胺的混合液。反应结束后，饱和氯化铵溶液淬灭，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩，柱层析纯化得标题产物。ESI-MS m/z:513.2[M+H]+.Add the product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.096 g, 0.35 mmol) and 2 mL of N,N-dimethylformamide to a 50 mL Schlenk tube and stir for 5 minutes under ice bath. Slowly add sodium hydride (0.028 g, 0.7 mmol), and then dropwise add phenyl(6-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)carbamate (0.12 g, 0.38 mmol) and 1.5 mL of N,N-dimethylformamide. After the reaction is completed, quench with saturated ammonium chloride solution, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Concentrate and purify with column chromatography to obtain the title product. ESI-MS m/z: 513.2 [M + H] + .
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.06(s,1H),8.47(s,1H),8.13(s,1H),7.92(s,1H),7.81(s,1H),7.74(s,1H),7.70(d,J＝7.9Hz,1H),7.64(d,J＝7.7Hz,1H),5.30(s,2H),5.13(dd,J＝13.2,4.9Hz,1H),4.48(d,J＝17.3Hz,1H),4.35(d,J＝17.4Hz,1H),3.86(s,3H),2.97-2.86(m,1H),2.61(d,J＝17.6Hz,1H),2.53(s,3H),2.44-2.34(m,1H),2.06-1.97(m,1H). 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.06 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.81 (s ,1H),7.74(s,1H),7.70(d,J＝7.9Hz,1H),7.64(d,J＝7.7Hz,1H),5.30(s,2H),5.1 3 (dd, J = 13.2, 4.9 Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 3.86 (s, 3H), 2.97-2.86 (m , 1H), 2.61(d, J＝17.6Hz, 1H), 2.53(s, 3H), 2.44-2.34(m, 1H), 2.06-1.97(m, 1H).
实施例8：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯基)氨基甲酸酯
Example 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate
步骤1：4-氟-3-((三甲基甲硅烷基)乙炔基)苯胺的合成
Step 1: Synthesis of 4-fluoro-3-((trimethylsilyl)ethynyl)aniline
向100mL封管中加入双(三苯基膦)氯化钯(1.1g,1.6mmol)、碘化亚铜(0.3g,1.6mmol)、3-溴-4-氟苯胺(1.5g,7.9mmol)、三甲基乙炔硅烷(1.65g,16.8mmol)、15mL 1,4-二氧六环和三乙胺(2.2mL,15.8mmol)。氩气保护下80℃反应12小时。反应结束后，浓缩溶剂，加入食盐水和乙酸乙酯，抽滤分液后，无水硫酸钠干燥。浓缩柱层析纯化得标题产物。ESI-MS m/z:208.1[M+H]+.Add bis(triphenylphosphine)palladium chloride (1.1 g, 1.6 mmol), cuprous iodide (0.3 g, 1.6 mmol), 3-bromo-4-fluoroaniline (1.5 g, 7.9 mmol), trimethylethynylsilane (1.65 g, 16.8 mmol), 15 mL 1,4-dioxane and triethylamine (2.2 mL, 15.8 mmol) to a 100 mL sealed tube. React at 80 °C for 12 hours under argon protection. After the reaction, concentrate the solvent, add brine and ethyl acetate, filter the liquid, and dry it over anhydrous sodium sulfate. Purify the concentrated column to obtain the title product. ESI-MS m/z: 208.1 [M+H] + .
步骤2：4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯胺的合成
Step 2: Synthesis of 4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)aniline
向50mL二口瓶中加入双(三苯基膦)氯化钯(0.35g,0.5mmol)、碘化亚铜(0.095g,0.5mmol)、4-碘-1-甲基吡唑(1g,5mmol)和氟化铯(1.5g,10mmol)，氩气保护下加入4-氟-3-((三甲基甲硅烷基)乙炔基)苯胺(1g,5mmol)、10mL N,N-二甲基甲酰胺、二异丙基乙胺(2.6mL,15mmol)，加热50℃下反应完全后，冷却，加入饱和食盐水淬灭。二氯甲烷:异丙醇＝4:1萃取3次，合并有机相，无水硫酸钠干燥。柱层析纯化得标题产物。ESI-MS m/z:216.1[M+H]+.Add bis(triphenylphosphine)palladium chloride (0.35 g, 0.5 mmol), cuprous iodide (0.095 g, 0.5 mmol), 4-iodo-1-methylpyrazole (1 g, 5 mmol) and cesium fluoride (1.5 g, 10 mmol) to a 50 mL two-necked flask, add 4-fluoro-3-((trimethylsilyl)ethynyl)aniline (1 g, 5 mmol), 10 mL N,N-dimethylformamide, diisopropylethylamine (2.6 mL, 15 mmol) under argon protection, heat to 50 ° C until the reaction is complete, cool, and add saturated brine to quench. Extract three times with dichloromethane: isopropanol = 4:1, combine the organic phases, and dry over anhydrous sodium sulfate. Purify by column chromatography to obtain the title product. ESI-MS m/z: 216.1 [M+H] + .
步骤3：苯基(4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯基)氨基甲酸酯的合成
Step 3: Synthesis of phenyl (4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate
向50mL单口瓶中加入4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯胺(0.3g,1.4mmol)、6mL二氯甲烷和吡啶(0.23mL,2.8mmol)，冰浴下搅拌10分钟。滴加氯甲酸苯酯(0.44g,2.8mmol)和0.5mL二氯甲烷混合液，结束后继续在冰浴下反应。反应完全后，饱和氯化铵溶液淬灭，二氯甲烷萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。柱层析纯化得标题产物。ESI-MS m/z:336.1[M+H]+.Add 4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)aniline (0.3g, 1.4mmol), 6mL dichloromethane and pyridine (0.23mL, 2.8mmol) to a 50mL single-mouth bottle and stir for 10 minutes in an ice bath. Add phenyl chloroformate (0.44g, 2.8mmol) and 0.5mL dichloromethane mixed solution dropwise, and continue to react in an ice bath after completion. After the reaction is complete, quench with saturated ammonium chloride solution, extract with dichloromethane 3 times, combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Purify by column chromatography to obtain the title product. ESI-MS m/z: 336.1[M+H] + .
步骤4：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯基)氨基甲酸酯的合成
Step 4: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate
向50mL Schlenk管中加入实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(0.1g,0.36mmol)和2mL N,N-二甲基甲酰胺，冰浴下搅拌5分钟。缓慢加入氢化钠(0.03g,0.7mmol)，再滴加苯基(4-氟-3-((1-甲基-1H-吡唑-4-基)乙炔基)苯基)氨基甲酸酯(0.13g,0.39mmol)的N,N-二甲基甲酰胺的混合液(1.5mL)。反应结束后，饱和氯化铵溶液淬灭，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥。浓缩，柱层析纯化得标题产物。ESI-MS m/z:516.2[M+H]+.Add the product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.1 g, 0.36 mmol) and 2 mL of N,N-dimethylformamide to a 50 mL Schlenk tube and stir for 5 minutes under ice bath. Slowly add sodium hydride (0.03 g, 0.7 mmol), and then dropwise add a mixture of phenyl(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)carbamate (0.13 g, 0.39 mmol) in N,N-dimethylformamide (1.5 mL). After the reaction is completed, quench with saturated ammonium chloride solution, extract with ethyl acetate three times, combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate and purify by column chromatography to obtain the title product. ESI-MS m/z: 516.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.97(s,1H),8.13(s,1H),7.80(s,1H),7.73(s,1H),7.69(d,J＝7.4Hz,1H),7.64(d,J＝7.2Hz,2H),7.44(s,1H),7.24(t,J＝9.1Hz,1H),5.28(s,2H),5.13(dd,J＝12.9,4.0Hz,1H),4.48(d,J＝17.5Hz,1H),4.34(d,J＝17.3Hz,1H),3.86(s,3H),2.93-2.86(m,1H),2.60(d,J＝17.5Hz,1H),2.40(dd,J＝12.5,3.4Hz,1H),2.06-1.96(m,1H). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.97 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.69 (d , J = 7.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.44 (s, 1H), 7.24 (t, J = 9.1 Hz, 1H), 5.28 (s, 2H) ,5.13(dd,J＝12.9,4.0Hz,1H),4.48(d,J＝17.5Hz,1H),4.34(d,J＝17.3Hz,1H),3.86(s,3H),2.93-2.86( m, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.40 (dd, J = 12.5, 3.4 Hz, 1H), 2.06-1.96 (m, 1H).
实施例9：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯基)氨基甲酸酯
Example 9: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate
步骤1：2-氟-5-碘代苯胺的制备
Step 1: Preparation of 2-fluoro-5-iodoaniline
将1-氟-4-碘-2-硝基苯(2g,7.5mmol)加入到三颈烧瓶中，加入醋酸(3mL)，惰性气体保护，100℃下反应3h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，柱层析得标题产物。ESI-MS m/z:238.1[M+H]+ Add 1-fluoro-4-iodo-2-nitrobenzene (2g, 7.5mmol) to a three-necked flask, add acetic acid (3mL), protect with inert gas, and react at 100℃ for 3h. After the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and obtain the title product by column chromatography. ESI-MS m/z: 238.1[M+H] +
步骤2：2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯胺的制备
Step 2: Preparation of 2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)aniline
将2-氟-5-碘代苯胺(1.4g,5.9mmol)加入到三颈烧瓶中，加入二氧六环(20mL)溶解，然后加入1,10-菲啰啉(426mg,2.4mmol)、碘化亚铜(225mg,1.2mmol)、N,N,N',N'-四甲基乙二胺(238mg,2.4mmol)、磷酸钾(3.76g，17.7)和2-(三氟甲基)吡啶-3-硫醇钠盐(1.06g,5.9mmol)，惰性气体保护，100℃下反应1.5h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得标题产物。ESI-MS m/z:289.1[M+H]+ 2-Fluoro-5-iodoaniline (1.4 g, 5.9 mmol) was added to a three-necked flask, and dioxane (20 mL) was added to dissolve, and then 1,10-phenanthroline (426 mg, 2.4 mmol), cuprous iodide (225 mg, 1.2 mmol), N,N,N',N'-tetramethylethylenediamine (238 mg, 2.4 mmol), potassium phosphate (3.76 g, 17.7) and 2-(trifluoromethyl)pyridine-3-thiol sodium salt (1.06 g, 5.9 mmol) were added, and the mixture was reacted at 100 ° C for 1.5 h under inert gas protection. After the reaction, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title product. ESI-MS m/z: 289.1 [M+H] +
步骤3：(2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯基)氨基甲酸酯的制备
Step 3: Preparation of (2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate
将2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯胺(400mg,1.39mmol)加入到三颈烧瓶中，加入二氯甲烷(3mL)溶解，氩气保护下，0℃滴加氯甲酸苯酯(326mg)，室温反应1h。反应结束后，反应液浓缩，柱层析，得标题产物。ESI-MS m/z:409.1[M+H]+ 2-Fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)aniline (400 mg, 1.39 mmol) was added to a three-necked flask, and dichloromethane (3 mL) was added to dissolve. Under argon protection, phenyl chloroformate (326 mg) was added dropwise at 0°C and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m/z: 409.1[M+H] +
步骤4：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯基)氨基甲酸酯的制备
Step 4: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate
将实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(100mg,0.36mmol)加入到三颈烧瓶中，0℃下加入氢化钠(30mg,0.73mmol)，并滴加(2-氟-5-((2-(三氟甲基)吡啶-3-基)硫代)苯基)氨基甲酸酯(149mg,0.36mmol)的N,N-二甲基甲酰胺(2mL)溶液，室温反应1h。反应结束后，调pH至6，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层 析，得标题产物。ESI-MS m/z:589.1[M+H]+ The product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was added to a three-necked flask, sodium hydride (30 mg, 0.73 mmol) was added at 0°C, and a solution of (2-fluoro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)phenyl)carbamate (149 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the mixture was reacted at room temperature for 1 h. After the reaction, the pH was adjusted to 6, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed. The title product was obtained by analysing. ESI-MS m/z: 589.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.86(s,1H),8.55(d,J＝3.5Hz,1H),7.94(d,1H),7.80(s,1H),7.69-7.54(m,4H),7.42-7.37(m,1H),7.33-7.28(m,1H),5.27(s,2H),5.17-5.10(m,1H),4.47(d,J＝17.2Hz,1H),4.33(d,J＝17.4Hz,1H),2.95-2.86(m,1H),2.63-2.57(m,1H),2.43-2.37(m,1H),2.05-1.98(m,1H). 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.86 (s, 1H), 8.55 (d, J = 3.5 Hz, 1H), 7.94 (d, 1H), 7.80 (s, 1H), 7.69-7.54 (m, 4H), 7.42-7.37 (m, 1H), 7.33-7.28 (m, 1H), 5.27 (s, 2H), 5.17-5.10 (m, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 2.95-2.86 (m, 1H), 2.63-2.57 (m, 1H), 2.43-2.37 (m, 1H), 2.05-1.98 (m, 1H).
实施例10：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯
Example 10: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
步骤1：(2-氟-5-(三氟甲氧基)苯基)氨基甲酸苯酯的制备
Step 1: Preparation of phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
将2-氟-5-(三氟甲氧基)苯胺(500mg,2.56mmol)加入到三颈烧瓶中，加入乙腈(150mL)溶解，0℃滴加氯甲酸苯酯(501mg)，室温反应2h。反应结束后，反应液浓缩，柱层析纯化得标题产物。ESI-MS m/z:316.1[M+H]+.Add 2-fluoro-5-(trifluoromethoxy)aniline (500 mg, 2.56 mmol) to a three-necked flask, add acetonitrile (150 mL) to dissolve, add phenyl chloroformate (501 mg) dropwise at 0°C, and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by column chromatography to obtain the title product. ESI-MS m/z: 316.1 [M+H] + .
步骤2：(2-(2,6-二氧-1-((2-(三甲基甲硅基)乙氧基)甲基)哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯的制备
Step 2: Preparation of (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
将3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)哌啶-2,6-二酮(200mg,0.494mmol)加入到三颈烧瓶中，加入N,N-二甲基甲酰胺(2.5mL)，0℃下加入氢化钠(40mg,0.99mmol)，滴加苯基(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯(171mg,0.55mmol)的N,N-二甲基甲酰胺(1mL)溶液，室温反应1h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析纯化得标题产物。ESI-MS m/z:624.2[M-H]-.3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.494 mmol) was added to a three-necked flask, and N,N-dimethylformamide (2.5 mL) was added. Sodium hydride (40 mg, 0.99 mmol) was added at 0°C, and a solution of phenyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (171 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) was added dropwise, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS m/z: 624.2[MH] - .
步骤3：(2-(2,6-二氧-1-((2-(三甲基甲硅基)乙氧基)甲基)哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯的制备
Step 3: Preparation of (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
将(2-(2,6-二氧-1-((2-(三甲基甲硅基)乙氧基)甲基)哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯(150mg,0.30mmol)加入到三颈烧瓶中，加入N,N-二甲基甲酰胺(3mL)溶解，然后加入碳酸铯(156mg,0.48mmol)和2,2-二氟乙基三氟甲磺酸酯(154mg，0.72mmol)，室温反应3h。反应结束后，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压浓缩，柱层析，得标题产物。ESI-MS m/z:688.2[M-H]-.(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (150 mg, 0.30 mmol) was added to a three-necked flask, N,N-dimethylformamide (3 mL) was added to dissolve, and then cesium carbonate (156 mg, 0.48 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (154 mg, 0.72 mmol) were added and reacted at room temperature for 3 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed to obtain the title product. ESI-MS m/z: 688.2[MH] - .
步骤4：(2-(1-(羟甲基)-2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯的制备
Step 4: Preparation of (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
将(2-(2,6-二氧-1-((2-(三甲基甲硅基)乙氧基)甲基)哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯(110mg，0.16mmol)加入到单颈烧瓶中，加入盐酸/1,4-二氧六环(5mL，2M)，50℃反应2h。反应结束后，反应液浓缩，得标题产物，直接用于下一步。ESI-MS m/z:590.2[M+H]+.(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (110 mg, 0.16 mmol) was added to a single-necked flask, and hydrochloric acid/1,4-dioxane (5 mL, 2 M) was added, and the reaction was carried out at 50°C for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain the title product, which was directly used in the next step. ESI-MS m/z: 590.2[M+H] + .
步骤5：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯的制备
Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
将实施例1步骤1产物(2-(1-(羟甲基)-2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(2,2-二氟乙基)(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯(100mg，0.17mmol)加入到单颈烧瓶中，加入乙腈(3mL)和氨水(0.02mL)，室温反应1h。反应结束后，反应液浓缩，柱层析，得标题产物。ESI-MS m/z:559.8[M+H]+ The product of step 1 of Example 1 (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2,2-difluoroethyl)(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (100 mg, 0.17 mmol) was added to a single-necked flask, and acetonitrile (3 mL) and ammonia water (0.02 mL) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m/z: 559.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.72-7.53(m,3H),7.53-7.34(m,3H),6.21(t,J＝54.9Hz,1H),5.24(s,2H),5.11(d,J＝8.6Hz,1H),4.45(d,J＝18.4Hz,1H),4.32(d,J＝18.0Hz,1H),4.06(t,J＝14.5Hz,2H),2.97-2.87(m,1H),2.60(d,J＝17.7Hz,1H),2.40(d,J＝14.1Hz,1H),2.00(s, 1H). 1 H NMR (400 MHz, DMSO-d6) δ10.98 (s, 1H), 7.72-7.53 (m, 3H), 7.53-7.34 (m, 3H), 6.21 (t, J = 54.9 Hz, 1H), 5.24 (s, 2H), 5.11 (d, J = 8.6 Hz, 1H), 4.45 (d, J = 18.4 Hz, 1H), 4.32 (d, J = 18.0 Hz, 1H), 4.06 (t, J = 14.5 Hz, 2H), 2.97-2.87 (m, 1H), 2.60 (d, J = 17.7 Hz, 1H), 2.40 (d, J = 14.1 Hz, 1H), 2.00 (s, 1H).
实施例11：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-2-氟-5-(7-氧代-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸酯
Example 11: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-2-fluoro-5-(7-oxo-2-azaspiro[3.5]nonan-2-yl)phenyl)carbamate
步骤1：5-溴-4-氯-2-氟苯胺的合成
Step 1: Synthesis of 5-bromo-4-chloro-2-fluoroaniline
向100mL二口瓶中加入1-溴-2-氯-4-氟-5-硝基苯(2g,7.9mmol)、还原铁粉(2.2g,39.5mmol)、氯化铵(2.1g,39.5mmol)。氩气保护下加入15mL乙醇和3mL水，体系升温至70℃反应2小时。反应结束后，浓缩溶剂，加水稀释，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩后得标题产物。ESI-MS m/z:224.0[M+H]+.Add 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (2g, 7.9mmol), reduced iron powder (2.2g, 39.5mmol), and ammonium chloride (2.1g, 39.5mmol) to a 100mL two-necked flask. Add 15mL of ethanol and 3mL of water under argon protection, and heat the system to 70℃ for 2 hours. After the reaction, concentrate the solvent, dilute with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain the title product. ESI-MS m/z: 224.0[M+H] + .
步骤2：5-溴-4-氯-2-氟苯基)氨基甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 5-bromo-4-chloro-2-fluorophenyl)carbamate
向100mL双口瓶中加入4-二甲氨基吡啶(0.10g,0.78mmol)、5-溴-4-氯-2-氟苯胺(1.74g,7.8mmol)、20mL四氢呋喃和三乙胺(3.2mL,23.3mmol)，室温下加入二碳酸二叔丁酯(5.4mL,23.2mmol)，体系升温至60℃。反应完全后，停止反应将体系冷却至室温，加入饱和食盐水淬灭。乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。粗产品柱层析纯化得标题产物。ESI-MS m/z:324.0[M+H]+.Add 4-dimethylaminopyridine (0.10g, 0.78mmol), 5-bromo-4-chloro-2-fluoroaniline (1.74g, 7.8mmol), 20mL tetrahydrofuran and triethylamine (3.2mL, 23.3mmol) to a 100mL two-necked bottle, add di-tert-butyl dicarbonate (5.4mL, 23.2mmol) at room temperature, and heat the system to 60°C. After the reaction is complete, stop the reaction, cool the system to room temperature, and add saturated brine to quench. Extract with ethyl acetate 3 times, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. The crude product is purified by column chromatography to obtain the title product. ESI-MS m/z: 324.0[M+H] + .
步骤3(4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸叔丁酯的合成
Step 3 Synthesis of tert-butyl (4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)carbamate
向50mL三口瓶中加入三(二亚苄基丙酮)二钯(0.18g,0.2mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.23g,0.4mmol)、(5-溴-4-氯-2-氟苯基)氨基甲酸叔丁酯(0.64g,2mmol)、叔丁醇钠(0.4g,4mmol)，氩气保护下加入10mL1,4-二氧六环和7-氧杂-2-氮杂螺[3.5]壬烷(0.3g,2.4mmol)，体系升温至110℃反应8小时。反应完全后，加饱和氯化铵溶液淬灭，水相用乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩后粗产品纯化得标题产物。ESI-MS m/z:371.2[M+H]+.Tris(dibenzylideneacetone)dipalladium (0.18 g, 0.2 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.23 g, 0.4 mmol), tert-butyl (5-bromo-4-chloro-2-fluorophenyl)carbamate (0.64 g, 2 mmol), sodium tert-butoxide (0.4 g, 4 mmol) were added to a 50 mL three-necked flask, and 10 mL of 1,4-dioxane and 7-oxa-2-azaspiro[3.5]nonane (0.3 g, 2.4 mmol) were added under argon protection. The system was heated to 110 °C for 8 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the crude product was purified to obtain the title product. ESI-MS m/z: 371.2[M+H] + .
步骤4：4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯胺的合成
Step 4: Synthesis of 4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)aniline
向50mL单口瓶中加入叔丁基(4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸酯(0.14g,0.38mmol)、4mL二氯甲烷溶解，缓慢加入2mL三氟乙酸，体系升温至40℃反应。反应完全后，浓缩溶剂，加饱和碳酸氢钠溶液调节pH至8-9，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。滤液浓缩得标题产物直接用于下步反应。ESI-MS m/z:271.2[M+H]+.Add tert-butyl (4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)carbamate (0.14 g, 0.38 mmol) and 4 mL of dichloromethane to a 50 mL single-mouth bottle to dissolve, slowly add 2 mL of trifluoroacetic acid, and heat the system to 40 ° C for reaction. After the reaction is complete, concentrate the solvent, add saturated sodium bicarbonate solution to adjust the pH to 8-9, extract with dichloromethane, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. The filtrate is concentrated to obtain the title product, which is directly used in the next step. ESI-MS m/z: 271.2 [M + H] + .
步骤5：(4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸苯酯的合成
Step 5: Synthesis of phenyl (4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)carbamate
向50mL单口瓶中依次加入4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯胺(0.11g,0.4mmol)、4mL二氯甲烷和吡啶(0.048mL)，冰浴下，滴加氯甲酸苯酯(0.1g,0.64mmol)，室温反应30分钟。加饱和氯化铵溶液淬灭，二氯甲烷萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩，粗产品经硅胶柱层析得标题产物。ESI-MS m/z:391.1[M+H]+.4-Chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]non-2-yl)aniline (0.11 g, 0.4 mmol), 4 mL of dichloromethane and pyridine (0.048 mL) were added to a 50 mL single-mouth bottle. Phenyl chloroformate (0.1 g, 0.64 mmol) was added dropwise under an ice bath and reacted at room temperature for 30 minutes. The mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration and chromatography of the crude product on a silica gel column gave the title product. ESI-MS m/z: 391.1 [M+H] + .
步骤6：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸酯的合成
Step 6: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-2-fluoro-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)carbamate
向10mL Schlenk管中加入实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(0.06g,0.2mmol)和1.6mL N,N-二甲基甲酰胺，冰浴下，缓慢加入氢化钠(0.02g,0.4mmol)及苯基(4- 氯-2-氟-5-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)氨基甲酸酯(0.09g,0.23mmol)的N,N-二甲基甲酰胺(1mL)溶液。反应结束后，加饱和氯化铵溶液淬灭，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩，柱层析纯化得标题产物。ESI-MS m/z:570.9[M+H]+.The product of step 1 in Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.06 g, 0.2 mmol) and 1.6 mL of N,N-dimethylformamide were added to a 10 mL Schlenk tube. Sodium hydride (0.02 g, 0.4 mmol) and phenyl (4- A solution of 2-chloro-5-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)carbamate (0.09 g, 0.23 mmol) in N,N-dimethylformamide (1 mL). After the reaction was completed, saturated ammonium chloride solution was added to quench, and ethyl acetate was extracted three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration and column chromatography were performed to obtain the title product. ESI-MS m/z: 570.9 [M + H] + .
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.58(s,1H),7.81(s,1H),7.66(dd,J＝15.9,7.4Hz,2H),7.25(d,J＝10.2Hz,1H),6.98(s,1H),5.27(s,2H),5.14(d,J＝8.9Hz,1H),4.47(d,J＝17.4Hz,1H),4.34(d,J＝17.4Hz,1H),3.70(s,4H),3.53(s,4H),2.92(t,J＝13.0Hz,1H),2.60(d,J＝16.7Hz,1H),2.45-2.34(m,1H),2.07-1.93(m,1H),1.71(s,4H). 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.58 (s, 1H), 7.81 (s, 1H), 7.66 (dd, J = 15.9, 7.4 Hz, 2H), 7.25 (d ,J＝10.2Hz,1H),6.98(s,1H),5.27(s,2H),5.14(d,J＝8.9Hz,1H),4. 47(d,J＝17.4Hz,1H),4.34(d,J＝17.4Hz,1H),3.70(s,4H),3.53(s,4H),2.92(t,J＝13.0Hz,1H), 2.60 (d, J = 16.7 Hz, 1H), 2.45-2.34 (m, 1H), 2.07-1.93 (m, 1H), 1.71 (s, 4H).
实施例12：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)氨基甲酸酯
Example 12: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)carbamate
步骤1：5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]的制备
Step 1: Preparation of 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]
将(4-溴-2-氟苯基)肼盐酸盐(2g,8.3mmol)加入到单颈烧瓶中，加入甲醇(30mL)溶解，然后加入三乙胺(1.7g,16.6mmol)及1-环戊基乙烷-1-酮(1.1g,9.1mmol)，惰性气体保护，室温反应3h。监测反应完全后，-5℃下加入浓硫酸(1.8ml,33.2mmol)，室温反应12h。反应结束后，减压浓缩，萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析，得标题产物。ESI-MS m/z:281.9[M+H]+.Add (4-bromo-2-fluorophenyl)hydrazine hydrochloride (2g, 8.3mmol) to a single-necked flask, add methanol (30mL) to dissolve, then add triethylamine (1.7g, 16.6mmol) and 1-cyclopentylethane-1-one (1.1g, 9.1mmol), protect with inert gas, and react at room temperature for 3h. After monitoring the reaction is complete, add concentrated sulfuric acid (1.8ml, 33.2mmol) at -5℃ and react at room temperature for 12h. After the reaction is completed, concentrate under reduced pressure, extract, wash with saturated brine, dry with anhydrous sodium sulfate, and column chromatography to obtain the title product. ESI-MS m/z: 281.9[M+H] + .
步骤2：(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)氨基甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl (7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)carbamate
将5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](700mg,2.5mmol)加入到双颈烧瓶中，加入二氧六环(5mL)溶解，然后依次加入2-二环己基膦-2',4',6'-三异丙基联苯(119mg,0.25mmol)、碳酸铯(163mg,0.5mmol)、醋酸钯(28mg,0.12mmol)及氨基甲酸叔丁酯(433mg,3.7mmol)，惰性气体保护，100℃反应4h。反应结束后，抽滤，将滤液浓缩，柱层析，得标题产物。ESI-MS m/z:319.2[M+H]+.5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] (700 mg, 2.5 mmol) was added to a double-necked flask, and dioxane (5 mL) was added to dissolve, and then 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (119 mg, 0.25 mmol), cesium carbonate (163 mg, 0.5 mmol), palladium acetate (28 mg, 0.12 mmol) and tert-butyl carbamate (433 mg, 3.7 mmol) were added in sequence, and the mixture was reacted at 100°C for 4 h under inert gas protection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and column chromatography was performed to obtain the title product. ESI-MS m/z: 319.2 [M+H] + .
步骤3：7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-胺的制备
Step 3: Preparation of 7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-amine
将(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)氨基甲酸叔丁酯(210mg,0.66mmol)加入到三颈烧瓶中，加入浓盐酸(4mL)使其溶解，常温反应0.5h。反应结束后，加入饱和碳酸氢钠溶液调节PH为中性，萃取，有机相浓缩，得标题产物。ESI-MS m/z:219.2[M+H]+.Add tert-butyl (7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)carbamate (210 mg, 0.66 mmol) to a three-necked flask, add concentrated hydrochloric acid (4 mL) to dissolve it, and react at room temperature for 0.5 h. After the reaction, add saturated sodium bicarbonate solution to adjust the pH to neutral, extract, and concentrate the organic phase to obtain the title product. ESI-MS m/z: 219.2 [M+H] + .
步骤4：7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)氨基甲酸苯酯的制备
Step 4: Preparation of phenyl 7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)carbamate
将7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-胺(100mg，0.46mmol)加入到单颈烧瓶中，加入二氯甲烷(2mL)使其溶解，加入吡啶(73mg，0.92mmol)，0℃滴加氯甲酸苯酯(79mg，0.51mmol)，常温反应2h。反应结束后，萃取，饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩，柱层析，得标题产物。ESI-MS m/z:339.2[M+H]+ 7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-amine (100 mg, 0.46 mmol) was added to a single-necked flask, dichloromethane (2 mL) was added to dissolve it, pyridine (73 mg, 0.92 mmol) was added, phenyl chloroformate (79 mg, 0.51 mmol) was added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, extraction was performed, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, the organic phase was concentrated, and column chromatography was performed to obtain the title product. ESI-MS m/z: 339.2[M+H] +
步骤5：(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基(4-氯-3-((3-氟氧杂环丁烷-3-基)乙炔基)苯基)氨基甲酸酯的制备
Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4-chloro-3-((3-fluorooxetane-3-yl)ethynyl)phenyl)carbamate
将实施例1步骤1产物3-(6-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(87mg，0.26mmol)加入到三颈烧瓶中，加入N,N-二甲基甲酰胺(2mL)使其溶解，0℃加入氢化钠(14mg，0.58mmol)及苯基(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)氨基甲酸酯(100mg，0.29mmol)，常温反应15min。反应结束后，用盐酸溶液(4mmol/L)调节PH至中性，萃取，饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩，柱层析，得标题产物。ESI-MS m/z:518.9[M+H]+.The product of step 1 of Example 1, 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87 mg, 0.26 mmol) was added to a three-necked flask, N,N-dimethylformamide (2 mL) was added to dissolve it, sodium hydride (14 mg, 0.58 mmol) and phenyl (7'-fluoro-2'-methylspiro [cyclopentane-1,3'-indole] -5'-yl) carbamate (100 mg, 0.29 mmol) were added at 0°C, and the reaction was carried out at room temperature for 15 minutes. After the reaction was completed, the pH was adjusted to neutral with hydrochloric acid solution (4 mmol/L), extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was concentrated, and column chromatography was performed to obtain the title product. ESI-MS m/z: 518.9 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.99(s,1H),7.79(s,1H),7.66(dd,J＝17.6,7.8Hz,2H),7.37(s,1H),7.25(d,J＝12.3Hz,1H),5.28(s,2H),5.14(dd,J＝13.1,4.8Hz,1H),4.48(d,J＝17.3Hz,1H),4.34(d,J＝17.4Hz,1H),2.97-2.87(m,1H),2.60(d,J＝17.1Hz,1H),2.40(dd,J＝13.2,4.1Hz,1H),2.22(s,3H),1.99(d,J＝15.6Hz,7H),1.66-1.60(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.99 (s, 1H), 7.79 (s, 1H), 7.66 (dd, J = 17.6, 7.8 Hz, 2H), 7.37 (s ,1H),7.25(d,J＝12.3Hz,1H),5.28(s,2H),5.14(dd,J＝13.1,4.8Hz,1H),4 .48(d,J＝17.3Hz,1H),4.34(d,J＝17.4Hz,1H),2.97-2.87(m,1H),2.60(d,J＝17.1Hz,1H),2.40(dd, J＝13.2,4.1Hz,1H),2.22(s,3H),1.99(d,J＝15.6Hz,7H),1.66-1.60(m,2H).
实施例13：(3-(2,6-二氧代哌啶-3-基)-2-氧代-2,3-二氢苯并[d]噁唑-7-基)甲基(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯
Example 13: (3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
步骤1：7-溴-苯并[d]噁唑-2(3H)-酮的制备
Step 1: Preparation of 7-bromo-benzo[d]oxazol-2(3H)-one
将2-氨基-6-溴苯酚(10g,53.5mmol)加入到单颈烧瓶中，加入四氢呋喃(60mL)溶解，然后加入N,N'-羰基二咪唑(15.6g,96.3mmol)，70℃反应4h。反应完全后，，浓缩后加入水，乙酸乙酯萃取，饱和氯化钠溶液洗涤，有机层经无水硫酸钠干燥后，减压浓缩，得标题产物。ESI-MS m/z:213.9[M+H]+.Add 2-amino-6-bromophenol (10g, 53.5mmol) to a single-necked flask, add tetrahydrofuran (60mL) to dissolve, then add N,N'-carbonyldiimidazole (15.6g, 96.3mmol), and react at 70℃ for 4h. After the reaction is complete, add water after concentration, extract with ethyl acetate, wash with saturated sodium chloride solution, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title product. ESI-MS m/z: 213.9[M+H] + .
步骤2：3-(7-溴-2--氧代苯并[d]噁唑-3(2H)-基)哌啶-2,6-二酮的制备
Step 2: Preparation of 3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione
将7-溴-苯并[d]噁唑-2(3H)-酮(1.5g,7.0mmol)加入到单颈烧瓶中，加入二甲基亚砜(20mL)溶解，然后加入氢氧化钾(590mg,10.5mmol)，再分批加入3-溴哌啶-2,6-二酮(1.48g,7.7mmol)室温过夜反应。反应结束后，加入饱和氯化铵溶液调节pH至酸性，乙酸乙酯萃取，饱和氯化钠溶液洗涤，有机相经无水硫酸钠干燥后，减压浓缩，柱层析，得标题产物。ESI-MS m/z:325.0[M+H]+.7-Bromo-benzo[d]oxazol-2(3H)-one (1.5 g, 7.0 mmol) was added to a single-necked flask, and dimethyl sulfoxide (20 mL) was added to dissolve, followed by potassium hydroxide (590 mg, 10.5 mmol), and then 3-bromopiperidine-2,6-dione (1.48 g, 7.7 mmol) was added in batches to react at room temperature overnight. After the reaction was completed, saturated ammonium chloride solution was added to adjust the pH to acidic, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain the title product. ESI-MS m/z: 325.0[M+H]+.
步骤3：3-(7-(羟甲基)-2-氧代苯并[d]噁唑-3(2H)-基)哌啶-2,6-二酮的制备
Step 3: Preparation of 3-(7-(hydroxymethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione
将3-(7-溴-2--氧代苯并[d]噁唑-3(2H)-基)哌啶-2,6-二酮(400mg,1.3mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯)[2-(2-氨基乙基苯基)]钯(II)G2(56mg,0.06mmol)和三丁基锡甲醇(476mg,1.48mmol)加入到单颈烧瓶中，加入二氧六环(20mL)溶解，80℃反应8h。反应结束后，反应液浓缩，抽滤，甲基叔丁基醚和二氯甲烷洗涤，烘干得标题产物。ESI-MS m/z:277.1[M+H]+.3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (400 mg, 1.3 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)G2 (56 mg, 0.06 mmol) and tributyltinmethanol (476 mg, 1.48 mmol) were added to a single-necked flask, and dioxane (20 mL) was added to dissolve, and the mixture was reacted at 80°C for 8 h. After the reaction was completed, the reaction solution was concentrated, filtered, washed with methyl tert-butyl ether and dichloromethane, and dried to obtain the title product. ESI-MS m/z: 277.1[M+H] + .
步骤4：(3-(2,6-二氧代哌啶-3-基)-2-氧代-2,3-二氢苯并[d]噁唑-7-基)甲基(2-氟-5-(三氟甲氧基)苯基) 氨基甲酸酯的制备
Step 4: (3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl) Preparation of carbamates
将3-(7-(羟甲基)-2-氧代苯并[d]噁唑-3(2H)-基)哌啶-2,6-二酮(200mg,0.722mmol)溶于N,N-二甲基甲酰胺(10mL)中，0℃下加入氢化钠(35mg,1.5mmol)，并滴加苯基(2-氟-5-(三氟甲氧基)苯基)氨基甲酸酯(250mg,0.8mmol)的N,N-二甲基甲酰胺(2mL)溶液，室温反应1h。反应结束后，调节pH至酸性，再用乙酸乙酯萃取，饱和氯化钠溶液洗涤，有机相经无水硫酸钠干燥后，减压浓缩，纯化得标题产物。ESI-MS m/z:498.1[M+H]+.3-(7-(Hydroxymethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (200 mg, 0.722 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (35 mg, 1.5 mmol) was added at 0°C, and a solution of phenyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (250 mg, 0.8 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the mixture was reacted at room temperature for 1 h. After the reaction, the pH was adjusted to acidic, and then the mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain the title product. ESI-MS m/z: 498.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.91(s,1H),7.82(s,1H),7.38(t,J＝8.0Hz,1H),7.27(d,J＝12.0Hz,3H),7.14(d,J＝8.0Hz,1H),5.40(dd,J＝12.0,4.0Hz,1H),5.33(s,2H),2.89(t,J＝12.0Hz,1H),2.70(dd,J＝24.0,12.0Hz,2H),2.25-2.09(m,1H).1H NMR (400MHz, DMSO-d6) δ11.23 (s, 1H), 9.91 (s, 1H), 7.82 (s, 1H), 7.38 (t, J＝8.0Hz, 1H), 7.27 (d, J＝12.0Hz, 3H), 7.14 (d, J＝8.0Hz, 1H), 5.40 (dd, J＝12.0, 4.0Hz, 1H), 5.33 (s, 2H), 2.89 (t, J＝12.0Hz, 1H), 2.70 (dd, J＝24.0, 12.0Hz, 2H), 2.25-2.09 (m, 1H).
利用不同的原料按照本发明实施例1-13的合成方法合成实施例14-31的化合物，实施例14-31的表征参数如表1所示。The compounds of Examples 14-31 were synthesized using different raw materials according to the synthesis method of Examples 1-13 of the present invention. The characterization parameters of Examples 14-31 are shown in Table 1.
表1

Table 1

比较例Comparative Example
参照WO2022/152822(PCT/EP2022/050702)中化合物345、365和407公开的方法制备下式代表 的化合物(化合物A、B、C)，并通过氢谱和质谱鉴定，
Referring to the method disclosed in WO2022/152822 (PCT/EP2022/050702) for compounds 345, 365 and 407, the following representative compounds were prepared: Compounds (compounds A, B, C) were identified by hydrogen spectrum and mass spectrum.
实验例1：化合物体外细胞活性评价Experimental Example 1: 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及比较例化合物A、化合物B、化合物C，每个化合物用DMSO配制成10mM母液，最终稀释为10个浓度进行检测，NCI-H1155细胞实验的化合物终浓度为20000nM、4000nM、800nM、160nM、32nM、6.4nM、1.28nM、0.26nM、0.051nM/30000nM、7500nM、1875nM、468.75nM、117.19nM、29.30nM、7.32nM、1.83nM、0.46nM、0.11nM。Test compounds: the compounds of the present invention and comparative example compounds A, B and C prepared in the above embodiments, each compound was prepared into a 10 mM stock solution with DMSO and finally diluted to 10 concentrations for detection. The final concentrations of the compounds in the NCI-H1155 cell experiment were 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.051 nM/30000 nM, 7500 nM, 1875 nM, 468.75 nM, 117.19 nM, 29.30 nM, 7.32 nM, 1.83 nM, 0.46 nM and 0.11 nM.
人肺癌细胞NCI-H1155细胞(高表达MYC)：ATCC。Human lung cancer cells NCI-H1155 cells (highly expressing MYC): ATCC.
试剂：TrypLETM Express Enzyme(1X),no phenol red，货号为Gibco 12604-021；Celltiter Glo assay kit(CTG)，货号为Promega G7573。Reagents: TrypLE TM Express Enzyme (1X), no phenol red, catalog number Gibco 12604-021; Celltiter Glo assay kit (CTG), catalog number Promega G7573.
2.实验方法2. Experimental Methods
2.1细胞培养与传代2.1 Cell culture and passaging
(1)所有细胞均参考ATCC推荐的方法培养，细胞在指数生长期进行实验。(1) All cells were cultured according to the method recommended by ATCC, and the experiments were performed in the exponential growth phase.
(2)细胞培养基：(2) Cell culture medium:
NCI-H1155细胞：mulated Leibovitz's L-15培养基，10％FBS，1％青链霉素。NCI-H1155 cells: mulated Leibovitz's L-15 medium, 10% FBS, 1% penicillin-streptomycin.
(3)细胞培养条件：37℃、5％CO2、95％空气(3) Cell culture conditions: 37°C, 5% CO 2 , 95% air
(4)视细胞生长情况每2-3天换一次培养液或进行传代。(4) Depending on the growth of the cells, the culture medium should be changed every 2-3 days or the cells should be subcultured.
2.2细胞铺板2.2 Cell plating
从细胞培养瓶中取出，用新鲜培养基重悬。将40μL细胞重悬液接种于384孔培养板内。Remove cells from the cell culture flask and resuspend in fresh culture medium. Inoculate 40 μL of the cell resuspension into a 384-well culture plate.
2.3给药2.3 Administration
NCI-H1155细胞在原培养基(40μL)的基础上，给药组加入40nL不同浓度的药物，DMSO组 加入40nL DMSO，每个浓度组设置两个复孔，继续放入5％CO2培养箱培养3天。化合物配制如下：提前称取化合物1-2mg，使用DMSO配置成10mM母液。使用DMSO稀释药物，药物浓度以10mM为起始最高浓度，按1:4梯度依次稀释至10个浓度梯度，给药终浓度为：30000nM、7500nM、1875nM、468.75nM、117.19nM、29.30nM、7.32nM、1.83nM、0.46nM、0.11nM。NCI-H1155 cells were cultured in the original medium (40 μL). The drug group was added with 40 nL of drugs of different concentrations. The DMSO group was Add 40nL DMSO, set up two replicate wells for each concentration group, and continue to culture in a 5% CO2 incubator for 3 days. The compound was prepared as follows: 1-2mg of the compound was weighed in advance and prepared into a 10mM stock solution using DMSO. The drug was diluted with DMSO, with a starting concentration of 10mM, and then diluted to 10 concentration gradients in a 1:4 gradient. The final concentrations of the drugs were: 30000nM, 7500nM, 1875nM, 468.75nM, 117.19nM, 29.30nM, 7.32nM, 1.83nM, 0.46nM, 0.11nM.
2.4检测2.4 Detection
在药物处理3天后，提前30min将Celltiter Glo assay kit取出，平衡至室温。然后PC孔、给药孔和DMSO孔都加入40μL的Celltiter-Glo reagent，震荡2min。室温避光孵育28min后，检测发光信号。根据LUM值，计算每个孔相对于溶剂对照孔的抑制率：Inhibition％＝(Ave_H-Sample)/(Ave_H-Ave_L)*100，注：H＝Ave(DMSO)，L＝Ave(Medium)。根据不同药物浓度及其所对应的抑制率，使用GraghPad 5.0软件进行IC50曲线绘制，分析数据，得出最终IC50值，实验结果见表2。After 3 days of drug treatment, the Celltiter Glo assay kit was taken out 30 minutes in advance and equilibrated to room temperature. Then 40 μL of Celltiter-Glo reagent was added to the PC well, the dosing well, and the DMSO well, and shaken for 2 minutes. After incubation at room temperature in the dark for 28 minutes, the luminescent signal was detected. According to the LUM value, the inhibition rate of each well relative to the solvent control well was calculated: Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) * 100, Note: H = Ave (DMSO), L = Ave (Medium). According to different drug concentrations and their corresponding inhibition rates, the IC 50 curve was drawn using GraghPad 5.0 software, and the data was analyzed to obtain the final IC 50 value. The experimental results are shown in Table 2.
表2化合物对肿瘤细胞生长的抑制

Table 2 Inhibition of tumor cell growth by compounds

实验结果表明，本发明的化合物对人肺癌细胞NCI-H1155细胞(高表达MYC)有较强的抑制作用。The experimental results show that the compound of the present invention has a strong inhibitory effect on human lung cancer cell NCI-H1155 cells (highly expressing MYC).
实验例2：人Cereblon(CRBN)结合实验(HTRF法)Experimental Example 2: Human Cereblon (CRBN) Binding Experiment (HTRF Method)
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及比较例化合物A，每个化合物用DMSO配制成10mM母液，最终稀释为10个浓度进行检测，化合物终浓度为100000nM、25000nM、6250nM、1562.5nM、390.62nM、97.65nM、24.41nM、6.10nM、1.52nM、0.38nM。Test compounds: the compounds of the present invention and comparative example compound A prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to 10 concentrations for detection, with the final concentrations of the compounds being 100000 nM, 25000 nM, 6250 nM, 1562.5 nM, 390.62 nM, 97.65 nM, 24.41 nM, 6.10 nM, 1.52 nM, and 0.38 nM.
试剂：HTRF HUMAN CEREBLON BINDING KITS，Perkinelmer 64BDCRBNPEGReagents: HTRF HUMAN CEREBLON BINDING KITS, Perkinelmer 64BDCRBNPEG
2.实验方法2. Experimental Methods
(1)将0.16μL化合物溶液转移到384反应板中，实验最高浓度为100μM，4倍稀释，终浓度为100000nM、25000nM、6250nM、1562.5nM、390.62nM、97.65nM、24.41nM、6.10nM、1.52nM、0.38nM；(1) 0.16 μL of compound solution was transferred to a 384-well reaction plate. The highest experimental concentration was 100 μM, and the final concentrations were 100000 nM, 25000 nM, 6250 nM, 1562.5 nM, 390.62 nM, 97.65 nM, 24.41 nM, 6.10 nM, 1.52 nM, and 0.38 nM after 4-fold dilution.
(2)将8μL 2×人cereblon蛋白加入384反应板，1000rpm离心1min，25℃孵育15min。(2) Add 8 μL 2× human cereblon protein to the 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min.
(3)将thalidomide red与GST EU的混合物置于384反应板中，1000rpm离心1min，25℃孵育180min。(3) Place the mixture of thalidomide red and GST EU in a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 180 min.
(4)用BMG酶标仪读取HTRF信号(Ratio 665/615nm)，根据不同药物浓度及其所对应的抑制率，使用GraghPad 5.0软件进行IC50曲线绘制，分析数据，得出最终IC50值，实验结果见表3。(4) The HTRF signal (Ratio 665/615 nm) was read using a BMG microplate reader. Based on different drug concentrations and their corresponding inhibition rates, the IC50 curve was drawn using GraphicPad 5.0 software. The data was analyzed to obtain the final IC50 value. The experimental results are shown in Table 3.
测试化合物的IC50值表示与CRBN蛋白结合的能力，数值越低结合力越强。The IC50 value of the test compound indicates the ability to bind to the CRBN protein, and the lower the value, the stronger the binding ability.
表3化合物与CRBN的结合能力

Table 3 Binding ability of compounds to CRBN

实验结果表明，本发明的化合物对Cereblon E3连接酶具有较好的抑制活性。The experimental results show that the compounds of the present invention have good inhibitory activity against Cereblon E3 ligase.
实验例3化合物对GSPT1蛋白降解能力评价Experimental Example 3 Evaluation of the ability of compounds to degrade GSPT1 protein
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及比较例化合物A，每个化合物用DMSO配制成10mM母液，最终稀释为3个浓度进行检测，NCI-H1155细胞实验的化合物终浓度为1000nM、100nM、10nM。使用0.5％的DMSO作为溶媒对照。Test compounds: The compounds of the present invention and comparative example compound A prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to three concentrations for detection, and the final concentrations of the compounds in the NCI-H1155 cell experiment were 1000 nM, 100 nM, and 10 nM. 0.5% DMSO was used as a solvent control.
NCI-H1155细胞(高表达MYC)：ATCC。NCI-H1155 cells (highly expressing MYC): ATCC.
试剂：TrypLETM Express Enzyme(1X),no phenol red，货号为Gibco 12604-021；eRF3，货号CST 14980S；BCA试剂盒，货号Beyotime P0010；彩色预染蛋白Ladder，Thermo 26619；抗兔二抗，CST 7074。Reagents: TrypLE TM Express Enzyme (1X), no phenol red, catalog number Gibco 12604-021; eRF3, catalog number CST 14980S; BCA kit, catalog number Beyotime P0010; color pre-stained protein ladder, Thermo 26619; anti-rabbit secondary antibody, CST 7074.
2.实验方法2. Experimental Methods
2.1总蛋白抽提2.1 Total protein extraction
每个处理组样品内加入100μL含有磷酸酶抑制剂和无EDTA的蛋白酶抑制剂的预冷蛋白酶裂解液，收取样品，于冰上孵育10min，4℃，14000rpm离心5min，小心吸取上清加入至新的EP管中备用或-80℃保存。Add 100 μL of pre-cooled protease lysis buffer containing phosphatase inhibitors and EDTA-free protease inhibitors to each treatment group sample, collect the sample, incubate on ice for 10 min, centrifuge at 4°C, 14000 rpm for 5 min, carefully aspirate the supernatant and add it to a new EP tube for later use or store at -80°C.
2.2 BCA蛋白定量2.2 BCA protein quantification
(1)配制BCA工作液：A液：B液＝50:1。(1) Prepare BCA working solution: Solution A: Solution B = 50:1.
(2)制作标准曲线。(2) Prepare a standard curve.
(3)粗略估算样品中蛋白的含量，将待测样品(或待测样品稀释液)各取20μL加入相应孔中。(3) Roughly estimate the protein content in the sample and add 20 μL of the sample to be tested (or the dilution of the sample to be tested) to the corresponding well.
(4)各实验孔加入200μL BCA工作液。振荡30s，37℃放置30min。(4) Add 200 μL of BCA working solution to each experimental well. Oscillate for 30 seconds and place at 37°C for 30 minutes.
(5)酶标仪波长562nm下检测OD值。(5) Detect the OD value at a wavelength of 562 nm using an enzyme reader.
(6)根据蛋白定量水平，取等量蛋白加入5×loading buffer，95℃ 10min，用于下一步实验。(6) According to the protein quantification level, take an equal amount of protein and add it to 5× loading buffer, incubate at 95℃ for 10 min for the next experiment.
2.3 Western blot实验2.3 Western blot experiment
(1)SDS-PAGE凝胶电泳(1) SDS-PAGE gel electrophoresis
将预制胶转移至电泳槽内，倒入1×Tris-Mops-SDS电泳缓冲液至没过胶块，拔出梳齿，用微量进样器吸取Ladder及样品加入孔中，每孔上样量根据BCA结果确定且不多于20μL，未上样的孔用20μL 1×SDS PAGE上样缓冲液补齐。80V电泳约30min，待溴酚蓝进入分离胶层后，120V继续电泳 直至溴酚蓝跑到胶最底部。Transfer the precast gel to the electrophoresis tank, pour 1×Tris-Mops-SDS electrophoresis buffer until the gel block is covered, pull out the comb teeth, use a microinjector to suck the ladder and sample into the wells, the sample volume per well is determined according to the BCA result and should not exceed 20μL, and the wells without sample are filled with 20μL 1×SDS PAGE loading buffer. Perform electrophoresis at 80V for about 30min, and continue electrophoresis at 120V after bromophenol blue enters the separation gel layer. Until bromophenol blue runs to the bottom of the gel.
(2)转膜(2) Transfer
剪取大小适宜的NC膜，置于平衡液中平衡1-5min，凝胶用ddH2O微微清洗后，依次放入黄色Pad底、NC膜、凝胶、Window和白色Pad顶，放入转膜仪中运行7min。Cut the NC membrane of appropriate size and place it in the equilibration solution for 1-5 minutes. After the gel is slightly washed with ddH2O, put the yellow pad bottom, NC membrane, gel, window and white pad top in sequence, and put them into the transfer instrument for 7 minutes.
(3)封闭(3) Closed
转膜完成后，取出NC膜，根据Ladder指示和目标蛋白大小小心裁剪NC膜，标记后置于足量封闭液中，低速振荡60min，弃去封闭液，1×TBST洗涤3次，每次10min。After the transfer is completed, take out the NC membrane, carefully cut the NC membrane according to the ladder instructions and the size of the target protein, place it in sufficient blocking solution after marking, shake at low speed for 60 minutes, discard the blocking solution, and wash 3 times with 1×TBST, 10 minutes each time.
(4)抗体孵育(4) Antibody incubation
根据说明书抗体稀释比例稀释适量抗体，孵育对应条带的NC膜，4℃过夜。次日取出NC膜，1×TBST洗涤3次，每次10min，根据一抗来源与二抗稀释比例稀释二抗，室温摇床低速孵育2h。Dilute the appropriate amount of antibody according to the antibody dilution ratio in the instruction manual, incubate the NC membrane of the corresponding band at 4°C overnight. Take out the NC membrane the next day, wash it 3 times with 1×TBST, 10 min each time, dilute the secondary antibody according to the source of the primary antibody and the dilution ratio of the secondary antibody, and incubate it at room temperature on a shaker at low speed for 2 h.
(5)曝光(5) Exposure
弃去二抗，1×TBST洗涤3次，每次10min，将显影液A与显影液B按1:1比例混合均匀备用(避光)。用滤纸吸干NC膜，放入曝光仪中，将显影混合液覆盖膜表面，调整曝光时间，获得最佳效果，保存照片。结果见表4。GSPT1(eRF3)蛋白量(％)越低表明化合物降解作用越强。Discard the secondary antibody, wash 3 times with 1×TBST, 10 min each time, mix developer A and developer B in a 1:1 ratio and set aside (protect from light). Use filter paper to dry the NC membrane, put it into the exposure instrument, cover the membrane surface with the developer mixture, adjust the exposure time to obtain the best effect, and save the photo. The results are shown in Table 4. The lower the GSPT1 (eRF3) protein amount (%), the stronger the degradation effect of the compound.
表4化合物对GSPT1(eRF3)的降解
Table 4 Degradation of GSPT1 (eRF3) by compounds
实验结果表明，在GSPT1(eRF3)蛋白降解实验中本发明的化合物表现出优异的蛋白降解能力。处理NCH-H1155细胞6h后，在10nM和100nM浓度下，实施例2和实施例4的化合物对GSPT1(eRF3)蛋白降解能力均优于化合物A。The experimental results show that the compounds of the present invention exhibit excellent protein degradation ability in the GSPT1 (eRF3) protein degradation experiment. After treating NCH-H1155 cells for 6 hours, at concentrations of 10 nM and 100 nM, the compounds of Example 2 and Example 4 have better GSPT1 (eRF3) protein degradation ability than Compound A.
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,
    X1选自-C(O)-、-S(O)-和-S(O)2-；X 1 is selected from -C(O)-, -S(O)- and -S(O) 2 -;
    X2选自-CH2-、-O-和-N＝CH-； X2 is selected from -CH2- , -O- and -N=CH-;
    X3和X4各自独立地选自键、-CH-和-S-； X3 and X4 are each independently selected from a bond, -CH- and -S-;
    X5和X6各自独立地选自-CH-和-N-； X5 and X6 are each independently selected from -CH- and -N-;
    L1选自-CH2-O-和-C≡C-；L 1 is selected from -CH 2 -O- and -C≡C-;
    L2选自键、-CH2-O-、-C≡C-和-S-；L 2 is selected from a bond, -CH 2 -O-, -C≡C- and -S-;
    Y选自氢、卤素、羟基、烷基、烯基、炔基、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、环烷基、杂环烷基、芳基和杂芳基，其任选被卤素、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、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基取代；Y is selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which is optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl;
    R1和R2各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、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、烷基氨基酰基和双烷基氨基；或者两个R1与它们所连接的原子形成环烷基、杂环烷基、芳基或杂芳基，其任选被卤素、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、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、环烷基、杂环烷基、芳基、杂芳基、螺环烷基、螺杂环烷基、螺芳基或螺杂芳基取代；R 1 and R 2 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino; or two R 1 and the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which is optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, spiroaryl or spiroheteroaryl;
    R3选自氢、烷基、卤代烷基和羟基烷基；和 R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl; and
    n和m各自独立地选自1、2、3、4和5。n and m are each independently selected from 1, 2, 3, 4 and 5.
  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，in,
    X1为-C(O)-； X1 is -C(O)-;
    X2为-CH2-； X2 is -CH2- ;
    X3和X4各自独立地为-CH-； X3 and X4 are each independently -CH-;
    X5和X6各自独立地为-CH-； X5 and X6 are each independently -CH-;
    L1为-CH2-O-； L1 is -CH2 -O-;
    L2选自键、-CH2-O-和-C≡C-；L 2 is selected from a bond, -CH 2 -O- and -C≡C-;
    Y选自卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、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、氨基酰基、C1-3烷基氨基酰基、双C1-3烷基氨基、C3-8环烷基、C3-8氧杂环烷基、C3-8氮杂环烷基、C6-12芳基和C5-12杂芳基，其任选被卤素、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基取代；Y is selected from halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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, aminoacyl, C 1-3 alkylaminoacyl, di C 1-3 alkylamino, C 3-8 cycloalkyl, C 3-8 oxacycloalkyl, C 3-8 azacycloalkyl, C 6-12 aryl and C 5-12 heteroaryl, which are optionally substituted by 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, amino, mono C substituted with C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, aminoacyl, or C 1-3 alkylaminoacyl;
    R1和R2各自独立地选自氢、卤素、羟基、C1-3烷基、C2-4烯基、C2-4炔基、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、氨基酰基、C1-3烷基氨基酰基和双C1-3烷基氨基；或者两个R1与它们所连接的原子形成C3-8环烷基、C3-8氧杂环烷基、C3-8氮杂环烷基、C6-12芳基或C5-12杂芳基，其任选被卤素、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基、C3-8螺环烷基、C3-8螺杂环烷基、C6-12螺芳基或C5-12螺杂芳基取代； R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, hydroxy C1-3 alkoxy , nitro , carboxyl, cyano , amino, mono C1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl , aminoacyl, C1-3 alkylaminoacyl and di- C1-3 alkylamino; or two R1 and the atoms to which they are attached form a C3-8 cycloalkyl, C3-8 oxacycloalkyl, C3-8 azacycloalkyl, C6-12 aryl or C5-12 heteroaryl, which is optionally substituted by halogen, hydroxy, C1-3 alkyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, The alkyl is substituted with C1-3 alkoxy, hydroxyC1-3 alkoxy, amino, monoC1-3 alkylamino, C1-3 alkylacylamino, C1-3 alkylacyl, aminoacyl, C1-3 alkylaminoacyl , C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-8 spirocycloalkyl , C3-8 spiroheterocycloalkyl , C6-12 spiroaryl or C5-12 spiroheteroaryl;
    R3选自氢、C1-3烷基、卤代C1-3烷基和羟基C1-3烷基；和 R3 is selected from hydrogen, C1-3 alkyl, halogenated C1-3 alkyl and hydroxy C1-3 alkyl; and
    n和m各自独立地选自1、2、3和4。n and m are each independently selected from 1, 2, 3 and 4.
  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，其中选自 其任选被一个或多个氟、氯、溴、碘、羟基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基如三氟甲基、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、氨基酰基、C1-6烷基氨基酰基和双C1-6烷基氨基取代。The compound according to claim 1 or 2, or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein Selected from It is optionally substituted by one or more fluorine, chlorine, bromine, iodine, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl such as trifluoromethyl, 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, aminoacyl, C 1-6 alkylaminoacyl and di-C 1-6 alkylamino.
  4. 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，其中 通式(I)具有以下通式(Ia)的结构，
    The compound according to claim 1 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein The general formula (I) has the following structure of the general formula (Ia),
    其中，in,
    环A选自环烷基、杂环烷基、芳基、杂芳基，其任选被卤素、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、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基取代；和Ring A is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, optionally substituted with halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl and alkylaminoacyl; and
    R1、R2、n和m如权利要求1所述的通式(I)中的定义。R 1 , R 2 , n and m are as defined in the general formula (I) as claimed in claim 1 .
  5. 根据权利要求4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，其中环A选自C3-8环烷基、C3-8杂环烷基、C6-12芳基、C5-12杂芳基，其任选被卤素、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、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基取代。The compound according to claim 4 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-12 aryl, C5-12 heteroaryl, which is optionally substituted with halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkoxy, amino , monoC1-6 alkylamino, C1-6 alkylacylamino , C1-6 alkylacyl, aminoacyl and C1-6 alkylaminoacyl.
  6. 根据权利要求5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，其中环A选自其任选被卤素、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、氨基、单C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基取代。The compound according to claim 5 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from It is optionally substituted with 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, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl and C 1-6 alkylaminoacyl.
  7. 根据权利要求4-6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R1和R2各自独立地选自氢、氟、氯、溴、碘、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，其任选被羟基、氢、氟、氯、溴、碘、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、氨基、单C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基所取代；和The compound according to any one of claims 4 to 6 or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, 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 alkylacylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl and di C 1-3 alkylamino, which are optionally substituted by hydroxy, hydrogen, fluorine, chlorine, bromine, iodine, 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, amino, mono C substituted by C 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, aminoacyl, or C 1-3 alkylaminoacyl; and
    n和m各自独立地选自1、2和3。n and m are each independently selected from 1, 2 and 3.
  8. 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，其中所述化合物为选自以下的化合物：

    The compound according to claim 1 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1-8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癌症的药物中的应用。 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 cancer.
PCT/CN2023/137785 2022-12-13 2023-12-11 Gspt1 degradation agent and use thereof WO2024125437A1 (en)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200009120A1 (en) * 2018-06-13 2020-01-09 Biotheryx, Inc. Aminoamide compounds
US20200347045A1 (en) * 2018-01-12 2020-11-05 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
WO2022152822A1 (en) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Treatment of myc-driven cancers with gspt1 degraders
WO2022152821A1 (en) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Isoindolinone compounds
WO2022200857A1 (en) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Pharmaceutical compositions for use in the prevention and treatment of a disease or disorder caused by or associated with one or more premature termination codons
WO2022219407A1 (en) * 2021-04-14 2022-10-20 Monte Rosa Therapeutics Ag Isoindolinone compounds
WO2022250224A1 (en) * 2021-05-26 2022-12-01 주식회사 이노큐어테라퓨틱스 Piperidinedione derivative
WO2024015565A1 (en) * 2022-07-14 2024-01-18 Monte Rosa Therapeutics, Inc. Methods of preparing an isoindolinone derivative and crystal forms thereof
WO2024015855A1 (en) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. COMBINATION THERAPY COMPRISING GSPT1-DIRECTED MOLECULAR GLUE DEGRADERS AND PI3K/AKT/mTOR PATHWAY INHIBITORS

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200347045A1 (en) * 2018-01-12 2020-11-05 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
US20200009120A1 (en) * 2018-06-13 2020-01-09 Biotheryx, Inc. Aminoamide compounds
WO2022152822A1 (en) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Treatment of myc-driven cancers with gspt1 degraders
WO2022152821A1 (en) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Isoindolinone compounds
WO2022200857A1 (en) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Pharmaceutical compositions for use in the prevention and treatment of a disease or disorder caused by or associated with one or more premature termination codons
WO2022219407A1 (en) * 2021-04-14 2022-10-20 Monte Rosa Therapeutics Ag Isoindolinone compounds
WO2022250224A1 (en) * 2021-05-26 2022-12-01 주식회사 이노큐어테라퓨틱스 Piperidinedione derivative
WO2024015855A1 (en) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. COMBINATION THERAPY COMPRISING GSPT1-DIRECTED MOLECULAR GLUE DEGRADERS AND PI3K/AKT/mTOR PATHWAY INHIBITORS
WO2024015565A1 (en) * 2022-07-14 2024-01-18 Monte Rosa Therapeutics, Inc. Methods of preparing an isoindolinone derivative and crystal forms thereof

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