WO2022188823A1 - Tricyclic hpk1 inhibitor and use thereof - Google Patents

Tricyclic hpk1 inhibitor and use thereof Download PDF

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Publication number
WO2022188823A1
WO2022188823A1 PCT/CN2022/080065 CN2022080065W WO2022188823A1 WO 2022188823 A1 WO2022188823 A1 WO 2022188823A1 CN 2022080065 W CN2022080065 W CN 2022080065W WO 2022188823 A1 WO2022188823 A1 WO 2022188823A1
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alkyl
amino
alkoxy
membered
independently selected
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PCT/CN2022/080065
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French (fr)
Chinese (zh)
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刘斌
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山东轩竹医药科技有限公司
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Priority to CN202280012271.1A priority Critical patent/CN116888127A/en
Publication of WO2022188823A1 publication Critical patent/WO2022188823A1/en

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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a tricyclic HPK1 compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, comprising the compound, a pharmaceutically acceptable compound thereof
  • Pharmaceutical compositions and formulations of salts and stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts and stereoisomers thereof, and the compounds, pharmaceutically acceptable salts and stereoisomers thereof Use of isomers.
  • T cell receptor (TCR)-mediated T cell activation plays an important role in thymic T cell development, T cell subset differentiation, and effector T cell function.
  • TCR can recognize the MHC (major histocompatibility complex) on the surface of antigen-presenting cells, and then recognize the signal transmitted to the inside of the cell. Signal transmission leads to activation of downstream signaling pathways.
  • Typical intracellular signals activated by TCR include signaling pathways such as MAPK (mitogen-activated protein kinase), PKC (protein kinase C), and calcium ions. Activation of these signals ultimately activates T cell-specific gene expression, causes cell proliferation, and allows T cells to differentiate into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of antitumor immunity.
  • T cells Sustained antigen exposure leads to progressive differentiation of T cells into an exhausted state characterized by a hierarchical loss of effector function and proliferative capacity, as well as marked transcriptional, epigenetic, and metabolic changes. How to prevent T cell exhaustion and expand effector T cell function is one of the most pressing issues in tumor immunology.
  • Hematopoietic progenitor kinase HPK1 (HematopoieticProgenitor Kinase1) is an immunosuppressive regulatory kinase with restricted expression in hematopoietic stem cells.
  • HPK1 is a negative signaling regulator of the T cell receptor (TCR).
  • TCR T cell receptor
  • cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3, which eventually leads to the instability of the TCR signaling complex. thereby downregulating TCR signaling.
  • HPK1 also known as MAP4K1
  • MAP4K1 is a member of the MAP4K family, which has five other members, MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase), and MAP4K6 (MINK kinase) .
  • MAP4K2 GCK kinase
  • MAP4K3 GLK kinase
  • MAP4K4 HGK kinase
  • MAP4K5 KHS kinase
  • MAP4K6 MINK kinase
  • the technical problem to be solved by the present invention is to provide a HPK1 inhibitor compound with novel structure and good inhibitory activity to HPK1. Further, the compounds can be used to inhibit the kinase activity of HPK1, thereby enhancing the immune effect of the body against tumors. Furthermore, the compounds can also be used to treat or prevent related diseases mediated by HPK1, especially cancer. The compounds have good inhibitory effect on various cancer cells and have good druggability.
  • the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
  • X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 5 is selected from -C(R 6 );
  • Y 6 is selected from -C(R 7 ) or -N-;
  • Each R 2 , R 3 , and each R 4 are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- 6 alkoxy or halogenated C 1-6 alkoxy;
  • R 5 and R 7 together with R 6 and the ring atoms to which they are attached respectively form 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered optionally substituted by 1-5 Q1 A membered aryl group or a 5-10 membered heteroaryl group;
  • the uncyclic R 5 or R 7 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any
  • the following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxy
  • Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substi
  • Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2
  • Each m and each p are independently selected from 0, 1, 2, 3, 4, or 5.
  • the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof has the following general formula (II-1) or general formula (II-2) the structure shown
  • X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 6 is selected from -C(R 7 ) or -N-;
  • Each R 2 , each R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any
  • the following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxy
  • Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substi
  • Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2
  • Each m, each n, and each p is independently selected from 0, 1, 2, 3, 4, or 5.
  • X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 6 is selected from -C(R 7 ) or -N-;
  • Each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected substituted by substituents: -( CH2 ) p -3-6 membered cycloalkyl, -( CH2 ) p -3-6 membered heterocyclyl, -( CH2 ) p -5-8 Member heteroaryl, -(CH 2 ) p -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C
  • Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -( CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl,
  • Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , Di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio , halogenated C 1-4 4 alkoxy, halogenated C 1-4 alkylthio, hydroxy C 1-4 alkoxy, hydroxy C 1-4 alkylthio, amino C 1-4 alkoxy, amino C 1-4 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m - 3-8 membered heterocyclyl, -(CH 2 ) m -5 -8-membered heteroaryl, -(
  • Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
  • X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • Y 2 and Y 4 are independently selected from -C(R 2 )- or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 6 is selected from -C(R 7 ) or -N-;
  • each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or haloC 1-4 alkyl;
  • R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR a -C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents selected from halogen, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • Ring A is selected from 5-10 membered cycloalkyl or 5-10 membered heterocyclyl
  • Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -C(O)R a , -C(O)OR a , -C( O) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, - (CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy
  • Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclic cyclic group; the substituent is selected from halogen, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
  • X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-; each R 2 , each R 3 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, or -N(R 4 )-; each R 2 , each R 3 , each R4 is each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • X 1 , Y 1 are each independently selected from CH 2 , O, or NH.
  • Y 2 , Y 4 are each independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • R 7 is selected from hydrogen, halogen, C 1-6 alkyl, or haloC 1-6 alkyl.
  • R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
  • R5 is hydrogen
  • Y 2 is N.
  • Y 3 , Y 4 are each independently selected from CH or N.
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2.
  • Each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2.
  • Each R4 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, halogen , C 1-6 alkyl or halogenated C 1-6 alkyl.
  • one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, fluoro , chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • X3 is selected from -C (R2)-, wherein R2 is selected from hydrogen , fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
  • R2 is selected from hydrogen , fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
  • one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently N or -N(R 4 )-; each R 4 is independently is selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • X 3 is N
  • one of X 2 and X 4 is -N(R 4 )- and the other is -C(R 2 )-
  • R 2 and R 4 are each independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, haloC 1-4 alkyl, -(CH 2 ) p -3-6 membered cycloalkane group, -(CH 2 ) p -3-6 membered heterocyclyl, -NR a -C(O)-R b -, -NR a R b or -OR a ; each p is independently selected from 0, 1 , 2 or 3.
  • R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, -NR a -C(O)-R b -, -NR a R b , -OR a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopropyl, oxa propyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothienyl.
  • Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.
  • Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered nitrogen-containing heterocyclyl.
  • Ring A is selected from 5-8 membered monocycloalkyl, 5-8 membered monoheterocyclyl, 6-8 membered fused heterocyclyl, 6-8 membered bridged heterocyclyl, or 6-8 membered heterocyclyl A membered spiro heterocyclyl.
  • Ring A is selected from 7-8 membered monocycloalkyl, 7-8 membered monoheterocyclyl, or 8 membered nitrogen-bridged heterocyclyl.
  • Ring A is selected from a 7-8 membered nitrogen-containing monoheterocyclyl group or a 7-8 membered oxygen-containing monoheterocyclyl group.
  • each Q1 is independently selected from halogen, hydroxy, nitro, hydroxy, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O ) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -( CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -(CH 2 ) m - Phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, hydroxyl C 1-4 alkyl, 3-8 membered
  • each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6-membered heterocyclic group, -(CH 2 ) m -5-6-membered heteroaryl group or -(CH 2 ) m -phenyl; the Q2 is independently selected from halogen, hydroxyl, nitro group, amino group, cyano group, carboxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, halogenated C 1-4 alkyl group or hydroxy C 1-4 alkyl group.
  • each Q1 is independently selected from the group consisting of fluorine, chlorine, bromine, amino, cyano, hydroxyl, carboxyl, nitro, -C(O)R a , -C(O)OR a , -C (O) NR a or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxy Ethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl radical, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -
  • each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy Ethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl base, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -
  • each R a , each R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, bis(C 1-4 Alkyl) amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, - (CH 2 ) m -5-8-membered heteroaryl or -(CH 2 ) m -phenyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl , C 1-4 alkoxy or halogenated C 1-4 alkyl.
  • each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, halo C 1-4 alkoxy Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; each R b is independently selected from hydrogen or C 1-4 alkyl.
  • each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoro Methyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy or optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, azetidinyl, azetidinyl, tetrahydropyrrolyl, pyrazolidine, imidazolidinyl, piperazinyl or piperidinyl; the substituents are selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxy
  • each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or any
  • substituents are selected to be substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidine or pyrrolidinyl; the substituents are selected from fluorine, chlorine , bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b is independently selected from hydrogen, methyl , ethyl, propyl or isopropyl.
  • a compound of general formula (I), general formula (II-1), general formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has the following general formula:
  • Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • Y 4 is selected from -C(R 2 ) or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 6 is selected from -C(R 7 ) or -N-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • each of R 2 , R 3 , R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR a - C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1- 4 alkyl;
  • Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O)NR a or optionally 1-2
  • Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxane , oxetanyl, azetidinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl,
  • each R b is independently selected from hydrogen or C 1-4 alkyl
  • Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
  • Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
  • Y 4 is selected from -C(R 2 ) or -N-;
  • Y 3 is selected from -C(R 5 ) or -N-;
  • Y 6 is selected from -C(R 7 ) or -N-;
  • X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
  • each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl , -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b ;
  • Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy propylpropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH2 ) m -cyclopentyl, -( CH2 ) m -cyclohexyl, -( CH2 ) m -oxopropyl, -( CH2
  • each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
  • each m, each n is independently selected from 0, 1, 2 or 3.
  • Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, Propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -oxetanyl, -(CH 2
  • each m, each n is independently selected from 0, 1, 2 or 3.
  • Ring A is selected from preferably selected from preferably selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl methoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl group, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxopropyl, -(CH 2 ) m -oxet
  • each m, each n is independently selected from 0, 1, 2 or 3.
  • each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted with 1-2 Q2: methyl, ethyl, Propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, propoxyethyl, cyclopropyl, cyclobutyl , oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, azetidinyl, azetidinyl, pyridyl or pyridazinyl; the Q2 are respectively Independently selected from fluoro, chloro, bromo, hydroxy, amino, cyano, carboxy, nitro, methyl, ethyl, propyl, isopropyl, methoxy, e
  • the compound of general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), its A pharmaceutically acceptable salt or a stereoisomer thereof has the structure represented by the following general formula (IV-1) or general formula (IV-2):
  • X 2 , X 3 , X 4 , ring A, R 1 , R 2 , R 4 , R a , R b , Q1 , Q2 , m, n, and p are as described in any one of the preceding schemes.
  • X 3 and X 4 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are as defined in any of the foregoing plan described.
  • X 2 and X 4 are independently selected from -C(R 2 )-; the definitions of ring A, R 1 , R 2 , R 4 , Q1, Q2, R a , R b , m, n, and p are as follows as described in any of the preceding scenarios.
  • X 2 and X 3 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are defined as any of the foregoing plan described.
  • X 2 , X 3 , and X 4 are each independently selected from -C(R 2 )-;
  • Each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, Or the following groups optionally substituted by substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents are selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • Ring A is selected from preferably selected from preferably selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2 : C 1- 4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3 -6-membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, C 1-4 alkyl , C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl;
  • Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1 -6 alkyl or halogenated C 1-6 alkyl;
  • each R b is independently selected from hydrogen or C 1-4 alkyl
  • Each m, each n, and each p is independently selected from 0, 1, or 2.
  • the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-1) or general formula (VII-2):
  • the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-3) or general formula (VII-4):
  • the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof has the structure shown in the following general formula (VII-5) or general formula (VII-6):
  • the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-7) or general formula (VII-8):
  • R 1 is selected from -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, or the following groups optionally substituted with substituents: -(CH 2 ) p -3 -6-membered cycloalkyl, -(CH 2 ) p -3-6-membered heterocyclyl; the substituent is selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: C 1-4 alkane group, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or benzene base; the Q2 is independently selected from halogen, hydroxyl, C 1-4 alkyl or halogenated C 1-4 alkyl;
  • Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1-6 alkyl or halogenated C 1-6 alkyl;
  • each R b is independently selected from hydrogen or C 1-4 alkyl
  • Each n and each p are independently selected from 0, 1 or 2.
  • R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b .
  • R 1 is selected from azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , each R a is independently selected from hydrogen, methyl radical, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or optionally substituted with substituents of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl
  • each R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl , difluoromethyl or trifluoromethyl;
  • Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
  • Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 is independently selected from fluorine, chlorine, bromine , hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;
  • Each R a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl Fluoromethoxy or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl , tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
  • Each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  • R 1 is selected from -NH 2 ,
  • the hydrogen on the ring nitrogen atom in the ring A can be optionally substituted by Q1.
  • Q1 substitutes one or more hydrogens on a ring nitrogen atom in Ring A.
  • each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,
  • the compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the medicament
  • the composition can be made into any clinically or pharmaceutically acceptable dosage form, such as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection solution, sterile powder for injection) and concentrated solutions for injection), suppositories, inhalants or sprays, etc.
  • the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug.
  • the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
  • the pharmaceutically acceptable carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the field of pharmaceutical formulations, and the choice of a particular carrier and/or diluent will depend on the Mode of administration or disease type and state to treat a particular patient.
  • the preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
  • the present invention also relates to the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for the prevention and/or treatment of diseases mediated by HPK1 and related diseases,
  • the drug can be used in combination with one or more other drugs to prevent or treat diseases and related disorders mediated by HPK1.
  • the disease and related conditions are selected from cancers or benign tumors, including carcinomas in situ and metastatic cancers.
  • the cancer includes but is not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, Liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibromas, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell Lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, etc.
  • the present invention also relates to the use of a pharmaceutical preparation containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament, which can be used in combination with one or more medicaments Treatment and/or prevention of diseases and related disorders mediated by HPK1.
  • the present invention relates to a medicament containing a compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which may be administered alone, or in combination with one or more second therapeutically active agents,
  • the second therapeutically active agent is used in combination with the HPK1 inhibitor compounds of the present application for the treatment and/or prevention of diseases and related disorders mediated by HPK1.
  • the pharmaceutical composition further contains one or more second therapeutically active agents.
  • the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and isoprenyl protein transferase inhibitors.
  • anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and
  • the ingredients to be combined may be administered simultaneously or sequentially and separately .
  • the second therapeutically active agent can be administered prior to, concurrently with, or subsequent to administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • the components to be combined may also be administered in combination in the same formulation or in separate different formulations.
  • the present invention also provides a method for treating diseases and related disorders mediated by HPK1, the method comprising administering to a patient in need an effective amount of the compound of the aforementioned general formula (I), its pharmacy An acceptable salt of the above or a stereoisomer thereof, the aforementioned formulation or pharmaceutical composition; the HPK1-mediated diseases and related disorders are as defined above.
  • the "effective amount” refers to a dose of a drug capable of alleviating, delaying, inhibiting or curing a disorder in a subject.
  • the size of the administered dose is determined by the mode of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual signs (sex, weight, height, age) and the like.
  • halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-4 alkyl group” and “C 1-3 alkyl group” , “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl", “C 2-4 alkyl", “C 2-3 alkyl", “C 3- 6 alkyl”, “C 3-5 alkyl", “C 3-4 alkyl", etc.
  • C 1-4 alkyl group in the present invention refers to a specific example of the C 1-6 alkyl group containing 1-4 carbon atoms.
  • C 1-6 alkoxy in the present invention refers to “C 1-6 alkyl-O-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkoxy in the present invention refers to “C 1-4 alkyl-O-”, and the “C 1-4 alkyl” is as defined above.
  • C 1-6 alkylthio in the present invention refers to “C 1-6 alkyl-S-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkylthio in the present invention refers to “C 1-4 alkyl-S-”, and the “C 1-4 alkyl” is as defined above.
  • hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl in the present invention means that one or more hydrogens in the C 1-6 alkyl are replaced by one or more Multiple hydroxy, amino or halogen substituted.
  • C 1-6 alkyl is as defined above
  • Hydrogen is replaced with one or more hydroxy, amino or halogen.
  • hydroxyl C 1-6 alkylthio, amino C 1-6 alkylthio, halogenated C 1-6 alkylthio refers to one or more of "C 1-6 alkylthio" Hydrogen is replaced with one or more hydroxy, amino or halogen.
  • C 1-6 alkylamino, di(C 1-6 alkyl) amino in the present invention refer to C 1-6 alkyl-NH-
  • C 2-6 alkenyl in the present invention refers to a straight-chain, branched or cyclic alkenyl containing at least one double bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkenyl""Wait.
  • Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexenyl Dienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.
  • C 2-6 alkynyl in the present invention refers to a straight-chain or branched alkynyl group containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkynyl” and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -hexynyl, 5-methyl-2-hexynyl, etc.
  • the "3-10 membered cycloalkyl” in the present invention refers to a saturated or partially saturated monocyclic or polycyclic group containing 3-10 carbon atoms and not having aromaticity.
  • the "monocyclic cycloalkyl group” is preferably “3-8 membered monocyclic alkyl group”
  • the "polycyclic cycloalkyl group” includes "fused ring group, bridged ring group and spirocyclic group”, preferably "7-10 membered fused cycloalkyl", "7-10-membered bridged cyclic group” and "7-10-membered spirocyclic group”.
  • the "3-8 membered monocyclic alkyl group” mentioned in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group containing 3-8 carbon atoms without aromaticity, including "3-8 membered saturated monocyclic cyclic alkyl group”.
  • 3-8 membered saturated monocycloalkyl include but are not limited to: cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentyl (cyclopentyl) , cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated monocycloalkyl” include but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptyl Alkenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5
  • the "7-10-membered fused ring group” in the present invention refers to a saturated or partially containing 7-10 ring atoms formed by two or more ring structures sharing two adjacent carbon atoms with each other.
  • Saturated, non-aromatic cyclic group one of the fused rings can be an aromatic ring, but the fused ring as a whole does not have aromaticity; including "8-9 membered fused ring group", "9-10 "Condensed ring group” etc., the condensing mode can be: 5-6-membered cycloalkyl, 5-6-membered cycloalkyl, benzo 5-6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl etc., optionally, ring atoms in the ring structure can be oxo.
  • Examples include, but are not limited to: bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decalinyl, tetrahydrophenanthryl, bicyclo[3.1.0]hex-2- Alkenyl, Bicyclo[4.1.0]hept-3-enyl, Bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,
  • the "7-10-membered bridged cyclic group" in the present invention refers to a cyclic ring containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. structure.
  • carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to: Wait.
  • the "7-10 membered spiroheterocyclyl" in the present invention refers to a cyclic structure containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing one carbon atom with each other.
  • carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to: Wait.
  • the "3-10-membered heterocyclic group” in the present invention refers to a saturated or partially saturated (containing 1 or 2 double bonds) consisting of 3-10 carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur.
  • Non-aromatic cyclic group this cyclic group can be a monocyclic or polycyclic group, in the present invention, the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, the nitrogen in the heterocyclic group is preferably 1, 2, 3 or 4.
  • carbon or sulfur atoms can be optionally oxidized.
  • the nitrogen atom may be optionally further substituted with other groups to form tertiary amines or quaternary ammonium salts.
  • the monocyclic heterocyclic group is preferably a "3-8 membered monoheterocyclic group", which means at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3 -8 saturated or partially saturated and non-aromatic monocyclic cyclic groups, the heteroatoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms in the ring structure ( For example carbon atoms, nitrogen atoms or sulfur atoms) can be oxo.
  • the "3-8 membered monoheterocyclic group" in the present invention includes "3-8 membered saturated monoheterocyclic group” and "3-8 membered partially saturated monoheterocyclic group”.
  • the "3-8-membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8-membered monoheterocyclic group” of the present invention contains 1-2 heteroatoms atom, and the heteroatom is selected from nitrogen atom and/or oxygen atom; preferably, the "3-8-membered monoheterocyclic group" of the present invention contains one nitrogen atom.
  • the "3-8 membered monoheterocyclic group” is preferably "3-7 membered monoheterocyclic group", "3-6 membered monoheterocyclic group”, “4-7 membered monoheterocyclic group”, “4-6 membered monoheterocyclic group” "Mono-heterocyclic group”, “6-8-membered mono-heterocyclic group”, “5-7-membered mono-heterocyclic group”, "5-6-membered mono-heterocyclic group”, “3-6-membered saturated mono-heterocyclic group” ", "5-6 membered saturated monoheterocyclic group”, “3-6 membered nitrogen-containing monoheterocyclic group”, “3-6 membered saturated nitrogen-containing monoheterocyclic group”, “5-6 membered nitrogen-containing monoheterocyclic group” ring group”, “5-6 membered saturated nitrogen-containing monoheterocyclic group”, etc.
  • 3-8 membered monoheterocyclyl include, but are not limited to: aziridyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridenyl, aza Cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxanyl Dialkenyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydro thienyl, tetrahydrothienyl, 4,5-
  • Polycyclic heterocyclic groups include "fused heterocyclic group", “spiro heterocyclic group” and “bridged heterocyclic group”, preferably "7-10 membered fused heterocyclic group", “7-10 membered spiro heterocyclic group” and “7-10 membered bridged heterocyclyl”.
  • the "7-10-membered fused heterocyclic group” in the present invention refers to at least one ring formed by two or more cyclic structures sharing two adjacent atoms with each other and containing 7-10 ring atoms
  • the atom is a heteroatom, saturated or partially saturated, non-aromatic cyclic group
  • one of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic
  • the heteroatom is nitrogen Atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo, including but not limited to "8-9 membered fused heterocyclic group" ", "9-10-membered fused heterocyclic group", etc.
  • the condensing mode can be 5-6-membered heterocyclic group and 5-6-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-
  • benzocyclopentyl the structure of which refers to (also referred to as 2,3-dihydro-1H-indenyl); the term “benzopyrrolidine” whose structure includes etc.; the term “pyridotetrahydrofuranyl” whose structure includes Specific examples of other "other fused heterocyclic groups as defined” previously defined have cyclic structures similar to them.
  • the "7-10 membered spiroheterocyclyl" in the present invention refers to a ring formed by two or more cyclic structures sharing one ring atom with each other, containing 7-10 ring atoms (at least one ring atom is A cyclic structure of a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), includes "7-10 membered saturated spiroheterocyclyl” and "7-10 membered partially saturated spiroheterocyclyl".
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • Specific examples include but are not limited to:
  • the "7-10-membered bridged heterocyclyl” in the present invention refers to a group formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, containing 7-10 ring atoms (wherein A cyclic structure in which at least one ring atom is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) includes "7-10 membered saturated bridged heterocyclyl" and "7-10 membered partially saturated bridged heterocyclyl".
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • Specific examples include but are not limited to:
  • the "6-10-membered aryl group" in the present invention includes “6-8-membered monocyclic aryl group” and "8-10-membered fused-ring aryl group”.
  • the "6-8-membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.
  • the "8-10-membered fused-ring aryl group” mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring carbon atoms, not
  • the saturated and aromatic cyclic group is preferably a "9-10-membered fused-ring aryl group", and specific examples are naphthyl and the like.
  • the "5-10-membered heteroaryl” in the present invention includes “5-8-membered monoheteroaryl” and "8-10-membered condensed heteroaryl”.
  • the "5-8-membered heteroaryl group” in the present invention refers to an aromatic mono-heteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom). Cyclic ring group.
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • ring structure may be oxo.
  • 5-8-membered monoheteroaryl includes, for example, "5-7-membered monoheteroaryl", “5-6-membered monoheteroaryl”, “5-6-membered nitrogen-containing monoheteroaryl", “6-membered monoheteroaryl”
  • Nitrogen-containing monoheteroaryl group etc., the heteroatom in the "nitrogen-containing heteroaryl group” contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or, contains one nitrogen atom and other nitrogen atoms 1 or 2 heteroatoms (eg oxygen and/or sulphur atoms), alternatively 2 nitrogen atoms and 1 or 2 other heteroatoms (eg oxygen and/or sulphur atoms).
  • 5-8 membered monocyclic heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-Triazinyl, 1,3,5-Triazinyl, 1,2,4,5-Tetrazinyl, Azacyclotrienyl, 1,3-Diazepinyl Alkenyl,
  • the "8-10-membered fused heteroaryl group” in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms), unsaturated aromatic ring structures.
  • Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms
  • unsaturated aromatic ring structures such as nitrogen atoms, oxygen atoms or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • Including "9-10-membered condensed heteroaryl", “8-9-membered condensed heteroaryl”, etc., and the condensing method can be benzo-5-6-membered heteroaryl, 5-6-membered heteroaryl and 5- 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benziso furanyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4 -quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyri
  • substituted refers to two situations in which one or more hydrogen atoms on the substituted group may be "substituted” or “unsubstituted” by one or more substituent groups.
  • the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds with appropriate inorganic or organic anions (acids), Included are salts formed with inorganic or organic acids such as carboxylic acids and the like.
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • Examples include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, bismuth, hydrochloride, sulfate, nitrate, phosphate, hydrobromide, hydroiodide, formate , acetate, propionate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate salt, ethanesulfonate, benzenesulfonate, tosylate, tetrafluoroborate, arginine, aspartate and glutamic acid, etc.
  • isomer refers to when the compound of the present invention contains one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomers mixtures and single diastereomers.
  • the compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers.
  • the scope of the present invention includes all possible optical isomers and mixtures thereof. If the compound of the present invention contains an olefinic double bond, unless otherwise specified, cis-isomer and trans-isomer are included.
  • the compounds described in the present invention may exist as tautomers (a type of functional group isomer) that have different hydrogen attachment points by displacement of one or more double bonds, eg, ketones and their alkenes
  • the alcohol form is the keto-enol tautomer.
  • the compound of the present invention contains a spiro ring structure, and under the influence of the steric space structure of the ring, the substituents on the ring can exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers.
  • cis cis
  • trans trans
  • Each tautomer and mixtures thereof are included within the scope of the present invention.
  • Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and the like are included in the scope of the present invention.
  • the compounds of the present invention can be prepared in the form of individual enantiomers by enantiospecific synthesis or by resolution from enantiomeric mixtures.
  • Conventional resolution techniques include the use of optically active acids to form salts of the free base of each isomer of the enantiomeric pair (followed by fractional crystallization and free base regeneration), the use of optically active amines to form Acid form salts of each enantiomer (followed by fractional crystallization and free acid regeneration), each enantiomer of an enantiomer pair formed using optically pure acids, amines, or alcohols esters or amides of the species (followed by chromatographic separation and removal of chiral auxiliary agents) or resolution of mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.
  • stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to other stereoisomers or 99.9% by weight pure.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure.
  • Optical purity weight % is the ratio of the weight of the enantiomer to the weight of the enantiomer plus its optical isomer.
  • the "dosage form” referred to in the present invention refers to the form that the drug is made into suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.
  • the compounds of the present invention have excellent inhibitory effect on HPK1 activity, good pharmacokinetic properties in vivo, long-lasting effects, and good liver microsome stability Sex, exposure and bioavailability, can treat and/or prevent diseases mediated by HPK1.
  • the compound of the present invention has the advantages of simple preparation process, high drug purity and stable quality, and is easy to carry out large-scale industrial production.
  • LiAlH 4 lithium aluminum hydride
  • 2,2'-(1,2-phenylene)diacetic acid (10.0 g, 51.5 mmol) was dissolved in tetrahydrofuran (200 mL).
  • LiAlH 4 (5.9 g, 0.15 mol) was added in batches at 0° C., the addition was completed, and the reaction was carried out at 15° C. for 18 hours.
  • LCMS detected the end of the reaction, 5.9 mL of water was added at 0°C to quench the reaction, a solid was precipitated, filtered through celite, the solid was washed with tetrahydrofuran, and the filtrate was dried and concentrated to obtain 7.0 g of the title compound, yield: 81.8%.
  • N-(3-Methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.9 g, 8.7 mmol) was dissolved in concentrated sulfuric acid (16 mL) ), fuming nitric acid (799.0 mg, 11.3 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 10 min.
  • 2,3,5,6-Tetrahydrobenzo[d]azepin-4(1H)-one (5.0 g, 28.5 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium tetrahydroaluminum (4.3 mmol) was added at 0°C. g, 113.2 mmol), reacted at 75°C for 1 hour.
  • Water (4.3 mL) was added to quench the reaction, 10% sodium hydroxide (4.3 mL) solution and water (12.9 mL) were added, the solid was removed by filtration, and extracted with water (100 mL) and ethyl acetate (200 mL) to obtain 4.2 g of crude product.
  • 1,2,3,4,5,6-hexahydrobenzo[d]azepine (2.0 g) was dissolved in formic acid (10 mL), formaldehyde (37%) (20 mL) was added, and the mixture was reacted at 70° C. for 1 hour. The pH was adjusted to 9 with saturated sodium bicarbonate (200 mL), and extracted with ethyl acetate (200 mL) to obtain 2.0 g of crude product.
  • 1,4-Dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine 300 mg, 1.2 mmol was dissolved in ethanol (10 mL), Pd/C (150 mg) was added, the addition was completed, and the reaction was carried out at 10° C. for 2 hours under nitrogen protection.
  • LCMS detected the end of the reaction. Filter through diatomaceous earth, concentrate the solvent to obtain the target compound and directly put it into the next step.
  • N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3 g , 7.7 mmol) was dissolved in concentrated sulfuric acid (16 mL), at 0 °C, fuming nitric acid (700.0 mg, 10.0 mmol) was added, the addition was completed, and the reaction was carried out at 0 °C for 2 hours.
  • LCMS detected the end of the reaction. It was poured into ice water, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain 2.3 g of the target compound, yield: 86.9%.
  • 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (5.0 g, 34.0 mmol) was dissolved in trifluoroacetic acid (20 mL), cooled to 0 °C, and concentrated sulfuric acid (7.5 mL) was added and potassium nitrate (5.5 g, 56.7 mmol), react at 0°C for 2 hours.
  • N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.5 g, 6.5 mmol) was dissolved in concentrated sulfuric acid (30 mL) ), fuming nitric acid (470 mg, 7.5 mmol) was added dropwise at 0 °C, and the reaction was completed at 0 °C for 10 min.
  • 3-Ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.0 g, 4.2 mmol) was dissolved in ethanol (100 mL), Pd/C (300 mg) was added, the mixture was purged with hydrogen 3 times, and hydrogenated at 15° C. for 4 hours under hydrogen.
  • 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride 2.0 g. 10.2 mmol was added, and the temperature was raised to 50° C. to react for 2 hours.
  • reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 300 mg of the target compound with a two-step yield of 39.6%.
  • N-(3-Cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.12 g, 8.65 mmol) was dissolved in concentrated sulfuric acid ( 22mL), fuming nitric acid (849mg, 13mmol) was added at 0°C, reacted at 25°C for 0.5h, the reaction was completed by LCMS, the pH was adjusted to 8-9 with 5M sodium hydroxide solution, extracted with DCM, and the organic phase was anhydrous sulfuric acid. Sodium-drying, spin-dried to obtain 2 g of product with a yield of 79.7%.
  • N-(3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.96 g, 6.76 mmol) It was dissolved in methanol (35 mL), potassium carbonate (4.6 g, 33.4 mmol) was added, and the reaction was carried out at 65 °C for 8 h.
  • the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (15 mL), added with methanol (1 mL) and ethyl acetate (1 mL), filtered and dried to obtain 7.5 mg of the target compound, yield: 3.5%.
  • N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (5.5 g , 18.3 mmol) was dissolved in concentrated sulfuric acid (50 mL), fuming nitric acid (1.5 g, 22.0 mmol) was added dropwise at 0 °C, the addition was completed, and the reaction was carried out at 0 °C for 1.5 hours. LCMS detected the end of the reaction.
  • 6-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine 400 mg, 1.9 mmol was dissolved in methanol (10 mL), and formaldehyde (37%) was added ) (791.2 mg, 9.7 mmol), acetic acid (114.0 mg, 1.9 mmol), react at 15° C. for 1 hour, add sodium cyanoborohydride (601.4 mg, 9.7 mmol), complete the addition, and react at 15° C. for 1 hour. LCMS detected the end of the reaction.
  • the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a solid.
  • the solid was slurried with methanol to obtain 16.2 mg of the title compound with a yield of 12.7%.
  • the crude product from the previous step was dissolved in 10 mL of methanol, 150 mg of potassium carbonate was added, and the reaction was carried out at 25° C. for 1 h. After the reaction was completed, the solvent was concentrated, and 16 mg of the target product was obtained by column chromatography, with a two-step yield of 7.9%.
  • Methyl 3-amino-4-methylthiophene-2-carboxylate (1.71 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol) were dissolved in water (20 mL) and reacted at 90° C. for 1 hour. The reaction solution was directly used in the next step.
  • reaction solution was poured into water (100 mL), suction filtered, the solid was collected, spin-dried, and purified by silica gel column (dichloromethane) to obtain 1.5 g of the target compound with a yield of 64.7%.
  • the reaction was quenched by adding saturated aqueous ammonium chloride solution at 0°C, extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product mixed with the intermediate.
  • the crude product in the previous step was dissolved in tetrahydrofuran (20 mL), and under nitrogen protection, LDA (9.7 mL, 19.3 mmol) was added at 40° C., the addition was completed, and the reaction was carried out at 40° C. for 2 hours.
  • the reaction was quenched with saturated aqueous ammonium chloride solution, the organic phase was concentrated, and purified by silica gel column (100% ethyl acetate) to obtain 710 mg of the title compound in a yield of 31%.
  • N-(3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide 400 mg, 1.26 mmol
  • concentrated sulfuric acid 4 mL
  • Fuming nitric acid 95 mg, 1.52 mmol was added dropwise at 0° C., the dropping was completed, and the reaction was carried out at 0° C. for 1 hour.
  • the solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried, and purified by reversed-phase purification under medium pressure (40% methanol/water (0.5% concentrated hydrochloric acid)) to obtain 40 mg of the target compound with a yield of 41.4%.
  • reaction solution was poured into saturated aqueous ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, and 18.5 mg of the target compound was obtained after beating with methanol, with a yield of 14.7%.
  • the target compound was 19 mg, and the yield was 37.8%.
  • N-(8-Nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (N/A, 0.49 mmol) was dissolved in methanol (5 mL) and added Potassium carbonate (166 mg, 1.2 mmol) was added and reacted at 55°C for 8 hours.
  • N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)acetamide (1.5 g, 5.9 mmol) was dissolved in concentrated sulfuric acid (15 mL), stirred at 0 °C for 1 hour, potassium nitrate (656 mg, 6.5 mmol) was added in batches, the addition was completed, and the reaction was carried out at 0 °C for 1 hour. LCMS detected the end of the reaction.
  • the reaction was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and slurried with methanol and dichloromethane to obtain 10 mg of the target compound with a yield of 8.1%.
  • Test substance some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
  • DMSO dimethyl sulfoxide
  • HEPES hydroxyethylpiperazine ethanethiosulfonic acid
  • Inhibition percentage (max-Lantha signal)/(max-min)*100
  • the “minimum” is the negative control well reading without enzyme; the “maximum” is the positive control well reading without compound.
  • the compounds of the present invention have good inhibitory activity on MAP4K1/HPK1, and the compounds of the present invention have excellent selectivity for HPK1.
  • Test substance some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
  • ELISA enzyme-linked immunosorbent assay
  • Jurkat human acute T-cell leukemia cells
  • SLP76 76kDa leukocyte protein with SH2 domain
  • CD3 cluster of differentiation 3 (leukocyte differentiation antigen);
  • PBS buffer Phosphate-balanced saline
  • TMB 3,3',5,5'-tetramethylbenzidine.
  • ELISA method was used to detect the inhibitory level of compounds on the phosphorylation of serine 376 of SLP76 in Jurkat cells in vitro.
  • Cell preparation Harvest Jurkat cells in logarithmic growth phase and adjust to an appropriate cell concentration; add 81 ⁇ L of cell suspension per well to a 96-well plate.
  • the experimental results show that the compounds of the present invention have good inhibitory activity on the phosphorylation of serine 376 of the downstream protein SLP76 of MAP4K1/HPK1, such as compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, compound 23 -1.
  • the IC 50 values of compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64, etc. are all less than 100 nM, that is, the compounds of the present invention have good inhibitory activity on HPK1.

Abstract

The present invention relates to the technical field of medicines, and in particular to a tricyclic HPK1 inhibitor compound or a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition and a preparation containing said compound or the pharmaceutically acceptable salt or stereoisomer thereof, a method for preparing said compound or the pharmaceutically acceptable salt or stereoisomer thereof, and a use of said compound or the pharmaceutically acceptable salt or stereoisomer thereof.

Description

三并环类HPK1抑制剂及其用途Tribicyclic HPK1 inhibitors and their uses 技术领域technical field
本发明属于医药技术领域，具体涉及通式(I)所示的三并环类HPK1化合物、其药学上可接受的盐、及其立体异构体，含有所述化合物、其药学上可接受的盐及其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐及其立体异构体的方法，以及所述化合物、其药学上可接受的盐及其立体异构体的用途。The invention belongs to the technical field of medicine, and specifically relates to a tricyclic HPK1 compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, comprising the compound, a pharmaceutically acceptable compound thereof Pharmaceutical compositions and formulations of salts and stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts and stereoisomers thereof, and the compounds, pharmaceutically acceptable salts and stereoisomers thereof Use of isomers.
背景技术Background technique
T细胞受体(TCR)介导的T细胞活化在胸腺T细胞发育、T细胞亚群分化以及效应T细胞功能发挥过程中均起着重要的作用。TCR可以识别抗原提呈细胞表面的MHC(主要组织相容性复合物)，进而识别向细胞内部传递的信号。信号传递后引起下游信号通路的活化。TCR活化的典型胞内信号包括MAPK(丝裂原活化蛋白激酶)、PKC(蛋白激酶C)以及钙离子等信号通路。这些信号的活化最终激活T细胞的特异性基因表达，引起细胞的增殖，并使得T细胞分化为效应T细胞。内源性或过继转移的效应T细胞是抗肿瘤免疫的重要介质。持续性的抗原暴露会导致T细胞逐渐分化为耗竭状态，其特征是效应器功能和增殖能力的层次性丧失，以及明显的转录、表观遗传和代谢变化。如何预防T细胞耗竭并拓展效应T细胞功能是目前肿瘤免疫学中最紧迫的问题之一。T cell receptor (TCR)-mediated T cell activation plays an important role in thymic T cell development, T cell subset differentiation, and effector T cell function. TCR can recognize the MHC (major histocompatibility complex) on the surface of antigen-presenting cells, and then recognize the signal transmitted to the inside of the cell. Signal transmission leads to activation of downstream signaling pathways. Typical intracellular signals activated by TCR include signaling pathways such as MAPK (mitogen-activated protein kinase), PKC (protein kinase C), and calcium ions. Activation of these signals ultimately activates T cell-specific gene expression, causes cell proliferation, and allows T cells to differentiate into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of antitumor immunity. Sustained antigen exposure leads to progressive differentiation of T cells into an exhausted state characterized by a hierarchical loss of effector function and proliferative capacity, as well as marked transcriptional, epigenetic, and metabolic changes. How to prevent T cell exhaustion and expand effector T cell function is one of the most pressing issues in tumor immunology.
造血祖细胞激酶HPK1(HematopoieticProgenitor Kinase1)是一种免疫抑制调节激酶，在造血干细胞中限制性表达。HPK1是T细胞受体(TCR)的负信号调节剂。TCR激活后，胞质HPK1被募集到细胞膜附近，活化的HPK1磷酸化衔接蛋白SLP76，以此激活SLP76作为负调节蛋白14-3-3的停靠位点，最终导致TCR信号复合物的不稳定，从而下调TCR信号。文献(Shui等，Nature Immunology(2007)8：84-91)披露HPK1缺乏导致TCR诱导的SLP-76和Erk磷酸化增强，Ca通量增加以及细胞因子和抗原特异性抗体的产生增加，表明HPK1负调节TCR信号传导和T细胞介导的免疫反应。此外，Sawasdikosol等发现HPK1(-/-)T细胞对***素PGE2的抑制和凋亡作用有抵抗力(Sawasdikosol等人，Cancer Immunol.Immunother.(2010)59:419-429)。2020年清华大学廖学斌课题组报道了HPK1在T细胞免疫疗法中的功能意义，【Siet al.,Hematopoietic Progenitor Kinase1(HPK1)Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies,Cancer Cell(2020)】研究人员首先在公开的肿瘤数据库中分析得知MAP4K1(编码HPK1)与T细胞耗竭相关的信号分子(如：PDCD1、TIGIT、CTLA4、LAG3等)呈现很强的正相关性。在低级别胶质瘤(LGG)、浸润性乳腺癌(BRAC)等肿瘤中显著的表现出，MAP4K1低表达的患者有着更长的生存期。接下来，研究人员选取多发性骨髓瘤组织活检，分选测量T细胞中HPK1与免疫抑制分子的蛋白表达情况，实验结果可知在耗竭的T细胞中，HPK1的表达上调。此实验结果表明HPK1与肿瘤浸润性T细胞耗竭的正相关性，HPK1可能是调节T细胞耗竭并抑制抗肿瘤免疫反应的一个重要激酶。Hematopoietic progenitor kinase HPK1 (HematopoieticProgenitor Kinase1) is an immunosuppressive regulatory kinase with restricted expression in hematopoietic stem cells. HPK1 is a negative signaling regulator of the T cell receptor (TCR). After TCR activation, cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3, which eventually leads to the instability of the TCR signaling complex. thereby downregulating TCR signaling. Literature (Shui et al., Nature Immunology (2007) 8:84-91) revealed that HPK1 deficiency resulted in enhanced TCR-induced phosphorylation of SLP-76 and Erk, increased Ca flux, and increased production of cytokines and antigen-specific antibodies, suggesting that HPK1 Negatively regulates TCR signaling and T cell-mediated immune responses. In addition, Sawasdikosol et al. found that HPK1(-/-) T cells were resistant to the inhibitory and apoptotic effects of the prostaglandin PGE2 (Sawasdikosol et al. Cancer Immunol. Immunother. (2010) 59:419-429). In 2020, Liao Xuebin's research group from Tsinghua University reported the functional significance of HPK1 in T cell immunotherapy, [Si et al., Hematopoietic Progenitor Kinase1(HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies, Cancer Cell (2020)] The researchers first analyzed the public tumor database and found that MAP4K1 (encoding HPK1) showed a strong positive correlation with T-cell exhaustion-related signaling molecules (such as PDCD1, TIGIT, CTLA4, LAG3, etc.). Significantly demonstrated in low-grade glioma (LGG), invasive breast cancer (BRAC) and other tumors, patients with low expression of MAP4K1 have longer survival. Next, the researchers selected multiple myeloma tissue biopsies to sort and measure the protein expression of HPK1 and immunosuppressive molecules in T cells. The experimental results showed that the expression of HPK1 was up-regulated in exhausted T cells. The results of this experiment indicate a positive correlation between HPK1 and tumor-infiltrating T cell exhaustion, and that HPK1 may be an important kinase that regulates T cell exhaustion and suppresses anti-tumor immune responses.
HPK1又称为MAP4K1，属于MAP4K家族的成员，该家族中还有其他5位成员MAP4K2(GCK激酶)、MAP4K3(GLK激酶)、MAP4K4(HGK激酶)、MAP4K5(KHS激酶)和MAP4K6(MINK激酶)。其中GLK激酶的生物学作用与HPK1的作用正好相反，GLK 可以通过与下游接头蛋白结合，促进TCR通路的激活。而文献【Huai-Chia Chuang等，Chapter Seven-MAP4K Family Kinases in Immunity and Inflammation,Advances in Immunology,2016(129)277-314】发现HGK激酶的丢失会导致小鼠自发性全身炎症和2型糖尿病，家族中其他激酶的作用暂时不详。为了保证更好的安全性，需要找到对MAP4K家族其他成员具有高选择性的HPK1激酶抑制剂。HPK1, also known as MAP4K1, is a member of the MAP4K family, which has five other members, MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase), and MAP4K6 (MINK kinase) . Among them, the biological role of GLK kinase is opposite to that of HPK1. GLK can promote the activation of TCR pathway by binding to downstream adaptor proteins. The literature [Huai-Chia Chuang et al., Chapter Seven-MAP4K Family Kinases in Immunity and Inflammation, Advances in Immunology, 2016(129) 277-314] found that the loss of HGK kinase leads to spontaneous systemic inflammation and type 2 diabetes in mice, The role of other kinases in the family is currently unknown. To ensure better safety, it is necessary to find HPK1 kinase inhibitors with high selectivity for other members of the MAP4K family.
目前，该靶点药物的研究仍处于临床实验阶段，尚无药物上市，为了更好的满足临床需求，开发一款选择性高、活性高、安全性强的HPK1激酶抑制剂具有重要的临床意义。At present, the research on this target drug is still in the clinical trial stage, and there is no drug on the market. In order to better meet the clinical needs, it is of great clinical significance to develop a HPK1 kinase inhibitor with high selectivity, high activity and strong safety. .
发明内容SUMMARY OF THE INVENTION
本发明要解决的技术问题是提供一种结构新颖的、对HPK1有良好抑制活性的HPK1抑制剂化合物。进一步的，该类化合物可用于抑制HPK1激酶活性，从而增强机体对肿瘤的免疫作用。更进一步的，该类化合物还可用于治疗或预防由HPK1所介导的相关疾病，尤其是癌症。该类化合物对多种癌细胞具有良好的抑制作用，并具有良好的成药性。The technical problem to be solved by the present invention is to provide a HPK1 inhibitor compound with novel structure and good inhibitory activity to HPK1. Further, the compounds can be used to inhibit the kinase activity of HPK1, thereby enhancing the immune effect of the body against tumors. Furthermore, the compounds can also be used to treat or prevent related diseases mediated by HPK1, especially cancer. The compounds have good inhibitory effect on various cancer cells and have good druggability.
本发明的技术方案如下：The technical scheme of the present invention is as follows:
在一方面，本发明提供了如下通式(I)所示的化合物、其药学上可接受的盐或其立体异构体，In one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
Figure PCTCN2022080065-appb-000001
Figure PCTCN2022080065-appb-000001
其中，in,
X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
Y 2、Y 4分别独立地选自-C(R 2)或-N-； Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
Y 5选自-C(R 6)； Y 5 is selected from -C(R 6 );
Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
各R 2、R 3、各R 4分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； Each R 2 , R 3 , and each R 4 are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- 6 alkoxy or halogenated C 1-6 alkoxy;
R 5和R 7中有一个与R 6以及和它们各自相连的环原子一起形成任选被1-5个Q1取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基；未成环的R 5或R 7选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； One of R 5 and R 7 together with R 6 and the ring atoms to which they are attached respectively form 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered optionally substituted by 1-5 Q1 A membered aryl group or a 5-10 membered heteroaryl group; the uncyclic R 5 or R 7 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、 -(CH 2) p-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl;
各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2 ) m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1 -6 alkoxy or halogenated C 1-6 alkyl;
各m、各p分别独立地选自0、1、2、3、4或5。Each m and each p are independently selected from 0, 1, 2, 3, 4, or 5.
在某些实施方案中，前述通式(I)所示的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(II-1)或通式(II-2)所示的结构In certain embodiments, the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, has the following general formula (II-1) or general formula (II-2) the structure shown
Figure PCTCN2022080065-appb-000002
Figure PCTCN2022080065-appb-000002
其中，in,
X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
Y 2、Y 4分别独立地选自-C(R 2)或-N-； Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
各R 2、各R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； Each R 2 , each R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、-(CH 2) p-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基；Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、- C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl;
各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2 ) m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1 -6 alkoxy or halogenated C 1-6 alkyl;
各m、各n、各p分别独立地选自0、1、2、3、4或5。Each m, each n, and each p is independently selected from 0, 1, 2, 3, 4, or 5.
在某些实施方案中，通式(I)、通式(II-1)或通式(II-2)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, the compound represented by general formula (I), general formula (II-1) or general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,
X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
Y 2、Y 4分别独立地选自-C(R 2)或-N-； Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
Y 3选自-C(R 5)或-N-；Y 6选自-C(R 7)或-N-； Y 3 is selected from -C(R 5 ) or -N-; Y 6 is selected from -C(R 7 ) or -N-;
各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基； Each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
R 1选自氢、卤素、羟基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基、-(CH 2) p-5-8元杂芳基、-(CH 2) p-苯基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected substituted by substituents: -( CH2 ) p -3-6 membered cycloalkyl, -( CH2 ) p -3-6 membered heterocyclyl, -( CH2 ) p -5-8 Member heteroaryl, -(CH 2 ) p -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基；Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -( CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;
各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1- 4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷硫基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、羟基C 1-4烷氧基、羟基C 1-4烷硫基、氨基C 1-4烷氧基、氨基C 1-4烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-8元环烷基、-(CH 2) m- 3-8元杂环基、-(CH 2) m-5-8元杂芳基、-(CH 2) m-苯基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , Di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio , halogenated C 1-4 4 alkoxy, halogenated C 1-4 alkylthio, hydroxy C 1-4 alkoxy, hydroxy C 1-4 alkylthio, amino C 1-4 alkoxy, amino C 1-4 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m - 3-8 membered heterocyclyl, -(CH 2 ) m -5 -8-membered heteroaryl, -(CH 2 ) m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
各m、各n、各p分别独立地选自0、1、2或3。Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
在某些实施方案中，通式(II-1)或通式(II-2)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, the compound represented by general formula (II-1) or general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,
X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
Y 2、Y 4分别独立地选自-C(R 2)-或-N-； Y 2 and Y 4 are independently selected from -C(R 2 )- or -N-;
Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or haloC 1-4 alkyl;
R 1选自氢、卤素、羟基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、-NR a-C(O)-R b-、-NR aR b、-OR a或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR a -C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents selected from halogen, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
环A选自5-10元环烷基或5-10元杂环基；Ring A is selected from 5-10 membered cycloalkyl or 5-10 membered heterocyclyl;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -C(O)R a , -C(O)OR a , -C( O) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, - (CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;
各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1- 4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基或任选被取代基取代的如下基团：-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基；所述取代基选自卤素、硝基、氨基、氰基、羧基、C 1-4烷基、C 1- 4烷氧基或卤代C 1-4烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclic cyclic group; the substituent is selected from halogen, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
各m、各n、各p分别独立地选自0、1、2或3。Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
在某些实施方案中，X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-；各R 2、各R 3、各R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-; each R 2 , each R 3 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-或-N(R 4)-；各R 2、各R 3、各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, or -N(R 4 )-; each R 2 , each R 3 , each R4 is each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，X 1、Y 1分别独立地选自CH 2、O或NH。 In certain embodiments, X 1 , Y 1 are each independently selected from CH 2 , O, or NH.
在某些实施方案中，Y 2、Y 4分别独立地选自-C(R 2)或-N-；各R 2分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, Y 2 , Y 4 are each independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，Y 2、Y 4分别独立地选自-C(R 2)或-N-；各R 2分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，R 7选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, R 7 is selected from hydrogen, halogen, C 1-6 alkyl, or haloC 1-6 alkyl.
在某些实施方案中，R 7选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
在某些实施方案中，R 5为氢。 In certain embodiments, R5 is hydrogen.
在某些实施方案中，Y 2为N。 In certain embodiments, Y 2 is N.
在某些实施方案中，Y 3、Y 4分别独立地选自CH或N。 In certain embodiments, Y 3 , Y 4 are each independently selected from CH or N.
在某些实施方案中，X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-；各R 2、各R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2. Each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-；各R 2、各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2. Each R4 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自S、O、N或-N(R 4)-，另两个分别独立地是-C(R 2)-；各R 2、各R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自S、O、N或-N(R 4)-，另两个分别独立地是-C(R 2)-；各R 2、各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自-C(R 2)-，另两个分别独立地是S、O、N或-N(R 4)-；各R 2、各R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自-C(R 2)-，另两个分别独立地是S、O、N或-N(R 4)-；各R 2、各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自S或O，另两个分别独立地是-C(R 2)-；各R 2分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, halogen , C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 2、X 3、X 4中的一个选自S或O，另两个分别独立地是-C(R 2)-；各R 2分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。 In certain embodiments, one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, fluoro , chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
在某些实施方案中，X 3选自-C(R 2)-，其中R 2选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。在某些实施方案中，X 2、X 3、X 4中的一个选自-C(R 2)-，另两个分别独立地是N或-N(R 4)-；各R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, X3 is selected from -C (R2)-, wherein R2 is selected from hydrogen , fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In certain embodiments, one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently N or -N(R 4 )-; each R 4 is independently is selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，X 3为N，X 2和X 4中的一个为-N(R 4)-，另一个为-C(R 2)-；R 2和R 4分别独立地选自氢、卤素、C 1-6烷基或卤代C 1-6烷基。 In certain embodiments, X 3 is N, one of X 2 and X 4 is -N(R 4 )- and the other is -C(R 2 )-; R 2 and R 4 are each independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
在某些实施方案中，R 1选自氢、卤素、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基、-NR a-C(O)-R b-、-NR aR b或-OR a；各p分别独立地选自0、1、2或3。 In certain embodiments, R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, haloC 1-4 alkyl, -(CH 2 ) p -3-6 membered cycloalkane group, -(CH 2 ) p -3-6 membered heterocyclyl, -NR a -C(O)-R b -, -NR a R b or -OR a ; each p is independently selected from 0, 1 , 2 or 3.
在某些实施方案中，R 1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、-NR a-C(O)-R b-、-NR aR b、-OR a、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基或四氢噻吩基。 In certain embodiments, R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, -NR a -C(O)-R b -, -NR a R b , -OR a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopropyl, oxa propyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothienyl.
在某些实施方案中，环A选自5-8元环烷基或5-8元杂环基。In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.
在某些实施方案中，环A选自5-8元环烷基或5-8元含氮杂环基。In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered nitrogen-containing heterocyclyl.
在某些实施方案中，环A选自5-8元单环烷基、5-8元单杂环基、6-8元稠杂环基、6-8元桥杂环基或6-8元螺杂环基。In certain embodiments, Ring A is selected from 5-8 membered monocycloalkyl, 5-8 membered monoheterocyclyl, 6-8 membered fused heterocyclyl, 6-8 membered bridged heterocyclyl, or 6-8 membered heterocyclyl A membered spiro heterocyclyl.
在某些实施方案中，环A选自7-8元单环烷基、7-8元单杂环基或8元含氮桥杂环基。In certain embodiments, Ring A is selected from 7-8 membered monocycloalkyl, 7-8 membered monoheterocyclyl, or 8 membered nitrogen-bridged heterocyclyl.
在某些实施方案中，环A选自7-8元含氮单杂环基或7-8元含氧单杂环基。In certain embodiments, Ring A is selected from a 7-8 membered nitrogen-containing monoheterocyclyl group or a 7-8 membered oxygen-containing monoheterocyclyl group.
在某些实施方案中，各Q1分别独立地选自卤素、羟基、硝基、羟基、氨基、氰基、羧基、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-8元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、羟基C 1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基。 In certain embodiments, each Q1 is independently selected from halogen, hydroxy, nitro, hydroxy, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O ) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -( CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -(CH 2 ) m - Phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, hydroxyl C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl.
在某些实施方案中，各Q1分别独立地选自-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或羟基C 1-4烷基。 In certain embodiments, each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6-membered heterocyclic group, -(CH 2 ) m -5-6-membered heteroaryl group or -(CH 2 ) m -phenyl; the Q2 is independently selected from halogen, hydroxyl, nitro group, amino group, cyano group, carboxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, halogenated C 1-4 alkyl group or hydroxy C 1-4 alkyl group.
在某些实施方案中，各Q1分别独立地选自氟、氯、溴、氨基、氰基、羟基、羧基、硝基、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-四氢吡咯基、-(CH 2) m-吡唑烷基、-(CH 2) m-咪唑烷基、-(CH 2) m-哌嗪基、-(CH 2) m-哌啶基、-(CH 2) m-吡唑基、-(CH 2) m-吡咯基、-(CH 2) m-咪唑基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基或-(CH 2) m-苯基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基或三氟甲基。 In certain embodiments, each Q1 is independently selected from the group consisting of fluorine, chlorine, bromine, amino, cyano, hydroxyl, carboxyl, nitro, -C(O)R a , -C(O)OR a , -C (O) NR a or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxy Ethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl radical, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclo Hexyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -pyrrolidinyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -piperazinyl, -(CH 2 ) m -tetrahydropyrrolyl, -(CH 2 ) m -pyrazolidine, -(CH 2 ) m -imidazolidinyl, -(CH 2 ) m -piperazinyl, -(CH 2 ) m -piperidinyl, -(CH 2 ) m -pyrazolyl, -(CH 2 ) m -pyrrolyl, -( CH2 ) m -imidazolyl, -( CH2 ) m -pyridyl, -( CH2 ) m -pyrimidinyl, -( CH2 ) m -pyridazinyl, -( CH2 ) m -pyrazine or -(CH 2 ) m -phenyl; the Q2 is independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl , methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.
在某些实施方案中，各Q1分别独立地选自-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲 基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基或三氟甲基。 In certain embodiments, each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy Ethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl base, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -Azacyclopropyl, -(CH2) m -Azacyclobutyl, -( CH2 ) m -pyrrolidinyl, -( CH2 ) m -piperidinyl, -( CH2 ) m- Piperazinyl, -( CH2 ) m -pyridyl, -( CH2 ) m -pyrimidinyl, -( CH2 ) m -pyridazinyl, -( CH2 ) m -pyrazinyl; the Q2 are respectively independently selected from fluoro, chloro, bromo, hydroxy, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoro methyl, difluoromethyl or trifluoromethyl.
在某些实施方案中，各R a、各R b分别独立地选自氢、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或任选被取代基取代的如下基团：-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基或-(CH 2) m-苯基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基。 In certain embodiments, each R a , each R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, bis(C 1-4 Alkyl) amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, - (CH 2 ) m -5-8-membered heteroaryl or -(CH 2 ) m -phenyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl , C 1-4 alkoxy or halogenated C 1-4 alkyl.
在某些实施方案中，各R a分别独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基或任选被取代基取代的如下基团：-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基；各R b分别独立地选自氢或C 1-4烷基。 In certain embodiments, each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, halo C 1-4 alkoxy Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; each R b is independently selected from hydrogen or C 1-4 alkyl.
在某些实施方案中，各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、三氟甲氧基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基或任选被取代基取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氮杂环丁基、氮杂环丙基、四氢吡咯基、吡唑烷基、咪唑烷基、哌嗪基或哌啶基；所述取代基选自氟、氯、溴、羟基、硝基、氨基、氰基、羧基、甲基、乙基、异丙基、甲氧基、乙氧基或三氟甲基；各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。 In certain embodiments, each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoro Methyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy or optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, azetidinyl, azetidinyl, tetrahydropyrrolyl, pyrazolidine, imidazolidinyl, piperazinyl or piperidinyl; the substituents are selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl group; each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
在某些实施方案中，各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或任选被取代基取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基或吡咯烷基；所述取代基选自氟、氯、溴、羟基、硝基、氨基、氰基、羧基、甲基、乙基、异丙基、甲氧基、乙氧基或三氟甲基；各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。 In certain embodiments, each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or any The following groups are selected to be substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidine or pyrrolidinyl; the substituents are selected from fluorine, chlorine , bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b is independently selected from hydrogen, methyl , ethyl, propyl or isopropyl.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(III-1)或通式(III-2)所示的结构：In certain embodiments, a compound of general formula (I), general formula (II-1), general formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has the following general formula: The structure represented by formula (III-1) or general formula (III-2):
Figure PCTCN2022080065-appb-000003
Figure PCTCN2022080065-appb-000003
其中，Y 1选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； wherein, Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
Y 4选自-C(R 2)或-N-； Y 4 is selected from -C(R 2 ) or -N-;
Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
各R 2、R 3、R 4、R 5、R 7分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； each of R 2 , R 3 , R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
R 1选自氢、卤素、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、3-6元环烷基、3-6元杂环基、-NR a-C(O)-R b-、-NR aR b、-OR a或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧 基或卤代C 1-4烷基； R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR a - C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1- 4 alkyl;
环A选自
Figure PCTCN2022080065-appb-000004
Figure PCTCN2022080065-appb-000005
Figure PCTCN2022080065-appb-000006
其中，环A中的各环原子任选的被氧代； Ring A is selected from
Figure PCTCN2022080065-appb-000004
Figure PCTCN2022080065-appb-000005
Figure PCTCN2022080065-appb-000006
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自卤素、硝基、氨基、氰基、羧基、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或羟基C 1-4烷基； Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O)NR a or optionally 1-2 The following groups substituted by Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkane base, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl;
各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、四氢呋喃基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基； Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxane , oxetanyl, azetidinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
各R b分别独立地选自氢或C 1-4烷基； each R b is independently selected from hydrogen or C 1-4 alkyl;
各m、各n、各p分别独立地选自0、1、2或3。Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, the compound represented by general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), its A pharmaceutically acceptable salt or a stereoisomer thereof, wherein,
Y 1选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
Y 4选自-C(R 2)或-N-； Y 4 is selected from -C(R 2 ) or -N-;
Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基； each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
R 1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、-NR a-C(O)-R b-、-NR aR b或-OR a，优选选自-NR aR b； R 1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl , -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b ;
环A选自
Figure PCTCN2022080065-appb-000007
Figure PCTCN2022080065-appb-000008
Figure PCTCN2022080065-appb-000009
其中，环A中的各环原子任选的被氧代； Ring A is selected from
Figure PCTCN2022080065-appb-000007
Figure PCTCN2022080065-appb-000008
Figure PCTCN2022080065-appb-000009
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自卤素、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基；各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基； Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy propylpropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH2 ) m -cyclopentyl, -( CH2 ) m -cyclohexyl, -( CH2 ) m -oxopropyl, -( CH2 ) m -oxygen Heterobutyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxa Cyclohexyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -pyrrolidinyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -piperazinyl, - (CH 2 ) m -pyridyl, -(CH 2 ) m -pyrimidinyl, -(CH 2 ) m -pyridazinyl, -(CH 2 ) m -pyrazinyl; the Q2 are each independently selected from fluorine , chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoro methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl ; each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl group, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or the following optionally substituted with substituents: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the The substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
各R b分别独立地选自氢、甲基、乙基、丙基或异丙基； each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
各m、各n分别独立地选自0、1、2或3。Each m, each n is independently selected from 0, 1, 2 or 3.
在某些实施方案中，环A选自
Figure PCTCN2022080065-appb-000010
Figure PCTCN2022080065-appb-000011
Figure PCTCN2022080065-appb-000012
其中，环A中的各环原子任选的被氧代； In certain embodiments, Ring A is selected from
Figure PCTCN2022080065-appb-000010
Figure PCTCN2022080065-appb-000011
Figure PCTCN2022080065-appb-000012
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基； Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, Propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -azepinyl, -(CH 2 ) m - Azacyclobutyl, -( CH2 ) m -pyrrolidinyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -piperazinyl, -( CH2 ) m -pyridinyl, - (CH 2 ) m -pyrimidinyl, -(CH 2 ) m -pyridazinyl, -(CH 2 ) m -pyrazinyl; the Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyanide radical, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;
各m、各n分别独立地选自0、1、2或3。Each m, each n is independently selected from 0, 1, 2 or 3.
在某些实施方案中，环A选自
Figure PCTCN2022080065-appb-000013
Figure PCTCN2022080065-appb-000014
Figure PCTCN2022080065-appb-000015
优选选自
Figure PCTCN2022080065-appb-000016
优选选自
Figure PCTCN2022080065-appb-000017
Figure PCTCN2022080065-appb-000018
其中，环A中的各环原子任选的被氧代； In certain embodiments, Ring A is selected from
Figure PCTCN2022080065-appb-000013
Figure PCTCN2022080065-appb-000014
Figure PCTCN2022080065-appb-000015
preferably selected from
Figure PCTCN2022080065-appb-000016
preferably selected from
Figure PCTCN2022080065-appb-000017
Figure PCTCN2022080065-appb-000018
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自卤素、-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基； Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl methoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl group, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxopropyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -tetrahydropyranyl, -(CH 2 ) m -azepanyl, -(CH 2 ) m -azetidine, -( CH2 ) m -pyrrolidinyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -piperazinyl, -( CH2 ) m -pyridinyl , -(CH 2 ) m -pyrimidinyl, -(CH 2 ) m -pyridazinyl, -(CH 2 ) m -pyrazinyl; the Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino , cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxy ethyl or hydroxypropyl;
各m、各n分别独立地选自0、1、2或3。Each m, each n is independently selected from 0, 1, 2 or 3.
在某些实施方案中，各Q1分别独立地选自-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡啶基或哒嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基。 In certain embodiments, each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted with 1-2 Q2: methyl, ethyl, Propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, propoxyethyl, cyclopropyl, cyclobutyl , oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, azetidinyl, azetidinyl, pyridyl or pyridazinyl; the Q2 are respectively Independently selected from fluoro, chloro, bromo, hydroxy, amino, cyano, carboxy, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(IV-1)或通式(IV-2)所示的结构：In certain embodiments, the compound of general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), its A pharmaceutically acceptable salt or a stereoisomer thereof has the structure represented by the following general formula (IV-1) or general formula (IV-2):
Figure PCTCN2022080065-appb-000019
Figure PCTCN2022080065-appb-000019
其中，X 2、X 3、X 4、环A、R 1、R 2、R 4、R a、R b、Q1、Q2、m、n、p的定义如前文任一方案所述。 Wherein, the definitions of X 2 , X 3 , X 4 , ring A, R 1 , R 2 , R 4 , R a , R b , Q1 , Q2 , m, n, and p are as described in any one of the preceding schemes.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)、通式(III-1)、通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(V-1)或通式(V-2)所示的结构：In certain embodiments, general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (IV- 1) or the compound described in general formula (IV-2), its pharmaceutically acceptable salt or its stereoisomer, having the structure shown in the following general formula (V-1) or general formula (V-2) :
Figure PCTCN2022080065-appb-000020
Figure PCTCN2022080065-appb-000020
其中，X 3、X 4分别独立地选自-C(R 2)-；环A、R 1、R 2、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, X 3 and X 4 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are as defined in any of the foregoing plan described.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体，具有如下 通式(V-3)或通式(V-4)所示的结构：In certain embodiments, general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), general formula (IV- 1) or the compound described in general formula (IV-2), its pharmaceutically acceptable salt or its stereoisomer, having the structure represented by the following general formula (V-3) or general formula (V-4) :
Figure PCTCN2022080065-appb-000021
Figure PCTCN2022080065-appb-000021
其中，X 2、X 4分别独立地选自-C(R 2)-；环A、R 1、R 2、R 4、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, X 2 and X 4 are independently selected from -C(R 2 )-; the definitions of ring A, R 1 , R 2 , R 4 , Q1, Q2, R a , R b , m, n, and p are as follows as described in any of the preceding scenarios.
在某些实施方案中，通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(VI-1)或通式(VI-2)所示的结构：In certain embodiments, general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), general formula (IV- 1) or the compound described in general formula (IV-2), its pharmaceutically acceptable salt or its stereoisomer, having the structure shown in the following general formula (VI-1) or general formula (VI-2) :
Figure PCTCN2022080065-appb-000022
Figure PCTCN2022080065-appb-000022
其中，X 2、X 3分别独立地选自-C(R 2)-；环A、R 1、R 2、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, X 2 and X 3 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are defined as any of the foregoing plan described.
在某些实施方案中，通式(V-1)、通式(V-2)、通式(V-3)、通式(V-4)、通式(VI-1)或通式(VI-2)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, general formula (V-1), general formula (V-2), general formula (V-3), general formula (V-4), general formula (VI-1) or general formula ( The compound shown in VI-2), its pharmaceutically acceptable salt or its stereoisomer, wherein,
X 2、X 3、X 4分别独立地选自-C(R 2)-； X 2 , X 3 , and X 4 are each independently selected from -C(R 2 )-;
各R 2、各R 4分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； Each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
R 1选自氢、卤素、C 1-6烷基、卤代C 1-6烷基、-NR aR b、-OR a、-SR a、-NH-C(O)-R b-、或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、C 1-4烷基或卤代C 1-4烷基； R 1 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, Or the following groups optionally substituted by substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents are selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
环A选自
Figure PCTCN2022080065-appb-000023
Figure PCTCN2022080065-appb-000024
Figure PCTCN2022080065-appb-000025
优选选自
Figure PCTCN2022080065-appb-000026
Figure PCTCN2022080065-appb-000027
优选选自
Figure PCTCN2022080065-appb-000028
Figure PCTCN2022080065-appb-000029
Figure PCTCN2022080065-appb-000030
其中，环A中的各环原子任选的被氧代； Ring A is selected from
Figure PCTCN2022080065-appb-000023
Figure PCTCN2022080065-appb-000024
Figure PCTCN2022080065-appb-000025
preferably selected from
Figure PCTCN2022080065-appb-000026
Figure PCTCN2022080065-appb-000027
preferably selected from
Figure PCTCN2022080065-appb-000028
Figure PCTCN2022080065-appb-000029
Figure PCTCN2022080065-appb-000030
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自卤素、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或羟基C 1-4烷基； Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2 : C 1- 4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3 -6-membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, C 1-4 alkyl , C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl;
各R a分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、或任选被取代基取代的以下基团：-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基；所述取代基选自卤素、羟基、C 1-6烷基或卤代C 1-6烷基； Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1 -6 alkyl or halogenated C 1-6 alkyl;
各R b分别独立地选自氢或C 1-4烷基； each R b is independently selected from hydrogen or C 1-4 alkyl;
各m、各n、各p分别独立地选自0、1或2。Each m, each n, and each p is independently selected from 0, 1, or 2.
在某些实施方案中，所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(VII-1)或通式(VII-2)所示的结构：In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-1) or general formula (VII-2):
Figure PCTCN2022080065-appb-000031
Figure PCTCN2022080065-appb-000031
其中，环A、R 1、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, the definitions of ring A, R 1 , Q1 , Q2 , Ra , R b , m, n, and p are as described in any one of the preceding schemes.
在某些实施方案中，所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(VII-3)或通式(VII-4)所示的结构：In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-3) or general formula (VII-4):
Figure PCTCN2022080065-appb-000032
Figure PCTCN2022080065-appb-000032
其中，环A、R 1、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, the definitions of ring A, R 1 , Q1 , Q2 , Ra , R b , m, n, and p are as described in any one of the preceding schemes.
在某些实施方案中，所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(VII-5)或通式(VII-6)所示的结构：In certain embodiments, the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof has the structure shown in the following general formula (VII-5) or general formula (VII-6):
Figure PCTCN2022080065-appb-000033
Figure PCTCN2022080065-appb-000033
其中，环A、R 1、R 4、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, the definitions of ring A, R 1 , R 4 , Q1 , Q2 , R a , R b , m, n, and p are as described in any one of the preceding schemes.
在某些实施方案中，所述的化合物、其药学上可接受的盐或其立体异构体，具有如下通式(VII-7)或通式(VII-8)所示的结构：In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-7) or general formula (VII-8):
Figure PCTCN2022080065-appb-000034
Figure PCTCN2022080065-appb-000034
其中，环A、R 1、R 4、Q1、Q2、R a、R b、m、n、p的定义如前文任一方案所述。 Wherein, the definitions of ring A, R 1 , R 4 , Q1 , Q2 , R a , R b , m, n, and p are as described in any one of the preceding schemes.
在某些实施方案中，通式(VII-1)、通式(VII-2)、通式(VII-3)、通式(VII-4)、通式(VII-5)、通式(VII-6)、通式(VII-7)或通式(VII-8)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, general formula (VII-1), general formula (VII-2), general formula (VII-3), general formula (VII-4), general formula (VII-5), general formula ( VII-6), the compound represented by general formula (VII-7) or general formula (VII-8), its pharmaceutically acceptable salt or its stereoisomer, wherein,
R 1选自-NR aR b、-OR a、-SR a、-NH-C(O)-R b-、或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、C 1-4烷基或卤代C 1-4烷基； R 1 is selected from -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, or the following groups optionally substituted with substituents: -(CH 2 ) p -3 -6-membered cycloalkyl, -(CH 2 ) p -3-6-membered heterocyclyl; the substituent is selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
各R 4分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
环A选自
Figure PCTCN2022080065-appb-000035
Figure PCTCN2022080065-appb-000036
Figure PCTCN2022080065-appb-000037
其中，环A中的各环原子任选的被氧代； Ring A is selected from
Figure PCTCN2022080065-appb-000035
Figure PCTCN2022080065-appb-000036
Figure PCTCN2022080065-appb-000037
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、3-6元环烷基、3-6元杂环基、5-6元杂芳基或苯基；所述Q2分别独立地选自卤素、羟基、C 1-4烷基或卤代C 1-4烷基； Each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: C 1-4 alkane group, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or benzene base; the Q2 is independently selected from halogen, hydroxyl, C 1-4 alkyl or halogenated C 1-4 alkyl;
各R a分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、或任选被取代基取代的以下基团：3-6元环烷基、3-6元杂环基；所述取代基选自卤素、羟基、C 1-6烷基或卤代C 1-6烷基； Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1-6 alkyl or halogenated C 1-6 alkyl;
各R b分别独立地选自氢或C 1-4烷基； each R b is independently selected from hydrogen or C 1-4 alkyl;
各n、各p分别独立地选自0、1或2。Each n and each p are independently selected from 0, 1 or 2.
在某些实施方案，R 1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、氮杂环丁基、氧杂环丁基、-NR a-C(O)-R b-、-NR aR b或-OR a，优选选自-NR aR b。 In certain embodiments, R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b .
在某些实施方案中，通式(VII-1)、通式(VII-2)、通式(VII-3)、通式(VII-4)、通式(VII- 5)、通式(VII-6)、通式(VII-7)或通式(VII-8)所示的化合物、其药学上可接受的盐或其立体异构体，其中，In certain embodiments, general formula (VII-1), general formula (VII-2), general formula (VII-3), general formula (VII-4), general formula (VII-5), general formula ( VII-6), the compound represented by general formula (VII-7) or general formula (VII-8), its pharmaceutically acceptable salt or its stereoisomer, wherein,
R 1选自氮杂环丁基、氧杂环丁基、-NR a-C(O)-R b-、-NR aR b或-OR a，各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基；各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。 R 1 is selected from azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , each R a is independently selected from hydrogen, methyl radical, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or optionally substituted with substituents of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基或三氟甲基； each R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl , difluoromethyl or trifluoromethyl;
环A选自
Figure PCTCN2022080065-appb-000038
Figure PCTCN2022080065-appb-000039
Figure PCTCN2022080065-appb-000040
其中，环A中的各环原子任选的被氧代； Ring A is selected from
Figure PCTCN2022080065-appb-000038
Figure PCTCN2022080065-appb-000039
Figure PCTCN2022080065-appb-000040
wherein each ring atom in Ring A is optionally oxo;
各Q1分别独立地选自-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡咯烷基、吡啶基或哒嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基； Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 is independently selected from fluorine, chlorine, bromine , hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;
各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、甲基、乙基、丙基、异丙基或三氟甲基； Each R a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl Fluoromethoxy or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl , tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。 Each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
在某些实施方案中，R 1选自-NH 2、
Figure PCTCN2022080065-appb-000041
Figure PCTCN2022080065-appb-000042
In certain embodiments, R 1 is selected from -NH 2 ,
Figure PCTCN2022080065-appb-000041
Figure PCTCN2022080065-appb-000042
在本发明技术方案中，所述环A中环氮原子上的氢可任选的被Q1取代。在某些实施方案，Q1对环A中环氮原子上的一个或多个氢进行取代。In the technical solution of the present invention, the hydrogen on the ring nitrogen atom in the ring A can be optionally substituted by Q1. In certain embodiments, Q1 substitutes one or more hydrogens on a ring nitrogen atom in Ring A.
在某些实施方案中，各Q1分别独立地选自甲基、乙基、环丙基、环丁基、
Figure PCTCN2022080065-appb-000043
Figure PCTCN2022080065-appb-000044
In certain embodiments, each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,
Figure PCTCN2022080065-appb-000043
Figure PCTCN2022080065-appb-000044
本发明中各技术方案之间可以相互组合形成新的技术方案，所形成的新的技术方案同样包括在本发明的范围之内。Various technical solutions in the present invention can be combined with each other to form new technical solutions, and the new technical solutions formed are also included in the scope of the present invention.
在某些实施方案中，前述通式(I)所述的化合物、其药学上可接受的盐或其立体异构体，选自如下化合物：In certain embodiments, the compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, is selected from the following compounds:
Figure PCTCN2022080065-appb-000045
Figure PCTCN2022080065-appb-000045
Figure PCTCN2022080065-appb-000046
Figure PCTCN2022080065-appb-000046
Figure PCTCN2022080065-appb-000047
Figure PCTCN2022080065-appb-000047
Figure PCTCN2022080065-appb-000048
Figure PCTCN2022080065-appb-000048
Figure PCTCN2022080065-appb-000049
Figure PCTCN2022080065-appb-000049
本发明还提供了一种药物组合物，其含有本发明的化合物、其药学上可接受的盐或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物组合物可以制成临床上或药学上可接受的任一剂型，如片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂等。The present invention also provides a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the medicament The composition can be made into any clinically or pharmaceutically acceptable dosage form, such as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection solution, sterile powder for injection) and concentrated solutions for injection), suppositories, inhalants or sprays, etc.
在本发明的某些实施方案中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。In certain embodiments of the present invention, the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc. When preparing an oral preparation, suitable fillers, binders, disintegrants, lubricants and the like can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂，特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。The pharmaceutically acceptable carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the field of pharmaceutical formulations, and the choice of a particular carrier and/or diluent will depend on the Mode of administration or disease type and state to treat a particular patient. The preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
在另一方面，本发明还涉及本发明的化合物、其药学上可接受的盐或其立体异构体在制备预防和/或治疗由HPK1所介导的疾病及相关疾病的药物中的用途，所述药物可与一种或多种其他药物联用以预防或治疗由HPK1所介导的疾病及相关病症。所述疾病及相关病症选自癌症或良性肿瘤，所述癌症包括原位癌和转移的癌症。进一步的，所述癌症包括但不限于肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、非小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤等。In another aspect, the present invention also relates to the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for the prevention and/or treatment of diseases mediated by HPK1 and related diseases, The drug can be used in combination with one or more other drugs to prevent or treat diseases and related disorders mediated by HPK1. The disease and related conditions are selected from cancers or benign tumors, including carcinomas in situ and metastatic cancers. Further, the cancer includes but is not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, Liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibromas, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell Lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, etc.
进一步的，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其立体异构体的药物制剂在制备药物中的用途，所述药物可与一种或多种药物联用以治疗及/或预防由HPK1所介导的疾病及相关病症。Further, the present invention also relates to the use of a pharmaceutical preparation containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament, which can be used in combination with one or more medicaments Treatment and/or prevention of diseases and related disorders mediated by HPK1.
在另一方面，本发明涉及的含有本发明的化合物、其药学上可接受的盐或其立体异构体 的药物可以单独给药，或者与一种或多种第二治疗活性剂联合使用，所述第二治疗活性剂与本申请的HPK1抑制剂化合物组合用于治疗和/或预防由HPK1所介导的疾病和相关病症。因此，在某些实施方案中，所述的药物组合物还含有一种或多种第二治疗活性剂。在某些实施方案中，所述的第二治疗活性剂选自抗癌剂，包括有丝***抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。In another aspect, the present invention relates to a medicament containing a compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which may be administered alone, or in combination with one or more second therapeutically active agents, The second therapeutically active agent is used in combination with the HPK1 inhibitor compounds of the present application for the treatment and/or prevention of diseases and related disorders mediated by HPK1. Thus, in certain embodiments, the pharmaceutical composition further contains one or more second therapeutically active agents. In certain embodiments, the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and isoprenyl protein transferase inhibitors.
在某些实施方案中，待组合的各成分(例如，本发明的化合物、其药学上可接受的盐、其立体异构体与第二治疗活性剂)可同时给药或依次顺序地分开用药。例如，可以在施用本发明化合物、其药学上可接受的盐或其立体异构体之前、同时或之后，施用第二治疗活性剂。此外，待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。In certain embodiments, the ingredients to be combined (eg, a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) may be administered simultaneously or sequentially and separately . For example, the second therapeutically active agent can be administered prior to, concurrently with, or subsequent to administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate different formulations.
在另一方面，本发明还提供了一种治疗由HPK1介导的疾病及相关病症的方法，该方法包括向有需要的患者施用有效量的前述通式(I)所述的化合物、其药学上可接受的盐或其立体异构体，前述制剂或药物组合物；所述由HPK1介导的疾病及相关病症如上定义。In another aspect, the present invention also provides a method for treating diseases and related disorders mediated by HPK1, the method comprising administering to a patient in need an effective amount of the compound of the aforementioned general formula (I), its pharmacy An acceptable salt of the above or a stereoisomer thereof, the aforementioned formulation or pharmaceutical composition; the HPK1-mediated diseases and related disorders are as defined above.
所述的“有效量”是指能够减轻、延缓、抑制或治愈受试者病症的药物剂量。给药剂量的大小与药物给药方式、药剂的药代动力学、疾病的严重程度、受试者的个性体征(性别、体重、身高、年龄)等来确定。The "effective amount" refers to a dose of a drug capable of alleviating, delaying, inhibiting or curing a disorder in a subject. The size of the administered dose is determined by the mode of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual signs (sex, weight, height, age) and the like.
【发明详述】[Detailed description of the invention]
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好的理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本发明所提供的术语的定义和解释为准。In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for better understanding of the present invention, definitions of some terms are provided below. When the definitions and explanations of terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in the present invention shall prevail.
本发明所述的“卤素”是指氟原子、氯原子、溴原子或碘原子。The "halogen" in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
本发明所述的“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C 1-4烷基”、“C 1-3烷基”、“C 1-2烷基”、“C 2-6烷基”、“C 2-5烷基”、“C 2-4烷基”、“C 2-3烷基”、“C 3-6烷基”、“C 3-5烷基”、“C 3-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C 1-4烷基”指C 1-6烷基中的含有1-4个碳原子的具体实例。 The "C 1-6 alkyl group" in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C 1-4 alkyl group" and "C 1-3 alkyl group" , "C 1-2 alkyl", "C 2-6 alkyl", "C 2-5 alkyl", "C 2-4 alkyl", "C 2-3 alkyl", "C 3- 6 alkyl", "C 3-5 alkyl", "C 3-4 alkyl", etc. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C 1-4 alkyl group" in the present invention refers to a specific example of the C 1-6 alkyl group containing 1-4 carbon atoms.
本发明所述的“C 1-6烷氧基”是指“C 1-6烷基-O-”，所述的“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷氧基”是指“C 1-4烷基-O-”，所述的“C 1-4烷基”如前文所定义。 The "C 1-6 alkoxy" in the present invention refers to "C 1-6 alkyl-O-", and the "C 1-6 alkyl" is as defined above. The "C 1-4 alkoxy" in the present invention refers to "C 1-4 alkyl-O-", and the "C 1-4 alkyl" is as defined above.
本发明所述的“C 1-6烷硫基”是指“C 1-6烷基-S-”，所述的“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷硫基”是指“C 1-4烷基-S-”，所述的“C 1-4烷基”如前文所定义。 The "C 1-6 alkylthio" in the present invention refers to "C 1-6 alkyl-S-", and the "C 1-6 alkyl" is as defined above. The "C 1-4 alkylthio" in the present invention refers to "C 1-4 alkyl-S-", and the "C 1-4 alkyl" is as defined above.
本发明所述的“羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基”是指C 1-6烷基中的一个或多个氢分别被一个或多个羟基、氨基或卤素所取代。C 1-6烷基如前文所定义 The "hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl" in the present invention means that one or more hydrogens in the C 1-6 alkyl are replaced by one or more Multiple hydroxy, amino or halogen substituted. C 1-6 alkyl is as defined above
本发明所述“羟基C 1-6烷氧基、氨基C 1-6烷氧基、卤代C 1-6烷氧基”是指“C 1-6烷氧基”中的一个或多个氢被一个或多个羟基、氨基或卤素所取代。 "Hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy, halogenated C 1-6 alkoxy" in the present invention refers to one or more of "C 1-6 alkoxy" Hydrogen is replaced with one or more hydroxy, amino or halogen.
本发明所述“羟基C 1-6烷硫基、氨基C 1-6烷硫基、卤代C 1-6烷硫基”是指“C 1-6烷硫基”中的一个或多个氢被一个或多个羟基、氨基或卤素所取代。 In the present invention, "hydroxyl C 1-6 alkylthio, amino C 1-6 alkylthio, halogenated C 1-6 alkylthio" refers to one or more of "C 1-6 alkylthio" Hydrogen is replaced with one or more hydroxy, amino or halogen.
本发明所述的“C 1-6烷基氨基、二(C 1-6烷基)氨基”分别是指C 1-6烷基-NH-、
Figure PCTCN2022080065-appb-000050
The "C 1-6 alkylamino, di(C 1-6 alkyl) amino" in the present invention refer to C 1-6 alkyl-NH-,
Figure PCTCN2022080065-appb-000050
本发明所述的“C 2-6烯基”是指含有至少一个双键且碳原子数为2-6的直链、支链或环状的烯基，包括例如“C 2-4烯基”等。其实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1,4-己二烯基、环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基等。 The "C 2-6 alkenyl" in the present invention refers to a straight-chain, branched or cyclic alkenyl containing at least one double bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkenyl""Wait. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexenyl Dienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.
本发明所述的“C 2-6炔基”是指含有至少一个三键且碳原子数为2-6的直链或支链的炔基，包括例如“C 2-4炔基”等。其实例包括但不限于：乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基等。 The "C 2-6 alkynyl" in the present invention refers to a straight-chain or branched alkynyl group containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkynyl" and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -hexynyl, 5-methyl-2-hexynyl, etc.
本发明所述的“3-10元环烷基”是指包含3-10个碳原子的饱和或部分饱和的且不具有芳香性的单环或多环基团。所述“单环环烷基”优选“3-8元单环烷基”，所述“多环环烷基”包括“稠环基、桥环基和螺环基”，优选“7-10元稠环烷基”、“7-10元桥环基”和“7-10元螺环基”。The "3-10 membered cycloalkyl" in the present invention refers to a saturated or partially saturated monocyclic or polycyclic group containing 3-10 carbon atoms and not having aromaticity. The "monocyclic cycloalkyl group" is preferably "3-8 membered monocyclic alkyl group", and the "polycyclic cycloalkyl group" includes "fused ring group, bridged ring group and spirocyclic group", preferably "7-10 membered fused cycloalkyl", "7-10-membered bridged cyclic group" and "7-10-membered spirocyclic group".
本发明所述的“3-8元单环烷基”是指含有3-8个碳原子的饱和或部分饱和的且不具有芳香性的单环环状烷基，包括“3-8元饱和单环烷基”和“3-8元部分饱和单环烷基”；优选“3-4元单环烷基”、“3-5元单环烷基”、“3-6元单环烷基”、“3-7元单环烷基”、“4-5元单环烷基”、“4-6元单环烷基”、“4-7元单环烷基”、“4-8元单环烷基”、“5-6元单环烷基”、“5-7元单环烷基”、“5-8元单环烷基”、“6-7元单环烷基”、“6-8元单环烷基”、“7-8元单环烷基”、“3-6元饱和单环烷基”、“5-8元饱和单环烷基”、“5-7元饱和单环烷基”、“5-6元饱和单环烷基”等，任选地，环状结构中的环碳原子可以被氧代。所述的“3-8元饱和单环烷基”的具体实例包括但不限于：环丙烷基(环丙基)、环丁烷基(环丁基)、环戊烷基(环戊基)、环己烷基(环己基)、环庚烷基(环庚基)、环辛烷基(环辛基)等；所述的“3-8元部分饱和单环烷基”的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己-1,3-二烯、环己-1,4-二烯、环庚烯基、环庚-1,3-二烯基、环庚-1,4-二烯基、环庚-1,3,5-三烯基，环辛烯基、环辛-1,3-二烯基、环辛-1,4-二烯基、环辛-1,5-二烯基、环辛-1,3,5-三烯基、环辛四烯基等。The "3-8 membered monocyclic alkyl group" mentioned in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group containing 3-8 carbon atoms without aromaticity, including "3-8 membered saturated monocyclic cyclic alkyl group". "Monocycloalkyl" and "3-8 membered partially saturated monocycloalkyl"; preferably "3-4 membered monocycloalkyl", "3-5 membered monocycloalkyl", "3-6 membered monocycloalkane" "base", "3-7 membered monocycloalkyl", "4-5 membered monocycloalkyl", "4-6 membered monocycloalkyl", "4-7 membered monocycloalkyl", "4- 8-membered monocycloalkyl", "5-6 membered monocycloalkyl", "5-7 membered monocycloalkyl", "5-8 membered monocycloalkyl", "6-7 membered monocycloalkyl" ", "6-8 membered monocycloalkyl", "7-8 membered monocycloalkyl", "3-6 membered saturated monocycloalkyl", "5-8 membered saturated monocycloalkyl", "5-membered saturated monocycloalkyl" -7-membered saturated monocycloalkyl", "5-6 membered saturated monocycloalkyl", etc., optionally, ring carbon atoms in the ring structure may be oxo. Specific examples of the "3-8 membered saturated monocycloalkyl" include but are not limited to: cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentyl (cyclopentyl) , cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated monocycloalkyl" include but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptyl Alkenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3- Dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl and the like.
本发明所述的“7-10元稠环基”是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的含有7-10个环原子的、饱和或部分饱和的、非芳香性环状基团，所述的稠环中的一个环可以为芳香性环，但稠环整体不具备芳香性；包括“8-9元稠环基”、“9-10元稠环基”等，其稠和方式可以为：5-6元环烷基并5-6元环烷基、苯并5-6元环烷基、苯并5-6元饱和环烷基等，任选地，环状结构中的环原子可以被氧代。其实例包括但不限于：二环[3.1.0]己烷基、 二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基、双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1,2,3,3a-四氢并环戊二烯基、2,3,3a,4,7,7a-六氢-1H-茚基、1,2,3,4,4a,5,6,8a-八氢化萘基、1,2,4a,5,6,8a-六氢化萘基、1,2,3,4,5,6,7,8,9,10-十氢菲基、苯并环戊基、苯并环己基、苯并环己烯基、苯并环戊烯基等。The "7-10-membered fused ring group" in the present invention refers to a saturated or partially containing 7-10 ring atoms formed by two or more ring structures sharing two adjacent carbon atoms with each other. Saturated, non-aromatic cyclic group, one of the fused rings can be an aromatic ring, but the fused ring as a whole does not have aromaticity; including "8-9 membered fused ring group", "9-10 "Condensed ring group" etc., the condensing mode can be: 5-6-membered cycloalkyl, 5-6-membered cycloalkyl, benzo 5-6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl etc., optionally, ring atoms in the ring structure can be oxo. Examples include, but are not limited to: bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decalinyl, tetrahydrophenanthryl, bicyclo[3.1.0]hex-2- Alkenyl, Bicyclo[4.1.0]hept-3-enyl, Bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzo Cyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.
本发明所述的“7-10元桥环基”是指由两个或两个以上环状结构彼此共用两个非相邻碳原子所形成的、含有7-10个环碳原子的环状结构。任选地，环状结构中的碳原子可以被氧代。具体实例包括但不仅限于：
Figure PCTCN2022080065-appb-000051
Figure PCTCN2022080065-appb-000052
等。 The "7-10-membered bridged cyclic group" in the present invention refers to a cyclic ring containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. structure. Optionally, carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to:
Figure PCTCN2022080065-appb-000051
Figure PCTCN2022080065-appb-000052
Wait.
本发明所述的“7-10元螺杂环基”是指由两个或两个以上环状结构彼此共用一个碳原子所形成的、含有7-10个环碳原子的环状结构。任选地，环状结构中的碳原子可以被氧代。其具体实例包括但不仅限于：
Figure PCTCN2022080065-appb-000053
Figure PCTCN2022080065-appb-000054
等。 The "7-10 membered spiroheterocyclyl" in the present invention refers to a cyclic structure containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing one carbon atom with each other. Optionally, carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to:
Figure PCTCN2022080065-appb-000053
Figure PCTCN2022080065-appb-000054
Wait.
本发明所述的“3-10元杂环基”是指由3-10个碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分饱和(包含1或2个双键)的非芳香环状基团，此环状基团可为单环或多环基团，在本发明中，杂环基中杂原子个数优选1、2、3或4，杂环基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。The "3-10-membered heterocyclic group" in the present invention refers to a saturated or partially saturated (containing 1 or 2 double bonds) consisting of 3-10 carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur. Non-aromatic cyclic group, this cyclic group can be a monocyclic or polycyclic group, in the present invention, the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, the nitrogen in the heterocyclic group is preferably 1, 2, 3 or 4. , carbon or sulfur atoms can be optionally oxidized. The nitrogen atom may be optionally further substituted with other groups to form tertiary amines or quaternary ammonium salts.
单环杂环基优选“3-8元单杂环基”，是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-8元单杂环基”包括“3-8元饱和单杂环基”和“3-8元部分饱和单杂环基”。优选地，本发明所述的“3-8元单杂环基”含有1-3个杂原子；优选地，本发明所述的“3-8元单杂环基”含有1-2个杂原子，且所述的杂原子选自氮原子和/或氧原子；优选地，本发明所述的“3-8元单杂环基”含有1个氮原子。所述“3-8元单杂环基”优选“3-7元单杂环基”、“3-6元单杂环基”、“4-7元单杂环基”、“4-6元单杂环基”、“6-8元单杂环基”、“5-7元单杂环基”、“5-6元单杂环基”、“3-6元饱和单杂环基”、“5-6元饱和单杂环基”、“3-6元含氮单杂环基”、“3-6元饱和含氮单杂环基”、“5-6元含氮单杂环基”、“5-6元饱和含氮单杂环基”等。例如，仅包含1个或2个氮原子，或者，包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“3-8元单杂环基”的具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡 咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、噁唑烷基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等。The monocyclic heterocyclic group is preferably a "3-8 membered monoheterocyclic group", which means at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3 -8 saturated or partially saturated and non-aromatic monocyclic cyclic groups, the heteroatoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms in the ring structure ( For example carbon atoms, nitrogen atoms or sulfur atoms) can be oxo. The "3-8 membered monoheterocyclic group" in the present invention includes "3-8 membered saturated monoheterocyclic group" and "3-8 membered partially saturated monoheterocyclic group". Preferably, the "3-8-membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8-membered monoheterocyclic group" of the present invention contains 1-2 heteroatoms atom, and the heteroatom is selected from nitrogen atom and/or oxygen atom; preferably, the "3-8-membered monoheterocyclic group" of the present invention contains one nitrogen atom. The "3-8 membered monoheterocyclic group" is preferably "3-7 membered monoheterocyclic group", "3-6 membered monoheterocyclic group", "4-7 membered monoheterocyclic group", "4-6 membered monoheterocyclic group" "Mono-heterocyclic group", "6-8-membered mono-heterocyclic group", "5-7-membered mono-heterocyclic group", "5-6-membered mono-heterocyclic group", "3-6-membered saturated mono-heterocyclic group" ", "5-6 membered saturated monoheterocyclic group", "3-6 membered nitrogen-containing monoheterocyclic group", "3-6 membered saturated nitrogen-containing monoheterocyclic group", "5-6 membered nitrogen-containing monoheterocyclic group" ring group", "5-6 membered saturated nitrogen-containing monoheterocyclic group", etc. For example, only 1 or 2 nitrogen atoms are included, or, alternatively, a nitrogen atom and 1 or 2 other heteroatoms (eg, oxygen and/or sulfur atoms) are included. Specific examples of "3-8 membered monoheterocyclyl" include, but are not limited to: aziridyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridenyl, aza Cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxanyl Dialkenyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydro thienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridyl, piperidonyl, tetrahydropyridone, dihydropiperidinone, piperazine base, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazolyl oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl Azinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyran Base et al.
多环杂环基包括“稠杂环基”、“螺杂环基”和“桥杂环基”，优选“7-10元稠杂环基”、“7-10元螺杂环基”和“7-10元桥杂环基”。Polycyclic heterocyclic groups include "fused heterocyclic group", "spiro heterocyclic group" and "bridged heterocyclic group", preferably "7-10 membered fused heterocyclic group", "7-10 membered spiro heterocyclic group" and "7-10 membered bridged heterocyclyl".
本发明所述“7-10元稠杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有7-10个环原子的、且至少一个环原子为杂原子的、饱和或部分饱和的、非芳香性环状基团，所述的稠环中其中一个环可以为芳香性环，但稠环整体不具备芳香性，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代，包括但不限于“8-9元稠杂环基”、“9-10元稠杂环基”等，其稠和方式可以为5-6元杂环基并5-6元杂环基、5-6元杂环基并5-6元环烷基、苯并5-6元杂环基、苯并5-6元饱和杂环基、5-6元杂芳基并5-6元杂环基、5-6元杂芳基并5-6元饱和杂环基；5-6元杂芳基如前文所定义；所述“8-10元稠杂环基”具体实例包括但不仅限于：吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基；四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。The "7-10-membered fused heterocyclic group" in the present invention refers to at least one ring formed by two or more cyclic structures sharing two adjacent atoms with each other and containing 7-10 ring atoms The atom is a heteroatom, saturated or partially saturated, non-aromatic cyclic group, one of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic, and the heteroatom is nitrogen Atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo, including but not limited to "8-9 membered fused heterocyclic group" ", "9-10-membered fused heterocyclic group", etc., the condensing mode can be 5-6-membered heterocyclic group and 5-6-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-membered cycloalkane base, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group Member saturated heterocyclic group; 5-6-membered heteroaryl group is as defined above; specific examples of the "8-10-membered fused heterocyclic group" include but are not limited to: pyrrolidinocyclopropyl, cyclopentylazepine Heterocyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, pyrrolidinomorpholinyl, piperidinopyridino Linyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, Benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, chromanyl, pyridocyclopentyl, pyridocyclic Hexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperidine Peridyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl , Pyrimidooxazolidinyl, Pyrimidothiazolidinyl, Pyrimidoisoxazolidinyl, Pyrimidoisothiazolidinyl, Pyrimidopiperidinyl, Pyrimidomorpholinyl, Pyrimidopiperazinyl, Pyrimidotetra Hydropyranyl; tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3 ]dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1,3-benzene oxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl , 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d ]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopentene And[c]pyrrolyl, 4H-1 , 3-benzoxazinyl, etc.
术语“苯并环戊基”，其结构是指
Figure PCTCN2022080065-appb-000055
(亦可称之为2,3-二氢-1H-茚基)；术语“苯并吡咯烷”其结构包括
Figure PCTCN2022080065-appb-000056
等；术语“吡啶并四氢呋喃基”其结构包括
Figure PCTCN2022080065-appb-000057
Figure PCTCN2022080065-appb-000058
前文所定义的其他“定义的其它稠杂环基”的具体实例具有与之类似的环状结构。 The term "benzocyclopentyl", the structure of which refers to
Figure PCTCN2022080065-appb-000055
(also referred to as 2,3-dihydro-1H-indenyl); the term "benzopyrrolidine" whose structure includes
Figure PCTCN2022080065-appb-000056
etc.; the term "pyridotetrahydrofuranyl" whose structure includes
Figure PCTCN2022080065-appb-000057
Figure PCTCN2022080065-appb-000058
Specific examples of other "other fused heterocyclic groups as defined" previously defined have cyclic structures similar to them.
本发明所述的“7-10元螺杂环基”是指由两个或两个以上环状结构彼此共用一个环原子所形成的、含有7-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的环状结构，包括“7-10元饱和螺杂环基”和“7-10元部分饱和螺杂环基”。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。其具体实例包括但不仅限于：The "7-10 membered spiroheterocyclyl" in the present invention refers to a ring formed by two or more cyclic structures sharing one ring atom with each other, containing 7-10 ring atoms (at least one ring atom is A cyclic structure of a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), includes "7-10 membered saturated spiroheterocyclyl" and "7-10 membered partially saturated spiroheterocyclyl". Optionally, ring atoms (eg, carbon, nitrogen, or sulfur atoms) in the ring structure may be oxo. Specific examples include but are not limited to:
Figure PCTCN2022080065-appb-000059
Figure PCTCN2022080065-appb-000060
等。
Figure PCTCN2022080065-appb-000059
Figure PCTCN2022080065-appb-000060
Wait.
本发明所述的“7-10元桥杂环基”是指由两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的、含有7-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的环状结构，包括“7-10元饱和桥杂环基”和“7-10元部分饱和桥杂环基”。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。具体实例包括但不仅限于：The "7-10-membered bridged heterocyclyl" in the present invention refers to a group formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, containing 7-10 ring atoms (wherein A cyclic structure in which at least one ring atom is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) includes "7-10 membered saturated bridged heterocyclyl" and "7-10 membered partially saturated bridged heterocyclyl". Optionally, ring atoms (eg, carbon, nitrogen, or sulfur atoms) in the ring structure may be oxo. Specific examples include but are not limited to:
Figure PCTCN2022080065-appb-000061
Figure PCTCN2022080065-appb-000062
等。
Figure PCTCN2022080065-appb-000061
Figure PCTCN2022080065-appb-000062
Wait.
本发明所述的“6-10元芳基”包括“6-8元单环芳基”和“8-10元稠环芳基”。The "6-10-membered aryl group" in the present invention includes "6-8-membered monocyclic aryl group" and "8-10-membered fused-ring aryl group".
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基，其实例包括但不限于：苯基、环辛四烯基等；优选苯基。The "6-8-membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团，优选“9-10元稠环芳基”，具体实例如萘基等。The "8-10-membered fused-ring aryl group" mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring carbon atoms, not The saturated and aromatic cyclic group is preferably a "9-10-membered fused-ring aryl group", and specific examples are naphthyl and the like.
本发明所述的“5-10元杂芳基”包括“5-8元单杂芳基”和“8-10元稠杂芳基”。The "5-10-membered heteroaryl" in the present invention includes "5-8-membered monoheteroaryl" and "8-10-membered condensed heteroaryl".
本发明所述的“5-8元单杂芳基”是指含有5-8个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的具有芳香性的单环环状基团。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单杂芳基”包括例如“5-7元单杂芳基”、“5-6元单杂芳基”、“5-6元含氮单杂芳基”、“6元含氮单杂芳基”等，所述的“含氮杂芳基”中的杂 原子至少含有一个氮原子，例如，仅包含1个或2个氮原子，或者，包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)，或者，包含2个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-***基、1,2,4-***基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元单杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。The "5-8-membered heteroaryl group" in the present invention refers to an aromatic mono-heteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom). Cyclic ring group. Optionally, ring atoms (eg, carbon, nitrogen, or sulfur atoms) in the ring structure may be oxo. "5-8-membered monoheteroaryl" includes, for example, "5-7-membered monoheteroaryl", "5-6-membered monoheteroaryl", "5-6-membered nitrogen-containing monoheteroaryl", "6-membered monoheteroaryl" Nitrogen-containing monoheteroaryl group", etc., the heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or, contains one nitrogen atom and other nitrogen atoms 1 or 2 heteroatoms (eg oxygen and/or sulphur atoms), alternatively 2 nitrogen atoms and 1 or 2 other heteroatoms (eg oxygen and/or sulphur atoms). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-Triazinyl, 1,3,5-Triazinyl, 1,2,4,5-Tetrazinyl, Azacyclotrienyl, 1,3-Diazepinyl Alkenyl, azacyclooctatetraenyl, etc. The "5-6-membered monoheteroaryl group" refers to a specific example of a 5-8-membered heteroaryl group containing 5-6 ring atoms.
本发明所述的“8-10元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“9-10元稠杂芳基”，“8-9元稠杂芳基”等，其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等；具体实例包括但不限于：吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。The "8-10-membered fused heteroaryl group" in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms), unsaturated aromatic ring structures. Optionally, ring atoms (eg, carbon, nitrogen, or sulfur atoms) in the ring structure may be oxo. Including "9-10-membered condensed heteroaryl", "8-9-membered condensed heteroaryl", etc., and the condensing method can be benzo-5-6-membered heteroaryl, 5-6-membered heteroaryl and 5- 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benziso furanyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4 -quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, Naphthyridinyl etc.
本发明所述的“碳原子、氮原子或硫原子被氧代”是指形成C＝O、N＝O、S＝O或SO 2的结构。 In the present invention, "carbon atom, nitrogen atom or sulfur atom is oxo-substituted" means to form a structure of C=O, N=O, S=O or SO 2 .
本发明所述“任选被取代”是指被取代基上的一个或多个氢原子可以被一个或多个取代基“取代”或“不取代”的两种情形。In the present invention, "optionally substituted" refers to two situations in which one or more hydrogen atoms on the substituted group may be "substituted" or "unsubstituted" by one or more substituent groups.
本发明所述的“药学上可接受的盐”指化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，包括与碱金属或碱土金属形成的盐、铵盐，以及与含氮有机碱形成的盐；以及化合物中存在的碱性官能团(例如-NH2等)与适当的无机或者有机阴离子(酸)形成的盐，包括与无机酸或有机酸(例如羧酸等)形成的盐。其实例包括但不限于锂盐、钠盐、钾盐、钙盐、镁盐、铋盐、盐酸盐、硫酸盐、硝酸盐、磷酸盐、氢溴酸盐、氢碘酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、四氟硼酸盐、精氨酸盐、天冬氨酸盐和谷氨酸等。 The "pharmaceutically acceptable salt" in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds with appropriate inorganic or organic anions (acids), Included are salts formed with inorganic or organic acids such as carboxylic acids and the like. Examples include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, bismuth, hydrochloride, sulfate, nitrate, phosphate, hydrobromide, hydroiodide, formate , acetate, propionate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate salt, ethanesulfonate, benzenesulfonate, tosylate, tetrafluoroborate, arginine, aspartate and glutamic acid, etc.
本发明所述的“异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心，这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。本发明所述的化合物若含有烯烃双键，除非特别说明，包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移而具有不同的氢的连接点，例如，酮和它的烯醇形式是酮-烯醇互变异构体。本发明化合物含有螺环结构，受环的立体空间结构的 影响，环上的取代基可存在于环两侧从而形成相对的顺式(cis)和反式(trans)异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。"Isomer" as used in the present invention refers to when the compound of the present invention contains one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomers mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compound of the present invention contains an olefinic double bond, unless otherwise specified, cis-isomer and trans-isomer are included. The compounds described in the present invention may exist as tautomers (a type of functional group isomer) that have different hydrogen attachment points by displacement of one or more double bonds, eg, ketones and their alkenes The alcohol form is the keto-enol tautomer. The compound of the present invention contains a spiro ring structure, and under the influence of the steric space structure of the ring, the substituents on the ring can exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and the like of all compounds Mixtures and the like are included in the scope of the present invention.
本发明化合物可通过对映体特异性合成或从对映异构体混合物拆分以得到个别对映异构体的形式制备。常规拆分技术包括使用光学活性酸形成对映异构体对的每一异构体的游离碱的盐(接着分步结晶和游离碱再生)、使用光学活性胺形成对映异构体对的每一对映异构体的酸形式的盐(接着分步结晶和游离酸再生)、使用光学纯酸、胺或醇形成对映异构体对的每一对映异构体中的每一种的酯或酰胺(接着为色谱分离和手性助剂去除)或使用各种众所周知的色谱方法拆分起始物质或最终产物的对映异构体的混合物。The compounds of the present invention can be prepared in the form of individual enantiomers by enantiospecific synthesis or by resolution from enantiomeric mixtures. Conventional resolution techniques include the use of optically active acids to form salts of the free base of each isomer of the enantiomeric pair (followed by fractional crystallization and free base regeneration), the use of optically active amines to form Acid form salts of each enantiomer (followed by fractional crystallization and free acid regeneration), each enantiomer of an enantiomer pair formed using optically pure acids, amines, or alcohols esters or amides of the species (followed by chromatographic separation and removal of chiral auxiliary agents) or resolution of mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.
当公开的化合物的立体化学通过结构命名或描绘时，命名或描绘的立体异构体相对于其他立体异构体为至少60％重量、70％重量、80％重量、90％重量、99％重量或99.9％重量纯。当单一异构体通过结构命名或描绘时，所描绘或命名的对映异构体为至少60％重量、70％重量、80％重量、90％重量、99％重量或99.9％重量纯。光学纯度重量％为对映异构体的重量与对映异构体重量加上其光学异构体的重量比率。When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to other stereoisomers or 99.9% by weight pure. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Optical purity weight % is the ratio of the weight of the enantiomer to the weight of the enantiomer plus its optical isomer.
本发明所述的“剂型”指将药物制成的适用于临床使用的形式，包括但不限于散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、贴剂、含漱剂或栓剂，更优选散剂、片剂、颗粒剂、胶囊剂、溶液剂、注射剂、软膏剂、含漱剂或栓剂。The "dosage form" referred to in the present invention refers to the form that the drug is made into suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.
发明的有益效果Beneficial Effects of Invention
1、本发明化合物、其药学上可接受的盐或其立体异构体具有优异的HPK1活性抑制作用，其在生物体内具有良好的药代动力学性质，作用持久，具有良好的肝微粒体稳定性、暴露量和生物利用度，能够治疗和/或预防由HPK1介导的疾病。1. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have excellent inhibitory effect on HPK1 activity, good pharmacokinetic properties in vivo, long-lasting effects, and good liver microsome stability Sex, exposure and bioavailability, can treat and/or prevent diseases mediated by HPK1.
2、本发明化合物、其药学上可接受的盐或其立体异构体对HPK1介导的癌症具有较好的治疗作用。2. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have better therapeutic effects on HPK1-mediated cancer.
3、本发明化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。3. The compound of the present invention has the advantages of simple preparation process, high drug purity and stable quality, and is easy to carry out large-scale industrial production.
具体实施方案specific implementation
下面将结合具体实施方式对本发明技术方案进行描述，对本发明的上述内容作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The technical solution of the present invention will be described below in conjunction with specific embodiments, and the above-mentioned content of the present invention will be described in further detail, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.
下述实验中所用缩写代表的含义如下：The abbreviations used in the experiments below have the following meanings:
LiAlH 4：氢化铝锂 LiAlH 4 : lithium aluminum hydride
LDA：二异丙基胺基锂LDA: lithium diisopropylamide
DCC：二环己基碳二亚胺DCC: Dicyclohexylcarbodiimide
制备例1：7-氨基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮制备(化合物1)Preparation Example 1: 7-amino-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 1)
Figure PCTCN2022080065-appb-000063
Figure PCTCN2022080065-appb-000063
1. 2,2'-(1,2-亚苯基)双(乙烷-1-醇)的制备1. Preparation of 2,2'-(1,2-phenylene)bis(ethane-1-ol)
将2,2'-(1,2-亚苯基)二乙酸(10.0g,51.5mmol)溶于四氢呋喃(200mL)。0℃下分批次加入LiAlH 4(5.9g,0.15mol)，加毕，15℃下反应18小时。LCMS检测反应结束，0℃下加入5.9mL水淬灭反应，有固体析出，硅藻土过滤，固体用四氢呋喃洗涤，滤液干燥浓缩得标题化合物7.0g，收率：81.8％。 2,2'-(1,2-phenylene)diacetic acid (10.0 g, 51.5 mmol) was dissolved in tetrahydrofuran (200 mL). LiAlH 4 (5.9 g, 0.15 mol) was added in batches at 0° C., the addition was completed, and the reaction was carried out at 15° C. for 18 hours. LCMS detected the end of the reaction, 5.9 mL of water was added at 0°C to quench the reaction, a solid was precipitated, filtered through celite, the solid was washed with tetrahydrofuran, and the filtrate was dried and concentrated to obtain 7.0 g of the title compound, yield: 81.8%.
2. 1,2-亚苯基双(乙烷-2,1-二基)二甲磺酸酯的制备2. Preparation of 1,2-phenylene bis(ethane-2,1-diyl)dimethanesulfonate
将2,2'-(1,2-亚苯基)双(乙烷-1-醇)(7.0g,42.2mmol)溶于二氯甲烷(150mL)，0℃下加入三乙胺(8.5g,84.4mmol)和甲基磺酰氯(9.8g,84.4mmol)，加毕，0℃下反应1小时。1M稀盐酸淬灭反应，分液，有机相干燥浓缩直接用于下一步。Dissolve 2,2'-(1,2-phenylene)bis(ethane-1-ol) (7.0 g, 42.2 mmol) in dichloromethane (150 mL), add triethylamine (8.5 g at 0°C) , 84.4 mmol) and methylsulfonyl chloride (9.8 g, 84.4 mmol), the addition was completed, and the reaction was carried out at 0 °C for 1 hour. The reaction was quenched with 1M dilute hydrochloric acid, the layers were separated, and the organic phase was dried and concentrated and used directly in the next step.
3. 2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备3. Preparation of 2,3,4,5-tetrahydro-1H-benzo[d]azepines
将1,2-亚苯基双(乙烷-2,1-二基)二甲磺酸酯(N/A,42.2mmol)溶于乙腈(50mL)，加入氨水(50mL)，闷罐90℃反应2小时。降温至15℃，浓缩溶剂，加水稀释，浓盐酸调pH＝4，乙酸乙酯萃取，水相用氢氧化钠水溶液调pH＝11，混合溶剂(二氯甲烷:甲醇＝10:1)萃取，有机相干燥浓缩得目标化合物3.0g，两步收率：48.4％。Dissolve 1,2-phenylene bis(ethane-2,1-diyl)dimethanesulfonate (N/A, 42.2 mmol) in acetonitrile (50 mL), add ammonia water (50 mL), and simmer at 90°C React for 2 hours. Cool to 15°C, concentrate the solvent, dilute with water, adjust pH=4 with concentrated hydrochloric acid, extract with ethyl acetate, adjust the aqueous phase to pH=11 with aqueous sodium hydroxide solution, extract with mixed solvent (dichloromethane:methanol=10:1), The organic phase was dried and concentrated to obtain 3.0 g of the target compound, two-step yield: 48.4%.
4. 2,2,2-三氟-1-(1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙基-1-酮的制备4. Preparation of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl-1-one
将2,3,4,5-四氢-1H-苯并[d]氮杂卓(3.0g,20.4mmol)溶于二氯甲烷(100mL)，加入吡啶(2.4g,30.6mmol)，0℃下滴加三氟乙酸酐(5.4g,25.5mmol)，加毕，15℃下反应15小时。LCMS检测反应结束，加水淬灭反应，二氯甲烷萃取，有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯＝3:1)得目标化合物4.0g，收率：80.8％。Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.0 g, 20.4 mmol) in dichloromethane (100 mL), add pyridine (2.4 g, 30.6 mmol), 0°C Trifluoroacetic anhydride (5.4 g, 25.5 mmol) was added dropwise, the addition was completed, and the reaction was carried out at 15° C. for 15 hours. The reaction was detected by LCMS, water was added to quench the reaction, extracted with dichloromethane, the organic phase was dried and concentrated and purified by silica gel column (petroleum ether:ethyl acetate=3:1) to obtain 4.0 g of the target compound, yield: 80.8%.
5. 2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙烷-1-酮的制备5. 2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethane-1- Preparation of ketones
将2,2,2-三氟-1-(1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙基-1-酮(4.0g,16.5mmol)溶于浓硫酸(30mL)，0℃下，分批次加入硝酸钾(1.7g,16.5mmol)，加毕，15℃下反应16小时。 LCMS检测反应结束。反应液倒入冰水中，乙酸乙酯萃取，有机相干燥浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝5:1)得目标化合物3.0g，收率：63.3％。2,2,2-Trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl-1-one (4.0 g, 16.5 mmol) was dissolved in concentrated sulfuric acid (30 mL), at 0 °C, potassium nitrate (1.7 g, 16.5 mmol) was added in batches, the addition was completed, and the reaction was carried out at 15 °C for 16 hours. LCMS detected the end of the reaction. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by silica gel column (petroleum ether:ethyl acetate=5:1) to obtain 3.0 g of the target compound, yield: 63.3%.
6. 7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备6. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepines
将2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙烷-1-酮(3.0g,10.4mmol)溶于甲醇(50mL)，加入碳酸钾(2.9g,20.8mmol)，加毕15℃反应15小时。LCMS检测反应结束。硅藻土过滤，浓缩溶剂，C18柱纯化(甲醇＝0-70％)得目标化合物1.9g，收率：95.5％。2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one (3.0 g, 10.4 mmol) was dissolved in methanol (50 mL), potassium carbonate (2.9 g, 20.8 mmol) was added, and the reaction was completed at 15° C. for 15 hours. LCMS detected the end of the reaction. Filter through celite, concentrate the solvent, and purify with C18 column (methanol=0-70%) to obtain 1.9 g of the target compound, yield: 95.5%.
7. 3-甲基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备7. Preparation of 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(65mg,0.19mmol)溶于甲醛(37％)(10mL)，甲酸(5mL)加毕15℃反应1小时，升温至70℃反应1小时。LCMS检测反应结束。饱和碳酸氢钠溶液调pH＝9，乙酸乙酯萃取有机相干燥浓缩得目标化合物1.9g，收率：93.1％。7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (65 mg, 0.19 mmol) was dissolved in formaldehyde (37%) (10 mL), formic acid (5 mL) was added The reaction was carried out at 15°C for 1 hour, and the temperature was raised to 70°C for 1 hour. LCMS detected the end of the reaction. The saturated sodium bicarbonate solution was adjusted to pH=9, and the organic phase was extracted with ethyl acetate, dried and concentrated to obtain 1.9 g of the target compound, yield: 93.1%.
8. 3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备8. Preparation of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将3-甲基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(1.9g,9.2mmol)溶于甲醇(30mL)，加入Pd/C(1.0g)，加毕15℃氢化反应1小时。LCMS检测反应结束。硅藻土过滤，滤液干燥浓缩得目标化合物1.6g，收率：98.6％。3-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.9 g, 9.2 mmol) was dissolved in methanol (30 mL), Pd/C was added (1.0 g), the hydrogenation reaction at 15°C was completed for 1 hour. The end of the reaction was detected by LCMS. The filtrate was dried and concentrated to obtain 1.6 g of the target compound, yield: 98.6%.
9. N-(3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备9. Preparation of N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.6g,9.1mmol)溶于乙酸(5mL)，加入乙酸酐(1.5mL)，加毕15℃反应12小时。LCMS检测反应结束。加水稀释，饱和碳酸氢钠水溶液调pH＝9，二氯甲烷萃取，水相浓缩C18柱纯化(甲醇＝0-80％)得目标化合物1.9g，收率：96.0％。3-Methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.6 g, 9.1 mmol) was dissolved in acetic acid (5 mL) and acetic anhydride (1.5 mL) was added. mL), and the reaction was completed at 15°C for 12 hours. The end of the reaction was detected by LCMS. Dilute with water, adjust pH=9 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, concentrate the aqueous phase and purify with C18 column (methanol=0-80%) to obtain 1.9 g of the target compound, yield: 96.0%.
10. N-(3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备10. Preparation of N-(3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将N-(3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.9g,8.7mmol)溶于浓硫酸(16mL)，0℃下滴加发烟硝酸(799.0mg,11.3mmol)，加毕0℃下反应10min。LCMS检测反应结束。倒入冰水中，氢氧化钠水溶液调pH＝7，浓缩溶剂，固体用二氯甲烷和甲醇洗涤，有机相浓缩得粗品直接用于下一步。N-(3-Methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.9 g, 8.7 mmol) was dissolved in concentrated sulfuric acid (16 mL) ), fuming nitric acid (799.0 mg, 11.3 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 10 min. LCMS detected the end of the reaction. Pour into ice water, adjust pH=7 with aqueous sodium hydroxide solution, concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain the crude product which is directly used in the next step.
11. 3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备11. Preparation of 3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(N/A,8.7mmol)溶于甲醇(20mL)，加入碳酸钾(2.4g,17.4mmol)，加毕，55℃下反应36小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩C18柱纯化(甲醇＝0-80％)得目标化合物1.6g，收率：83.2％。N-(3-Methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (N/A, 8.7 mmol) It was dissolved in methanol (20 mL), potassium carbonate (2.4 g, 17.4 mmol) was added, the addition was completed, and the reaction was carried out at 55° C. for 36 hours. LCMS detected the end of the reaction. The filtrate was concentrated and purified by C18 column (methanol=0-80%) to obtain 1.6 g of the target compound, yield: 83.2%.
12. 2-(7-甲基-1,5,6,7,8,9-六氢咪唑基并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备12. 2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate
将3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.6g,7.2mmol)溶于乙醇(30mL)，加入Pd/C(1.0g)，加毕15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(3.4g.17.4mmol)，升至50℃反应2小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩硅胶柱柱纯化(二氯甲烷:甲醇＝8:1)得目标化合物1.2g，收率：57.7％。3-Methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.6 g, 7.2 mmol) was dissolved in ethanol (30 mL), Pd/C (1.0 g) was added, and the hydrogenation reaction was carried out at 15° C. for 2 hours. The end of the reaction was detected by LCMS. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (3.4 g. 17.4 mmol) was added, and the temperature was raised to 50° C. to react for 2 hours. The end of the reaction was detected by LCMS. The filtrate was filtered through celite, and the filtrate was concentrated and purified by silica gel column (dichloromethane:methanol=8:1) to obtain 1.2 g of the target compound, yield: 57.7%.
13. 7-羟基-4-(4-甲氧基苄基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂 卓-2-基)噻吩并[3,2-b]吡啶-5(4H)1-酮的制备13. 7-Hydroxy-4-(4-methoxybenzyl)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4 Preparation of ,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)1-one
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑基苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(200mg,0.7mmol)，1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(221.5mg,0.77mmol)溶于四氢呋喃(5mL)，加入LDA(1.4mL,2.8mmol)，加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应，二氯甲烷萃取，有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇＝4:1)得目标化合物60mg，收率：17.7％。Ethyl 2-(7-methyl-1,5,6,7,8,9-hexahydroimidazolylbenzo[1,2-d]azepin-2-yl)acetate (200 mg, 0.7 mmol ), 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (221.5 mg, 0.77 mmol) was dissolved in In tetrahydrofuran (5 mL), LDA (1.4 mL, 2.8 mmol) was added, and the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, and the organic phase was dried and concentrated for purification on a silica gel column (dichloromethane:methanol=4:1) to obtain 60 mg of the target compound, yield: 17.7%.
14. 4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯的制备14. 4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole do[4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b] Preparation of pyridin-7-yl trifluoromethanesulfonate
将7-羟基-4-(4-甲氧基苄基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)1-酮(60mg,0.12mmol)溶于二氯甲烷(10mL)，0℃下加入吡啶(189.8mg,2.4mmol)，三氟甲磺酸酐(203.1mg，0.72mmol)，加毕。0℃下反应1小时。LCMS检测反应结束。加入二氯甲烷稀释，碳酸氢钠水溶液洗涤，有机相干燥浓缩直接用于下一步。7-Hydroxy-4-(4-methoxybenzyl)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4, 5] Benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)1-one (60 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL) ), pyridine (189.8 mg, 2.4 mmol) and trifluoromethanesulfonic anhydride (203.1 mg, 0.72 mmol) were added at 0° C., and the addition was completed. The reaction was carried out at 0°C for 1 hour. LCMS detected the end of the reaction. Dichloromethane was added to dilute, washed with aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated and used directly in the next step.
15. 7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮制备15. 7-(((2,4-Dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1 ,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2- b] Preparation of pyridin-5(4H)-1-one
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.12mmol)溶于乙腈(5mL)，加入2,4-二甲氧基苄胺(60.1mg,0.36mmol)，加毕升至45℃反应2小时。LCMS检测反应结束。浓缩溶剂，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物90.0mg，两步收率95.0％。4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl trifluoromethanesulfonate (N/A, 0.12 mmol) was dissolved in acetonitrile (5 mL), 2,4-dimethoxybenzylamine (60.1 mg, 0.36 mmol) was added, and the temperature was raised to 45 °C React for 2 hours. The end of the reaction was detected by LCMS. The solvent was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 90.0 mg of the title compound in a two-step yield of 95.0%.
16. 7-氨基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮制备16. 7-Amino-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(90mg,0.12mmol)溶于浓盐酸(1mL)，三氟乙酸(7mL)，加毕升至110℃反应24小时。LCMS检测反应结束。饱和碳酸氢钠水溶液调节pH＝7，浓缩溶剂，Pre-HPLC纯化(乙腈＝0-40％)得标题化合物10.0mg，收率23.4％。7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1, 5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b ] Pyridin-5(4H)-1-one (90mg, 0.12mmol) was dissolved in concentrated hydrochloric acid (1mL), trifluoroacetic acid (7mL), and the addition was raised to 110°C for 24 hours. The reaction was detected by LCMS and the reaction was completed. Saturated bicarbonate Aqueous sodium solution was adjusted to pH=7, the solvent was concentrated, and purified by Pre-HPLC (acetonitrile=0-40%) to obtain 10.0 mg of the title compound, yield 23.4%.
分子式:C 19H 19N 5OS 分子量:365.5 LC-MS(M/e):366.1(M+H +) Molecular formula: C 19 H 19 N 5 OS Molecular weight: 365.5 LC-MS (M/e): 366.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:11.83(s,1H),9.67(m,1H),7.96(d,J＝5.2Hz,1H),7.51(s,2H),7.02(d,J＝5.6Hz,1H),3.55-3.95(m,4H),2.95-3.28(m,4H),2.88(s,3H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 11.83(s, 1H), 9.67(m, 1H), 7.96(d, J=5.2Hz, 1H), 7.51(s, 2H), 7.02(d , J=5.6Hz, 1H), 3.55-3.95(m, 4H), 2.95-3.28(m, 4H), 2.88(s, 3H).
制备例2：4-氨基-5-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物2)Preparation Example 2: 4-Amino-5-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 2)
Figure PCTCN2022080065-appb-000064
Figure PCTCN2022080065-appb-000064
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.35mmol)，2-氨基噻吩-3-甲腈(47.5mg,0.38mmol)溶于四氢呋喃(5mL)，加热至40℃，滴加LDA(0.53mL,1.05mmol)，加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应，乙酸乙酯萃取，有机相干燥浓缩C18柱纯化(乙腈＝0-60％)得目标化合物6.6mg，收率：5.2％。2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2- yl) ethyl acetate (100 mg, 0.35 mmol), 2-aminothiophene-3-carbonitrile (47.5 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL), heated to 40 °C, LDA (0.53 mL, 1.05 mmol) was added dropwise , and the reaction was completed at 40 °C for 2 hours. LCMS detected the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried and concentrated for purification by C18 column (acetonitrile=0-60%) to obtain 6.6 mg of the target compound, yield: 5.2%.
分子式:C 19H 19N 5OS 分子量:365.5 LC-MS(M/e):366.1(M+H +) Molecular formula: C 19 H 19 N 5 OS Molecular weight: 365.5 LC-MS (M/e): 366.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:9.91(m,1H),7.57(m,2H),7.23(m,2H),4.45(m,2H),3.20-3.34(m,4H),3.17(s,3H),2.98-3.14(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 9.91(m, 1H), 7.57(m, 2H), 7.23(m, 2H), 4.45(m, 2H), 3.20-3.34(m, 4H) ,3.17(s,3H),2.98-3.14(m,4H).
制备例3：4-氨基-5-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物4)Preparation Example 3: 4-Amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 4)
Figure PCTCN2022080065-appb-000065
Figure PCTCN2022080065-appb-000065
1. 2,3,5,6-四氢苯并[d]吖辛因-4(1H)-酮的制备1. Preparation of 2,3,5,6-tetrahydrobenzo[d]azine-4(1H)-one
将5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(8.0g,49.9mmol)溶于三氟乙酸(60mL)，加入叠氮化钠(4.9g,75.4mol)。65℃下反应7小时。用饱和碳酸氢钠(200mL)和乙酸乙酯(100mL)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物5.0g，收率：57.1％。5,6,8,9-Tetrahydro-7H-benzo[7]rotaxen-7-one (8.0 g, 49.9 mmol) was dissolved in trifluoroacetic acid (60 mL), and sodium azide (4.9 g, 49.9 mmol) was added. 75.4mol). The reaction was carried out at 65°C for 7 hours. Extracted with saturated sodium bicarbonate (200 mL) and ethyl acetate (100 mL), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 5.0 g of the target compound, yield: 57.1%.
2. 1,2,3,4,5,6-六氢苯并[d]吖辛因的制备2. Preparation of 1,2,3,4,5,6-hexahydrobenzo[d]azine
将2,3,5,6-四氢苯并[d]吖辛因-4(1H)-酮(5.0g,28.5mmol)溶于四氢呋喃(200mL)，0℃下加入四氢铝锂(4.3g,113.2mmol)，75℃下反应1小时。加水(4.3mL)淬灭反应，加入10％氢氧化钠(4.3mL)溶液和水(12.9mL)，过滤除去固体，用水(100mL)和乙酸乙酯(200mL)萃取，得粗品4.2g。2,3,5,6-Tetrahydrobenzo[d]azepin-4(1H)-one (5.0 g, 28.5 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium tetrahydroaluminum (4.3 mmol) was added at 0°C. g, 113.2 mmol), reacted at 75°C for 1 hour. Water (4.3 mL) was added to quench the reaction, 10% sodium hydroxide (4.3 mL) solution and water (12.9 mL) were added, the solid was removed by filtration, and extracted with water (100 mL) and ethyl acetate (200 mL) to obtain 4.2 g of crude product.
3. 3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因的制备3. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azine
将1,2,3,4,5,6-六氢苯并[d]吖辛因(2.0g)溶于甲酸(10mL)，加入甲醛(37％)(20mL)，70℃反应1小时。用饱和碳酸氢钠(200mL)调节pH至9，乙酸乙酯(200mL)萃取，得粗品2.0g。1,2,3,4,5,6-hexahydrobenzo[d]azepine (2.0 g) was dissolved in formic acid (10 mL), formaldehyde (37%) (20 mL) was added, and the mixture was reacted at 70° C. for 1 hour. The pH was adjusted to 9 with saturated sodium bicarbonate (200 mL), and extracted with ethyl acetate (200 mL) to obtain 2.0 g of crude product.
4. 3-甲基-8-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因的制备4. Preparation of 3-methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azine
将3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因(2.0g)溶于浓硫酸(15mL)，降温至加入0℃加入硝酸钾(1.2g,11.9mmol)，15℃下反应15小时。用2N氢氧化钠调节pH至12，用二 氯甲烷/甲醇＝9:1(100mL)萃取，有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇＝9:1)得目标化合物1.3g。3-Methyl-1,2,3,4,5,6-hexahydrobenzo[d]azine (2.0g) was dissolved in concentrated sulfuric acid (15mL), cooled to 0°C and potassium nitrate (1.2g) was added. g, 11.9 mmol), reacted at 15°C for 15 hours. Adjust pH to 12 with 2N sodium hydroxide, extract with dichloromethane/methanol=9:1 (100 mL), dry the organic phase and concentrate on silica gel column purification (dichloromethane:methanol=9:1) to obtain 1.3 g of the target compound.
5. 3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺制备5. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azine-8-amine
将3-甲基-8-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因(1.2g,5.4mmol)溶于甲醇(40mL)，加入Pd/C(1.0g)，加毕，15℃氢化反应1小时。硅藻土过滤，滤液干燥浓缩得目标化合物1.0g，收率96.46％。3-Methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azeine (1.2g, 5.4mmol) was dissolved in methanol (40mL), Pd/ C (1.0 g), after the addition, was hydrogenated at 15°C for 1 hour. The filtrate was dried and concentrated to obtain 1.0 g of the target compound with a yield of 96.46%.
6. N-(3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺的制备6. Preparation of N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide
将3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺(1.0g,5.2mmol)溶于乙酸(8mL)，加入乙酸酐(2mL)，加毕，15℃反应12小时。LCMS检测反应结束。加水稀释，饱和碳酸氢钠水溶液调pH＝9，二氯甲烷/甲醇＝9:1(100mL)萃取，浓缩C18柱纯化(甲醇＝0-60％)得目标化合物1.0g，收率：81.9％。3-Methyl-1,2,3,4,5,6-hexahydrobenzo[d]azein-8-amine (1.0 g, 5.2 mmol) was dissolved in acetic acid (8 mL), and acetic anhydride ( 2mL), the addition was completed, and the reaction was carried out at 15°C for 12 hours. LCMS detected the end of the reaction. Dilute with water, adjust pH=9 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane/methanol=9:1 (100 mL), concentrate on C18 column for purification (methanol=0-60%) to obtain 1.0 g of the target compound, yield: 81.9% .
7. N-(3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺的制备7. Preparation of N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide
将N-(3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺(1.0g,4.3mmol)溶于浓硫酸(15mL)，0℃下滴加发烟硝酸(339mg,5.4mmol)，加毕，0℃下反应10min。LCMS检测反应结束。倒入冰水中，用2N氢氧化钠水溶液调pH＝10，二氯甲烷/甲醇＝9:1(100mL)萃取，有机相浓缩得粗品1.8g。Dissolve N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide (1.0 g, 4.3 mmol) in concentrated sulfuric acid ( 15 mL), fuming nitric acid (339 mg, 5.4 mmol) was added dropwise at 0 °C, the addition was completed, and the reaction was carried out at 0 °C for 10 min. LCMS detected the end of the reaction. Pour into ice water, adjust pH=10 with 2N aqueous sodium hydroxide solution, extract with dichloromethane/methanol=9:1 (100 mL), and concentrate the organic phase to obtain 1.8 g of crude product.
8. 3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺的制备8. Preparation of 3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azacin-8-amine
将N-(3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺(1.8g)溶于甲醇(50mL)，加入碳酸钾(1.7g,12.3mmol)，加毕，55℃下反应48小时。浓缩，用二氯甲烷/甲醇＝9:1(100mL)萃取，C18柱纯化(甲醇＝0-70％)得目标化合物800mg，两步收率：79.0％。Dissolve N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide (1.8 g) in methanol (50 mL), potassium carbonate (1.7 g, 12.3 mmol) was added, the addition was completed, and the reaction was carried out at 55° C. for 48 hours. Concentrate, extract with dichloromethane/methanol=9:1 (100 mL), and purify with C18 column (methanol=0-70%) to obtain 800 mg of the target compound, two-step yield: 79.0%.
9. 2-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)乙酸乙酯的制备9. 2-(7-Methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]acridine Preparation of ocin-2-yl)ethyl acetate
将3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺(800mg,3.4mmol)溶于乙醇(30mL)，加入Pd/C(320mg)，加毕，15℃下氢化反应1小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.66g,8.5mmol)，升温至50℃反应2小时。硅藻土过滤，滤液浓缩，经硅胶柱柱纯化(二氯甲烷:甲醇＝6:1)得目标化合物500mg，收率：48.8％。3-Methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azein-8-amine (800 mg, 3.4 mmol) was dissolved in ethanol (30 mL), Pd/C (320 mg) was added, the addition was completed, and the reaction was hydrogenated at 15°C for 1 hour. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.66 g, 8.5 mmol) was added, and the temperature was raised to 50° C. to react for 2 hours. Filter through celite, concentrate the filtrate, and purify by silica gel column (dichloromethane:methanol=6:1) to obtain 500 mg of the target compound, yield: 48.8%.
10. 4-氨基-5-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备10. 4-Amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2 Preparation of -d]azin-2-yl)thieno[2,3-b]pyridin-6(7H)-one
将2-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)乙酸乙酯(70mg,0.23mmol)、2-氨基噻吩-3-甲腈(32mg,0.26mmol)溶于四氢呋喃(10mL)，40℃下加入LDA(0.3mL,0.9mmol)，加毕40℃下反应2小时。饱和氯化铵淬灭反应，乙酸乙酯(50mL)萃取，有机相经干燥、浓缩、制备板纯化(二氯甲烷:甲醇＝6:1)得目标化合物粗品40mg，再次经制备板纯化(二氯甲烷:甲醇＝6:1)得目标化合物2.8mg，收率：3.2％。2-(7-Methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azine In-2-yl)ethyl acetate (70 mg, 0.23 mmol), 2-aminothiophene-3-carbonitrile (32 mg, 0.26 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (0.3 mL, 0.9 mmol) was added at 40°C , and the reaction was completed at 40 °C for 2 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (50 mL), and the organic phase was dried, concentrated, and purified by preparative plate (dichloromethane:methanol=6:1) to obtain 40 mg of crude target compound, which was purified by preparative plate again (dichloromethane:methanol=6:1). Methyl chloride: methanol = 6: 1) to obtain 2.8 mg of the target compound, yield: 3.2%.
分子式:C 20H 21N 5OS 分子量:379.5 LC-MS(M/e):380.1(M+H+) Molecular formula: C 20 H 21 N 5 OS Molecular weight: 379.5 LC-MS(M/e): 380.1(M+H+)
1H-NMR(400MHz,DMSO-d 6)δ:7.45(s,1H),7.32(s,1H),7.22-7.17(m,2H),4.20(s,2H),3.15-3.07(m,4H),2.95-2.87(m,4H),2.70-2.54(m,3H),1.95-1.79(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 7.45(s, 1H), 7.32(s, 1H), 7.22-7.17(m, 2H), 4.20(s, 2H), 3.15-3.07(m, 4H), 2.95-2.87(m, 4H), 2.70-2.54(m, 3H), 1.95-1.79(m, 2H).
制备例4:7-氨基-6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物7)Preparation Example 4: 7-amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzene Preparation of [1,2-e][1,4]bisazin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 7)
Figure PCTCN2022080065-appb-000066
Figure PCTCN2022080065-appb-000066
1. 2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙-1-醇的制备1. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol
将2-(2-氯-4-氟-5-硝基苯基)乙-1-醇(4.0g,18.3mmol)溶于NMP(50mL)中，加入2,4-二甲氧基苄基胺(3.7g,21.9mmol)，和N,N-二异丙基乙胺(4.7g,36.4mmol)，加毕，50℃下反应0.5小时。LCMS检测反应结束，加水淬灭反应，乙酸乙酯萃取，有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯＝3:1)得目标化合物4.0g，收率：68.1％。2-(2-Chloro-4-fluoro-5-nitrophenyl)ethan-1-ol (4.0 g, 18.3 mmol) was dissolved in NMP (50 mL) and 2,4-dimethoxybenzyl was added Amine (3.7 g, 21.9 mmol), and N,N-diisopropylethylamine (4.7 g, 36.4 mmol), were added and reacted at 50° C. for 0.5 hour. LCMS detected the end of the reaction, added water to quench the reaction, extracted with ethyl acetate, dried and concentrated the organic phase and purified with silica gel column (petroleum ether:ethyl acetate=3:1) to obtain 4.0 g of the target compound, yield: 68.1%.
2. 2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙醛的制备2. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde
将2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙-1-醇(4.0g,10.9mmol)溶于二氯甲烷(100mL)，0℃下加入戴斯-马丁试剂(5.6g,13.1mmol)，加毕，15℃下反应1小时。LCMS检测反应结束。反应液加入二氯甲烷，然后加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相干燥浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝5:1)得目标化合物3.9g，收率：98.3％。2-(2-Chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol (4.0 g, 10.9 mmol) was dissolved in dichloromethane ( 100 mL), Dess-Martin reagent (5.6 g, 13.1 mmol) was added at 0 °C, the addition was completed, and the reaction was carried out at 15 °C for 1 hour. LCMS detected the end of the reaction. Dichloromethane was added to the reaction solution, then saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane, the organic phase was dried and concentrated, and purified by silica gel column (petroleum ether:ethyl acetate=5:1) to obtain 3.9 g of the target compound, which was collected Rate: 98.3%.
3. (2-((2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯乙基)(甲基)氨基)乙基)(甲基)氨基甲酸叔丁酯的制备3. (2-((2-Chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenethyl)(methyl)amino)ethyl)(methyl)amino Preparation of tert-butyl formate
将2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙醛(2.5g,6.9mmol)溶于二氯甲烷(50mL)，加入甲基(2-(甲基氨基)乙基)氨基甲酸叔丁酯(1.6g,8.2mmol)，加毕15℃反应10分钟后。加入醋酸硼氢化钠(3.2g,15.0mmol)和醋酸(900mg,15.0mmol)，15℃反应16小时。LCMS检测反应结束。加入1M氢氧化钠水溶液后用二氯甲烷萃取，收集有机相，干燥，浓缩溶剂柱层析(甲醇/二氯甲烷＝0-8％)得目标化合物3.1g，收率：83.8％。2-(2-Chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde (2.5 g, 6.9 mmol) was dissolved in dichloromethane (50 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (1.6 g, 8.2 mmol) was added, and the reaction was completed at 15° C. for 10 minutes. Sodium borohydride acetate (3.2 g, 15.0 mmol) and acetic acid (900 mg, 15.0 mmol) were added, and the mixture was reacted at 15° C. for 16 hours. LCMS detected the end of the reaction. After adding 1M aqueous sodium hydroxide solution, it was extracted with dichloromethane, the organic phase was collected, dried, and concentrated by solvent column chromatography (methanol/dichloromethane=0-8%) to obtain 3.1 g of the target compound, yield: 83.8%.
4. N 1-(4-氨基-2-氯-5-硝基苯乙基)-N 1,N 2-二甲基乙烷-1,2-二胺的制备 4. Preparation of N 1 -(4-amino-2-chloro-5-nitrophenethyl)-N 1 ,N 2 -dimethylethane-1,2-diamine
将(2-((2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯乙基)(甲基)氨基)乙基)(甲基)氨基甲酸叔丁酯(3.1g,5.8mmol)溶于二氯甲烷(30mL)，三氟乙酸(10mL)，加毕，10℃反应1小时。LCMS检测反应结束。浓缩后直接投入下一步。(2-((2-Chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenethyl)(methyl)amino)ethyl)(methyl)carbamic acid The tert-butyl ester (3.1 g, 5.8 mmol) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (10 mL), the addition was completed, and the reaction was carried out at 10° C. for 1 hour. LCMS detected the end of the reaction. After concentration, it was directly put into the next step.
5. 1,4-二甲基-8-硝基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-9-胺的制备5. Preparation of 1,4-dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine
将N1-(4-氨基-2-氯-5-硝基苯乙基)-N1,N2-二甲基乙烷-1,2-二胺粗品溶于N,N-二甲基 乙酰胺(50mL)，加入碳酸钾(3.3g,23.8mmol)，加毕110℃反应2小时。LCMS检测反应结束。加入水淬灭反应，乙酸乙酯萃取，收集有机相，干燥，浓缩溶剂柱层析(甲醇/二氯甲烷＝0-8％)得目标化合物0.3g，两步收率：20.6％。The crude N1-(4-amino-2-chloro-5-nitrophenethyl)-N1,N2-dimethylethane-1,2-diamine was dissolved in N,N-dimethylacetamide ( 50 mL), potassium carbonate (3.3 g, 23.8 mmol) was added, and the reaction was completed at 110° C. for 2 hours. LCMS detected the end of the reaction. Water was added to quench the reaction, extracted with ethyl acetate, the organic phase was collected, dried, and concentrated by solvent column chromatography (methanol/dichloromethane=0-8%) to obtain 0.3 g of the target compound, two-step yield: 20.6%.
6. 1,4-二甲基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-8,9-二胺的制备6. Preparation of 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]bisazine-8,9-diamine
将1,4-二甲基-8-硝基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-9-胺(300mg,1.2mmol)溶于乙醇(10mL)，加入Pd/C(150mg)，加毕，在氮气保护下10℃反应2小时。LCMS检测反应结束。硅藻土过滤，浓缩溶剂得目标化合物直接投入下一步。1,4-Dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine (300 mg, 1.2 mmol) was dissolved in ethanol (10 mL), Pd/C (150 mg) was added, the addition was completed, and the reaction was carried out at 10° C. for 2 hours under nitrogen protection. LCMS detected the end of the reaction. Filter through diatomaceous earth, concentrate the solvent to obtain the target compound and directly put it into the next step.
7. 2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)乙酸乙酯的制备7. 2-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- Preparation of ethyl acetate e][1,4]bisazine-2-yl)acetate
将1,4-二甲基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-8,9-二胺粗品溶于乙醇(10mL)，加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(704mg,3.6mmol)，加毕50℃下反应3小时。LCMS检测反应结束。浓缩溶剂柱层析(甲醇/二氯甲烷＝0-15％)得目标化合物300mg，两步收率：79.1％。The crude 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]bisazine-8,9-diamine was dissolved in ethanol (10 mL ), 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (704 mg, 3.6 mmol) was added, and the reaction was completed at 50° C. for 3 hours. LCMS detected the end of the reaction. Concentrated solvent column chromatography (methanol/dichloromethane=0-15%) afforded 300 mg of the target compound, two-step yield: 79.1%.
8. 1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮的制备8. Preparation of 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione
将2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(5.0g,29.5mmol)溶于N,N-二甲基甲酰胺(50mL)，加入对甲氧基苯甲基氯(7.9g,50.2mmol)，碳酸钾(4.9g,35.5mmol)，碘化钾(2.0g,12.0mmol)，加毕10℃下反应2小时。LCMS检测反应结束。反应液中加入水，固体析出，过滤得标题化合物3.0g，收率35.1％。2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (5.0 g, 29.5 mmol) was dissolved in N,N-dimethylformamide (50 mL) , was added p-methoxybenzyl chloride (7.9 g, 50.2 mmol), potassium carbonate (4.9 g, 35.5 mmol), potassium iodide (2.0 g, 12.0 mmol), and the reaction was completed at 10 °C for 2 hours. LCMS detected the end of the reaction. Water was added to the reaction solution, and a solid was precipitated, which was filtered to obtain 3.0 g of the title compound in a yield of 35.1%.
9. 6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备9. 6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- e][1,4]Diazcin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridine-5(4H)-1- Preparation of ketones
将2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)乙酸乙酯(350mg,1.1mmol)，1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(415mg,1.4mmol)溶于四氢呋喃(10mL)，加热至40℃，在氮气保护下，滴加LDA(1.7mL,3.3mmol)，加毕40℃下反应2小时。饱和氯化铵淬灭反应，二氯甲烷萃取，有机相干燥浓缩柱层析(甲醇/二氯甲烷＝0-15％)得中间体，复加入四氢呋喃(10mL)在氮气保护下滴加LDA(1.2mL)反应两个小时重复上面操作得目标化合物150mg，收率：26.5％。2-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4] Ethyl diazin-2-yl)acetate (350 mg, 1.1 mmol), 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1 ,3]oxazine-2,4(1H)-dione (415 mg, 1.4 mmol) was dissolved in tetrahydrofuran (10 mL), heated to 40°C, under nitrogen protection, LDA (1.7 mL, 3.3 mmol) was added dropwise. The reaction was carried out at 40°C for 2 hours. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, and the organic phase was dried and concentrated by column chromatography (methanol/dichloromethane=0-15%) to obtain the intermediate, which was added dropwise with tetrahydrofuran (10 mL) under nitrogen protection and added dropwise LDA ( 1.2 mL) The above operation was repeated for two hours to obtain 150 mg of the target compound, yield: 26.5%.
10. 6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备10. 6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- e][1,4]Diazcin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridine-5(4H)-1- Preparation of ketones
将6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(150mg,0.29mmol)溶于二氯甲烷(10mL)，0℃下加入吡啶(460mg,5.8mmol)，三氟甲磺酸酐(490mg，1.74mmol)，加毕。0℃下反应1小时。LCMS检测反应结束。加入二氯甲烷稀释，碳酸氢钠水溶液洗涤，有机相干燥浓缩直接用于下一步。6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]Diazin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (150 mg, 0.29 mmol) was dissolved in dichloromethane (10 mL), and pyridine (460 mg, 5.8 mmol) and trifluoromethanesulfonic anhydride (490 mg, 1.74 mmol) were added at 0° C., and the addition was completed. The reaction was carried out at 0°C for 1 hour. LCMS detected the end of the reaction. Dichloromethane was added to dilute, washed with aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated and used directly in the next step.
11. 6-(5,8-二甲基-3-((三氟甲基)磺酰基)-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备11. 6-(5,8-Dimethyl-3-((trifluoromethyl)sulfonyl)-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5 ':4,5]benzo[1,2-e][1,4]bisazin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-( Preparation of 4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one
将6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(N/A,0.29mmol)溶于乙腈(5mL)，加入2,4-二甲氧基苄胺(130mg,0.78mmol)，加毕升至45℃反应2小时。LCMS检测反应结束。浓缩溶剂，硅胶柱纯化(二氯甲烷:甲醇＝20:1)得标题化合物200mg，两步收率90.2％。6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]Diazin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (N/A, 0.29 mmol) was dissolved in acetonitrile (5 mL), 2,4-dimethoxybenzylamine (130 mg, 0.78 mmol) was added, and the mixture was heated to 45° C. for 2 hours. LCMS detected the end of the reaction. The solvent was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 200 mg of the title compound in a two-step yield of 90.2%.
12. 7-氨基-6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备12. 7-Amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[ Preparation of 1,2-e][1,4]bisazin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将6-(5,8-二甲基-3-((三氟甲基)磺酰基)-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(200mg,0.25mmol)溶于浓盐酸(1mL)，三氟乙酸(7mL)，加毕升至110℃反应24小时。LCMS检测反应结束。调节pH＝7，浓缩溶剂，Pre-HPLC纯化(乙腈＝0-40％)得标题化合物20mg，收率20.1％。6-(5,8-Dimethyl-3-((trifluoromethyl)sulfonyl)-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5' :4,5]benzo[1,2-e][1,4]bisazin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-(4 -Methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (200 mg, 0.25 mmol) was dissolved in concentrated hydrochloric acid (1 mL), trifluoroacetic acid (7 mL), and the temperature was raised to 110 °C to react for 24 hours. LCMS detected the end of the reaction. The pH was adjusted to 7, the solvent was concentrated, and purified by Pre-HPLC (acetonitrile=0-40%) to obtain 20 mg of the title compound in a yield of 20.1%.
分子式:C 20H 22N 6OS 分子量:394.5 LC-MS(M/e):395.1(M+H +) Molecular formula: C 20 H 22 N 6 OS Molecular weight: 394.5 LC-MS (M/e): 395.1 (M+H + )
1H-NMR(400MHz,MeOD)δ:7.83(d,J＝5.2Hz,1H),7.37-7.52(m,2H),7.08(d,J＝5.2Hz,1H),3.10-3.12(m,2H),2.89-2.90(m,7H),2.48(s,3H),2.21-2.37(m,2H). 1 H-NMR(400MHz,MeOD)δ:7.83(d,J=5.2Hz,1H),7.37-7.52(m,2H),7.08(d,J=5.2Hz,1H),3.10-3.12(m, 2H), 2.89-2.90(m, 7H), 2.48(s, 3H), 2.21-2.37(m, 2H).
制备例5:4-氨基-5-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物8)Preparation Example 5: 4-Amino-5-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzene Preparation of [1,2-e][1,4]bisazin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 8)
Figure PCTCN2022080065-appb-000067
Figure PCTCN2022080065-appb-000067
将2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二唑-2-基)乙酸乙酯(100mg,0.32mmol)溶于四氢呋喃(5mL)，在氮气保护下加入2-氨基噻吩-3-甲腈(40mg,0.32mmol)，加入LDA(0.32mL,0.64mmol)，加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应，二氯甲烷萃取，有机相干燥浓缩C18拌样，反向柱层析纯化(甲醇/水＝0-45％)得标题化合物30.0mg，收率23.7％。2-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]Diazol-2-yl)ethyl acetate (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), 2-aminothiophene-3-carbonitrile (40 mg, 0.32 mmol) was added under nitrogen protection, LDA (0.32 mL, 0.64 mmol) was added, and the reaction was completed at 40° C. for 2 hours. LCMS detected the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phase was dried and concentrated, and the mixed sample of C18 was purified by reverse column chromatography (methanol/water=0-45%) to obtain 30.0 mg of the title compound, yield 23.7%.
分子式:C 20H 22N 6OS 分子量:394.5 LC-MS(M/e):395.1(M+H +) Molecular formula: C 20 H 22 N 6 OS Molecular weight: 394.5 LC-MS (M/e): 395.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:7.34-7.41(m,1H),7.28(s,1H),6.95(d,J＝5.6Hz,1H),6.84(d,J＝5.6Hz,1H),4.10(s,2H),3.03-3.09(m,2H),2.90-2.91(m,2H),2.84-2.88(m,5H),2.41-2.46(m,3H),2.02-2.04(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 7.34-7.41 (m, 1H), 7.28 (s, 1H), 6.95 (d, J=5.6Hz, 1H), 6.84 (d, J=5.6Hz) ,1H),4.10(s,2H),3.03-3.09(m,2H),2.90-2.91(m,2H),2.84-2.88(m,5H),2.41-2.46(m,3H),2.02-2.04 (m,2H).
制备例6:4-氨基-5-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮盐酸盐的制备(化合物9的盐酸盐)Preparation Example 6: 4-Amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride (hydrochloride of compound 9)
Figure PCTCN2022080065-appb-000068
Figure PCTCN2022080065-appb-000068
1. 1-(7-氨基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮的制备1. 1-(7-Amino-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2,2,2-trifluoroethane-1-one preparation
将2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙-1-酮(3.0g,10.4mmol)溶于甲醇(50mL)，加入Pd/C(1.0g)，加毕15℃反应15小时。LCMS检测反应结束。硅藻土过滤，浓缩溶剂得目标化合物2.6g，收率：96.7％。2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one ( 3.0 g, 10.4 mmol) was dissolved in methanol (50 mL), Pd/C (1.0 g) was added, and the reaction was completed at 15° C. for 15 hours. LCMS detected the end of the reaction. Filter through celite, and concentrate the solvent to obtain 2.6 g of the target compound, yield: 96.7%.
2. N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备2. Preparation of N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将1-(7-氨基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮(2.6g,10.1mmol)溶于乙酸(30mL)，加入乙酸酐(1.5mL)加毕15℃反应16小时。LCMS检测反应结束。加水，继续搅拌1小时，固体析出，过滤，固体用水洗涤，干燥得目标化合物2.3g，收率：76.2％。1-(7-Amino-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2,2,2-trifluoroethane-1-one ( 2.6 g, 10.1 mmol) was dissolved in acetic acid (30 mL), and acetic anhydride (1.5 mL) was added to complete the reaction at 15° C. for 16 hours. LCMS detected the end of the reaction. Water was added, stirring was continued for 1 hour, the solid was precipitated, filtered, the solid was washed with water, and dried to obtain 2.3 g of the target compound, yield: 76.2%.
3. N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备3. N-(8-Nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl ) Preparation of acetamide
将N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.3g,7.7mmol)溶于浓硫酸(16mL)，0℃下，加入发烟硝酸(700.0mg,10.0mmol)，加毕，0℃下反应2小时。LCMS检测反应结束。倒入冰水中，二氯甲烷萃取，有机相干燥浓缩得目标化合物2.3g，收率：86.9％。N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3 g , 7.7 mmol) was dissolved in concentrated sulfuric acid (16 mL), at 0 °C, fuming nitric acid (700.0 mg, 10.0 mmol) was added, the addition was completed, and the reaction was carried out at 0 °C for 2 hours. LCMS detected the end of the reaction. It was poured into ice water, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain 2.3 g of the target compound, yield: 86.9%.
4. 7-氨基-8-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-羧酸叔丁酯的制备4. Preparation of 7-amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester
将N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.3g,6.7mmol)溶于甲醇(30mL)，升温至55℃，加入碳酸钾(2.8g,20.1mmol)，加毕55℃反应16小时。硅藻土过滤，滤液中加入Boc 2O(2.2g,10.1mmol)，加毕，15℃反应2小时。浓缩硅胶柱纯化(石油醚:乙酸乙酯＝5:1)得目标化合物1.7g，收率：82.9％。 N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl) Acetamide (2.3 g, 6.7 mmol) was dissolved in methanol (30 mL), the temperature was raised to 55 °C, potassium carbonate (2.8 g, 20.1 mmol) was added, and the reaction was completed at 55 °C for 16 hours. Celite was filtered, Boc 2 O (2.2 g, 10.1 mmol) was added to the filtrate, and the addition was completed, and the reaction was carried out at 15° C. for 2 hours. Concentrated silica gel column purification (petroleum ether:ethyl acetate=5:1) to obtain 1.7 g of the target compound, yield: 82.9%.
5. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备5. 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepine-7(1H)-carboxylate tert-butyl ester
将7-氨基-8-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-羧酸叔丁酯(1.7g,5.5mmol)溶于乙醇(100mL)，加入Pd/C(800mg)，加毕15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.6g.13.3mmol)，加毕，升温至50℃反应2小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩硅胶柱纯化(乙酸乙酯)得目标化合物1.6g，收率：60.4％7-Amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate tert-butyl ester (1.7 g, 5.5 mmol) was dissolved in ethanol ( 100 mL), Pd/C (800 mg) was added, and the hydrogenation reaction was carried out at 15° C. for 2 hours. LCMS detected the end of the reaction. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (2.6 g. 13.3 mmol) was added, and after the addition was completed, the temperature was raised to 50° C. to react for 2 hours. LCMS detected the end of the reaction. The filtrate was concentrated and purified by silica gel column (ethyl acetate) to obtain 1.6 g of the target compound, yield: 60.4%
6. 2-(4-氨基-6-氧代-6,7-二氢噻吩并[2,3-b]吡啶基-5-基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓7(1H)-羧酸叔丁酯的制备6. 2-(4-Amino-6-oxo-6,7-dihydrothieno[2,3-b]pyridyl-5-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepine 7(1H)-carboxylate tert-butyl ester
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.8mmol)，2-氨基噻吩-3-甲腈(109.9mg,0.88mmol)溶于四氢呋喃(5mL)，氮气保护下加热至40℃，滴加LDA(1.2mL,2.4mmol)，加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应，乙酸乙酯萃取，有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯＝5:1)得目标化合物260mg，收率：71.7％2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Hetero-7(1H)-carboxylate tert-butyl ester (300mg, 0.8mmol), 2-aminothiophene-3-carbonitrile (109.9mg, 0.88mmol) was dissolved in tetrahydrofuran (5mL), heated to 40 ℃ under nitrogen protection , LDA (1.2 mL, 2.4 mmol) was added dropwise, and the reaction was completed at 40° C. for 2 hours. LCMS detected the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried and concentrated, purified by silica gel column (petroleum ether:ethyl acetate=5:1) to obtain 260 mg of the target compound, yield: 71.7%
7. 4-氨基-5-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮盐酸盐的制备7. 4-Amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride
将2-(4-氨基-6-氧代-6,7-二氢噻吩并[2,3-b]吡啶基-5-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓7(1H)-羧酸叔丁酯(45.0mg,0.1mmol)溶于乙醇(2mL)，加入HCl/乙醇(1.5mL)，加毕15℃下反应4小时。LCMS检测反应结束。加入0.5mL水，过滤，固体干燥得目标化合物12.0mg，收率：31.0％。2-(4-Amino-6-oxo-6,7-dihydrothieno[2,3-b]pyridinyl-5-yl)-5,6,8,9-tetrahydroimidazo[4 ',5':4,5]benzo[1,2-d]azepine 7(1H)-carboxylate tert-butyl ester (45.0 mg, 0.1 mmol) was dissolved in ethanol (2 mL), and HCl/ethanol ( 1.5mL), and the reaction was carried out at 15°C for 4 hours. LCMS detected the end of the reaction. Add 0.5 mL of water, filter, and dry the solid to obtain 12.0 mg of the target compound, yield: 31.0%.
分子式:C 18H 17N 5OS 分子量:351.4 LC-MS(M/e):352.1(M+H +) Molecular formula: C 18 H 17 N 5 OS Molecular weight: 351.4 LC-MS (M/e): 352.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:9.39(m,2H),7.67(s,2H),7.23-7.26(m,2H),4.64(s,2H),3.26-3.36(m,4H),3.15-3.25(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 9.39(m, 2H), 7.67(s, 2H), 7.23-7.26(m, 2H), 4.64(s, 2H), 3.26-3.36(m, 4H),3.15-3.25(m,4H).
制备例7：7-氨基-6-(7-乙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物10)Preparation Example 7: 7-amino-6-(7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 10)
Figure PCTCN2022080065-appb-000069
Figure PCTCN2022080065-appb-000069
1. 7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备1. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepines
将2,3,4,5-四氢-1H-苯并[d]氮杂卓(5.0g,34.0mmol)溶于三氟乙酸(20mL)，降温至0℃，加入浓硫酸(7.5mL)和硝酸钾(5.5g,56.7mmol)，0℃下反应2小时。将反应液倾入冰水中，用2N氢氧化钠调节pH至11，用二氯甲烷/甲醇＝9:1(100mL)萃取，得粗品5.0g。2,3,4,5-Tetrahydro-1H-benzo[d]azepine (5.0 g, 34.0 mmol) was dissolved in trifluoroacetic acid (20 mL), cooled to 0 °C, and concentrated sulfuric acid (7.5 mL) was added and potassium nitrate (5.5 g, 56.7 mmol), react at 0°C for 2 hours. The reaction solution was poured into ice water, adjusted to pH 11 with 2N sodium hydroxide, and extracted with dichloromethane/methanol=9:1 (100 mL) to obtain 5.0 g of crude product.
2. 3-乙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备2. Preparation of 3-ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(5.0g,粗品)溶于四氢呋喃(100mL)，加入 乙醛水溶液(40％)(15.75g,142.9mmol)，醋酸(3.1g,51.6mmol)和三乙酰氧基硼氢化钠(9.65g,45.5mmol),15℃下反应2小时。用1N氢氧化钠调节pH至10左右，用二氯甲烷/甲醇＝9:1(200mL)萃取，有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物2.0g，两步反应收率26.8％。7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, crude product) was dissolved in tetrahydrofuran (100 mL), and an aqueous solution of acetaldehyde (40%) was added (15.75 g) g, 142.9 mmol), acetic acid (3.1 g, 51.6 mmol) and sodium triacetoxyborohydride (9.65 g, 45.5 mmol) were reacted at 15° C. for 2 hours. Adjust pH to about 10 with 1N sodium hydroxide, extract with dichloromethane/methanol=9:1 (200 mL), dry the organic phase and concentrate on silica gel column purification (dichloromethane:methanol=10:1) to obtain 2.0 g of the target compound, The two-step reaction yield was 26.8%.
3. 3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备3. Preparation of 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将3-乙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(2.0g,9.1mmol)溶于甲醇(40mL)，加入Pd/C(500mg)，用氢气换气3次，在氢气下15℃氢化反应2小时。硅藻土过滤，滤液干燥浓缩得目标化合物1.9g。3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0 g, 9.1 mmol) was dissolved in methanol (40 mL), Pd/C was added (500 mg), purged with hydrogen 3 times, and hydrogenated at 15° C. for 2 hours under hydrogen. The filtrate was filtered through celite, and the filtrate was dried and concentrated to obtain 1.9 g of the target compound.
4. N-(3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备4. Preparation of N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.9g,粗品)溶于乙酸(16mL)，加入乙酸酐(4mL)，加毕15℃反应1小时。加水稀释，用氢氧化钠调pH＝11，二氯甲烷/甲醇＝9:1(100mL)萃取，C18柱纯化(甲醇＝0-60％)得目标化合物1.5g，两步收率71.4％。3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.9 g, crude) was dissolved in acetic acid (16 mL), and acetic anhydride (4 mL) was added , and the reaction was completed at 15°C for 1 hour. Add water to dilute, adjust pH=11 with sodium hydroxide, extract with dichloromethane/methanol=9:1 (100 mL), and purify with C18 column (methanol=0-60%) to obtain 1.5 g of the target compound with a two-step yield of 71.4%.
5. N-(3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备5. Preparation of N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将N-(3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.5g,6.5mmol)溶于浓硫酸(30mL)，0℃下滴加发烟硝酸(470mg,7.5mmol)，加毕0℃下反应10min。LCMS检测反应结束。倒入冰水中，用2N氢氧化钠水溶液调pH＝10，二氯甲烷/甲醇＝9:1(100mL)萃取，C18柱纯化(甲醇＝0-65％)得目标化合物1.2g，收率：66.7％。N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.5 g, 6.5 mmol) was dissolved in concentrated sulfuric acid (30 mL) ), fuming nitric acid (470 mg, 7.5 mmol) was added dropwise at 0 °C, and the reaction was completed at 0 °C for 10 min. LCMS detected the end of the reaction. Pour into ice water, adjust pH=10 with 2N aqueous sodium hydroxide solution, extract with dichloromethane/methanol=9:1 (100 mL), and purify with C18 column (methanol=0-65%) to obtain 1.2 g of the target compound, yield: 66.7%.
6. 3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备6. Preparation of 3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.2g,4.33mmol)溶于甲醇(150mL)，加入碳酸钾(2.3g,16.6mmol)，加毕，50℃下反应2小时。浓缩，用硅胶柱层析纯化(二氯甲烷:甲醇＝8:1)得目标化合物1.0g，收率：98.2％。N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.2 g, 4.33 mmol) was dissolved in Potassium carbonate (2.3 g, 16.6 mmol) was added to methanol (150 mL), the addition was completed, and the reaction was carried out at 50° C. for 2 hours. Concentrate and purify by silica gel column chromatography (dichloromethane:methanol=8:1) to obtain 1.0 g of the target compound, yield: 98.2%.
7. 2-(7-乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备7. 2-(7-Ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl) ethyl acetate
将3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.0g,4.2mmol)溶于乙醇(100mL)，加入Pd/C(300mg)，用氢气换气3次，在氢气下15℃氢化反应4小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.0g.10.2mmol)，升至50℃反应2小时。硅藻土过滤，滤液浓缩，用饱和碳酸氢钠(10mL)，水(20mL)和二氯甲烷/甲醇＝9:1(100mL)萃取，硅胶柱柱纯化(二氯甲烷:甲醇＝15:1)得目标化合物800mg，收率：63.5％。3-Ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.0 g, 4.2 mmol) was dissolved in ethanol (100 mL), Pd/C (300 mg) was added, the mixture was purged with hydrogen 3 times, and hydrogenated at 15° C. for 4 hours under hydrogen. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (2.0 g. 10.2 mmol) was added, and the temperature was raised to 50° C. to react for 2 hours. Celite was filtered, the filtrate was concentrated, extracted with saturated sodium bicarbonate (10 mL), water (20 mL) and dichloromethane/methanol=9:1 (100 mL), and purified by silica gel column (dichloromethane:methanol=15:1) ) to obtain 800 mg of the target compound, yield: 63.5%.
8. 7-氨基-6-(7-乙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备8. 7-Amino-6-(7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(50mg,0.17mmol)，3-氨基噻吩-2-甲腈(21mg,0.17mmol)溶于四氢呋喃(10mL)，40℃下加入LDA(0.43mL,0.86mmol)，加毕40℃下反应3小时。饱和氯化铵淬灭反应，用水(15mL)和乙酸乙酯(15mL)萃取，加入甲醇(3mL)，过滤，干燥，得目标化合物21mg，收率：32.6％。2-(7-Ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 -yl)ethyl acetate (50 mg, 0.17 mmol), 3-aminothiophene-2-carbonitrile (21 mg, 0.17 mmol) was dissolved in tetrahydrofuran (10 mL), LDA (0.43 mL, 0.86 mmol) was added at 40°C, and the addition was complete The reaction was carried out at 40°C for 3 hours. The reaction was quenched with saturated ammonium chloride, extracted with water (15 mL) and ethyl acetate (15 mL), added with methanol (3 mL), filtered and dried to obtain 21 mg of the target compound, yield: 32.6%.
分子式:C 20H 21N 5OS 分子量:379.5 LC-MS(M/e):380.1(M+H +) Molecular formula: C 20 H 21 N 5 OS Molecular weight: 379.5 LC-MS (M/e): 380.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.77(s,1H),11.80(s,1H),10.85-10.51(brs,1H),7.94(s, 1H),7.98-7.71(brs,1H),7.40-7.34(m,2H),7.02(s,1H),2.98-2.86(m,4H),2.72-2.44(m,6H),1.02(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.77(s, 1H), 11.80(s, 1H), 10.85-10.51(brs, 1H), 7.94(s, 1H), 7.98-7.71(brs, 1H), 7.40-7.34(m, 2H), 7.02(s, 1H), 2.98-2.86(m, 4H), 2.72-2.44(m, 6H), 1.02(t, J=7.2Hz, 3H).
制备例8：7-氨基-6-(7-环丁基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物11)Preparation Example 8: 7-Amino-6-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 11)
Figure PCTCN2022080065-appb-000070
Figure PCTCN2022080065-appb-000070
1. 8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备1. Preparation of 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.0g,2.9mmol)溶于甲醇(10.0mL)中，加入碳酸钾(600.0mg,4.3mmol)，20℃反应2.0h，反应结束后，经过滤、水洗、二氯甲烷萃取浓缩后，粗品直接用于下一步反应。N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl) Acetamide (1.0 g, 2.9 mmol) was dissolved in methanol (10.0 mL), potassium carbonate (600.0 mg, 4.3 mmol) was added, and the reaction was carried out at 20°C for 2.0 h. , the crude product was directly used in the next reaction.
2. 3-环丁基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备2. Preparation of 3-cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(上步粗品)溶于10.0mL甲醇中，加入氰基硼氢化钠(550.0mg,8.8mmol)、醋酸(1.7g,28.3mmol)，0℃下滴加环丁酮(410.0mg,5.8mmol)，20℃下反应2.0h。向反应液中加水(100mL)淬灭，乙酸乙酯萃取，有机相经无水硫酸钠干燥、旋干，得目标化合物300mg，两步收率39.6％。8-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (crude product from the previous step) was dissolved in 10.0 mL of methanol, and sodium cyanoborohydride was added ( 550.0 mg, 8.8 mmol), acetic acid (1.7 g, 28.3 mmol), cyclobutanone (410.0 mg, 5.8 mmol) was added dropwise at 0 °C, and the reaction was carried out at 20 °C for 2.0 h. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 300 mg of the target compound with a two-step yield of 39.6%.
3. 3-环丁基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺的制备3. Preparation of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine
将3-环丁基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(250mg)溶于乙醇(10mL)中，加入Pd/C(50.0mg)，氢气条件下25℃下反应1.5h结束，反应液直接用于下一步反应。3-Cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (250 mg) was dissolved in ethanol (10 mL) and Pd was added /C (50.0 mg), the reaction was completed at 25 °C for 1.5 h under hydrogen conditions, and the reaction solution was directly used for the next reaction.
4. 2-(7-环丁基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备4. 2-(7-Cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate
向上步反应液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(330.0mg,1.7mmol),体系升至80℃后反应2h结束。过滤后用饱和碳酸氢钠溶液调pH至8，经浓缩后柱层析(二氯甲烷:甲醇＝10:1)得目标化合物200mg，两步收率为63.9％。3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (330.0 mg, 1.7 mmol) was added to the reaction solution in the previous step, and the reaction was completed after the system was raised to 80 °C for 2 h. After filtration, the pH was adjusted to 8 with saturated sodium bicarbonate solution. After concentration, column chromatography (dichloromethane:methanol=10:1) was used to obtain 200 mg of the target compound with a two-step yield of 63.9%.
5. 7-氨基-6-(7-环丁基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备5. 7-Amino-6-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-环丁基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(30.0mg,0.09mmol)和3-氨基噻吩-2-腈(13.0mg，0.10mmol)溶于四氢呋喃(3.0mL)中，氮气保护下，40℃下滴加LDA(0.3mL,0.60mmol)，继续反应2.0h。反应完成后，将体系倒入饱和氯化铵溶液中淬灭，乙酸乙酯萃取，有机相旋干，粗品经硅胶柱层析分离(DCM:MeOH＝10:1)纯化，甲醇打浆纯化得产品12.0mg，产率32.3％。2-(7-Cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (30.0 mg, 0.09 mmol) and 3-aminothiophene-2-carbonitrile (13.0 mg, 0.10 mmol) were dissolved in tetrahydrofuran (3.0 mL), and LDA ( 0.3mL, 0.60mmol), continue to react for 2.0h. After the reaction was completed, the system was poured into saturated ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, the crude product was purified by silica gel column chromatography (DCM:MeOH=10:1), and purified by beating with methanol to obtain the product 12.0 mg, 32.3% yield.
分子式:C 22H 23N 5OS 分子量:405.5 LC-MS(M/e):406.0(M+H +) Molecular formula: C 22 H 23 N 5 OS Molecular weight: 405.5 LC-MS (M/e): 406.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.73(s,1H),11.76(s,1H),10.80-10.55(br s,1H),7.91(s,1H),7.90-7.75(br s,1H),7.40(s,1H),7.31(s,1H),7.00(s,1H),2.95-2.85(m,4H),2.81-2.71(m,1H),2.47-2.35(m,4H),2.08-1.98(m,2H),1.90-1.85(m,2H),1.65-1.51(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.73(s, 1H), 11.76(s, 1H), 10.80-10.55(br s, 1H), 7.91(s, 1H), 7.90-7.75(br s,1H),7.40(s,1H),7.31(s,1H),7.00(s,1H),2.95-2.85(m,4H),2.81-2.71(m,1H),2.47-2.35(m, 4H), 2.08-1.98(m, 2H), 1.90-1.85(m, 2H), 1.65-1.51(m, 2H).
制备例9：7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物12)Preparation Example 9: 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 12)
Figure PCTCN2022080065-appb-000071
Figure PCTCN2022080065-appb-000071
1. 3-环丙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备1. Preparation of 3-cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(4.2g,21.8mmol)、氰基硼氢化钠(8.7g,139.5mmol)、醋酸(13.6g,230.6mmol)溶于甲醇(120mL)中，0℃下滴加(1-乙氧基环丙氧基)三甲基硅烷(8.7g,50.1mmol)，60℃下反应4h，LCMS检测反应完成，向反应液中加水(100mL)淬灭，乙酸乙酯萃取，有机相无水硫酸钠干燥，旋干，得目标化合物4g，收率78.7％。Combine 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.2 g, 21.8 mmol), sodium cyanoborohydride (8.7 g, 139.5 mmol), acetic acid ( 13.6 g, 230.6 mmol) was dissolved in methanol (120 mL), (1-ethoxycyclopropoxy)trimethylsilane (8.7 g, 50.1 mmol) was added dropwise at 0 °C, and the reaction was carried out at 60 °C for 4 h, and detected by LCMS. After the reaction was completed, water (100 mL) was added to the reaction solution to quench, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and spin-dried to obtain 4 g of the target compound with a yield of 78.7%.
2. 3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备2. Preparation of 3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将3-环丙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(3.8g,16.3mmol)溶于甲醇(50mL)中，加入Pd/C(1.9g)，氢气条件下25℃下反应16h，LCMS检测反应完成，抽滤，滤液旋干得粗品3.5g。3-Cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.8 g, 16.3 mmol) was dissolved in methanol (50 mL) and Pd was added /C (1.9g), reacted at 25°C for 16h under hydrogen condition, the reaction was completed by LCMS, suction filtered, and the filtrate was spin-dried to obtain 3.5g of crude product.
3. N-(3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备3. Preparation of N-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(3.5g,粗品)溶于醋酸(20mL)中，加入乙酸酐(3mL)，25℃下反应4h，LCMS检测反应完成，反应液旋干，饱和碳酸氢钠水溶液调pH至8-9，二氯甲烷萃取，有机相旋干，硅胶柱层析分离(二氯甲烷:甲醇＝20：1)得目标化合物2.12g，收率53.1％。3-Cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (3.5 g, crude product) was dissolved in acetic acid (20 mL), and acetic anhydride ( 3mL), reacted at 25°C for 4h, LCMS detected that the reaction was complete, the reaction solution was spin-dried, the saturated aqueous sodium bicarbonate solution was adjusted to pH 8-9, extracted with dichloromethane, the organic phase was spin-dried, and separated by silica gel column chromatography (dichloromethane : methanol = 20: 1) to obtain 2.12 g of the target compound with a yield of 53.1%.
4. N-(3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备4. Preparation of N-(3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将N-(3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.12g,8.65mmol)溶于浓硫酸(22mL)中，0℃下加入发烟硝酸(849mg，13mmol)，25℃下反应0.5h，LCMS检测反应完成，用5M氢氧化钠溶液调pH至8-9，DCM萃取，有机相无水硫酸钠干燥，旋干得产品2g，收率79.7％。N-(3-Cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.12 g, 8.65 mmol) was dissolved in concentrated sulfuric acid ( 22mL), fuming nitric acid (849mg, 13mmol) was added at 0°C, reacted at 25°C for 0.5h, the reaction was completed by LCMS, the pH was adjusted to 8-9 with 5M sodium hydroxide solution, extracted with DCM, and the organic phase was anhydrous sulfuric acid. Sodium-drying, spin-dried to obtain 2 g of product with a yield of 79.7%.
5. 3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备5. Preparation of 3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.96g,6.76mmol)溶于甲醇(35mL)中，加入碳酸钾(4.6g,33.4mmol)，65℃反应8h，LCMS检测反应完成，硅藻土过滤,硅胶柱层析分离(甲醇:二氯甲烷＝1：15)得目标化合物1.1g，收率65.1％。N-(3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.96 g, 6.76 mmol) It was dissolved in methanol (35 mL), potassium carbonate (4.6 g, 33.4 mmol) was added, and the reaction was carried out at 65 °C for 8 h. LCMS detected the completion of the reaction, filtered through celite, and separated by silica gel column chromatography (methanol:dichloromethane=1:15) 1.1 g of the target compound was obtained with a yield of 65.1%.
6. 2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备6. 2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate
将3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.1g,4.4mmol)溶于乙醇(25mL)中，氢气条件下25℃下反应2h，加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.7g,8.8mmol),LCMS检测反应完成，过滤，滤液旋干，硅胶柱层析分离(二氯甲烷:甲醇＝10:1)得产品900mg，收率65.1％。3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.1 g, 4.4 mmol) was dissolved in ethanol (25 mL) 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.7 g, 8.8 mmol) was added, the reaction was completed by LCMS, filtered, the filtrate was spin-dried, silica gel column Chromatographic separation (dichloromethane:methanol=10:1) gave 900 mg of the product with a yield of 65.1%.
7. 7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备7. 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(200mg,0.64mmol)和3-氨基噻吩-2-腈(76mg,0.61mmol)溶于四氢呋喃(5mL)中，氮气保护，40℃下滴加LDA(1.5Ml,2.88mmol)，继续反应6h，LCMS检测反应完成。倒入饱和氯化铵溶液中淬灭，乙酸乙酯萃取，有机相旋干，粗品经硅胶柱层析分离(二氯甲烷:甲醇＝10:1)纯化，甲醇打浆纯化得产品77mg，产率30.7％。2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (200 mg, 0.64 mmol) and 3-aminothiophene-2-carbonitrile (76 mg, 0.61 mmol) were dissolved in tetrahydrofuran (5 mL), under nitrogen protection, LDA (1.5 Ml, 2.88 g was added dropwise at 40°C) mmol), continue to react for 6h, and LCMS detects that the reaction is complete. Poured into saturated ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1), and purified by methanol beating to obtain 77 mg of product in a yield of 77 mg. 30.7%.
分子式:C 21H 21N 5OS 分子量:391.5 LC-MS(M/e):392.0(M+H +) Molecular formula: C 21 H 21 N 5 OS Molecular weight: 391.5 LC-MS (M/e): 392.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.96(s,1H),11.79(s,1H),10.55-10.80(br s,1H),7.98(s,1H),7.75-7.95(br s,1H),7.40(s,1H)，7.38(s,1H),7.02(s,1H)，2.85-2.95(m,4H),2.70-2.84(m,4H),1.75-1.85(m,1H),0.30-0.50(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.96(s, 1H), 11.79(s, 1H), 10.55-10.80(br s, 1H), 7.98(s, 1H), 7.75-7.95(br s, 1H), 7.40(s, 1H), 7.38(s, 1H), 7.02(s, 1H), 2.85-2.95(m, 4H), 2.70-2.84(m, 4H), 1.75-1.85(m, 1H),0.30-0.50(m,4H).
制备例10：6-(7-乙酰基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-氨基噻吩并[3,2-b]吡啶-5(4H)的制备(化合物13)Preparation Example 10: 6-(7-Acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zo-2-yl)-7-aminothieno[3,2-b]pyridine-5(4H) (Compound 13)
Figure PCTCN2022080065-appb-000072
Figure PCTCN2022080065-appb-000072
1. 2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐的制备1. 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetic acid Preparation of ethyl ester hydrochloride
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(373mg,1.0mmol)溶于4M HCl/二氧六环(10mL)，15℃反应2小时，浓缩得241mg，用于下一步。2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Hetero-7(1H)-carboxylate tert-butyl ester (373 mg, 1.0 mmol) was dissolved in 4M HCl/dioxane (10 mL), reacted at 15°C for 2 hours, and concentrated to obtain 241 mg, which was used in the next step.
2.(7-乙酰基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备2. (7-Acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine-2- base) preparation of ethyl acetate
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(210mg,粗品)溶于二氯甲烷(10mL)，0℃下滴加乙酸酐(86mg,0.85mmol)，0℃反应2小时。浓缩， 有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物200mg，两步收率：63.5％Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate The ester (210 mg, crude product) was dissolved in dichloromethane (10 mL), acetic anhydride (86 mg, 0.85 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 2 hours. Concentrate, dry and concentrate the organic phase and purify with silica gel column (dichloromethane:methanol=10:1) to obtain 200 mg of the target compound, two-step yield: 63.5%
3. 6-(7-乙酰基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-氨基噻吩并[3,2-b]吡啶-5(4H)的制备3. 6-(7-Acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-aminothieno[3,2-b]pyridine-5(4H)
将7-乙酰基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(170mg,0.54mmol)、3-氨基噻吩-2-甲腈(74mg,0.59mmol)溶于四氢呋喃(10mL)，40℃下加入LDA(1.1mL,2.16mmol)，加毕40℃下反应5小时。饱和氯化铵淬灭反应，乙酸乙酯(15mL)萃取，加入甲醇(1mL)和乙酸乙酯(1mL)，过滤，干燥，得目标化合物7.5mg，收率：3.5％。7-acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl) Ethyl acetate (170 mg, 0.54 mmol), 3-aminothiophene-2-carbonitrile (74 mg, 0.59 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (1.1 mL, 2.16 mmol) was added at 40 °C, and the addition was completed at 40 °C The reaction was carried out for 5 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (15 mL), added with methanol (1 mL) and ethyl acetate (1 mL), filtered and dried to obtain 7.5 mg of the target compound, yield: 3.5%.
分子式:C 20H 19N 5O 2S 分子量:393.13 LC-MS(M/e):394.47(M+H +) Molecular formula: C 20 H 19 N 5 O 2 S Molecular weight: 393.13 LC-MS (M/e): 394.47 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.81(s,1H),11.80(s,1H),10.85-10.51(brs,1H),7.95(s,1H),7.94-7.71(brs,1H),7.46-7.40(m,2H),7.02(s,1H),3.59-3.57(m,4H),3.05-2.97(m,2H),2.99-2.90(m,2H),2.08(s,3H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.81(s,1H), 11.80(s,1H), 10.85-10.51(brs,1H), 7.95(s,1H), 7.94-7.71(brs, 1H), 7.46-7.40(m, 2H), 7.02(s, 1H), 3.59-3.57(m, 4H), 3.05-2.97(m, 2H), 2.99-2.90(m, 2H), 2.08(s, 3H).
制备例11：7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物14-1)Preparation Example 11: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4' Preparation of ,5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 14-1)
Figure PCTCN2022080065-appb-000073
Figure PCTCN2022080065-appb-000073
1. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl) sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno Preparation of [3,2-b]pyridin-5(4H)-one
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.37mmol)溶于乙腈(20mL)，加入(1s,4s)-4-氨基环己-1-醇(170.5mg,1.48mmol)，加毕45℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物216mg，两步收率：81.8％。4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl trifluoromethanesulfonate (N/A, 0.37 mmol) was dissolved in acetonitrile (20 mL), (1s, 4s)-4-aminocyclohexan-1-ol (170.5 mg, 1.48 mmol) was added, and The reaction was completed at 45°C for 2 hours. The end of the reaction was detected by LCMS. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 216 mg of the target compound, two-step yield: 81.8%.
2. 7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5 Preparation of ':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(216mg,0.3mmol)溶于浓盐酸(2mL)，三氟乙酸(14mL)，加毕，升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂，二氯甲烷溶解，饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇＝7:1)得标题化合物12.7mg，收率9.1％。7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonic acid acyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[ 3,2-b]pyridin-5(4H)-one (216 mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL), the addition was completed, and the reaction was heated to 110° C. for 24 hours. The end of the reaction was detected by LCMS. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated for Pre-TLC purification (dichloromethane:methanol=7:1) to obtain 12.7 mg of the title compound, yield 9.1%.
分子式:C 25H 29N 5O 2S 分子量:463.6 LC-MS(M/e):464.0(M+H +) Molecular formula: C 25 H 29 N 5 O 2 S Molecular weight: 463.6 LC-MS (M/e): 464.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.08(s,1H),12.24(d,J＝8.4Hz 1H),11.87(s,1H),8.03(d,J＝5.2Hz,1H),7.50(s,1H),7.42(s,1H),7.05(d,J＝5.2Hz,1H),4.65(d,J＝3.2Hz,1H),4.31(m,1H),3.73(m,1H),3.05-3.17(m,4H),2.56-2.72(m,4H),2.51(s,3H),1.81-1.95(m,4H),1.65-1.80(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.08(s, 1H), 12.24(d, J=8.4Hz 1H), 11.87(s, 1H), 8.03(d, J=5.2Hz, 1H) ,7.50(s,1H),7.42(s,1H),7.05(d,J＝5.2Hz,1H),4.65(d,J＝3.2Hz,1H),4.31(m,1H),3.73(m, 1H), 3.05-3.17(m, 4H), 2.56-2.72(m, 4H), 2.51(s, 3H), 1.81-1.95(m, 4H), 1.65-1.80(m, 4H).
制备例12：7-(异丙基氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物15)Preparation Example 12: 7-(isopropylamino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 15)
Figure PCTCN2022080065-appb-000074
Figure PCTCN2022080065-appb-000074
1. 7-(异丙氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 7-(Isopropylamino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7 ,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5( Preparation of 4H)-ketone
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.23mmol)溶于乙腈(10mL)，加入异丙胺(54.3mg,0.92mmol)，加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物100mg。4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl trifluoromethanesulfonate (N/A, 0.23 mmol) was dissolved in acetonitrile (10 mL), isopropylamine (54.3 mg, 0.92 mmol) was added, and the reaction was completed at 40° C. for 2 hours. The end of the reaction was detected by LCMS. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 100 mg of the target compound.
2. 7-(异丙基氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-(Isopropylamino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将7-(异丙氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(100mg,0.15mmol)溶于浓盐酸(1.5mL)，三氟乙酸(10.5mL)，加毕，升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂，二氯甲烷溶解，饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇＝7:1)得标题化合物12.5mg，收率20.2％。7-(isopropylamino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7, 8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H )-ketone (100 mg, 0.15 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL) and trifluoroacetic acid (10.5 mL), the addition was completed, and the reaction was carried out at 110° C. for 24 hours. The end of the reaction was detected by LCMS. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated for Pre-TLC purification (dichloromethane:methanol=7:1) to obtain 12.5 mg of the title compound, yield 20.2%.
分子式:C 22H 25N 5OS 分子量:407.5 LC-MS(M/e):408.0(M+H +) Molecular formula: C 22 H 25 N 5 OS Molecular weight: 407.5 LC-MS (M/e): 408.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.05(s,1H),12.14(d,J＝8.0Hz 1H),11.87(s,1H),8.04(d,J＝5.2Hz,1H),7.45(s,1H),7.39(s,1H),7.05(d,J＝5.2Hz,1H),4.45-4.54(m,1H),3.04-3.14(m,4H),2.74-2.83(m,4H),2.51(s,3H),1.45(d,J＝6.0Hz,6H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.05(s, 1H), 12.14(d, J=8.0Hz 1H), 11.87(s, 1H), 8.04(d, J=5.2Hz, 1H) ,7.45(s,1H),7.39(s,1H),7.05(d,J＝5.2Hz,1H),4.45-4.54(m,1H),3.04-3.14(m,4H),2.74-2.83(m ,4H),2.51(s,3H),1.45(d,J＝6.0Hz,6H).
制备例13：4-氨基-5-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物19)Preparation Example 13: 4-Amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2- Preparation of d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 19)
Figure PCTCN2022080065-appb-000075
Figure PCTCN2022080065-appb-000075
1. N-(6-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备1. N-(6-Nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl ) Preparation of acetamide
将N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(5.5g,18.3mmol)溶于浓硫酸(50mL)中，0℃下滴加发烟硝酸(1.5g,22.0mmol)，加毕，0℃反应1.5小时。LCMS检测反应结束。倒入冰水中，二氯甲烷萃取，有机相干燥浓缩，硅胶柱层析分离(石油醚:乙酸乙酯＝2:1)得标题化合物800mg，收率12.6％。N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (5.5 g , 18.3 mmol) was dissolved in concentrated sulfuric acid (50 mL), fuming nitric acid (1.5 g, 22.0 mmol) was added dropwise at 0 °C, the addition was completed, and the reaction was carried out at 0 °C for 1.5 hours. LCMS detected the end of the reaction. It was poured into ice water, extracted with dichloromethane, the organic phase was dried and concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain 800 mg of the title compound with a yield of 12.6%.
2. 6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备2. Preparation of 6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(6-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(800mg,2.3mmol)溶于甲醇(20mL)，加入碳酸钾(960mg,6.9mmol)，加毕，55℃反应24小时。硅藻土过滤，滤液浓缩，C18柱纯化(甲醇＝0-50％)得标题化合物400mg，收率83.3％。N-(6-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl) Acetamide (800 mg, 2.3 mmol) was dissolved in methanol (20 mL), potassium carbonate (960 mg, 6.9 mmol) was added, the addition was completed, and the reaction was carried out at 55° C. for 24 hours. Filter through celite, concentrate the filtrate, and purify with C18 column (methanol=0-50%) to obtain 400 mg of the title compound with a yield of 83.3%.
3. 3-甲基-6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备3. Preparation of 3-methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(400mg,1.9mmol)溶于甲醇(10mL)中，加入甲醛(37％)(791.2mg,9.7mmol)、乙酸(114.0mg,1.9mmol)，15℃反应1小时，加入氰基硼氢化钠(601.4mg,9.7mmol)，加毕，15℃反应1小时。LCMS检测反应结束。浓缩溶剂，固体用二氯甲烷溶解，饱和氯化钠和饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:10)得标题化合物有280mg，收率65.6％。6-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (400 mg, 1.9 mmol) was dissolved in methanol (10 mL), and formaldehyde (37%) was added ) (791.2 mg, 9.7 mmol), acetic acid (114.0 mg, 1.9 mmol), react at 15° C. for 1 hour, add sodium cyanoborohydride (601.4 mg, 9.7 mmol), complete the addition, and react at 15° C. for 1 hour. LCMS detected the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane = 1:10) to obtain 280 mg of the title compound, with a yield of 65.6%.
4. 2-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备4. 2-(8-Methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepine- Preparation of 2-yl) ethyl acetate
将3-甲基-6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(280mg,1.3mmol)溶于乙醇(10mL)中，加入Pd/C(100mg)，加毕15℃下氢化反应1小时，加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(594.8mg,3.0mmol)，加毕，55℃反应1小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩，得固体用二氯甲烷溶解，饱和碳酸氢钠水溶液洗涤，分液，二氯甲烷萃取，有机相干燥浓缩硅胶柱层析分离(甲醇:二氯甲烷＝1:4)得标题化合物250mg，收率68.8％。3-Methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (280 mg, 1.3 mmol) was dissolved in ethanol (10 mL), Pd/C (100mg) was added, the hydrogenation reaction was carried out at 15°C for 1 hour, 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (594.8mg, 3.0mmol) was added, the addition was completed, and the reaction was carried out at 55°C 1 hour. The end of the reaction was detected by LCMS. The celite was filtered, the filtrate was concentrated, and the solid was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, separated, extracted with dichloromethane, and the organic phase was dried and concentrated, and separated by silica gel column chromatography (methanol:dichloromethane=1:4 ) to obtain 250 mg of the title compound with a yield of 68.8%.
5. 4-氨基-5-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备5. 4-Amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d] Preparation of azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one
将2-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.35mmol)和2-氨基-3-氰基噻吩(43.4mg,0.35mmol)溶于四氢呋喃(10mL)中，氮气保护下40℃下滴加LDA(0.7mL,1.4mmol)，加毕，40℃下反应2小时。LCMS检测反应结束。饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥浓缩得固体，固体用甲醇打浆得标题化合物16.2mg，收率12.7％。2-(8-Methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepine-2 -yl)ethyl acetate (100 mg, 0.35 mmol) and 2-amino-3-cyanothiophene (43.4 mg, 0.35 mmol) were dissolved in tetrahydrofuran (10 mL), and LDA (0.7 mL, 1.4 mmol), the addition was completed, and the reaction was carried out at 40 °C for 2 hours. LCMS detected the end of the reaction. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a solid. The solid was slurried with methanol to obtain 16.2 mg of the title compound with a yield of 12.7%.
分子式:C 19H 19N 5OS 分子量:365.5 LC-MS(M/e):366.0(M+H +) Molecular formula: C 19 H 19 N 5 OS Molecular weight: 365.5 LC-MS (M/e): 366.0 (M+H + )
1H-NMR(400MHz,MeOD)δ:7.28(d,J＝8.0Hz,1H),7.03-7.06(m,3H),3.31-3.34(m,3H),3.07-3.10(m,2H),2.20-2.35(m,4H),2.47(s,3H),2.47(s,3H). 1 H-NMR (400MHz, MeOD)δ: 7.28(d, J=8.0Hz, 1H), 7.03-7.06(m, 3H), 3.31-3.34(m, 3H), 3.07-3.10(m, 2H), 2.20-2.35(m, 4H), 2.47(s, 3H), 2.47(s, 3H).
制备例14：6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙氨基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物20的盐酸盐)Preparation Example 14: 6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 -d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 20)
Figure PCTCN2022080065-appb-000076
Figure PCTCN2022080065-appb-000076
1. 2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-(Isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6- yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zo-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.60mmol)溶于乙腈(10mL)，加入异丙胺(141.8mg,2.4mmoL)，加毕，40℃反应2小时。LCMS检测反应结束。反应液浓缩，经硅胶柱纯化(乙酸乙酯:石油醚＝1:1)得目标化合物180mg，收率40.2％。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylate tert-butyl ester (500mg, 0.60mmol) was dissolved in acetonitrile (10mL), isopropylamine (141.8mg, 2.4mmol) was added, the addition was completed, and the reaction was carried out at 40°C for 2 Hour. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate:petroleum ether=1:1) to obtain 180 mg of the target compound with a yield of 40.2%.
2. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)- Preparation of 7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(180mg,0.24mmol)溶于浓盐酸(1.0mL)和三氟乙酸(7.0mL)，110℃下反应48小时。LCMS检测反应结束。浓缩溶剂，直接用于下一步反应。2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine -7(1H)-Carboxylic acid tert-butyl ester (180 mg, 0.24 mmol) was dissolved in concentrated hydrochloric acid (1.0 mL) and trifluoroacetic acid (7.0 mL), and reacted at 110° C. for 48 hours. LCMS detected the end of the reaction. The solvent was concentrated and used directly in the next reaction.
3. 6-(7-(2-(((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 6-(7-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]Benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one preparation
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(N/A,0.51mmol)溶于甲醇(10mL)，25℃下加入2-((叔丁基二甲基甲硅烷基)氧基)乙醛(266.7mg,1.5mmol)和醋酸(30.6mg,0.51mmol))，加入氰基硼氢化钠(96.1mg,1.5mmol))，继续反应4小时。反应加入水淬灭反应，二氯甲烷(50mL)萃取，有机相浓缩硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物170.0mg，两步收率60.5％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(Isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (N/A, 0.51 mmol) was dissolved in methanol (10 mL), 2-((tert-butyl Dimethylsilyl)oxy)acetaldehyde (266.7 mg, 1.5 mmol) and acetic acid (30.6 mg, 0.51 mmol)), sodium cyanoborohydride (96.1 mg, 1.5 mmol)) was added, and the reaction was continued for 4 hours. The reaction was quenched by adding water, extracted with dichloromethane (50 mL), and the organic phase was concentrated and purified by silica gel column (methanol/dichloromethane=1:10) to obtain 170.0 mg of the target compound with a two-step yield of 60.5%.
4. 6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙氨基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备4. 6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one hydrochloride
将6-(7-(2-(((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(160.0mg,0.29mmol)溶于四氢呋喃(4mL)和浓盐酸(4mL)中，反应1小时。反应完毕后，过滤，收集滤饼，乙酸乙酯和二氯甲烷洗涤，得目标化合物19.4mg，收率15.3％。6-(7-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5 ':4,5]Benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one ( 160.0 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL) and concentrated hydrochloric acid (4 mL), and reacted for 1 hour. After the reaction was completed, filter, collect the filter cake, and wash with ethyl acetate and dichloromethane to obtain 19.4 mg of the target compound. rate 15.3%.
分子式:C 23H 27N 5O 2S 分子量:437.6 LC-MS(M/e):438.2(M+H +) Molecular formula: C 23 H 27 N 5 O 2 S Molecular weight: 437.6 LC-MS (M/e): 438.2 (M+H + )
1H-NMR(400MHz,MeOD)8.01(d,J＝5.6Hz,1H),7.63(s,2H),7.09(d,J＝5.6Hz,1H),4.33-4.27(m,1H),3.96-3.86(m,4H),3.53-3.47(m,2H),3.40-3.36(m,5H),3.29-3.17(m,2H),1.35(s,6H). 1 H-NMR (400MHz, MeOD) 8.01(d, J=5.6Hz, 1H), 7.63(s, 2H), 7.09(d, J=5.6Hz, 1H), 4.33-4.27(m, 1H), 3.96 -3.86(m,4H),3.53-3.47(m,2H),3.40-3.36(m,5H),3.29-3.17(m,2H),1.35(s,6H).
制备例15：7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物21-1)Preparation Example 15: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8, 9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H)- Preparation of ketone (compound 21-1)
Figure PCTCN2022080065-appb-000077
Figure PCTCN2022080065-appb-000077
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(80mg,0.18mmol)，溶于甲醇(10mL)中，加入3-氧杂环丁酮(38.5mg,0.54mmol)\乙酸(10.8mg,0.18mmol)，20℃反应30分钟，加入氰基硼氢化钠(33.5mg,0.54mmol)，加毕，20℃反应17小时。LCMS检测反应结束。浓缩溶剂，固体用二氯甲烷溶解，饱和氯化钠和饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:15)得目标化合物13.6mg，收率15.1％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one (80 mg, 0.18 mmol), dissolved in methanol (10 mL), added 3-oxetanone (38.5mg, 0.54mmol)\acetic acid (10.8mg, 0.18mmol), react at 20°C for 30 minutes, add sodium cyanoborohydride (33.5mg, 0.54mmol), complete the addition, react at 20°C 17 hours. LCMS detected the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane =1:15) to obtain 13.6 mg of the target compound with a yield of 15.1%.
分子式:C 27H 31N 5O 3S 分子量:505.6 LC-MS(M/e):506.0(M+H +) Molecular formula: C 27 H 31 N 5 O 3 S Molecular weight: 505.6 LC-MS (M/e): 506.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.97(s,1H),12.24(d,J＝4.0Hz,1H),11.80(s,1H),7.98(d,J＝5.2Hz,1H),7.39(s,1H),7.30(s,1H),7.01(d,J＝5.6Hz,1H),4.60(s,1H),4.45-4.52(m,4H),4.20-4.30(m,1H),3.65-3.72(m,1H),3.45-3.48(m,1H),3.14-3.29(m,4H),2.90-3.01(m,4H),1.65-1.86(m,8H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.97(s, 1H), 12.24(d, J=4.0Hz, 1H), 11.80(s, 1H), 7.98(d, J=5.2Hz, 1H) ), 7.39(s, 1H), 7.30(s, 1H), 7.01(d, J=5.6Hz, 1H), 4.60(s, 1H), 4.45-4.52(m, 4H), 4.20-4.30(m, 1H), 3.65-3.72(m, 1H), 3.45-3.48(m, 1H), 3.14-3.29(m, 4H), 2.90-3.01(m, 4H), 1.65-1.86(m, 8H).
制备例16：7-(((1s,3s)-3-羟基环丁基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备(化合物22-1)Preparation Example 16: 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8 ,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H) Preparation of -1-one (Compound 22-1)
Figure PCTCN2022080065-appb-000078
Figure PCTCN2022080065-appb-000078
1. 2-(7-(((1s,3s)-3-羟基环丁基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-(((1s,3s)-3-hydroxycyclobutyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno [3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5] Preparation of Benzo[1,2-d]azepine-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡 啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.6mmol)溶于乙腈(10mL)中，加入顺式-3-氨基环丁醇盐酸盐(295.7mg,2.4mmol)，加毕，40℃反应2小时。LCMS检测反应结束。浓缩溶剂，经硅胶柱层析分离(甲醇:二氯甲烷＝1:20)得目标化合物400mg，收率86.6％。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylate tert-butyl ester (500mg, 0.6mmol) was dissolved in acetonitrile (10mL), cis-3-aminocyclobutanol hydrochloride (295.7mg, 2.4 mmol), the addition was completed, and the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. The solvent was concentrated and separated by silica gel column chromatography (methanol:dichloromethane=1:20) to obtain 400 mg of the target compound with a yield of 86.6%.
2. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)- Preparation of 7-(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(((1s,3s)-3-羟基环丁基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(400mg,0.52mmol)溶于浓盐酸(2mL)和三氟乙酸(14mL)中，110℃反应20小时。浓缩溶剂，固体用二氯甲烷溶解，饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，C18柱层析分离(甲醇＝0-60％)得目标化合物150mg，收率68.8％。2-(7-(((1s,3s)-3-hydroxycyclobutyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[ 3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzene And [1,2-d]azepine-7(1H)-carboxylate tert-butyl ester (400 mg, 0.52 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL), and reacted at 110° C. for 20 hours. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by C18 column chromatography (methanol=0-60%) to obtain the target compound 150mg, yield 68.8%.
3. 7-(((1s,3s)-3-羟基环丁基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备3. 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9 - Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H)-1 - Preparation of ketones
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.36mmol)溶于甲醇(15mL)中，加入3-氧杂环丁酮(77.1mg,1.1mmol)、乙酸(21.6mg,0.36mmol)，20℃反应30分钟，加入氰基硼氢化钠(68.2mg,1.1mmol)，加毕，20℃反应17小时。LCMS检测反应结束。浓缩溶剂，固体用二氯甲烷溶解，饱和氯化钠和饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:15)得目标化合物16.9mg，收率9.9％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one (150 mg, 0.36 mmol) was dissolved in methanol (15 mL) and added 3-oxetanone (77.1 mg, 1.1 mmol), acetic acid (21.6 mg, 0.36 mmol), react at 20 °C for 30 minutes, add sodium cyanoborohydride (68.2 mg, 1.1 mmol), complete the addition, and react at 20 °C 17 hours. LCMS detected the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane =1:15) to obtain 16.9 mg of the target compound with a yield of 9.9%.
分子式:C 25H 27N 5O 3S 分子量:477.6 LC-MS(M/e):478.0(M+H +) Molecular formula: C 25 H 27 N 5 O 3 S Molecular weight: 477.6 LC-MS (M/e): 478.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.93(s,1H),12.26(d,J＝6.8Hz,1H),11.83(s,1H),8.01(d,J＝5.2Hz,1H),7.39(s,1H),7.35(s,1H),7.01(d,J＝5.6Hz,1H),4.60(s,1H),4.43-4.53(m,4H),4.19-4.21(m,1H),3.96-4.06(m,1H),3.45-3.48(m,1H),2.91-3.15(m,8H),2.33(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.93(s, 1H), 12.26(d, J=6.8Hz, 1H), 11.83(s, 1H), 8.01(d, J=5.2Hz, 1H) ), 7.39(s, 1H), 7.35(s, 1H), 7.01(d, J=5.6Hz, 1H), 4.60(s, 1H), 4.43-4.53(m, 4H), 4.19-4.21(m, 1H), 3.96-4.06(m, 1H), 3.45-3.48(m, 1H), 2.91-3.15(m, 8H), 2.33(m, 4H).
制备例17：6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物23-1)Preparation Example 17: 6-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one (Compound 23- 1)
Figure PCTCN2022080065-appb-000079
Figure PCTCN2022080065-appb-000079
1. 2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备1. 2-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Preparation of heterozo-2-yl)ethyl acetate
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(1.7g5.5mmol)、三乙胺(3.9g,38.5mmol)和环丙酰氯(600mg,5.7mmol)溶于40mL二氯甲烷中，在0℃下反应1.5小时。反应结束后，浓缩，经硅胶柱纯化(甲醇:二氯甲烷＝10％)得目标化合物1.5g，收率：71.8％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester hydrochloride (1.7 g, 5.5 mmol), triethylamine (3.9 g, 38.5 mmol) and cyclopropionyl chloride (600 mg, 5.7 mmol) were dissolved in 40 mL of dichloromethane and reacted at 0°C for 1.5 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column (methanol:dichloromethane=10%) to obtain 1.5 g of the target compound, yield: 71.8%.
2. (E)-2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-羟基-3-(3-((4-甲氧基苄基)氨基)噻吩-2-基)丙酸乙酯的制备2. (E)-2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- d] Preparation of ethyl azepin-2-yl)-3-hydroxy-3-(3-((4-methoxybenzyl)amino)thiophen-2-yl)propanoate
将2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(850mg,2.5mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(790mg,2.7mmol)溶于四氢呋喃(10mL)，40℃下加入LDA(5.0mL,10.0mmol)，并反应2小时。反应结束后，加入饱和氯化铵水溶液淬灭，二氯甲烷萃取，浓缩有机相，粗品直接用于下一步。2-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Ethyl zo-2-yl)acetate (850 mg, 2.5 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4 (1H)-dione (790 mg, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL), LDA (5.0 mL, 10.0 mmol) was added at 40° C., and reacted for 2 hours. After the reaction, saturated aqueous ammonium chloride solution was added to quench, extracted with dichloromethane, the organic phase was concentrated, and the crude product was directly used in the next step.
3. 6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 6-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one
将上步粗品溶于15mL四氢呋喃中，在40℃下滴加LDA(5.0mL)，并反应1.5h结束，结束后加入饱和氯化铵水溶液淬灭，二氯甲烷萃取，浓缩有机相，得目标化合物粗品650mg。The crude product of the previous step was dissolved in 15 mL of tetrahydrofuran, and LDA (5.0 mL) was added dropwise at 40 °C, and the reaction was completed for 1.5 h. After the completion of the reaction, saturated aqueous ammonium chloride was added to quench, extracted with dichloromethane, and the organic phase was concentrated to obtain the target. Crude compound 650mg.
4. 6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯的制备4. 6-(7-(Cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4, 5]Benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b Preparation of ]pyridin-7-yl trifluoromethanesulfonate
将6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(600mg,1.1mmol)溶于二氯甲烷(15mL)，降温至-15℃，加入吡啶(1.8g,22.8mmol)和三氟甲磺酸酐(3.0g,10.6mmol)，并反应1.0小时结束，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，有机相经干燥浓缩得目标化 合物粗品，直接用于下一步反应。6-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine -2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (600 mg, 1.1 mmol) was dissolved in dichloromethane ( 15 mL), cooled to -15 ° C, added pyridine (1.8 g, 22.8 mmol) and trifluoromethanesulfonic anhydride (3.0 g, 10.6 mmol), and the reaction was completed for 1.0 hour, added saturated sodium bicarbonate solution to quench the reaction, dichloromethane Methane extraction, the organic phase was dried and concentrated to obtain the crude product of the target compound, which was directly used in the next reaction.
5. 6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮制备5. 6-(7-(cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4, 5]Benzo[1,2-d]azepin-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl) Preparation of Thieno[3,2-b]pyridin-5(4H)-one
将上步粗品溶于10mL乙腈中，加入(1s,4s)-4-氨基环己-1-醇(160mg 1.4mmol)，加毕，50℃反应1小时。硅藻土过滤，滤液干燥、浓缩、经柱层析(甲醇:二氯甲烷＝10％)得目标化合物300mg，两步收率为35.1％。The crude product from the previous step was dissolved in 10 mL of acetonitrile, and (1s, 4s)-4-aminocyclohexan-1-ol (160 mg 1.4 mmol) was added, and the reaction was carried out at 50 °C for 1 hour after the addition was completed. Celite was filtered, the filtrate was dried, concentrated, and subjected to column chromatography (methanol:dichloromethane=10%) to obtain 300 mg of the target compound with a yield of 35.1% in two steps.
6.(1s,4s)-4-((6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基)氨基)环己基-2,2,2-三氟乙酸酯的制备6. (1s,4s)-4-((6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzene and [1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl)amino)cyclohexyl-2, Preparation of 2,2-trifluoroacetate
将6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(300mg,0.39mmol)溶于三氟乙酸(3mL)和浓盐酸1mL中，在115℃下反应22h后，浓缩，直接进行下一步反应。6-(7-(Cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5 ]Benzo[1,2-d]azepin-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)thiophene and [3,2-b]pyridin-5(4H)-one (300 mg, 0.39 mmol) was dissolved in trifluoroacetic acid (3 mL) and concentrated hydrochloric acid 1 mL, reacted at 115 °C for 22 h, concentrated, and proceeded directly to the next step reaction.
7. 6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备7. 6-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zoro-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one
将上步粗品溶于甲醇10mL中，加入碳酸钾150mg，在25℃下反应1h。反应结束后，浓缩溶剂，经柱层析得目标产物16mg，两步收率为7.9％。The crude product from the previous step was dissolved in 10 mL of methanol, 150 mg of potassium carbonate was added, and the reaction was carried out at 25° C. for 1 h. After the reaction was completed, the solvent was concentrated, and 16 mg of the target product was obtained by column chromatography, with a two-step yield of 7.9%.
分子式:C 28H 31N 5O 3S 分子量:517.6 LC-MS(M/e):518.0(M+H +) Molecular formula: C 28 H 31 N 5 O 3 S Molecular weight: 517.6 LC-MS (M/e): 518.0 (M+H + )
1H-NMR(400MHz,CDCl 3)δ:12.99(s,1H),12.22(s,1H),11.92-11.82(m,1H),8.0(s,1H),7.51-7.41(m,2H),7.01(s,1H),4.61(s,1H),4.41-4.31(m,1H),3.81(s,2H),3.80(s,1H),3.71-3.61(m,2H),3.08-2.96(m,2H),2.91-2.86(m,2H),2.01(s,1H),1.91-1.61(m,8H),0.88-0.71(m,4H). 1 H-NMR (400MHz, CDCl 3 )δ: 12.99(s, 1H), 12.22(s, 1H), 11.92-11.82(m, 1H), 8.0(s, 1H), 7.51-7.41(m, 2H) ,7.01(s,1H),4.61(s,1H),4.41-4.31(m,1H),3.81(s,2H),3.80(s,1H),3.71-3.61(m,2H),3.08-2.96 (m,2H),2.91-2.86(m,2H),2.01(s,1H),1.91-1.61(m,8H),0.88-0.71(m,4H).
制备例18：7-氨基-6-(7-(3-羟基环丁基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物24的溴酸盐)Preparation Example 18: 7-amino-6-(7-(3-hydroxycyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzene Preparation of [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (bromate salt of compound 24)
Figure PCTCN2022080065-appb-000080
Figure PCTCN2022080065-appb-000080
1. 2-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯)的制备1. 2-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)ethyl acetate)
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(230mg,0.74mmol)、3-(苄氧基)环丁-1-酮(196mg,1.11mmol)、乙酸(44mg,0.74mmol)溶于二氯甲烷(10mL)中，0℃下加入醋酸硼氢化钠(314mg，1.48mmol)，25℃下反应8h， LCMS检测反应完成。反应液倒入饱和氢氧化钠水溶液(50mL)中，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:10)得目标化合物260mg，收率81.0％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester hydrochloride (230 mg, 0.74 mmol), 3-(benzyloxy)cyclobutan-1-one (196 mg, 1.11 mmol), acetic acid (44 mg, 0.74 mmol) were dissolved in dichloromethane (10 mL), 0°C Sodium borohydride acetate (314 mg, 1.48 mmol) was added and reacted at 25° C. for 8 h, and the reaction was completed by LCMS. The reaction solution was poured into saturated aqueous sodium hydroxide solution (50 mL), extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane=1:10) to obtain the target compound 260 mg, yield 81.0%.
2. 7-氨基-6-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-Amino-6-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5] Preparation of Benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(150mg,0.35mmol)和3-氨基噻吩-2-腈(43mg,0.35mmol)溶于四氢呋喃(5mL)中，40℃下滴加LDA(1.05mL,2.1mmol),继续反应4h，LCMS检测反应完成，反应液倒入饱和氯化铵水溶液中淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:10)得目标化合物100mg，收率55.8％。2-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)ethyl acetate (150 mg, 0.35 mmol) and 3-aminothiophene-2-carbonitrile (43 mg, 0.35 mmol) were dissolved in tetrahydrofuran (5 mL) and added dropwise at 40°C LDA (1.05mL, 2.1mmol), continued to react for 4h, LCMS detected the completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution to quench, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and a silica gel column Chromatographic separation (methanol:dichloromethane=1:10) gave 100 mg of the target compound with a yield of 55.8%.
3. 7-氨基-6-(7-(3-羟基环丁基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮溴酸盐的制备3. 7-Amino-6-(7-(3-hydroxycyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one bromate
将7-氨基-6-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(50mg,0.10mmol)溶于二氯甲烷(5mL)中，-40℃下滴加三溴化硼(100mg,0.40mmol)，25℃下反应1h，LCMS检测反应完成。加入甲醇淬灭，溶剂旋干，粗品经甲醇打浆得目标化合物19mg，收率37.8％。7-amino-6-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzene [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (50 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), - Boron tribromide (100 mg, 0.40 mmol) was added dropwise at 40°C, the reaction was carried out at 25°C for 1 h, and the reaction was completed by LCMS. Methanol was added to quench, the solvent was spin-dried, and the crude product was slurried with methanol to obtain 19 mg of the target compound with a yield of 37.8%.
分子式:C 22H 24BrN 5O 2S 分子量:502.4 LC-MS(M/e):422.0(M+H +) Molecular formula: C 22 H 24 BrN 5 O 2 S Molecular weight: 502.4 LC-MS (M/e): 422.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:11.81(s,1H),9.71(s,1H),7.95(d,J＝5.2Hz,1H),7.51(s,2H),6.99(d,J＝5.2Hz,1H),3.82-3.92(m,1H),3.52-3.62(m,2H),3.18-3.32(m,3H),3.02-3.17(m,2H),2.75-2.90(m,2H),2.58-2.62(m,2H),2.02-2.18(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 11.81(s, 1H), 9.71(s, 1H), 7.95(d, J=5.2Hz, 1H), 7.51(s, 2H), 6.99(d , J=5.2Hz, 1H), 3.82-3.92(m, 1H), 3.52-3.62(m, 2H), 3.18-3.32(m, 3H), 3.02-3.17(m, 2H), 2.75-2.90(m ,2H),2.58-2.62(m,2H),2.02-2.18(m,2H).
制备例19：7-氨基-6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-吡啶-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备(化合物25的盐酸盐)Preparation Example 19: 7-Amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 25)
Figure PCTCN2022080065-appb-000081
Figure PCTCN2022080065-appb-000081
1. 2-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备1. 2-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)ethyl-1,5,6,7,8,9-hexahydroimidazo[4' Preparation of ethyl acetate ,5':4,5]benzo[1,2-d]azepin-2-yl)acetate
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(240mg,0.88mmol)溶于甲醇(10mL)，20℃下加入2-((叔丁基二甲基甲硅烷基)氧基)乙醛(352mg,2.0mmol)和醋酸(560mg,9.3mmol))，20℃下反应5分钟后，加入氰基硼氢化钠(352mg,6.4mmol)，加毕20℃反应6小时。反应完毕后，旋干溶剂，加入饱和碳酸氢钠水溶液(20mL)淬灭反应，乙酸乙酯(50mL)萃取，有机相浓缩，经硅胶柱纯化(甲醇/二氯甲烷＝1:20)得目 标化合物250mg，收率65.8％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate The ester (240 mg, 0.88 mmol) was dissolved in methanol (10 mL), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (352 mg, 2.0 mmol) and acetic acid (560 mg, 9.3 mmol) were added at 20°C )), after 5 minutes of reaction at 20°C, sodium cyanoborohydride (352 mg, 6.4 mmol) was added, and the reaction was completed at 20°C for 6 hours. After the reaction was completed, the solvent was spin-dried, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL), the organic phase was concentrated, and purified by silica gel column (methanol/dichloromethane=1:20) to obtain the target Compound 250 mg, yield 65.8%.
2. 7-氨基-6-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-Amino-6-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4 Preparation of ',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(250mg,0.58mmol)与3-氨基噻吩-2-腈(71mg,0.57mmol)溶于无水四氢呋喃(5mL)，40℃下加入LDA(1.2ml，2.3mmol)。反应结束后，0℃下加入饱和氯化铵水溶液淬灭反应，有机相干燥，浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物80mg，收率：27.0％。2-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)ethyl-1,5,6,7,8,9-hexahydroimidazo[4', Ethyl 5':4,5]benzo[1,2-d]azepin-2-yl)acetate (250 mg, 0.58 mmol) and 3-aminothiophene-2-carbonitrile (71 mg, 0.57 mmol) were dissolved in Anhydrous tetrahydrofuran (5 mL) was added LDA (1.2 mL, 2.3 mmol) at 40°C. After the reaction, saturated aqueous ammonium chloride solution was added at 0°C to quench the reaction, the organic phase was dried, concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 80 mg of the title compound, yield: 27.0%.
3. 7-氨基-6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-吡啶-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备3. 7-Amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride
将7-氨基-6-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(50mg,0.1mmol)溶于1ml四氢呋喃和1ml浓盐酸中，反应0.5小时。反应完毕后，过滤收集滤饼，乙酸乙酯和二氯甲烷洗涤，得目标化合物12.4mg，收率26.4％。7-amino-6-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4 ',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (50 mg, 0.1 mmol) in solution In 1 ml of tetrahydrofuran and 1 ml of concentrated hydrochloric acid, the reaction was carried out for 0.5 hours. After the reaction was completed, the filter cake was collected by filtration, washed with ethyl acetate and dichloromethane to obtain 12.4 mg of the target compound with a yield of 26.4%.
分子式:C 20H 22ClN 5O 2S 分子量:431.9 LC-MS(M/e):396.5(M+H +) Molecular formula: C 20 H 22 ClN 5 O 2 S Molecular weight: 431.9 LC-MS (M/e): 396.5 (M+H + )
1H-NMR(400MHz,MeOD)δ:7.98-7.96(m,1H),7.65(s,2H),7.09-7.08(m,1H),3.97-3.90(m,4H),3.55-3.48(m,2H),3.40-3.30(m,4H),3.24-3.18(m,2H). 1 H-NMR (400MHz, MeOD)δ: 7.98-7.96(m, 1H), 7.65(s, 2H), 7.09-7.08(m, 1H), 3.97-3.90(m, 4H), 3.55-3.48(m ,2H),3.40-3.30(m,4H),3.24-3.18(m,2H).
制备例20：7-氨基-6-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物26)Preparation Example 20: 7-amino-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5] Preparation of Benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 26)
Figure PCTCN2022080065-appb-000082
Figure PCTCN2022080065-appb-000082
1. 2-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-乙酸乙酯的制备1. 2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepin-2-yl)-ethyl acetate
将2-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(309.1mg,1.0mmol)溶于甲醇(30mL)中，加入3-氧杂环丁酮(216.3mg,3.0mmol)，乙酸(60.0mg,1.0mmol)，20℃反应30分钟，加入氰基硼氢化钠(186.0mg,3.0mmol)，加毕，20℃反应17小时。LCMS检测反应结束。浓缩溶剂，固体用二氯甲烷溶解，饱和氯化钠和饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1：15)得标题化合物200mg，收率60.8％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester hydrochloride (309.1 mg, 1.0 mmol) was dissolved in methanol (30 mL), 3-oxetanone (216.3 mg, 3.0 mmol), acetic acid (60.0 mg, 1.0 mmol) were added, and the reaction was carried out at 20°C for 30 minutes, Sodium cyanoborohydride (186.0 mg, 3.0 mmol) was added, the addition was completed, and the reaction was carried out at 20° C. for 17 hours. LCMS detected the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane =1:15) to obtain 200 mg of the title compound with a yield of 60.8%.
2. 7-氨基-6-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-Amino-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将6-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.36mmol)溶于甲醇(15mL)中，加入3-氧杂环丁酮(77.1mg,1.1mmol)、乙酸(21.6mg,0.36mmol)，20℃反应30分钟，加入氰基硼氢化 钠(68.2mg,1.1mmol)，加毕，20℃反应17小时。LCMS检测反应结束。浓缩溶剂，固体用二氯甲烷溶解，饱和氯化钠和饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，硅胶柱层析分离(甲醇:二氯甲烷＝1:15)得目标化合物16.9mg，收率9.1％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one (150 mg, 0.36 mmol) was dissolved in methanol (15 mL) and added 3-oxetanone (77.1 mg, 1.1 mmol), acetic acid (21.6 mg, 0.36 mmol), react at 20 °C for 30 minutes, add sodium cyanoborohydride (68.2 mg, 1.1 mmol), complete the addition, and react at 20 °C 17 hours. LCMS detected the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane =1:15) to obtain 16.9 mg of the target compound with a yield of 9.1%.
分子式:C 21H 21N 5O 2S 分子量:407.5 LC-MS(M/e):408.1(M+H +) Molecular formula: C 21 H 21 N 5 O 2 S Molecular weight: 407.5 LC-MS (M/e): 408.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.74(s,1H),11.76(s,1H),10.54-10.62(m,1H),7.91(d,J＝5.2Hz,1H),7.72-7.91(m,1H),7.38(s,1H),7.33(s,1H),6.98(d,J＝5.2Hz,1H),4.44-4.53(m,4H),3.44-3.50(m,1H),2.88-2.95(m,4H),2.25-2.40(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.74(s, 1H), 11.76(s, 1H), 10.54-10.62(m, 1H), 7.91(d, J=5.2Hz, 1H), 7.72 -7.91(m, 1H), 7.38(s, 1H), 7.33(s, 1H), 6.98(d, J=5.2Hz, 1H), 4.44-4.53(m, 4H), 3.44-3.50(m, 1H) ),2.88-2.95(m,4H),2.25-2.40(m,4H).
制备例21：7-(((1s,4s)-4-羟基环己基)氨基)-3-甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物27-1的盐酸盐)Preparation Example 21: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-3-methyl-6-(7-methyl-1-(1,5,6,7,8,9 - Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one Hydrochloride (hydrochloride of compound 27-1)
Figure PCTCN2022080065-appb-000083
Figure PCTCN2022080065-appb-000083
1. 3-氨基-4-甲基噻吩-2-羧酸的制备1. Preparation of 3-amino-4-methylthiophene-2-carboxylic acid
将3-氨基-4-甲基噻吩-2-羧酸甲酯(1.71g,10mmol)和氢氧化钾(1.12g,20mmol)溶于水(20mL)中，90℃下反应1小时。反应液直接用于下一步。Methyl 3-amino-4-methylthiophene-2-carboxylate (1.71 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol) were dissolved in water (20 mL) and reacted at 90° C. for 1 hour. The reaction solution was directly used in the next step.
2. 7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮的制备2. Preparation of 7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione
将3-氨基-4-甲基噻吩-2-羧酸(上步反应液)降温至0℃，加入氯甲酸三氯甲酯(2.37g,12mol)，加毕，20℃下反应2小时。抽滤，收集固体旋干得标题化合物1.6g，收率87.3％。The 3-amino-4-methylthiophene-2-carboxylic acid (reaction solution in the previous step) was cooled to 0 °C, trichloromethyl chloroformate (2.37 g, 12 mol) was added, and the reaction was carried out at 20 °C for 2 hours. After suction filtration, the collected solid was spin-dried to obtain 1.6 g of the title compound with a yield of 87.3%.
3. 1-(4-甲氧基苄基)-7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4-(1H)-二酮的制备3. Preparation of 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4-(1H)-dione
将7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(1.6g,8.7mmol)、1-(氯甲基)-4-甲氧基苯(1.65g,10.5mmol)、碳酸钾(1.45g,10.5mmol)和碘化钾(282mg,1.7mmol)溶于N,N-二甲基甲酰胺(23mL)，20℃下反应16小时。将反应液倒入水(100mL)中，抽滤，收集固体，旋干，硅胶柱纯化(二氯甲烷)得目标化合物1.5g，收率64.7％。7-Methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (1.6 g, 8.7 mmol), 1-(chloromethyl)- 4-Methoxybenzene (1.65g, 10.5mmol), potassium carbonate (1.45g, 10.5mmol) and potassium iodide (282mg, 1.7mmol) were dissolved in N,N-dimethylformamide (23mL) and reacted at 20°C 16 hours. The reaction solution was poured into water (100 mL), suction filtered, the solid was collected, spin-dried, and purified by silica gel column (dichloromethane) to obtain 1.5 g of the target compound with a yield of 64.7%.
4. 3-(3-(((4-甲氧基苄基)氨基)-4-甲基噻吩-2-基)-2-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-氧代丙酸乙酯的制备4. 3-(3-(((4-methoxybenzyl)amino)-4-methylthiophen-2-yl)-2-(7-methyl-1,5,6,7,8, Preparation of 9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-3-oxopropionic acid ethyl ester
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(475mg,1.65mmol)和1-(4-甲氧基苄基)-7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(500mg,1.65mmol)溶于四氢呋喃(20mL)。氮气保护下，40℃下加入LDA(3.3mL,6.6mmol)，加毕，40℃下反应4小时。0℃下饱和氯化铵水溶液淬灭反应，有机相干燥，浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物480mg，收率53.3％。2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine-2 -yl)ethyl acetate (475 mg, 1.65 mmol) and 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2 , 4(1H)-dione (500 mg, 1.65 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, LDA (3.3 mL, 6.6 mmol) was added at 40° C., the addition was completed, and the reaction was carried out at 40° C. for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride solution at 0°C, the organic phase was dried, concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 480 mg of the title compound with a yield of 53.3%.
5. 7-羟基-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备5. 7-Hydroxy-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4' Preparation of ,5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将3-(3-(((4-甲氧基苄基)氨基)-4-甲基噻吩-2-基)-2-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-氧代丙酸乙酯(480mg,0.88mmol)溶于四氢呋喃(8mL)，氮气保护下，40℃下加入LDA(1.76mL,3.52mol)，加毕，40℃下反应2小时。用饱和氯化铵水溶液(8mL)淬灭反应，有机相浓缩，硅胶柱纯化(二氯甲烷:甲醇＝4:1)得标题化合物390mg，收率88.7％。3-(3-(((4-methoxybenzyl)amino)-4-methylthiophen-2-yl)-2-(7-methyl-1,5,6,7,8,9 - Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-3-oxopropionic acid ethyl ester (480 mg, 0.88 mmol) was dissolved in Tetrahydrofuran (8 mL), under nitrogen protection, LDA (1.76 mL, 3.52 mol) was added at 40 ° C, the addition was completed, and the reaction was carried out at 40 ° C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (8 mL), the organic phase was concentrated, silica gel Column purification (dichloromethane:methanol=4:1) afforded 390 mg of the title compound in a yield of 88.7%.
6. 4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯的制备6. 4-(4-Methoxybenzyl)-3-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8, 9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3, Preparation of 2-b]pyridin-7-yl trifluoromethanesulfonate
将7-羟基-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(390mg,0.78mmol)溶于二氯甲烷(8mL)，0℃下加入吡啶(1232mg,15.6mmol)，三氟甲磺酸酐(1318mg,4.68mmol)，加毕，0℃下反应1小时。饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相干燥浓缩直接用于下一步。7-Hydroxy-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4', 5':4,5]Benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (390 mg, 0.78 mmol) was dissolved in Chloromethane (8 mL) was added at 0°C with pyridine (1232 mg, 15.6 mmol) and trifluoromethanesulfonic anhydride (1318 mg, 4.68 mmol), the addition was completed, and the reaction was carried out at 0°C for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated and used directly in the next step.
7. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-(((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备7. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-(( (trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)thieno[3,2-b]pyridin-5(4H)-one
将4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.39mmol)溶于乙腈(5mL)，加入(1s,4s)-4-氨基环己-1-醇(179mg,1.56mmol)，加毕40℃反应2小时。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物180mg，两步收率63.3％。4-(4-Methoxybenzyl)-3-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9 - Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2 -b] Pyridin-7-yl trifluoromethanesulfonate (N/A, 0.39 mmol) was dissolved in acetonitrile (5 mL), and (1s, 4s)-4-aminocyclohexan-1-ol (179 mg, 1.56 mmol) was added ), and the reaction was completed at 40°C for 2 hours. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 180 mg of the target compound with a two-step yield of 63.3%.
8. 7-(((1s,4s)-4-羟基环己基)氨基)-3-甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备8. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-3-methyl-6-(7-methyl-1-(1,5,6,7,8,9-hexa) Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride Preparation of salt
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-(((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.25mmol)溶于浓盐酸(1mL)与三氟乙酸(7mL)，加毕升至110℃反应24小时。浓缩溶剂，加入二氯甲烷(20mL)溶解，加入NaOH(1N,20mL)溶液搅拌0.2小时， 有机相浓缩，经中压反相制备(0-50％甲醇/水(0.5％浓盐酸))得标题化合物70mg，收率59.4％。7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-(((( Trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 -yl)thieno[3,2-b]pyridin-5(4H)-one (180 mg, 0.25 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL), and the reaction was carried out at 110 °C for 24 hours after the addition was completed. 。 Concentrate the solvent, add dichloromethane (20 mL) to dissolve, add NaOH (1N, 20 mL) solution and stir for 0.2 hours, the organic phase is concentrated, prepared by medium pressure reverse phase (0-50% methanol/water (0.5% concentrated hydrochloric acid)) The title compound was obtained in 70 mg with a yield of 59.4%.
分子式:C 26H 32ClN 5O 2S 分子量:514.1 LC-MS(M/e):478.0(M+H +) Molecular formula: C 26 H 32 ClN 5 O 2 S Molecular weight: 514.1 LC-MS (M/e): 478.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.08(s,1H),12.08(s,1H),11.47(s,1H),10.39(s,1H),7.66(s,1H),7.47(s,2H),4.28-4.26(m,1H),3.75-3.65(m,2H),3.40-3.25(m,4H),3.10-2.90(m,4H),2.81(s,3H),2.28(s,3H),1.91-1.75(m,4H),1.75-1.60(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.08(s, 1H), 12.08(s, 1H), 11.47(s, 1H), 10.39(s, 1H), 7.66(s, 1H), 7.47 (s,2H),4.28-4.26(m,1H),3.75-3.65(m,2H),3.40-3.25(m,4H),3.10-2.90(m,4H),2.81(s,3H),2.28 (s,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).
制备例22：7-(((1S,4S)-4-羟基环己基)氨基)-2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物28-1)Preparation Example 22: 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydro Imidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 28 -1)
Figure PCTCN2022080065-appb-000084
Figure PCTCN2022080065-appb-000084
1. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-2-methyl-6-(7-methyl-1-(( Trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[3,2-b]pyridin-5(4H)-one
选用3-氨基-5-甲基噻吩-2-羧酸甲酯作为起始原料，参照制备例21的方法制备得到7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮。Using methyl 3-amino-5-methylthiophene-2-carboxylate as the starting material, 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4 was prepared with reference to the method of Preparation Example 21. -(4-Methoxybenzyl)-2-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexa Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one.
2.(1s,4s)-4-((2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基)氨基)环己基2,2,2-三氟乙酸盐的制备2. (1s,4s)-4-((2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5] ]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl)amino)cyclohexyl2 Preparation of ,2,2-trifluoroacetate
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.21mmol)溶于浓盐酸(1mL)与三氟乙酸(4mL)，加毕升至115℃反应5.0小时。浓缩溶剂，直接用于下一步反应。7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-2-methyl-6-(7-methyl-1-((tri Fluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2- yl)thieno[3,2-b]pyridin-5(4H)-one (150 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (4 mL), and the mixture was heated to 115 °C for 5.0 hours. The solvent was concentrated and used directly in the next reaction.
3. 7-(((1S,4S)-4-羟基环己基)氨基)-2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo Preparation of [4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将上步粗品溶于5mL甲醇中，加入碳酸钾(300mg,2.2mmol),在25℃反应1小时后浓缩溶剂，经柱层析(二氯甲烷:甲醇＝10:1)得目标化合物15mg，两步收率为15.3％。The crude product of the previous step was dissolved in 5 mL of methanol, potassium carbonate (300 mg, 2.2 mmol) was added, the solvent was concentrated after reacting at 25 ° C for 1 hour, and 15 mg of the target compound was obtained by column chromatography (dichloromethane: methanol = 10: 1), The two-step yield was 15.3%.
分子式:C 26H 31N 5O 2S 分子量:477.6 LC-MS(M/e):478.0(M+H +) Molecular formula: C 26 H 31 N 5 O 2 S Molecular weight: 477.6 LC-MS (M/e): 478.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.00(s,1H),12.13(s,1H),11.74(s,1H),10.39(s,1H),7.42(s,1H),7.33(s,1H),6.77(s,1H),4.62-4.4.58(s,1H),4.28-4.21(m,1H)3.75-3.65(m,1H),3.10-3.25(m,8H),2.48(m,3H),1.91-1.75(m,4H),1.75-1.60(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.00(s, 1H), 12.13(s, 1H), 11.74(s, 1H), 10.39(s, 1H), 7.42(s, 1H), 7.33 (s,1H),6.77(s,1H),4.62-4.4.58(s,1H),4.28-4.21(m,1H)3.75-3.65(m,1H),3.10-3.25(m,8H), 2.48(m,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).
制备例23：7-(((1s,4s)-4-羟基环己基)氨基)-2,3-二甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物29-1的盐酸盐)Preparation Example 23: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-2,3-dimethyl-6-(7-methyl-1-(1,5,6,7, 8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H )-keto hydrochloride (hydrochloride of compound 29-1)
Figure PCTCN2022080065-appb-000085
Figure PCTCN2022080065-appb-000085
选用3-氨基-4,5-二甲基噻吩-2-羧酸作为起始原料，参照制备例21的方法制备得到7-(((1s,4s)-4-羟基环己基)氨基)-2,3-二甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐。Using 3-amino-4,5-dimethylthiophene-2-carboxylic acid as the starting material, 7-(((1s,4s)-4-hydroxycyclohexyl)amino)- 2,3-Dimethyl-6-(7-methyl-1-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride.
分子式:C 27H 34ClN 5O 2S 分子量:528.1 LC-MS(M/e):492.0(M+H +) Molecular formula: C 27 H 34 ClN 5 O 2 S Molecular weight: 528.1 LC-MS (M/e): 492.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.08(s,1H),11.98(s,1H),11.33(s,1H),10.64(s,1H),7.47(s,2H),4.25-4.15(m,1H),3.80-3.70(m,4H),3.40-3.30(m,2H),3.10-2.90(m,4H),2.80(s,3H),2.41(s,3H),2.18(s,3H),1.80-1.60(m,8H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.08(s, 1H), 11.98(s, 1H), 11.33(s, 1H), 10.64(s, 1H), 7.47(s, 2H), 4.25 -4.15(m, 1H), 3.80-3.70(m, 4H), 3.40-3.30(m, 2H), 3.10-2.90(m, 4H), 2.80(s, 3H), 2.41(s, 3H), 2.18 (s,3H),1.80-1.60(m,8H).
制备例24：7-((1s,4s)-4-羟基环己基)氨基)-4-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物30-1)Preparation Example 24: 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazole Do[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 30- 1)
Figure PCTCN2022080065-appb-000086
Figure PCTCN2022080065-appb-000086
1. 2-(7-羟基-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-Hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydro Preparation of imidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate tert-butyl ester
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(1.8g,4.83mmol)和1-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(972mg,5.3mmol)溶于四氢呋喃(50mL)。氮气保护下，40℃下加入LDA(9.7mL,19.3mmol)，加 毕，40℃下反应4小时。0℃下加入饱和氯化铵水溶液淬灭反应，用二氯甲烷萃取分液，有机相浓缩得到产物与中间体混合粗品。将上步粗品溶于四氢呋喃(20mL)，氮气保护下，40℃下加入LDA(9.7mL,19.3mmol)，加毕，40℃下反应2小时。饱和氯化铵水溶液淬灭反应，有机相浓缩，硅胶柱纯化(100％乙酸乙酯)得标题化合物710mg，收率31％。2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Heterochrome-7(1H)-carboxylate tert-butyl ester (1.8 g, 4.83 mmol) and 1-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H )-dione (972 mg, 5.3 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, LDA (9.7 mL, 19.3 mmol) was added at 40°C, and after the addition was completed, the reaction was carried out at 40°C for 4 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution at 0°C, extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product mixed with the intermediate. The crude product in the previous step was dissolved in tetrahydrofuran (20 mL), and under nitrogen protection, LDA (9.7 mL, 19.3 mmol) was added at 40° C., the addition was completed, and the reaction was carried out at 40° C. for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, the organic phase was concentrated, and purified by silica gel column (100% ethyl acetate) to obtain 710 mg of the title compound in a yield of 31%.
2. 2-(4-甲基-5-氧代-7-((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备2. 2-(4-Methyl-5-oxo-7-((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -7(1H)-Carboxylic acid tert-butyl ester
将2-(7-羟基-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(710mg,1.52mmol)溶于二氯甲烷(15mL)，0℃下加入吡啶(2.4g,30.4mmol)，三氟甲磺酸酐(2.6g,9.12mmol)，加毕，0℃下反应1小时。浓缩反应液，二氯甲烷萃取，饱和碳酸氢钠水溶液洗，饱和食盐水洗，有机相经无水硫酸钠干燥，柱层析(乙酸乙酯/正庚烷＝0-60％)得到目标化合物450mg，收率41％。2-(7-Hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazole [4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate tert-butyl ester (710 mg, 1.52 mmol) was dissolved in dichloromethane (15 mL), Pyridine (2.4 g, 30.4 mmol) and trifluoromethanesulfonic anhydride (2.6 g, 9.12 mmol) were added at 0° C., the addition was completed, and the reaction was carried out at 0° C. for 1 hour. The reaction solution was concentrated, extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and column chromatography (ethyl acetate/n-heptane=0-60%) was used to obtain 450 mg of the target compound , the yield is 41%.
3. 2-(7-(((1s,4s)-4-羟基环己基)氨基)-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备3. 2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine- 6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Preparation of heterozo-7(1H)-carboxylate tert-butyl ester
将2-(4-甲基-5-氧代-7-((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(450mg,0.62mmol)溶于乙腈(10mL)，加入(1s,4s)-4-氨基环己-1-醇(284mg,2.5mmol)，加毕40℃反应2小时。反应液浓缩，经硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物430mg，收率99％。2-(4-Methyl-5-oxo-7-((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophen[3,2-b]pyridin-6-yl) -1-((Trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 7(1H)-tert-butyl carboxylate (450 mg, 0.62 mmol) was dissolved in acetonitrile (10 mL), (1s,4s)-4-aminocyclohexan-1-ol (284 mg, 2.5 mmol) was added, and the addition was completed at 40°C React for 2 hours. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 430 mg of the target compound with a yield of 99%.
4. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1s,4s)-4-羟基环己基)氨基)-4-甲基噻吩[3,2-b]吡啶-5(4H)-酮的制备4. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)- Preparation of 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methylthiophene[3,2-b]pyridin-5(4H)-one
将2-(7-(((1s,4s)-4-羟基环己基)氨基)-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(120mg,0.17mmol)溶于三氟乙酸(4mL)，25℃反应1小时，浓缩。将四氢呋喃/水(5/5mL)混合溶剂加入反应液，加入NaOH调节pH＝10,25℃反应1小时，浓缩直接用于下步反应。2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-6 -yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Zo-7(1H)-carboxylate tert-butyl ester (120 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (4 mL), reacted at 25° C. for 1 hour, and concentrated. A mixed solvent of tetrahydrofuran/water (5/5 mL) was added to the reaction solution, NaOH was added to adjust pH=10, the reaction was performed at 25° C. for 1 hour, and the mixture was concentrated and used directly for the next reaction.
5. 7-((1s,4s)-4-羟基环己基)氨基)-4-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备5. 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1s,4s)-4-羟基环己基)氨基)-4-甲基噻吩[3,2-b]吡啶-5(4H)-酮(上步粗品)溶于10mL甲醇中加入40％甲醛水溶液(0.1mL)和氰基硼氢化钠(70mg,1.1mmol)，在20℃反应3小时后浓缩溶剂，经柱层析(二氯甲烷:甲醇＝7:1)，(0.3％TFA in MeOH/H 2O＝0-75％)得目标化合物40mg，两步收率为49％。 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -((1s,4s)-4-hydroxycyclohexyl)amino)-4-methylthiophene[3,2-b]pyridin-5(4H)-one (crude product from the previous step) was dissolved in 10 mL of methanol and added 40% Aqueous formaldehyde solution (0.1 mL) and sodium cyanoborohydride (70 mg, 1.1 mmol) were reacted at 20° C. for 3 hours and then the solvent was concentrated and subjected to column chromatography (dichloromethane: methanol = 7: 1), (0.3% TFA in MeOH/H 2 O = 0-75%) to obtain 40 mg of the target compound with a two-step yield of 49%.
分子式:C 26H 31N 5O 2S 分子量:477.6 LC-MS(M/e):478.2(M+H +) Molecular formula: C 26 H 31 N 5 O 2 S Molecular weight: 477.6 LC-MS (M/e): 478.2 (M+H + )
1H-NMR(400MHz,MeOD)δ:7.95(m,1H),7.49(s,2H),7.31(m,1H),7.4(m,1H),3.87-3.68(m,6H),3.38-2.95(m,9H),2.12-1.73(m,8H). 1 H-NMR (400MHz, MeOD)δ: 7.95(m, 1H), 7.49(s, 2H), 7.31(m, 1H), 7.4(m, 1H), 3.87-3.68(m, 6H), 3.38- 2.95(m,9H),2.12-1.73(m,8H).
制备例25：7-氨基-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物33)Preparation Example 25: 7-Amino-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 33)
Figure PCTCN2022080065-appb-000087
Figure PCTCN2022080065-appb-000087
1. 2-(7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[ 3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzene Preparation of [1,2-d]azepine-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(N/A,0.26mmol)溶于乙腈(10mL)，加入2,4-二甲氧基苄胺(130.3mg,0.78mmoL)，加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物80mg，两步收率：37.4％。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylate tert-butyl ester (N/A, 0.26 mmol) was dissolved in acetonitrile (10 mL), 2,4-dimethoxybenzylamine (130.3 mg, 0.78 mmoL), and the reaction was completed at 40 °C for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 80 mg of the target compound, two-step yield: 37.4%.
2. 7-氨基-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-Amino-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(80mg,98.3μmol)溶于浓盐酸(0.5mL)，三氟乙酸(3.5mL)，110℃下反应48小时。LCMS检测反应结束。浓缩溶剂，饱和碳酸氢钠水溶液调节pH＝8，Pre-TLC板纯化(二氯甲烷：甲醇＝7:1)得目标化合物4.2mg，收率：12.8％。2-(7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3 ,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo [1,2-d]azepine-7(1H)-carboxylate tert-butyl ester (80 mg, 98.3 μmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL), and reacted at 110°C for 48 hours The reaction was detected by LCMS. The solvent was concentrated, the saturated aqueous sodium bicarbonate solution was adjusted to pH=8, and purified by Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 4.2 mg of the target compound, yield: 12.8%.
分子式:C 18H 17N 5OS 分子量:351.4 LC-MS(M/e):352.1(M+H +) Molecular formula: C 18 H 17 N 5 OS Molecular weight: 351.4 LC-MS (M/e): 352.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.85(s,1H),11.83(m,1H),7.95(d,J＝5.2Hz,1H),7.49(s,1H),7.44(s,1H),7.02(d,J＝5.6Hz,1H),4.07-4.11(m,2H),3.18-3.23(m,4H),3.13-3.17(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.85(s, 1H), 11.83(m, 1H), 7.95(d, J=5.2Hz, 1H), 7.49(s, 1H), 7.44(s) ,1H),7.02(d,J＝5.6Hz,1H),4.07-4.11(m,2H),3.18-3.23(m,4H),3.13-3.17(m,4H).
制备例26：2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备(化合物37)Preparation Example 26: 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate isopropyl ester (Compound 37)
Figure PCTCN2022080065-appb-000088
Figure PCTCN2022080065-appb-000088
1. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备1. 2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of Azazepine-7(1H)-Isopropyl Carboxylate
将2-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(330mg,1.2mmol)，三乙胺(607mg,6.0mmol)溶于二氯甲烷(10mL)中，降温至-10℃，加入氯甲酸异丙酯(111mg,0.91mmol)，-10℃下反应2h，体系用甲醇(1mL)淬灭反应。体系旋干，经硅胶柱层析分离(甲醇:二氯甲烷＝1:15)得目标化合物110mg，收率25.5％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester (330mg, 1.2mmol), triethylamine (607mg, 6.0mmol) was dissolved in dichloromethane (10mL), cooled to -10°C, added isopropyl chloroformate (111mg, 0.91mmol), at -10°C The reaction was continued for 2 h, and the system was quenched with methanol (1 mL). The system was spin-dried and separated by silica gel column chromatography (methanol:dichloromethane=1:15) to obtain 110 mg of the target compound with a yield of 25.5%.
2. 2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备2. 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4' Preparation of ,5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate isopropyl ester
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯(90mg,0.25mmol)和3-氨基噻吩-2-腈(32mg，0.26mmol)溶于四氢呋喃(8mL)中，40℃下滴加LDA(2M,0.63mL,1.26mmol)，继续反应2h。反应结束后，加入饱和氯化铵水溶液(5mL)淬灭，后加入乙酸乙酯(20mL)和水(10mL)萃取分液，有机相用无水硫酸钠干燥，旋干得粗品80mg，后加入甲醇(5mL)超声打浆，析出固体后经减压抽滤得目标化合物40mg，收率36.6％。2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Hetero-7(1H)-carboxylate isopropyl ester (90mg, 0.25mmol) and 3-aminothiophene-2-carbonitrile (32mg, 0.26mmol) were dissolved in tetrahydrofuran (8mL), LDA (2M) was added dropwise at 40°C , 0.63mL, 1.26mmol), continue to react for 2h. After the reaction, saturated aqueous ammonium chloride solution (5 mL) was added to quench, and then ethyl acetate (20 mL) and water (10 mL) were added to extract and separate the liquid. Methanol (5 mL) was ultrasonically slurried, and the solid was precipitated and filtered under reduced pressure to obtain 40 mg of the target compound with a yield of 36.6%.
分子式:C 22H 23N 5O 3S 分子量:437.5 LC-MS(M/e):438.0(M+H +) Molecular formula: C 22 H 23 N 5 O 3 S Molecular weight: 437.5 LC-MS (M/e): 438.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.77(s,1H),11.76(s,1H),10.70-10.55(m,1H),7.92(d,J＝2.8Hz,1H),7.84-7.71(m,1H),7.42(s,1H),7.37(s,1H),6.99(d,J＝2.8Hz,1H),4.82-4.75(m,1H),3.52-3.46(m,4H),2.96-2.89(m,4H),1.22-1.18(m,6H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.77(s, 1H), 11.76(s, 1H), 10.70-10.55(m, 1H), 7.92(d, J=2.8Hz, 1H), 7.84 -7.71(m, 1H), 7.42(s, 1H), 7.37(s, 1H), 6.99(d, J=2.8Hz, 1H), 4.82-4.75(m, 1H), 3.52-3.46(m, 4H) ),2.96-2.89(m,4H),1.22-1.18(m,6H).
制备例27：2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备(化合物40)Preparation Example 27: 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of methyl 4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (Compound 40)
Figure PCTCN2022080065-appb-000089
Figure PCTCN2022080065-appb-000089
1. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备1. 2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of methyl azepine-7(1H)-carboxylate
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(300mg,1.1mmol)，三乙胺(445mg,4.4mmol)溶于二氯甲烷(40mL)中，降温至0℃后，加入氯甲酸甲酯溶液(0.3M/L,3.7mL,1.1mmol)，0℃下反应2h，体系用甲醇(2mL)淬灭反应。体系旋干，经硅胶柱层析分离后(甲醇:二氯甲烷＝1:20)得目标化合物220mg，收率60.4％。Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester (300mg, 1.1mmol), triethylamine (445mg, 4.4mmol) was dissolved in dichloromethane (40mL), after cooling to 0 ℃, methyl chloroformate solution (0.3M/L, 3.7mL, 1.1mmol) was added ), reacted at 0 °C for 2 h, and the system was quenched with methanol (2 mL). The system was spin-dried and separated by silica gel column chromatography (methanol:dichloromethane=1:20) to obtain 220 mg of the target compound with a yield of 60.4%.
2. 2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备2. 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4' Preparation of ,5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate methyl ester
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯(100mg,0.30mmol)和3-氨基噻吩-2-腈(45mg,0.36mmol)溶于四氢呋喃(15mL)中，40℃下滴加LDA(2M,0.75mL,1.5mmol)，继续反应2h。反应液加入饱和氯化铵水溶液(3mL)淬灭，后加入乙酸乙酯(20mL)和水(10mL)萃取分液，有机相用无水硫酸钠干燥，旋干得粗品，加入甲醇(10mL)超声打浆，析出固体后经减压抽滤得目标化合物35mg，收率28.5％。2-(2-Ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Hetero-7(1H)-carboxylate methyl ester (100mg, 0.30mmol) and 3-aminothiophene-2-carbonitrile (45mg, 0.36mmol) were dissolved in tetrahydrofuran (15mL), LDA (2M, 0.75mL, 1.5mmol), continue to react for 2h. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (3 mL), and then ethyl acetate (20 mL) and water (10 mL) were added to extract and separate the liquid. Ultrasonic beating, solids were precipitated, 35 mg of the target compound was obtained by suction filtration under reduced pressure, and the yield was 28.5%.
分子式:C 20H 19N 5O 3S 分子量:409.5 LC-MS(M/e):409.9(M+H +) Molecular formula: C 20 H 19 N 5 O 3 S Molecular weight: 409.5 LC-MS (M/e): 409.9 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.77(s,1H),11.77(s,1H),10.70-10.55(m,1H),7.92-7.85(m,2H),7.45-7.32(m,2H),6.99-6.93(m,1H),3.60(s,3H),3.52–3.46(m,4H),2.96-2.89(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.77(s, 1H), 11.77(s, 1H), 10.70-10.55(m, 1H), 7.92-7.85(m, 2H), 7.45-7.32( m,2H),6.99-6.93(m,1H),3.60(s,3H),3.52-3.46(m,4H),2.96-2.89(m,4H).
制备例28：6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(氧杂 -3-环丁氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物42)Preparation Example 28: 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Preparation of Heterozol-2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one (Compound 42)
Figure PCTCN2022080065-appb-000090
Figure PCTCN2022080065-appb-000090
1. 7-氯-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备1. 7-Chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将7-氯-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-甲醛(500mg,2.35mmol)、3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺(510mg,2.35mmol)、三氯化铁(1.5g,9.4mmol)溶于1,4-二氧六环(30mL)，升温至110℃，反应1小时。LCMS检测反应结束。降至25℃，饱和碳酸氢钠水溶液调节体系pH＝9，用二氯甲烷萃取，有机相经干燥、浓缩、硅胶柱纯化(二氯甲烷：甲醇＝10:1)得目标化合物220g，收率22.9％。7-Chloro-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-6-carbaldehyde (500 mg, 2.35 mmol), 3-cyclopropyl-2,3,4,5- Tetrahydro-1H-benzo[d]azepine-7,8-diamine (510 mg, 2.35 mmol), ferric chloride (1.5 g, 9.4 mmol) were dissolved in 1,4-dioxane (30 mL) ), the temperature was raised to 110°C, and the reaction was carried out for 1 hour. LCMS detected the end of the reaction. The temperature was lowered to 25°C, the pH of the system was adjusted to 9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 220 g of the target compound in a yield of 220 g. 22.9%.
2. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(氧杂-3-环丁氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备2. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one
将7-氯-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮(220mg,0.54mmol)、3-氨基氧杂环丁烷(59.2mg,0.81mmol)、碳酸氢钠(136.1mg,1.6mmol)和四丁基碘化铵(19.9mg,54.0μmol)溶于水(3mL)和氯仿(18mL)中，升温至60℃，反应16小时。LCMS检测反应结束。降温至25℃，加入二氯甲烷稀释，加水洗涤，有机相经干燥、浓缩得固体，固体用甲醇打浆得目标化合物14.5mg，收率6.0％。7-Chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Azepin-2-yl)thiophen[3,2-b]pyridin-5(4H)-one (220 mg, 0.54 mmol), 3-aminooxetane (59.2 mg, 0.81 mmol), sodium bicarbonate (136.1 mg, 1.6 mmol) and tetrabutylammonium iodide (19.9 mg, 54.0 μmol) were dissolved in water (3 mL) and chloroform (18 mL), heated to 60° C., and reacted for 16 hours. LCMS detected the end of the reaction. It was cooled to 25°C, diluted with dichloromethane, washed with water, the organic phase was dried and concentrated to obtain a solid, and the solid was slurried with methanol to obtain 14.5 mg of the target compound with a yield of 6.0%.
分子式:C 24H 25N 5O 2S 分子量:447.6 LC-MS(M/e):448.0(M+H +) Molecular formula: C 24 H 25 N 5 O 2 S Molecular weight: 447.6 LC-MS (M/e): 448.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.91(s,1H),12.74(d,J＝6.0Hz,1H),11.96(s,1H),8.05(d,J＝5.6Hz,1H),7.43(s,1H),7.42(s,1H),7.06(d,J＝5.2Hz,1H),5.70-5.80(m,1H),5.06-5.10(m,2H),4.67-4.70(m,2H),2.90-2.92(m,4H),2.76-2.90(m,4H),1.75-1.85(m,1H),0.48-0.49(m,2H),0.35-0.40(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.91(s, 1H), 12.74(d, J=6.0Hz, 1H), 11.96(s, 1H), 8.05(d, J=5.6Hz, 1H) ), 7.43(s, 1H), 7.42(s, 1H), 7.06(d, J＝5.2Hz, 1H), 5.70-5.80(m, 1H), 5.06-5.10(m, 2H), 4.67-4.70( m,2H),2.90-2.92(m,4H),2.76-2.90(m,4H),1.75-1.85(m,1H),0.48-0.49(m,2H),0.35-0.40(m,2H).
制备例29：7-(((1r,4r)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物44)Preparation Example 29: 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4', Preparation of 5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 44)
Figure PCTCN2022080065-appb-000091
Figure PCTCN2022080065-appb-000091
1. 2-(((1r,4r)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ 4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯的制备 1. 2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2- b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ 4 -imidazo[4',5':4,5] Preparation of Benzo[1,2-d]azepine-7-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ 4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200.0mg,0.24mmol)溶于乙腈(5mL)中，加入(1r,4r)-4-氨基环己烷-1-醇(110.1mg,0.96mmol)，加毕，45℃下反应2小时。反应液经浓缩、硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物200.0mg粗品。 2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene[3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ 4 -imidazo[4',5':4,5]benzene [1,2-d]azepine-7-carboxylate tert-butyl ester (200.0 mg, 0.24 mmol) was dissolved in acetonitrile (5 mL), and (1r,4r)-4-aminocyclohexane-1- Alcohol (110.1 mg, 0.96 mmol) was added and reacted at 45°C for 2 hours. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 200.0 mg of the target compound as a crude product.
2. 6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1r,4r)-4-羟基环己基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备2. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 Preparation of -((1r,4r)-4-hydroxycyclohexyl)amino)thiophene[3,2-b]pyridin-5(4H)-one
将2-(((1r,4r)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ 4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200.0mg粗品,N/A)溶于浓盐酸(4mL)与三氟乙酸(28mL)中，加毕，升温至110℃反应24小时。浓缩溶剂，用二氯甲烷(20mL)溶解，1N NaOH(20mL)搅拌0.2小时，有机相浓缩，经中压反相制备(0-50％甲醇/水(0.5％浓盐酸))得目标化合物75.0mg，两步收率70.8％。 2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ 4 -imidazo[4',5':4,5]benzene and [1,2-d]azepine-7-carboxylate tert-butyl ester (200.0 mg crude product, N/A) was dissolved in concentrated hydrochloric acid (4 mL) and trifluoroacetic acid (28 mL), the addition was completed, and the temperature was raised to 110 °C to react for 24 hours. The solvent was concentrated, dissolved in dichloromethane (20 mL), stirred with 1N NaOH (20 mL) for 0.2 hours, the organic phase was concentrated, and the target compound 75.0 was obtained by reverse-phase preparation at medium pressure (0-50% methanol/water (0.5% concentrated hydrochloric acid)) mg, two-step yield 70.8%.
3. 7-(((1r,4r)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5' : Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1r,4r)-4-羟基环己基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮(75.0mg,0.17mmol)溶于10.0mL甲醇中，加入1.0mL甲醛，氰基硼氢化钠(21.0mg，0.33mmol)，25℃搅拌1h，浓缩溶剂，过正相柱分离(甲醇:二氯甲烷＝1:99)得7.6mg，收率9.8％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7- ((1r,4r)-4-hydroxycyclohexyl)amino)thiophene[3,2-b]pyridin-5(4H)-one (75.0 mg, 0.17 mmol) was dissolved in 10.0 mL of methanol, 1.0 mL of formaldehyde was added, Sodium cyanoborohydride (21.0 mg, 0.33 mmol) was stirred at 25°C for 1 h, the solvent was concentrated, and separated through a normal phase column (methanol:dichloromethane=1:99) to obtain 7.6 mg with a yield of 9.8%.
分子式:C 25H 29N 5O 2S 分子量:463.2 LC-MS(M/e):464.0(M+H +) Molecular formula: C 25 H 29 N 5 O 2 S Molecular weight: 463.2 LC-MS (M/e): 464.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.99(s,1H),12.17(s,1H),11.85(s,1H),8.02(d,1H),7.40(s,1H),7.32(s,1H),7.05(d,1H),4.66-4.65(m,1H),4.21-4.12(m,1H),3.80-3.60(m,1H),3.32(d,4H),2.95(s,4H),2.27(s,3H),2.17-2.16(m,2H),1.99-1.96(m,2H),1.58-1.56(m,2H),1.45-1.42(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.99(s, 1H), 12.17(s, 1H), 11.85(s, 1H), 8.02(d, 1H), 7.40(s, 1H), 7.32 (s,1H),7.05(d,1H),4.66-4.65(m,1H),4.21-4.12(m,1H),3.80-3.60(m,1H),3.32(d,4H),2.95(s ,4H),2.27(s,3H),2.17-2.16(m,2H),1.99-1.96(m,2H),1.58-1.56(m,2H),1.45-1.42(m,2H).
制备例30：7-(氮杂环丁烷-1-基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物45)Preparation Example 30: 7-(azetidin-1-yl)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole Preparation of zo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 45)
Figure PCTCN2022080065-appb-000092
Figure PCTCN2022080065-appb-000092
1. 2-(7-(氮杂环丁烷-1-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-(azetidin-1-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b] Pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2- d] Preparation of azepine-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧)-4,5-二氢噻吩[3,2-b]吡啶-6- 基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200mg,0.24mmol)溶于乙腈(5mL)，加入氮杂环丁烷(55mg,0.96mmol)，加毕，40℃下反应2小时。LCMS检测反应结束。反应液经浓缩、硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物粗品。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene[3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2- d] tert-butyl azetidine-7-carboxylate (200 mg, 0.24 mmol) was dissolved in acetonitrile (5 mL), azetidine (55 mg, 0.96 mmol) was added, and the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain the crude product of the target compound.
2. 7-(氮杂环丁烷-1-基)-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-(azetidin-1-yl)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(氮杂环丁烷-1-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(粗品)溶于浓盐酸(1mL)和三氟乙酸(7mL)中，加毕，升温至110℃反应24小时。LCMS检测反应结束。浓缩溶剂，用二氯甲烷溶解，经饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇＝7:1)得目标化合物40mg，两步反应收率43％。2-(7-(azetidin-1-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine -6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d ] Azazepine-7(1H)-carboxylate tert-butyl ester (crude product) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL), the addition was completed, and the temperature was raised to 110° C. to react for 24 hours. LCMS detected the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried, concentrated, and purified by Pre-TLC (dichloromethane:methanol=7:1) to obtain 40 mg of the target compound with a two-step reaction yield of 43%.
3. 7-(氮杂环丁烷-1-基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 7-(azetidin-1-yl)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将7-(氮杂环丁烷-1-基)-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(40mg,0.1mmol)溶于甲醇(6mL)中，加入3-氧杂环丁酮(22mg,0.3mmol)和冰醋酸(6mg,0.1mmol)，20℃下反应30min，加入氰基硼氢化钠(19mg,0.3mmol)，20℃下反应4h。反应完毕，加入二氯甲烷和饱和碳酸氢钠溶液分液萃取三次，有机相旋干，经正向制备分离(二氯甲烷:甲醇＝5:1)得目标化合物5mg。7-(azetidin-1-yl)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, 2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (40 mg, 0.1 mmol) was dissolved in methanol (6 mL), 3-oxetine was added Ketone (22 mg, 0.3 mmol) and glacial acetic acid (6 mg, 0.1 mmol) were reacted at 20 °C for 30 min, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, and the reaction was conducted at 20 °C for 4 h. After the reaction was completed, dichloromethane and saturated sodium bicarbonate solution were added for liquid separation and extraction three times, the organic phase was spin-dried, and 5 mg of the target compound was obtained by forward preparation and separation (dichloromethane:methanol=5:1).
分子式:C 24H 25N 5O 2S 分子量:447.5 LC-MS(M/e):448.2(M+H +) Molecular formula: C 24 H 25 N 5 O 2 S Molecular weight: 447.5 LC-MS (M/e): 448.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.10(s,1H),11.50(s,1H),7.90-7.91(d,J＝4Hz,1H),7.32(s,1H),7.19(s,1H),6.97-6.98(d,J＝4Hz,1H),4.46-4.55(m,4H),3.94(s,4H),3.48-3.51(t,1H),2.96(s,4H),2.36(s,4H),2.09-2.11(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.10(s, 1H), 11.50(s, 1H), 7.90-7.91(d, J=4Hz, 1H), 7.32(s, 1H), 7.19( s, 1H), 6.97-6.98(d, J=4Hz, 1H), 4.46-4.55(m, 4H), 3.94(s, 4H), 3.48-3.51(t, 1H), 2.96(s, 4H), 2.36(s, 4H), 2.09-2.11(m, 2H).
制备例31：7-氨基-6-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物46)Preparation Example 31: 7-Amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4, 5] Preparation of Benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 46)
Figure PCTCN2022080065-appb-000093
Figure PCTCN2022080065-appb-000093
1. 3-(6-氯吡嗪-3-基)-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备1. Preparation of 3-(6-chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(961mg,5mmol)，三乙胺(1012mg,10mmol)与3,6-二氯吡嗪(894mg,6mmol)溶于二甲基亚砜(50mL)，110℃下反应1小时。反应结 束后使用水(50mL)淬灭反应，二氯甲烷(50mL)萃取，有机相浓缩经硅胶柱纯化(乙酸乙酯/二氯甲烷＝1:9)得目标化合物500mg，收率32.8％。Combine 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (961 mg, 5 mmol), triethylamine (1012 mg, 10 mmol) with 3,6-dichloropyrazine (894 mg, 6 mmol) was dissolved in dimethyl sulfoxide (50 mL) and reacted at 110° C. for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL), and the organic phase was concentrated and purified by silica gel column (ethyl acetate/dichloromethane=1:9) to obtain 500 mg of the target compound with a yield of 32.8%.
2. 3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备2. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将3-(6-氯吡嗪-3-基)-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(500mg,1.64mmol)、氯化铵(351mg,6.56mmol)与铁粉(275mg,4.92mmol)溶于乙醇(15mL)和水(15mL)中，95℃下反应3小时。二氯甲烷(50mL)萃取，有机相浓缩直接用于下一步。3-(6-Chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.64 mmol), chlorinated Ammonium (351 mg, 6.56 mmol) and iron powder (275 mg, 4.92 mmol) were dissolved in ethanol (15 mL) and water (15 mL) and reacted at 95° C. for 3 hours. Extracted with dichloromethane (50 mL), the organic phase was concentrated and used directly in the next step.
3. N-(3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备3. Preparation of N-(3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(上步粗品)溶于乙酸酐(2mL)和乙酸(5mL)中，25℃反应1小时。加入水(50mL)淬灭反应，二氯甲烷(50mL)萃取，有机相浓缩得目标化合物400mg，两步反应收率76.9％。3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (crude from previous step) was dissolved in acetic anhydride ( 2 mL) and acetic acid (5 mL), react at 25°C for 1 hour. The reaction was quenched by adding water (50 mL), extracted with dichloromethane (50 mL), and the organic phase was concentrated to obtain 400 mg of the target compound. The yield of the two-step reaction was 76.9%.
4. N-(3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备4. N-(3-(6-Chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl) Preparation of acetamide
将N-(3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(400mg,1.26mmol)溶于浓硫酸(4mL)。0℃下滴加发烟硝酸(95mg,1.52mmol)，滴毕，0℃下反应1小时。反应结束后使用二氯甲烷(50mL)稀释，水(50mL)洗涤，有机相浓缩经硅胶柱纯化(乙酸乙酯/二氯甲烷＝1:4)得目标化合物230mg，收率50.3％。N-(3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (400 mg, 1.26 mmol) in concentrated sulfuric acid (4 mL). Fuming nitric acid (95 mg, 1.52 mmol) was added dropwise at 0° C., the dropping was completed, and the reaction was carried out at 0° C. for 1 hour. After the reaction, it was diluted with dichloromethane (50 mL), washed with water (50 mL), and the organic phase was concentrated and purified by silica gel column (ethyl acetate/dichloromethane=1:4) to obtain 230 mg of the target compound with a yield of 50.3%.
5. 3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备5. Preparation of 3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将N-(3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(230mg,0.64mol)与碳酸钾(263mg,1.91mol)溶于甲醇(6mL)，50℃下反应2小时。水(30mL)淬灭，抽滤，收集固体旋干得目标化合物200mg，收率98.4％。N-(3-(6-Chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)ethane The amide (230 mg, 0.64 mol) and potassium carbonate (263 mg, 1.91 mol) were dissolved in methanol (6 mL) and reacted at 50°C for 2 hours. It was quenched with water (30 mL), filtered with suction, and the solid was collected and spin-dried to obtain 200 mg of the target compound with a yield of 98.4%.
6. 3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺的制备6. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine
将3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(200mg,0.63mmol)、氯化铵(167mg,3.13mmol)与铁粉(105mg,1.88mmol)溶于乙醇(10mL)和水(10mL)中，95℃下反应2小时。二氯甲烷(50mL)萃取，水(20mL)洗涤，有机相用无水硫酸钠干燥，经过滤、浓缩得目标化合物180mg，收率99.3％。3-(6-Chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (200 mg, 0.63 mmol ), ammonium chloride (167 mg, 3.13 mmol) and iron powder (105 mg, 1.88 mmol) were dissolved in ethanol (10 mL) and water (10 mL), and reacted at 95° C. for 2 hours. Extracted with dichloromethane (50 mL), washed with water (20 mL), dried the organic phase with anhydrous sodium sulfate, filtered and concentrated to obtain 180 mg of the target compound with a yield of 99.3%.
7. 2-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备7. 2-(7-(6-Chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)ethyl acetate
将3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺(180mg,0.62mmol)和3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(292mg,1.49mmol)溶于乙醇(10mL)。55℃下反应1小时。旋干，二氯甲烷(50mL)稀释，氨水(10mL)洗涤，有机相干燥，浓缩，硅胶柱纯化(二氯甲烷:甲醇＝19:1)得目标化合物160mg，收率66.8％。3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine (180 mg, 0.62 mmol) and Ethyl 3-ethoxy-3-iminopropionate hydrochloride (292 mg, 1.49 mmol) was dissolved in ethanol (10 mL). The reaction was carried out at 55°C for 1 hour. Spin dry, dilute with dichloromethane (50 mL), wash with ammonia water (10 mL), dry the organic phase, concentrate, and purify on silica gel column (dichloromethane: methanol=19:1) to obtain 160 mg of the target compound with a yield of 66.8%.
8. 7-氨基-6-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备8. 7-Amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5] Preparation of Benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将2-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(60mg,0.16mmol)与3-氨基噻吩-2-甲腈(20mg,0.16mmol)溶于四氢呋喃(4mL)，氮气保护下，40℃下加入LDA(0.32mL,0.64mol)，加毕，40℃下反应2小时。饱和氯化铵水溶液(8mL)淬灭反应，有机相浓缩，经反相柱纯化(乙腈:水(0.5％盐酸)＝30％)得目 标化合物7mg，收率9.7％。2-(7-(6-Chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Ethyl 2-d]azepin-2-yl)acetate (60mg, 0.16mmol) and 3-aminothiophene-2-carbonitrile (20mg, 0.16mmol) were dissolved in tetrahydrofuran (4mL), under nitrogen protection, 40 ℃ LDA (0.32 mL, 0.64 mol) was added at the bottom, the addition was completed, and the reaction was carried out at 40° C. for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (8 mL), the organic phase was concentrated, and purified by reverse-phase column (acetonitrile: water (0.5% hydrochloric acid) = 30%) to obtain 7 mg of the target compound in a yield of 9.7%.
分子式:C 22H 18ClN 7OS 分子量:463.9 LC-MS(M/e):464.0(M+H +) Molecular formula: C 22 H 18 ClN 7 OS Molecular weight: 463.9 LC-MS (M/e): 464.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:11.92(s,2H),8.25-8.09(m,1H),8.02(d,J＝5.2,1H),7.60-7.50(m,4H),7.03(d,J＝5.2,1H),3.95-3.85(m,4H),3.15-3.05(m,4H) 1 H-NMR (400MHz, DMSO-d 6 )δ: 11.92(s, 2H), 8.25-8.09(m, 1H), 8.02(d, J=5.2, 1H), 7.60-7.50(m, 4H), 7.03(d, J=5.2, 1H), 3.95-3.85(m, 4H), 3.15-3.05(m, 4H)
制备例32：7-氨基-6-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物47)Preparation Example 32: 7-Amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 47)
Figure PCTCN2022080065-appb-000094
Figure PCTCN2022080065-appb-000094
1. 2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备1. 2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl) ethyl acetate
于3-甲基-8-氨基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-酚的乙醇溶液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(3.75g.19.3mmol)，升至50℃反应16小时。反应结束后，用硅藻土过滤，滤液加入碳酸氢钠溶液调节pH至8左右，用二氯甲烷(100mL)萃取，有机相干燥浓缩，经硅胶柱纯化(二氯甲烷:甲醇＝10:1)，得目标化合物820mg，反应收率59.0％。Add 3-ethoxy-3-imino to the ethanolic solution of 3-methyl-8-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol Ethyl propionate hydrochloride (3.75 g. 19.3 mmol) was raised to 50°C and reacted for 16 hours. After the reaction, it was filtered with celite, the filtrate was added with sodium bicarbonate solution to adjust the pH to about 8, extracted with dichloromethane (100 mL), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=10:1 ) to obtain 820 mg of the target compound with a reaction yield of 59.0%.
2. 2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸的制备2. 2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)acetic acid
将2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(750mg,2.6mmol)溶于甲醇(10mL)和水(10mL)中，加入氢氧化钠(312.0mg,7.8mmol)，25℃下反应3小时。反应结束后，向体系中加入2M稀盐酸溶液调节pH至中性，体系经浓缩旋干得到目标化合物粗品直接用于下一步反应。2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine-2 -yl)ethyl acetate (750 mg, 2.6 mmol) was dissolved in methanol (10 mL) and water (10 mL), sodium hydroxide (312.0 mg, 7.8 mmol) was added, and the reaction was carried out at 25° C. for 3 hours. After the reaction, 2M dilute hydrochloric acid solution was added to the system to adjust the pH to neutrality, and the system was concentrated and spin-dried to obtain the crude product of the target compound, which was directly used in the next reaction.
3. N-(2-氰基噻吩-3-基)-2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酰胺的制备3. N-(2-cyanothiophen-3-yl)-2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5 ] Preparation of benzo[1,2-d]azepin-2-yl)acetamide
将2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸(N/A,2.6mmol)溶于二氯甲烷(50mL)中，依次加入2-氨基噻吩-3-甲腈(387.5mg,3.1mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.5g,3.9mmol)和三乙胺(526.2mg,5.2mmol)，体系于25℃下反应8小时。反应结束后，体系加水淬灭反应，用二氯甲烷(100mL)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝9:1)得目标化合物粗品700mg，直接用于下一步反应。2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine-2 -yl)acetic acid (N/A, 2.6 mmol) was dissolved in dichloromethane (50 mL), 2-aminothiophene-3-carbonitrile (387.5 mg, 3.1 mmol), 2-(7-azobenzonitrile) were added successively Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5g, 3.9mmol) and triethylamine (526.2mg, 5.2mmol), the system was reacted at 25°C for 8 hours . After the reaction, water was added to the system to quench the reaction, extracted with dichloromethane (100 mL), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=9:1) to obtain 700 mg of crude target compound, which was directly used in the next reaction .
4. 7-氨基-6-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备4. 7-Amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将N-(2-氰基噻吩-3-基)-2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酰胺(600mg,1.6mmol)溶于甲醇(50mL)中，加入甲醇钠(5.2g,28.9mmol)后将体系置于70℃下反应2小时。反应结束后，加入2M稀盐酸溶液调节体系pH至中性，浓缩 旋干，经硅胶柱纯化(二氯甲烷:甲醇＝7:3)、旋干溶剂、甲醇打浆、过滤、洗涤、干燥后得目标化合物19.0mg，三步反应收率2.3％。N-(2-cyanothiophen-3-yl)-2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5] Benzo[1,2-d]azepin-2-yl)acetamide (600 mg, 1.6 mmol) was dissolved in methanol (50 mL), sodium methoxide (5.2 g, 28.9 mmol) was added, and the system was placed at 70 °C The reaction was continued for 2 hours. After the reaction, 2M dilute hydrochloric acid solution was added to adjust the pH of the system to neutral, concentrated and spin-dried, purified by silica gel column (dichloromethane:methanol=7:3), spin-dried solvent, slurried with methanol, filtered, washed, and dried to obtain The target compound was 19.0 mg, and the three-step reaction yield was 2.3%.
分子式:C 19H 18N 4O 2S 分子量:366.4 LC-MS(M/e):367.4.1(M+H +) Molecular formula: C 19 H 18 N 4 O 2 S Molecular weight: 366.4 LC-MS (M/e): 367.4.1 (M+H + )
1H-NMR(400MHz,CDCl 3)δ:11.51(s,1H),9.30-8.40(m,2H),7.95(d,J＝5.2HZ,1H),7.47(s,2H),6.94(d,J＝5.2HZ,1H),3.30-3.20(m,4H),3.10-2.90(m,4H),2.28(s,3H). 1 H-NMR (400MHz, CDCl 3 )δ: 11.51(s, 1H), 9.30-8.40(m, 2H), 7.95(d, J=5.2HZ, 1H), 7.47(s, 2H), 6.94(d , J=5.2HZ, 1H), 3.30-3.20(m, 4H), 3.10-2.90(m, 4H), 2.28(s, 3H).
制备例33：6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物48)Preparation Example 33: 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (Compound 48)
Figure PCTCN2022080065-appb-000095
Figure PCTCN2022080065-appb-000095
1. 2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-(Isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6- yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zo-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.60mmol)溶于乙腈(10mL)，加入异丙胺(106mg,1.80mmoL)，升温至40℃反应2小时。LCMS检测反应结束。反应液浓缩经硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物300mg，收率：67.1％。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylate tert-butyl ester (500 mg, 0.60 mmol) was dissolved in acetonitrile (10 mL), isopropylamine (106 mg, 1.80 mmol) was added, and the temperature was raised to 40° C. to react for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 300 mg of the target compound, yield: 67.1%.
2. 7-(异丙基氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-(Isopropylamino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9 - Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one preparation
将2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.4mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(2ml)反应1小时。LCMS检测反应结束。二氯甲烷稀释，饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩直接用于下一步。2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine -7(1H)-Carboxylic acid tert-butyl ester (300 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added to react for 1 hour. LCMS detected the end of the reaction. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated and used directly in the next step.
3. 6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4' ,5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3 Preparation of ,2-b]pyridin-5(4H)-one
将7-(异丙基氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(N/A,0.4mmoL)溶于乙腈(5mL)，加入N,N二异丙基乙胺(155mg,1.2mmoL)、2,2-二氟乙基三氟甲磺酸酯(256mg,1.2mmoL)，加毕反应2小时。LCMS检测反应结束。反应液浓缩经硅胶柱纯化(乙酸乙酯:石油醚＝1:1)得目标化合物150mg，两步收率：52.9％。7-(isopropylamino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9- Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one ( N/A, 0.4mmoL) was dissolved in acetonitrile (5mL), N,N diisopropylethylamine (155mg, 1.2mmoL), 2,2-difluoroethyl trifluoromethanesulfonate (256mg, 1.2mmoL) were added ), and the reaction was completed for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate:petroleum ether=1:1) to obtain 150 mg of the target compound, two-step yield: 52.9%.
4. 6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙 基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备4. 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one
将6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.25mmol)溶于浓盐酸(0.5mL)，加入三氟乙酸(3.5mL)，110℃下反应48小时。LCMS检测反应结束。浓缩溶剂，用饱和碳酸氢钠水溶液调节体系pH＝8，经Pre-TLC板纯化(二氯甲烷:甲醇＝7:1)得目标化合物17mg，收率：14.9％。6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3, 2-b]pyridin-5(4H)-one (180 mg, 0.25 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added, and the reaction was carried out at 110° C. for 48 hours. LCMS detected the end of the reaction. The solvent was concentrated, the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and purified by Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 17 mg of the target compound, yield: 14.9%.
分子式:C 23H 25F 2N 5OS 分子量:457.5 LC-MS(M/e):458.0(M+H +) Molecular formula: C 23 H 25 F 2 N 5 OS Molecular weight: 457.5 LC-MS (M/e): 458.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.00(s,1H),11.14(d,J＝8.4Hz,1H),11.84(s,1H),8.03(d,J＝5.6Hz,1H),7.40(s,1H),7.33(s,1H),7.05(d,J＝5.6Hz,1H),6.18-6.14(m,1H)，4.50-4.48(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H)，1.45-1.44(m,6H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.00(s, 1H), 11.14(d, J=8.4Hz, 1H), 11.84(s, 1H), 8.03(d, J=5.6Hz, 1H) ), 7.40(s, 1H), 7.33(s, 1H), 7.05(d, J＝5.6Hz, 1H), 6.18-6.14(m, 1H), 4.50-4.48(m, 1H), 2.95-2.90( m, 6H), 2.87-2.78 (m, 4H), 1.45-1.44 (m, 6H).
制备例34：6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物49)Preparation Example 34: 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (Compound 49)
Figure PCTCN2022080065-appb-000096
Figure PCTCN2022080065-appb-000096
1. 7-氨基-6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 7-Amino-6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole Do[4',5':4,5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)thieno[3,2-b] Preparation of Pyridin-5(4H)-one
将7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(400mg，0.53mmoL)溶于乙腈(5mL)，加入N,N二异丙基乙胺(206mg，1.6mmoL)、2,2-二氟乙基三氟甲磺酸酯(342mg，1.6mmoL)，加毕反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(乙酸乙酯:石油醚＝1:1)得目标化合物250mg，收率：70.7％。7-((3,4-Dimethylbenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5, 6,7,8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine -5(4H)-one (400 mg, 0.53 mmoL) was dissolved in acetonitrile (5 mL), N,N diisopropylethylamine (206 mg, 1.6 mmoL), 2,2-difluoroethyl trifluoromethanesulfonic acid were added Ester (342 mg, 1.6 mmol) was added and reacted for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate:petroleum ether=1:1) to obtain 250 mg of the target compound, yield: 70.7%.
2. 6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one
将7-氨基-6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.27mmol)溶于浓盐酸(0.5mL)，加入三氟乙酸(3.5mL)，110℃下反应48小时。LCMS检测反应结束。浓缩溶剂，用饱和碳酸氢钠水溶液调节体系pH＝8，经Pre-TLC板纯化(二氯甲烷:甲醇＝7:1)得目标化合物20mg，收率：17.8％。7-amino-6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine -5(4H)-one (180 mg, 0.27 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added, and the reaction was carried out at 110° C. for 48 hours. LCMS detected the end of the reaction. The solvent was concentrated, the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and purified by Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 20 mg of the target compound, yield: 17.8%.
分子式:C 20H 19F 2N 5OS 分子量:415.5 LC-MS(M/e):416.0(M+H +) Molecular formula: C 20 H 19 F 2 N 5 OS Molecular weight: 415.5 LC-MS (M/e): 416.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.99(s,1H),7.92(d,J＝5.6Hz,1H),7.39-7.34(m,2H),7.01(d,J＝5.2Hz,1H),6.19-6.23(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.99(s, 1H), 7.92(d, J=5.6Hz, 1H), 7.39-7.34(m, 2H), 7.01(d, J=5.2Hz) ,1H),6.19-6.23(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H).
制备例35：6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物50)Preparation Example 35: 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zoro-2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one (Compound 50)
Figure PCTCN2022080065-appb-000097
Figure PCTCN2022080065-appb-000097
1. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯的制备1. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzene [1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine- Preparation of 7-yl trifluoromethanesulfonate
将6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮(600mg,1.2mmol)溶于二氯甲烷(12mL)，0℃下加入吡啶(1.90g,24mmol)、三氟甲磺酸酐(2.03g,7.2mmol)，加毕，0℃下反应30分钟。用饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相干燥浓缩直接用于下一步。6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)-7-hydroxy-4-(4-methoxybenzyl)thiophene[3,2-b]pyridin-5(4H)-one (600 mg, 1.2 mmol) was dissolved in dichloromethane (12 mL) , pyridine (1.90 g, 24 mmol) and trifluoromethanesulfonic anhydride (2.03 g, 7.2 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated and used directly in the next step.
2. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮的制备2. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzene [1,2-d]azepin-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophene[3,2- Preparation of b]pyridin-5(4H)-one
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸盐酯(上步粗品)溶于乙腈(10mL)，加入2,2-二氟乙胺(389mg,4.8mmol)，加毕，40℃反应1小时。反应液浓缩，经硅胶柱纯化(二氯甲烷:甲醇＝13:1)得目标化合物300mg，两步收率36.2％。6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzoyl [1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-7 -yl trifluoromethanesulfonate ester (crude product in the previous step) was dissolved in acetonitrile (10 mL), 2,2-difluoroethylamine (389 mg, 4.8 mmol) was added, the addition was completed, and the reaction was carried out at 40° C. for 1 hour. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=13:1) to obtain 300 mg of the target compound with a two-step yield of 36.2%.
3. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备3. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂吡啶-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮(150mg,0.21mmol)溶于浓盐酸(1mL)，加入三氟乙酸(7mL)，加毕，升温至110℃反应24小时。浓缩溶剂，二氯甲烷溶解，饱和碳酸氢钠水溶液洗涤，有机相干燥，经中压反相纯化(40％甲醇/水(0.5％浓盐酸))得目标化合物40mg，收率41.4％。6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzoyl [1,2-d]Azapyridin-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophene[3,2-b ] Pyridin-5(4H)-one (150 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (1 mL), trifluoroacetic acid (7 mL) was added, and the temperature was raised to 110 °C for 24 hours. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried, and purified by reversed-phase purification under medium pressure (40% methanol/water (0.5% concentrated hydrochloric acid)) to obtain 40 mg of the target compound with a yield of 41.4%.
分子式:C 23H 23F 2N 5OS 分子量:455.5 LC-MS(M/e):456.1(M+H +) Molecular formula: C 23 H 23 F 2 N 5 OS Molecular weight: 455.5 LC-MS (M/e): 456.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.21(s,1H),12.05(s,1H),10.38(s,1H),8.08(d,J＝5.6Hz,1H),7.50(s,2H),7.09(d,J＝5.6Hz,1H),6.46(t,J＝14.8Hz,1H),4.40-4.30(m,2H),3.80-3.70(m,2H),3.60-3.50(m,2H),3.30-3.05(m,4H),2.95-2.85(m,1H),1.25-1.20(m,2H),0.90-0.80(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.21(s, 1H), 12.05(s, 1H), 10.38(s, 1H), 8.08(d, J=5.6Hz, 1H), 7.50(s ,2H),7.09(d,J＝5.6Hz,1H),6.46(t,J＝14.8Hz,1H),4.40-4.30(m,2H),3.80-3.70(m,2H),3.60-3.50( m,2H),3.30-3.05(m,4H),2.95-2.85(m,1H),1.25-1.20(m,2H),0.90-0.80(m,2H).
制备例36：6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩[3,2-b]吡啶-5(4H)-酮盐酸盐的制备(化合物52的盐酸盐)Preparation Example 36: 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zolo-2-yl)-7-(isopropylamino)thiophen[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 52)
Figure PCTCN2022080065-appb-000098
Figure PCTCN2022080065-appb-000098
1. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2- 基)-7-异丙基氨基-4-(4-甲氧基苄基)-噻吩并[3,2-b]吡啶-5(4H)酮的制备1. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzene Do[1,2-d]azepin-2-yl)-7-isopropylamino-4-(4-methoxybenzyl)-thieno[3,2-b]pyridine-5(4H ) Preparation of ketones
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯溶于乙腈(30mL)，加入异丙胺(141.6mg,2.4mmol)，加毕，45℃下反应1小时。反应液浓缩，经硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物200mg。6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzoyl [1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-7 -yl trifluoromethanesulfonate was dissolved in acetonitrile (30 mL), isopropylamine (141.6 mg, 2.4 mmol) was added, the addition was completed, and the reaction was carried out at 45° C. for 1 hour. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 200 mg of the target compound.
2. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩[3,2-b]吡啶-5(4H)-酮盐酸盐的制备2. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-(isopropylamino)thiophen[3,2-b]pyridin-5(4H)-one hydrochloride
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-7-异丙基氨基-4-(4-甲氧基苄基)-噻吩并[3,2-b]吡啶-5(4H)酮(200mg,0.29mmol)溶于浓盐酸(2mL)，加入三氟乙酸(14mL)，加毕，升至110℃反应16小时。浓缩溶剂，经C 18柱纯化(乙腈＝0-30％)得目标化合物11.5mg，收率8.4％。 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzoyl [1,2-d]azepin-2-yl)-7-isopropylamino-4-(4-methoxybenzyl)-thieno[3,2-b]pyridine-5(4H) The ketone (200 mg, 0.29 mmol) was dissolved in concentrated hydrochloric acid (2 mL), trifluoroacetic acid (14 mL) was added, the addition was completed, and the reaction was carried out at 110° C. for 16 hours. The solvent was concentrated and purified by C 18 column (acetonitrile=0-30%) to obtain 11.5 mg of the target compound in a yield of 8.4%.
分子式:C 24H 28N 5OSCl 分子量:469.2 LC-MS(M/e):434.0(M+H +) Molecular formula: C 24 H 28 N 5 OSCl Molecular weight: 469.2 LC-MS (M/e): 434.0 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.11(m,1H),12.09(m,1H),11.87(s,1H),9.03(m,1H),8.04(d,J＝5.2Hz,1H),7.51(s,2H),7.05(d,J＝5.2Hz,1H),4.47-4.52(m,1H),3.70-3.85(m,2H),3.14-3.24(m,4H),2.96-3.05(m,2H),1.45(d,J＝6.4Hz,6H),1.20-1.30(m,1H),1.02-1.10(m,2H),0.89-0.91(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.11(m, 1H), 12.09(m, 1H), 11.87(s, 1H), 9.03(m, 1H), 8.04(d, J=5.2Hz ,1H),7.51(s,2H),7.05(d,J＝5.2Hz,1H),4.47-4.52(m,1H),3.70-3.85(m,2H),3.14-3.24(m,4H), 2.96-3.05(m, 2H), 1.45(d, J=6.4Hz, 6H), 1.20-1.30(m, 1H), 1.02-1.10(m, 2H), 0.89-0.91(m, 2H).
制备例37：7-氨基-6-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物53)Preparation Example 37: 7-amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 53)
Figure PCTCN2022080065-appb-000099
Figure PCTCN2022080065-appb-000099
1. 1,5-二氢苯并[d]氧杂卓-2,4-二酮的制备1. Preparation of 1,5-dihydrobenzo[d]oxazol-2,4-dione
将2,2'-(1,2-亚苯基)二乙酸(12g,61.9mmol)溶于二氯甲烷(200mL)中，25℃下加入DCC(12.8g,61.9mmol)，25℃下反应4h，LCMS检测反应完成，过滤，滤饼干燥得目标化合物粗品12g。Dissolve 2,2'-(1,2-phenylene)diacetic acid (12 g, 61.9 mmol) in dichloromethane (200 mL), add DCC (12.8 g, 61.9 mmol) at 25°C, and react at 25°C 4h, LCMS detected the completion of the reaction, filtered, and dried the filter cake to obtain 12 g of crude target compound.
2. 2-(2-(2-(乙氨基)-2-氧乙基)苯基)乙酸的制备2. Preparation of 2-(2-(2-(ethylamino)-2-oxoethyl)phenyl)acetic acid
将1,5-二氢苯并[d]氧杂卓-2,4-二酮(12g，粗品)溶于二氯甲烷(200mL)中，0℃下加入乙胺盐酸盐(2.7g,33mmol)和三乙胺(13.7g,136mmol)，25℃下反应4h，LCMS检 测反应完成，体系加入水淬灭反应，二氯甲烷萃取有机相，有机相浓缩经硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物7g，两步收率50.9％。1,5-Dihydrobenzo[d]oxazepine-2,4-dione (12 g, crude product) was dissolved in dichloromethane (200 mL), and ethylamine hydrochloride (2.7 g, 33mmol) and triethylamine (13.7g, 136mmol), reacted at 25°C for 4h, LCMS detected that the reaction was completed, water was added to the system to quench the reaction, the organic phase was extracted with dichloromethane, the organic phase was concentrated and purified by silica gel column (methanol/dichloromethane) Methane=1:10) to obtain the target compound 7g, the two-step yield is 50.9%.
3. N-乙基-2-(2-(2-羟乙基)苯基)乙酰胺的制备3. Preparation of N-ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide
将2-(2-(2-(乙氨基)-2-氧乙基)苯基)乙酸(7g,31.5mmol)溶于四氢呋喃(10mL)中，0℃下滴加硼烷(37.8mL,37.8mmol)，滴加完毕，体系于25℃下反应3h，LCMS检测反应完成，体系加入甲醇淬灭反应，经水洗、乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物5g，收率76.3％。2-(2-(2-(ethylamino)-2-oxoethyl)phenyl)acetic acid (7 g, 31.5 mmol) was dissolved in tetrahydrofuran (10 mL), and borane (37.8 mL, 37.8 mL) was added dropwise at 0°C mmol), the dropwise addition was completed, the system was reacted at 25°C for 3 h, and the reaction was detected by LCMS, methanol was added to the system to quench the reaction, washed with water, extracted with ethyl acetate, concentrated in the organic phase, and purified by silica gel column (methanol/dichloromethane=1 : 10) to obtain 5 g of the target compound with a yield of 76.3%.
4. 2-(2-(乙基氨基)-2-氧乙基)苯乙基甲磺酸盐的制备4. Preparation of 2-(2-(ethylamino)-2-oxyethyl) phenethyl methanesulfonate
将N-乙基-2-(2-(2-羟乙基)苯基)乙酰胺(5g,24mmol)溶于四氢呋喃(10mL)中，0℃下滴加甲磺酰氯(5.6g，48mmol)和三乙胺(7.3g，72mmol)，滴加完毕，体系于0℃下反应3h，LCMS检测反应完成，体系加入水淬灭反应，经乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物4.9g，收率71.4％。N-ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide (5 g, 24 mmol) was dissolved in tetrahydrofuran (10 mL), and methanesulfonyl chloride (5.6 g, 48 mmol) was added dropwise at 0°C and triethylamine (7.3g, 72mmol), the dropwise addition was completed, the system was reacted at 0°C for 3h, the reaction was completed by LCMS, water was added to the system to quench the reaction, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column (methanol). /dichloromethane=1:10) to obtain 4.9 g of the target compound with a yield of 71.4%.
5. 3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备5. Preparation of 3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one
将2-(2-(乙基氨基)-2-氧乙基)苯乙基甲磺酸盐(4.5g,15.7mmol)溶于N,N-二甲基甲酰胺(10mL)中，0℃下滴加氢化钠(1.2g,31.4mmol)，滴加完毕后，体系于0℃下反应2h，LCMS检测反应完成，体系加入水淬灭反应，乙酸乙酯萃取，有机相浓缩硅胶柱纯化(乙酸乙酯/石油醚＝1:1)得粗品2.35g。Dissolve 2-(2-(ethylamino)-2-oxoethyl)phenethylmethanesulfonate (4.5 g, 15.7 mmol) in N,N-dimethylformamide (10 mL) at 0°C Sodium hydride (1.2 g, 31.4 mmol) was added dropwise. After the addition was completed, the system was reacted at 0 °C for 2 h. The reaction was detected by LCMS. Water was added to the system to quench the reaction, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column. (ethyl acetate/petroleum ether=1:1) to obtain 2.35 g of crude product.
6. 3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备6. Preparation of 3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one
将3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(2.35g,粗品)溶于浓硫酸(10mL)中，0℃下加入硝酸钾(1.4g,13.8mmol)，滴加完毕后，体系于0℃下反应2h，LCMS检测反应完成。将反应液滴加到冰水中淬灭反应，经乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(乙酸乙酯/石油醚＝1:3)得目标化合物1g，两步收率27.1％3-Ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (2.35 g, crude product) was dissolved in concentrated sulfuric acid (10 mL), added at 0°C Potassium nitrate (1.4 g, 13.8 mmol) was added dropwise, the system was reacted at 0° C. for 2 h, and the reaction was completed by LCMS. The reaction was added dropwise to ice water to quench the reaction, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column (ethyl acetate/petroleum ether=1:3) to obtain 1 g of the target compound, with a two-step yield of 27.1%
7. 8-胺基-3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备7. Preparation of 8-amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one
将3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(1g,4.3mmol)溶于甲醇(20mL)中，加入Pd/C(500mg)，25℃反应2h，LCMS检测反应完成。过滤，滤液旋干得目标化合物860mg，收率90.4％。3-Ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (1 g, 4.3 mmol) was dissolved in methanol (20 mL), Pd/C (500 mg) was added, and the reaction was carried out at 25° C. for 2 h. The reaction was completed by LCMS. After filtration, the filtrate was spin-dried to obtain 860 mg of the target compound with a yield of 90.4%.
8. N-(3-乙基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备8. Preparation of N-(3-ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将8-胺基-3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(860mg,4.20mmol)溶于乙酸(10mL)中，加入乙酸酐(2mL)，25℃下反应2h，LCMS检测反应完成。反应液旋干，经二氯甲烷稀释、饱和碳酸氢钠溶液洗、有机相旋干、硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:1)得目标化合物650mg，收率62.7％8-Amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (860 mg, 4.20 mmol) was dissolved in acetic acid (10 mL), Acetic anhydride (2 mL) was added, and the reaction was carried out at 25° C. for 2 h. The reaction was completed by LCMS. The reaction solution was spin-dried, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was spin-dried, and separated and purified by silica gel column chromatography (methanol/dichloromethane=1:1) to obtain 650 mg of the target compound with a yield of 62.7%
9. N-(3-乙基-8-硝基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备9. Preparation of N-(3-ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide
将N-(3-乙基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(580mg,2.35mmol)溶于浓硫酸(10mL)中，0℃下滴加发烟硝酸(181mg，2.82mmol)25℃反应2h，LCMS检测反应完成，反应液滴加到冰入水淬灭反应，二氯甲烷萃取有机相，有机相浓缩硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物230mg，收率33.5％N-(3-ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (580 mg, 2.35 mmol) was dissolved in In concentrated sulfuric acid (10 mL), fuming nitric acid (181 mg, 2.82 mmol) was added dropwise at 0 °C and reacted at 25 °C for 2 h. LCMS detected the completion of the reaction. The reaction was added dropwise to ice and water to quench the reaction, and the organic phase was extracted with dichloromethane. Phase concentrated silica gel column purification (methanol/dichloromethane=1:10) to obtain 230 mg of the target compound, yield 33.5%
10. 7-胺基-3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备10. Preparation of 7-amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one
将N-(3-乙基-8-硝基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(230mg,0.79mmol)溶于甲醇(10mL)中，加入碳酸钾(327mg，2.37mmol)，25℃反应4h，LCMS检测反应完成，反应液旋干，粗品经硅胶柱纯化(甲醇/二氯甲烷＝1:10)得目标化合物190mg，收率96.54％N-(3-ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (230 mg, 0.79 mmol) was dissolved in methanol (10 mL), potassium carbonate (327 mg, 2.37 mmol) was added, and the reaction was carried out at 25° C. for 4 h. LCMS detected that the reaction was complete, the reaction solution was spin-dried, and the crude product was purified by silica gel column (methanol/dichloromethane=1: 10) 190 mg of the target compound was obtained, the yield was 96.54%
11. 2-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯的制备11. 2-(7-Ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl) ethyl acetate
将7-胺基-3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(190mg,0.76mmol)溶于乙醇(10mL)中，加入Pd/C(120mg)，25℃下反应2h，LCMS检测反应完成，加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(297mg,1.52mmol)，50℃下反应2h，LCMS检测反应完成。过滤，滤液旋干，用二氯甲烷稀释，饱和碳酸氢钠水溶液洗涤，有机相旋干，经硅胶柱层析分离(甲醇/二氯甲烷＝1:10)得目标化合物150mg，收率62.4％。7-Amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (190 mg, 0.76 mmol) was dissolved in ethanol (10 mL), added Pd/C (120 mg), reacted at 25 ° C for 2 h, LCMS detected the reaction was complete, added 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (297 mg, 1.52 mmol), 50 The reaction was carried out at °C for 2 h, and the reaction was completed by LCMS. Filter, spin dry the filtrate, dilute with dichloromethane, wash with saturated aqueous sodium bicarbonate solution, spin dry the organic phase, and separate by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain 150 mg of the target compound, yield 62.4% .
12. 7-氨基-6-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备12. 7-Amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将2-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯(100mg,0.32mmol)和3-氨基噻吩-2-甲腈(40mg,0.32mmol)溶于四氢呋喃(10mL)中，40℃下加入LDA(1mL，1.92mmol)，40℃下反应2h，LCMS检测反应完成。将反应液倒入饱和氯化铵水溶液中淬灭，经乙酸乙酯萃取，有机相旋干，甲醇打浆后得目标化合物18.5mg，收率14.7％。2-(7-Ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Heterozol-2-yl)ethyl acetate (100 mg, 0.32 mmol) and 3-aminothiophene-2-carbonitrile (40 mg, 0.32 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (1 mL, 1.92 mmol) was added at 40°C ), reacted at 40 °C for 2 h, and the reaction was completed by LCMS detection. The reaction solution was poured into saturated aqueous ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, and 18.5 mg of the target compound was obtained after beating with methanol, with a yield of 14.7%.
分子式:C 20H 19N 5O 2S 分子量:393.5 LC-MS(M/e):394.0(M+H+) Molecular formula: C 20 H 19 N 5 O 2 S Molecular weight: 393.5 LC-MS(M/e): 394.0(M+H+)
1H-NMR(400MHz,DMSO-d 6)δ:12.80(d,J＝6.0Hz,1H),11.79(d,J＝6.8Hz,1H),10.50-10.70(br s,1H),7.94(d,J＝4.2Hz,1H),7.80-7.94(br s,1H),7.30-7.45(m,2H),7.03(d,J＝4.2Hz,1H),3.88(d,J＝9.2Hz,2H),3.71(t,J＝5.2Hz,1H),3.35-3.40(m,2H),3.21(s,2H),1.03(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.80 (d, J=6.0 Hz, 1H), 11.79 (d, J=6.8 Hz, 1H), 10.50-10.70 (br s, 1H), 7.94 ( d,J=4.2Hz,1H),7.80-7.94(br s,1H),7.30-7.45(m,2H),7.03(d,J=4.2Hz,1H),3.88(d,J=9.2Hz, 2H), 3.71(t, J=5.2Hz, 1H), 3.35-3.40(m, 2H), 3.21(s, 2H), 1.03(t, J=7.2Hz, 3H).
制备例38：7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢-5,9-桥亚甲基咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物54)Preparation Example 38: 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-methyleneimidazo[4',5':4, 5] Preparation of Benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 54)
Figure PCTCN2022080065-appb-000100
Figure PCTCN2022080065-appb-000100
1. 7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲醇苯并[d]氮杂卓制备1. Preparation of 7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methanol benzo[d]azepine
将1-(7,8-二硝基-1,2,4,5-四氢-3H-1,5-甲氧基苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮(200.0mg,0.58mol)溶于甲醇(8mL)和水(3mL)中，加入碳酸钠(127.2mg,1.2mmol)， 继续反应16小时。向体系中加水淬灭反应，用二氯甲烷(100mL)萃取，有机相经干燥浓缩得目标化合物粗品170mg，直接用于下一步反应。1-(7,8-Dinitro-1,2,4,5-tetrahydro-3H-1,5-methoxybenzo[d]azepin-3-yl)-2,2, 2-Trifluoroethane-1-one (200.0 mg, 0.58 mol) was dissolved in methanol (8 mL) and water (3 mL), sodium carbonate (127.2 mg, 1.2 mmol) was added, and the reaction was continued for 16 hours. Water was added to the system to quench the reaction, extracted with dichloromethane (100 mL), and the organic phase was dried and concentrated to obtain 170 mg of crude target compound, which was directly used in the next reaction.
2. 3-环丙基-7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓的制备2. Preparation of 3-cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine
将7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲醇苯并[d]氮杂卓(粗品)(170.0mg,0.68mmol)溶于甲醇(10.0mL)中，加入乙酸(432.0mg,7.2mmol)、氰基硼氢化钠(276.3mg,4.4mmol)和(1-乙氧基环丙氧基)三甲基硅烷(278.9mg,1.6mmol)，体系于65℃下反应3h。向体系中加入水淬灭反应，用二氯甲烷萃取有机相，有机相浓缩经硅胶柱纯化(乙酸乙酯/石油醚＝2:3)得目标化合物127.0mg，两步收率75.7％。7,8-Dinitro-2,3,4,5-tetrahydro-1H-1,5-methanolbenzo[d]azepine (crude) (170.0 mg, 0.68 mmol) was dissolved in methanol (10.0 mL), add acetic acid (432.0 mg, 7.2 mmol), sodium cyanoborohydride (276.3 mg, 4.4 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (278.9 mg, 1.6 mmol), The system was reacted at 65°C for 3h. Water was added to the system to quench the reaction, and the organic phase was extracted with dichloromethane. The organic phase was concentrated and purified by silica gel column (ethyl acetate/petroleum ether=2:3) to obtain 127.0 mg of the target compound with a two-step yield of 75.7%.
3. 3-环丙基-7,8-二氨基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓的制备3. Preparation of 3-cyclopropyl-7,8-diamino-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine
将3-环丙基-7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓(320.0mg,1.1mmol)溶于乙醇(10mL)中，加入Pd/C(200.0mg)，氢气氛围下将体系置于25℃氢化反应40分钟。反应液直接用于下一步反应。3-Cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine (320.0 mg, 1.1 mmol) was dissolved in In ethanol (10 mL), Pd/C (200.0 mg) was added, and the system was placed at 25° C. for hydrogenation reaction under a hydrogen atmosphere for 40 minutes. The reaction solution was directly used in the next reaction.
4. 2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备4. 2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate
于上一步反应液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(508.6mg.2.6mmol)，升至50℃反应2小时。硅藻土过滤，滤液浓缩旋干，加入水稀释，用碳酸氢钠溶液调节PH至碱性，用二氯甲烷(100mL)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)，得目标化合物250.0mg，收率(两步)：69.4％。3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (508.6 mg. 2.6 mmol) was added to the reaction solution in the previous step, and the temperature was raised to 50° C. for 2 hours. Celite was filtered, the filtrate was concentrated and spin-dried, diluted with water, the pH was adjusted to alkaline with sodium bicarbonate solution, extracted with dichloromethane (100 mL), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane: methanol=10 : 1) to obtain 250.0 mg of the target compound, yield (two steps): 69.4%.
5. 7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢-5,9-桥亚甲基咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备5. 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-methyleneimidazole[4',5':4,5] Preparation of Benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(250mg,0.66mmol)溶于四氢呋喃(15mL)中，加入2-氨基噻吩-3-甲腈(113.1mg,0.91mmol)，氮气氛围下将混合物置于40℃下，加入二异丙基氨基锂(1.5mL,3.0mmol)，继续搅拌1小时。体系加氯化铵水溶液淬灭反应，用乙酸乙酯(100mL)萃取，有机相经干燥浓缩、硅胶柱纯化(乙酸乙酯＝100％)得目标化合物19.0mg，产率：7.1％。2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (250 mg, 0.66 mmol) was dissolved in tetrahydrofuran (15 mL), 2-aminothiophene-3-carbonitrile (113.1 mg, 0.91 mmol) was added, and the mixture was placed at 40 °C under nitrogen atmosphere, Lithium diisopropylamide (1.5 mL, 3.0 mmol) was added and stirring was continued for 1 hour. The system was quenched by adding aqueous ammonium chloride solution, extracted with ethyl acetate (100 mL), the organic phase was dried and concentrated, and purified by silica gel column (ethyl acetate=100%) to obtain 19.0 mg of the target compound, yield: 7.1%.
分子式:C 22H 21N 5OS 分子量:403.5 LC-MS(M/e):404.0(M+H +) Molecular formula: C 22 H 21 N 5 OS Molecular weight: 403.5 LC-MS (M/e): 404.0 (M+H + )
1H-NMR(400MHz,CDCl 3)δ:12.75(s,1H),11.75(s,1H),10.72-10.52(m,1H),7.94(d,J＝8.8HZ,1H),7.91-7.67(m,1H),7.36(s,1H),7.28(s,1H),7.01(d,J＝5.2HZ,1H),3.20-3.10(m,2H),2.92-2.82(m,2H),2.64-2.50(m,2H),2.25-2.15(m,1H),1.85-1.75(m,1H),1.70-1.60(m,1H),0.30-0.20(m,2H),-0.1--0.2(m,2H). 1 H-NMR (400MHz, CDCl 3 )δ: 12.75(s, 1H), 11.75(s, 1H), 10.72-10.52(m, 1H), 7.94(d, J=8.8HZ, 1H), 7.91-7.67 (m, 1H), 7.36(s, 1H), 7.28(s, 1H), 7.01(d, J=5.2HZ, 1H), 3.20-3.10(m, 2H), 2.92-2.82(m, 2H), 2.64-2.50(m,2H),2.25-2.15(m,1H),1.85-1.75(m,1H),1.70-1.60(m,1H),0.30-0.20(m,2H),-0.1--0.2 (m,2H).
制备例39：7-氨基-6-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5]:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物55)Preparation Example 39: 7-Amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5]:4,5]benzo Preparation of [1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 55)
Figure PCTCN2022080065-appb-000101
Figure PCTCN2022080065-appb-000101
Figure PCTCN2022080065-appb-000102
Figure PCTCN2022080065-appb-000102
1. 2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备1. 2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- d] Preparation of azepin-2-yl) ethyl acetate
选用1,5-二氢苯并[d]氧杂卓-2,4-二酮和环丙胺作为起始原料，参照制备例37的制备方法，制备得到2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯。Using 1,5-dihydrobenzo[d]oxazol-2,4-dione and cyclopropylamine as starting materials, with reference to the preparation method of Preparation Example 37, 2-(7-cyclopropyl-6 Ethyl -oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate ester.
2. 7-氨基-6-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5]:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备2. 7-Amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5]:4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one
将2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓吡啶-2-基)乙酸乙酯(32.7mg,0.1mmol)、2-氰基-3-氨基噻吩(12.4mg,0.1mmol)溶于四氢呋喃(5mL)中，氮气保护下升温至40℃，40℃下滴加2M的二异丙基氨基锂溶液(0.25mL,0.5mmol)，加毕，40℃反应3小时。LCMS检测反应结束。降温至25℃，饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥浓缩，得到的固体用甲醇打浆，过滤得固体，固体干燥得标题化合物14.5mg，收率：35.8％。2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d ] ethyl azepin-2-yl)acetate (32.7 mg, 0.1 mmol), 2-cyano-3-aminothiophene (12.4 mg, 0.1 mmol) were dissolved in tetrahydrofuran (5 mL), and the temperature was raised to 2M lithium diisopropylamide solution (0.25 mL, 0.5 mmol) was added dropwise at 40° C. at 40° C., the addition was completed, and the reaction was carried out at 40° C. for 3 hours. LCMS detected the end of the reaction. The temperature was lowered to 25°C, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, the obtained solid was slurried with methanol, filtered to obtain a solid, and the solid was dried to obtain 14.5 mg of the title compound, yield: 35.8%.
分子式:C 21H 19N 5O 2S 分子量:405.5 LC-MS(M/e):406.1(M+H +) Molecular formula: C 21 H 19 N 5 O 2 S Molecular weight: 405.5 LC-MS (M/e): 406.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.80(s,1H),11.81(m,1H),7.94(d,J＝5.2Hz,1H),7.89(m,1H),7.41(s,1H),7.36(s,1H),7.01(d,J＝5.2Hz,1H),3.87(s,2H),3.72-3.70(m,2H),3.15-3.20(m,2H),2.65-2.75(m,1H),0.69-0.71(m,2H),0.60-0.62(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.80(s, 1H), 11.81(m, 1H), 7.94(d, J=5.2Hz, 1H), 7.89(m, 1H), 7.41(s ,1H),7.36(s,1H),7.01(d,J＝5.2Hz,1H),3.87(s,2H),3.72-3.70(m,2H),3.15-3.20(m,2H),2.65- 2.75(m,1H),0.69-0.71(m,2H),0.60-0.62(m,2H).
制备例40：7-((2,2-二氟乙基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮三氟乙酸盐的制备(化合物58的三氟乙酸盐)Preparation Example 40: 7-((2,2-difluoroethyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexa Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one trifluoro Preparation of acetate salt (trifluoroacetate salt of compound 58)
Figure PCTCN2022080065-appb-000103
Figure PCTCN2022080065-appb-000103
1. 2-(7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备1. 2-(7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepine-7(1H)-carboxylate tert-butyl ester
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧 酸叔丁酯(500mg,0.60mmol),溶于乙腈(5mL)中，加入2,2-二氟乙基-1-胺(388mg,4.78mmol)，40℃下反应2h。LCMS检测反应完成，旋干溶剂，经硅胶柱层析分离(乙酸乙酯:石油醚＝1:1)得目标化合物300mg，收率65.4％。2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylate tert-butyl ester (500mg, 0.60mmol), dissolved in acetonitrile (5mL), added 2,2-difluoroethyl-1-amine (388mg, 4.78mmol), reacted at 40°C for 2h. LCMS detected the completion of the reaction, spin-dried the solvent, and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 300 mg of the target compound with a yield of 65.4%.
2. 7-((2,2-二氟乙基)氨基)-6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 7-((2,2-Difluoroethyl)amino)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.39mmol)溶于三氟乙酸(3.5ml)和盐酸(0.5mL)中，升温至110℃反应24h，LCMS检测反应完成。将反应液旋干，用饱和碳酸氢钠水溶液调节体系pH＝8，经二氯甲烷萃取、干燥、浓缩得目标化合物粗品200mg。2-(7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2- b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1, 2-d]Azazepine-7(1H)-carboxylate tert-butyl ester (300mg, 0.39mmol) was dissolved in trifluoroacetic acid (3.5ml) and hydrochloric acid (0.5mL), the temperature was raised to 110°C for reaction for 24h, LCMS detection The reaction is complete. The reaction solution was spin-dried, the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried and concentrated to obtain 200 mg of crude target compound.
3. 7-((2,2-二氟乙基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮三氟乙酸盐的制备3. 7-((2,2-Difluoroethyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole Do[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one trifluoroacetic acid Preparation of salt
将7-((2,2-二氟乙基)氨基)-6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(200mg，N/A)溶于甲醇(5mL)中，加入氧杂环丁烷-3-酮(30mg,0.40mmol)和乙酸(144mg,2.4mmol)，25℃下反应1小时后，加入氰基硼氢化钠(150mg,2.4mmol)，继续反应8小时，LCMS检测反应完成。向体系中加入碳酸氢钠水溶液，用二氯甲烷萃取，收集有机相溶剂旋干，经反相柱层析(甲醇/水＝0-40％其中两相各含有0.3％的三氟乙酸)得目标化合物19mg，收率37.8％。7-((2,2-Difluoroethyl)amino)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (200 mg, N/A) was dissolved in methanol (5 mL), oxetane was added Alkane-3-one (30mg, 0.40mmol) and acetic acid (144mg, 2.4mmol), react at 25°C for 1 hour, add sodium cyanoborohydride (150mg, 2.4mmol), continue to react for 8 hours, LCMS detects that the reaction is complete . Aqueous sodium bicarbonate solution was added to the system, extracted with dichloromethane, the organic phase solvent was collected and spin-dried, and then reversed-phase column chromatography (methanol/water=0-40% in which each of the two phases contained 0.3% trifluoroacetic acid) to obtain The target compound was 19 mg, and the yield was 37.8%.
分子式:C 25H 24F 5N 5O 3S 分子量:569.15 LC-MS(M/e):472.5(M+H +) Molecular formula: C 25 H 24 F 5 N 5 O 3 S Molecular weight: 569.15 LC-MS (M/e): 472.5 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.06(s,1H),12.35-12.33(m,1H),12.04(s,1H),11.07(s,1H),8.09-8.07(d,J＝5.6Hz,1H),7.54-7.47(m,2H),7.10-7.08(d,J＝5.6Hz,1H),6.46-6.33(m,1H),4.91-4.89(m,2H),4.75-4.72(m,2H),4.47-4.41(m,3H),3.54-3.48(m,4H),3.12-3.10(m,2H),2.88-2.86(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.06(s, 1H), 12.35-12.33(m, 1H), 12.04(s, 1H), 11.07(s, 1H), 8.09-8.07(d, J=5.6Hz, 1H), 7.54-7.47(m, 2H), 7.10-7.08(d, J=5.6Hz, 1H), 6.46-6.33(m, 1H), 4.91-4.89(m, 2H), 4.75 -4.72(m,2H),4.47-4.41(m,3H),3.54-3.48(m,4H),3.12-3.10(m,2H),2.88-2.86(m,2H).
制备例41：6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物59)Preparation Example 41: 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2 Preparation of -d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one (Compound 59)
Figure PCTCN2022080065-appb-000104
Figure PCTCN2022080065-appb-000104
1. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d Preparation of ]imidazol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)乙酸 乙酯(130mg,0.4mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(173mg，0.6mmol)溶于四氢呋喃(20mL)，升温至40℃，氮气保护下加入LDA(2mL,4mmol)，加入完毕后反应2小时。LCMS检测反应结束。加入饱和氯化铵溶液淬灭，用乙酸乙酯和甲醇混合溶液萃取(乙酸乙酯:甲醇＝10:1(100mL×4))萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物190mg，收率90％。2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Imidazol-2-yl)ethyl acetate (130 mg, 0.4 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4 (1H)-dione (173 mg, 0.6 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was raised to 40° C., LDA (2 mL, 4 mmol) was added under nitrogen protection, and the reaction was performed for 2 hours. LCMS detected the end of the reaction. It was quenched by adding saturated ammonium chloride solution, extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1 (100mL×4)), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol) =10:1) to obtain 190 mg of the title compound with a yield of 90%.
2. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐的制备2. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl [4,5]Benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2 Preparation of -b]pyridin-7-yl trifluoromethanesulfonate
0℃下，将6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(190mg，0.36mmol)溶于二氯甲烷(100mL)中，加入吡啶(285mg,3.3mmol)和三氟甲磺酸酐(620mg,2mmol)，反应1小时。LCMS检测反应结束。浓缩溶剂，加入饱和碳酸氢钠淬灭反应，二氯甲烷(100mL×4次)萃取，有机相干燥浓缩，得标题化合物粗品390mg，不作进一步处理，投入下一步。6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1, 2-d]imidazol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (190 mg, 0.36 mmol) was dissolved in In dichloromethane (100 mL), pyridine (285 mg, 3.3 mmol) and trifluoromethanesulfonic anhydride (620 mg, 2 mmol) were added and reacted for 1 hour. LCMS detected the end of the reaction. The solvent was concentrated, saturated sodium bicarbonate was added to quench the reaction, extracted with dichloromethane (100 mL×4 times), and the organic phase was dried and concentrated to obtain 390 mg of the crude title compound, which was put into the next step without further treatment.
3. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl [4,5]Benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thieno Preparation of [3,2-b]pyridin-5(4H)-one
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐(390mg)溶于乙腈(100mL)，加入二氟乙氨(291mg,3.6mmol)，升温至40℃下反应4小时。LCMS检测反应结束。有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物140mg，两步收率66％。6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]Benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2- b] Pyridin-7-yl trifluoromethanesulfonate (390 mg) was dissolved in acetonitrile (100 mL), difluoroethylamine (291 mg, 3.6 mmol) was added, and the temperature was raised to 40° C. to react for 4 hours. LCMS detected the end of the reaction. The organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 140 mg of the title compound with a two-step yield of 66%.
4. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备4. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d Preparation of ]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(140mg,0.24mmol)置于100mL单口瓶中，加入三氟乙酸(6mL)和浓盐酸(1mL)，升温至110℃反应24小时。LCMS检测反应结束。有机相浓缩，反相柱层析纯化(水:甲醇＝10:3)得标题化合物52mg，收率57％。6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]Benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thieno[ 3,2-b]pyridin-5(4H)-one (140 mg, 0.24 mmol) was placed in a 100 mL single-necked flask, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110° C. to react for 24 hours. LCMS detected the end of the reaction. The organic phase was concentrated and purified by reverse-phase column chromatography (water:methanol=10:3) to obtain 52 mg of the title compound with a yield of 57%.
分子式:C 24H 25F 2N 5OS 分子量:469.6 LC-MS(M/e):470.2(M+H +) Molecular formula: C 24 H 25 F 2 N 5 OS Molecular weight: 469.6 LC-MS (M/e): 470.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.22(s,1H),7.99(d,J＝5.6Hz 1H),7.37(s,1H),7.28(s,1H),7.07(d,J＝5.6Hz 1H),6.57-6.29(t,J＝15.2Hz,1H),4.37-4.28(m,2H),3.12-3.08(m,4H),2.95-2.90(m,2H),2.71-2.65(m,2H),2.34(s,1H),2.26-2.23(m,1H),2.00-1.90(m,1H),1.89-1.75(m,4H),1.15-1.08(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.22(s, 1H), 7.99(d, J=5.6Hz 1H), 7.37(s, 1H), 7.28(s, 1H), 7.07(d, J=5.6Hz 1H), 6.57-6.29(t, J=15.2Hz, 1H), 4.37-4.28(m, 2H), 3.12-3.08(m, 4H), 2.95-2.90(m, 2H), 2.71- 2.65(m, 2H), 2.34(s, 1H), 2.26-2.23(m, 1H), 2.00-1.90(m, 1H), 1.89-1.75(m, 4H), 1.15-1.08(m, 2H).
制备例42：7-氨基-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物60)Preparation Example 42: 7-Amino-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazole- Preparation of 2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 60)
Figure PCTCN2022080065-appb-000105
Figure PCTCN2022080065-appb-000105
1. 7-胺基-1,2,4,5-四氢苯并[d]氧杂卓的制备1. Preparation of 7-amino-1,2,4,5-tetrahydrobenzo[d]oxazepine
将7-硝基-1,2,4,5-四氢苯并[d]氧杂卓(140mg,0.73mmol)溶于甲醇(5mL)，加入钯碳(100mg,N/A)，在氢气氛围下反应2小时。LCMS检测反应结束。过滤，收集滤液浓缩得目标化合物粗品，直接用于下一步。7-Nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine (140 mg, 0.73 mmol) was dissolved in methanol (5 mL), palladium on carbon (100 mg, N/A) was added, and the solution was heated under hydrogen The reaction was carried out under the atmosphere for 2 hours. LCMS detected the end of the reaction. After filtration, the filtrate was collected and concentrated to obtain the crude product of the target compound, which was directly used in the next step.
2. N-(1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺的制备2. Preparation of N-(1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide
将7-胺基-1,2,4,5-四氢苯并[d]氧杂卓(上一步粗品)溶于乙酸(2mL)，加入乙酸酐(2mL)，加毕15℃反应1小时。LCMS检测反应结束。加水稀释，饱和碳酸氢钠水溶液调pH＝9，二氯甲烷萃取，水相浓缩，经C18柱纯化(甲醇＝0-80％)得目标化合物100mg，两步收率66.8％。7-Amino-1,2,4,5-tetrahydrobenzo[d]oxazepine (crude product from the previous step) was dissolved in acetic acid (2 mL), acetic anhydride (2 mL) was added, and the reaction was completed at 15°C for 1 hour . LCMS detected the end of the reaction. Add water to dilute, adjust pH=9 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, concentrate the aqueous phase, and purify by C18 column (methanol=0-80%) to obtain 100 mg of the target compound with a two-step yield of 66.8%.
3. N-(8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺的制备3. Preparation of N-(8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide
将N-(1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺(100mg,0.49mmol)溶于浓硫酸(2mL)，0℃下滴加发烟硝酸(38mg,0.61mmol)，加毕，0℃下反应10min。LCMS检测反应结束。倒入冰水中，氢氧化钠水溶液调pH＝7，浓缩溶剂，固体用二氯甲烷和甲醇洗涤，有机相浓缩得目标化合物粗品，直接用于下一步。Dissolve N-(1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (100 mg, 0.49 mmol) in concentrated sulfuric acid (2 mL), add dropwise at 0°C to emit smoke Nitric acid (38 mg, 0.61 mmol) was added and reacted at 0 °C for 10 min. LCMS detected the end of the reaction. Pour into ice water, adjust pH=7 with aqueous sodium hydroxide solution, concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain the crude product of the target compound, which is directly used in the next step.
4. 8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-胺的制备4. Preparation of 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-amine
将N-(8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺(N/A,0.49mmol)溶于甲醇(5mL)，加入碳酸钾(166mg,1.2mmol)，加毕，55℃下反应8小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩，经C18柱纯化(甲醇＝0-80％)得目标化合物80mg，收率78.1％。N-(8-Nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (N/A, 0.49 mmol) was dissolved in methanol (5 mL) and added Potassium carbonate (166 mg, 1.2 mmol) was added and reacted at 55°C for 8 hours. LCMS detected the end of the reaction. Filter through celite, concentrate the filtrate, and purify by C18 column (methanol=0-80%) to obtain 80 mg of the target compound with a yield of 78.1%.
5. 2-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯的制备5. Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate Preparation of esters
将8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-胺(80mg,0.38mmol)溶于乙醇(3mL)，加入Pd/C(100mg)，加毕，15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(149mg,0.76mmol)，升至50℃反应2小时。LCMS检测反应结束。硅藻土过滤，滤液浓缩，经硅胶柱柱纯化(二氯甲烷:甲醇＝15:1)得目标化合物100mg，收率94.9％。Dissolve 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-amine (80 mg, 0.38 mmol) in ethanol (3 mL), add Pd/C (100 mg), add After completion, the hydrogenation reaction was carried out at 15°C for 2 hours. LCMS detected the end of the reaction. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (149 mg, 0.76 mmol) was added, and the temperature was raised to 50° C. to react for 2 hours. LCMS detected the end of the reaction. Filter through celite, concentrate the filtrate, and purify by silica gel column (dichloromethane:methanol=15:1) to obtain 100 mg of the target compound with a yield of 94.9%.
6. 7-氨基-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备6. 7-Amino-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazole-2- Preparation of yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(50mg,0.18mmol)、3-氨基噻吩-2-腈(27mg,0.22mmol)溶于四氢呋喃(2mL)，加入LDA(0.41mL,0.81mmol)，加毕，40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵淬灭反应，二氯甲烷萃取，有机相经干燥、浓缩、甲醇打浆得目标化合物5mg，收率7.98％。Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate (50 mg, 0.18 mmol), 3-aminothiophene-2-carbonitrile (27 mg, 0.22 mmol) were dissolved in tetrahydrofuran (2 mL), LDA (0.41 mL, 0.81 mmol) was added, the addition was completed, and the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. Saturated ammonium chloride was added to quench the reaction, extracted with dichloromethane, and the organic phase was dried, concentrated, and slurried with methanol to obtain 5 mg of the target compound with a yield of 7.98%.
分子式:C 18H 16N 4O 2S 分子量:352.1 LC-MS(M/e):353.1(M+H +) Molecular formula: C 18 H 16 N 4 O 2 S Molecular weight: 352.1 LC-MS (M/e): 353.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.78(s,1H),11.81(s,1H),10.60(s,1H),7.98-7.93(m,2H),742(d,J＝5.2Hz,2H),7.02-7.00(m,1H),3.92-3.88(m,4H),3.17-3.00(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.78(s, 1H), 11.81(s, 1H), 10.60(s, 1H), 7.98-7.93(m, 2H), 742(d, J= 5.2Hz, 2H), 7.02-7.00(m, 1H), 3.92-3.88(m, 4H), 3.17-3.00(m, 4H).
制备例43：7-((2,2-二氟乙基)氨基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物61)Preparation Example 43: 7-((2,2-difluoroethyl)amino)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5 ] Preparation of Benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 61)
Figure PCTCN2022080065-appb-000106
Figure PCTCN2022080065-appb-000106
1. 7-羟基-4-(4-甲氧基苄基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 7-Hydroxy-4-(4-methoxybenzyl)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzene Preparation of [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(5,6,8,9-四氢-1H-氧杂卓并[4’,5’:4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(500mg,1.8mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(686mg,2.4mmol)溶于四氢呋喃(10mL)。氮气保护下，40℃下加入LDA(4.5mL,5mol)，加毕，40℃下反应1小时。LCMS检测反应结束，降温至15℃，饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，有机相干燥，浓缩，得目标化合物粗品。将目标化合物粗品再次加入四氢呋喃(10mL)中，在氮气保护下加入LDA(4.5mL,5mol)，加毕，40℃下反应1小时。降温至15℃，加入饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，有机相经干燥、浓缩、硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物320mg，收率37.1％。Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate (500 mg, 1.8 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (686 mg, 2.4 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, LDA (4.5 mL, 5 mol) was added at 40°C, and the addition was completed, and the reaction was carried out at 40°C for 1 hour. LCMS detected the end of the reaction, cooled to 15°C, quenched the reaction with saturated aqueous ammonium chloride solution, extracted with dichloromethane, dried the organic phase, and concentrated to obtain the crude product of the target compound. The crude product of the target compound was added to tetrahydrofuran (10 mL) again, LDA (4.5 mL, 5 mol) was added under nitrogen protection, the addition was completed, and the reaction was carried out at 40° C. for 1 hour. The temperature was lowered to 15°C, saturated aqueous ammonium chloride solution was added to quench the reaction, extracted with dichloromethane, and the organic phase was dried, concentrated, and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 320 mg of the target compound, yield 37.1% .
2. 4-(4-甲氧基苄基)-5-氧代-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲基磺酸酯的制备2. 4-(4-Methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxa Zolo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yltris Preparation of fluoromethanesulfonate
将7-羟基-4-(4-甲氧基苄基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(320mg,0.68mmol)溶于二氯甲烷(10mL)中，0℃下加入吡啶(1.1g,13.6mmol)和三氟甲磺酸酐(1.2g,4.1mmol)，加毕，0℃下反应30分钟。LCMS检测反应结束。加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相干燥浓缩，直接用于下一步。7-Hydroxy-4-(4-methoxybenzyl)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (320 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL) and added at 0°C Pyridine (1.1 g, 13.6 mmol) and trifluoromethanesulfonic anhydride (1.2 g, 4.1 mmol) were added and reacted at 0°C for 30 minutes. LCMS detected the end of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated, which was directly used in the next step.
3. 7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备3. 7-((2,2-Difluoroethyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-5,6, 8,9-Tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridine- Preparation of 5(4H)-ketone
将4-(4-甲氧基苄基)-5-氧代-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲基磺酸酯(N/A,0.68mmol)溶于乙腈(10mL)，加入2,2-二氟乙-1-胺(440mg,5.4mmol)，加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇＝20:1)得目标化合物 130mg，两步收率28.6％4-(4-Methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxa Do[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yltrifluoro Methanesulfonate (N/A, 0.68 mmol) was dissolved in acetonitrile (10 mL), 2,2-difluoroethan-1-amine (440 mg, 5.4 mmol) was added, and the reaction was completed at 40° C. for 2 hours. LCMS detected the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol = 20: 1) to obtain 130 mg of the target compound with a two-step yield of 28.6%
4. 7-((2,2-二氟乙基)氨基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备4. 7-((2,2-Difluoroethyl)amino)-6-(5,6,8,9-tetrahydro-1H-oxazeno[4',5':4,5]benzene Preparation of [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(130mg,0.19mmol)溶于浓盐酸(1.5mL)，加入三氟乙酸(10.5mL)，加毕，升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂，二氯甲烷溶解，加入饱和碳酸氢钠水溶液，过滤，滤饼用甲醇打浆得目标化合物40mg，收率50.5％。7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-5,6,8 ,9-Tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridine-5 (4H)-ketone (130 mg, 0.19 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL), trifluoroacetic acid (10.5 mL) was added, the addition was completed, and the reaction was carried out at 110° C. for 24 hours. LCMS detected the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, saturated aqueous sodium bicarbonate solution was added, filtered, and the filter cake was slurried with methanol to obtain 40 mg of the target compound with a yield of 50.5%.
分子式:C 20H 18F 2N 4O 2S 分子量:416.4 LC-MS(M/e):417.1(M+H +) Molecular formula: C 20 H 18 F 2 N 4 O 2 S Molecular weight: 416.4 LC-MS (M/e): 417.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.96(s,1H),12.38(s,1H),12.03(s,1H),8.04(d,J＝5.2Hz,1H),7.44(s,1H),7.32(s,1H),7.07(d,J＝4.8Hz,1H),6.75-6.38(m,1H),4.38-4.31(m,2H),3.88-3.74(m,4H),3.02-2.98(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.96(s, 1H), 12.38(s, 1H), 12.03(s, 1H), 8.04(d, J=5.2Hz, 1H), 7.44(s) ,1H),7.32(s,1H),7.07(d,J＝4.8Hz,1H),6.75-6.38(m,1H),4.38-4.31(m,2H),3.88-3.74(m,4H), 3.02-2.98(m,4H).
制备例44：7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1-甲基-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物62)Preparation Example 44: 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Compound 62)
Figure PCTCN2022080065-appb-000107
Figure PCTCN2022080065-appb-000107
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(50mg,0.16mmol)溶于四氢呋喃(3mL)中，在氮气保护下加入4-氨基-1-甲基-1H-吡唑-5-腈(20mg,0.16mmol)，40℃下加入二异丙基氨基锂(0.40mL,0.80mmol)，加毕，40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵淬灭反应，用乙酸乙酯萃取，有机相经干燥、浓缩、甲醇打浆得标题化合物33mg，收率53.0％。2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (20 mg, 0.16 mmol) was added under nitrogen protection, Lithium diisopropylamide (0.40 mL, 0.80 mmol) was added at 40°C, the addition was completed, and the reaction was carried out at 40°C for 2 hours. LCMS detected the end of the reaction. Saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate, and the organic phase was dried, concentrated, and slurried with methanol to obtain 33 mg of the title compound with a yield of 53.0%.
分子式:C 21H 23N 7O 分子量:389.5 LC-MS(M/e):390.2(M+H +) Molecular formula: C 21 H 23 N 7 O Molecular weight: 389.5 LC-MS (M/e): 390.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.90(s,1H),11.23(s,1H),7.40-7.35(m,3H),4.27(s,3H),2.90-2.85(m,4H),2.75-2.65(m,4H),1.78-1.76(m,1H),0.49-0.43(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.90(s, 1H), 11.23(s, 1H), 7.40-7.35(m, 3H), 4.27(s, 3H), 2.90-2.85(m, 4H), 2.75-2.65(m, 4H), 1.78-1.76(m, 1H), 0.49-0.43(m, 4H).
制备例45：7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物63)Preparation Example 45: 7-Amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[ Preparation of 1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 63)
Figure PCTCN2022080065-appb-000108
Figure PCTCN2022080065-appb-000108
1. 2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的制备1. Preparation of 2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]rotaxen-7-one
将5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(2.0g,12.4mmol)溶于浓硫酸(20mL)，搅拌1h后，分批次缓慢加入硝酸钾(1.5g,14.9mmol)，加毕，0℃下反应2小时。LCMS检测反应结束。倒入冰水(200mL)中，乙酸乙酯(100mL×4次)萃取，有机相干燥浓缩，硅胶柱纯化(正庚烷:乙酸乙酯＝5:1)得标题化合物2.0g，收率79％。5,6,8,9-Tetrahydro-7H-benzo[7]rotaxen-7-one (2.0 g, 12.4 mmol) was dissolved in concentrated sulfuric acid (20 mL), and after stirring for 1 h, nitric acid was slowly added in batches Potassium (1.5 g, 14.9 mmol) was added and reacted at 0°C for 2 hours. LCMS detected the end of the reaction. Poured into ice water (200 mL), extracted with ethyl acetate (100 mL×4 times), the organic phase was dried and concentrated, and purified by silica gel column (n-heptane:ethyl acetate=5:1) to obtain the title compound 2.0g, yield 79 %.
2. 1-(2-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-7-基)氮杂环丁烷的制备2. Preparation of 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-7-yl)azetidine
将2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(2.0g,9.7mmol)溶于甲醇(100mL)中，加入氰基硼氢化钠(1.6g,23.5mmol)和氮杂环丁烷(673mg,11.8mmol)，加毕，35℃下反应12小时。LCMS检测反应结束。浓缩溶剂，加入饱和碳酸氢钠淬灭反应，乙酸乙酯(100mL×4次)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物2.3g，收率96％。2-Nitro-5,6,8,9-tetrahydro-7H-benzo[7]rotaxen-7-one (2.0 g, 9.7 mmol) was dissolved in methanol (100 mL), cyanoborohydrogenation was added Sodium (1.6 g, 23.5 mmol) and azetidine (673 mg, 11.8 mmol) were added and reacted at 35°C for 12 hours. LCMS detected the end of the reaction. The solvent was concentrated, saturated sodium bicarbonate was added to quench the reaction, extracted with ethyl acetate (100 mL×4 times), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain the title compound 2.3 g, yield 96%.
3. 7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺的制备3. Preparation of 7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxene-2-amine
将1-(2-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-7-基)氮杂环丁烷(2.3g,9.3mmol)溶于甲醇(100mL)，加入雷尼镍(790mg,9.3mmol)，30℃下反应4小时。LCMS检测反应结束。硅藻土抽滤，浓缩得标题化合物1.6g，粗品收率80％。1-(2-Nitro-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-7-yl)azetidine (2.3 g, 9.3 mmol) was dissolved in methanol ( 100 mL), Raney nickel (790 mg, 9.3 mmol) was added, and the reaction was carried out at 30° C. for 4 hours. LCMS detected the end of the reaction. Suction filtration through celite, and concentration to obtain 1.6 g of the title compound with a crude yield of 80%.
4. N-(7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺的制备4. Preparation of N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)acetamide
将7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺(1.6g,7.5mmol)置于100mL单口瓶中，加入乙酸(5mL)和乙酸酐(5mL)，25℃反应1小时。LCMS检测反应结束。浓缩半干，用饱和碳酸氢钠淬灭，用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇＝5:1)(100mL×4次)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物1.5g，收率78％。7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-amine (1.6 g, 7.5 mmol) was placed in a 100 mL single port In the bottle, acetic acid (5 mL) and acetic anhydride (5 mL) were added, and the reaction was carried out at 25° C. for 1 hour. LCMS detected the end of the reaction. Concentrated to semi-dry, quenched with saturated sodium bicarbonate, extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate: methanol = 5:1) (100 mL × 4 times), the organic phase was dried and concentrated, and purified by silica gel column (dichloromethane). Methane:methanol=10:1) to obtain 1.5 g of the title compound with a yield of 78%.
5. N-(7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺的制备5. N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)ethyl Preparation of amides
将N-(7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺(1.5g,5.9mmol)溶于浓硫酸(15mL)中，0℃下搅拌1小时,分批次加入硝酸钾(656mg,6.5mmol)，加毕，0℃反应1小时。LCMS检测反应结束。倒入冰水中，用饱和碳酸钠淬灭反应，用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇＝10:1)(200mL×4次)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物1.6g，收率89％。N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)acetamide (1.5 g, 5.9 mmol) was dissolved in concentrated sulfuric acid (15 mL), stirred at 0 °C for 1 hour, potassium nitrate (656 mg, 6.5 mmol) was added in batches, the addition was completed, and the reaction was carried out at 0 °C for 1 hour. LCMS detected the end of the reaction. Poured into ice water, quenched the reaction with saturated sodium carbonate, extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate: methanol = 10:1) (200 mL × 4 times), the organic phase was dried and concentrated, and purified by silica gel column (2 Chloromethane: methanol = 10: 1) to obtain 1.6 g of the title compound with a yield of 89%.
6. 7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺的制备6. Preparation of 7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]rotaxene-2-amine
将N-(7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺(1.6g,5.3mmol)溶于甲醇(100mL)，加入碳酸钾(2.2g,15.8mmol)，加毕，50℃下继续反应4小时。LCMS检测反应结束。硅藻土抽滤，有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇酯＝10:1)得标题化合物854mg，收率62％。N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)acetamide (1.6 g, 5.3 mmol) was dissolved in methanol (100 mL), potassium carbonate (2.2 g, 15.8 mmol) was added, the addition was completed, and the reaction was continued at 50° C. for 4 hours. LCMS detected the end of the reaction. Filter through celite with suction, dry the organic phase and concentrate on silica gel column purification (dichloromethane:methanol ester=10:1) to obtain 854 mg of the title compound with a yield of 62%.
7. 2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯的制备7. 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Preparation of imidazol-2-yl)ethyl acetate
将7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺(854mg,3.3mmol) 溶于乙醇(50mL)，加入Pd/C(489mg,1.7mmol)，加毕，25℃下氢化反应8小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.5g,7.9mmol)，升温至50℃，搅拌回流反应3小时，LCMS检测反应结束。加入硅藻土过滤，有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇酯＝10:1)得标题化合物755mg，两步收率70.6％。7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]cycloen-2-amine (854 mg, 3.3 mmol) Dissolve in ethanol (50 mL), add Pd/C (489 mg, 1.7 mmol), complete the addition, and conduct hydrogenation reaction at 25° C. for 8 hours. LCMS detected the end of the reaction. 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.5 g, 7.9 mmol) was added, the temperature was raised to 50° C., and the reaction was stirred and refluxed for 3 hours, and the reaction was completed by LCMS detection. After adding celite for filtration, the organic phase was dried and concentrated and purified by silica gel column (dichloromethane:methanol ester=10:1) to obtain 755 mg of the title compound, with a two-step yield of 70.6%.
8. 7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备8. 7-Amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1, Preparation of 2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(755mg,2.3mmol)和2-氰基-3-氨基噻酚(682mg,5.5mmol)溶于四氢呋喃(15mL)中，氮气保护下升温至40℃，缓慢加入LDA(1.2mmol,0.6mL)，加毕，40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥浓缩，用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇＝10:1)(200mL×4次)萃取，有机相干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物401mg，收率：43％。2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazole -2-yl)ethyl acetate (755 mg, 2.3 mmol) and 2-cyano-3-aminothiophene (682 mg, 5.5 mmol) were dissolved in tetrahydrofuran (15 mL), heated to 40 °C under nitrogen protection, and LDA was slowly added (1.2 mmol, 0.6 mL), the addition was completed, and the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. Saturated aqueous ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate, the organic phase was dried and concentrated, extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1) (200 mL×4 times), and the organic phase was dried Concentration and silica gel column purification (dichloromethane:methanol=10:1) gave 401 mg of the title compound, yield: 43%.
分子式:C 22H 23N 5OS 分子量:405.5 LC-MS(M/e):406.1(M+H +) Molecular formula: C 22 H 23 N 5 OS Molecular weight: 405.5 LC-MS (M/e): 406.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.73(s,1H),11.79(s,1H),7.94-7.93(d,J＝5.2Hz,1H),7.38(s,1H),7.33(s,1H),7.01-7.00(d,J＝5.2Hz,1H),3.12-3.09(m,4H),2.93-2.92(m,2H),2.70-2.63(m,2H),2.49-2.51(m,1H),1.90-1.80(m,4H),1.30-1.23(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.73(s, 1H), 11.79(s, 1H), 7.94-7.93(d, J=5.2Hz, 1H), 7.38(s, 1H), 7.33 (s,1H),7.01-7.00(d,J＝5.2Hz,1H),3.12-3.09(m,4H),2.93-2.92(m,2H),2.70-2.63(m,2H),2.49-2.51 (m,1H),1.90-1.80(m,4H),1.30-1.23(m,2H).
制备例46：7-(异丙基氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物64)Preparation Example 46: 7-(isopropylamino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4', Preparation of 5:4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 64)
Figure PCTCN2022080065-appb-000109
Figure PCTCN2022080065-appb-000109
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(120mg,0.30mmol)溶于甲醇(10mL)中，加入3-氧杂环丁酮(90mg,0.54mmol)和乙酸(186mg,0.18mmol)，25℃反应30分钟后，加入氰基硼氢化钠(96mg,0.54mmol)，加毕，35℃反应16小时。LCMS检测反应结束。加入饱和碳酸氢钠调节pH＝8，用二氯甲烷(40mL)萃取，用硅胶柱层析分离(甲醇:二氯甲烷＝1:15)得目标化合物60mg，收率43.8％。6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(Isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (120 mg, 0.30 mmol) was dissolved in methanol (10 mL), 3-oxetanone (90 mg, 0.54 mmol) was added mmol) and acetic acid (186 mg, 0.18 mmol), react at 25° C. for 30 minutes, then add sodium cyanoborohydride (96 mg, 0.54 mmol), and after the addition, react at 35° C. for 16 hours. LCMS detected the end of the reaction. Saturated sodium bicarbonate was added to adjust pH=8, extracted with dichloromethane (40 mL), and separated by silica gel column chromatography (methanol:dichloromethane=1:15) to obtain 60 mg of the target compound with a yield of 43.8%.
分子式:C 24H 27N 5O 2S 分子量:449.6 LC-MS(M/e):450.2(M+H +) Molecular formula: C 24 H 27 N 5 O 2 S Molecular weight: 449.6 LC-MS (M/e): 450.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.00(s,1H),12.15(d,J＝8.2,1H),11.86(s,1H),8.03(d,J＝5.2,1H),7.40(s,1H),7.34(s,1H),7.04(s,1H),4.54-4.45(m,5H),3.49-3.47(m,1H),3.01-2.85(m,4H),2.49-2.25(m,4H),1.50-1.40(m,6H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 13.00(s, 1H), 12.15(d, J=8.2, 1H), 11.86(s, 1H), 8.03(d, J=5.2, 1H), 7.40(s, 1H), 7.34(s, 1H), 7.04(s, 1H), 4.54-4.45(m, 5H), 3.49-3.47(m, 1H), 3.01-2.85(m, 4H), 2.49- 2.25(m,4H),1.50-1.40(m,6H).
制备例47：6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物65)Preparation Example 47: 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2- d] Imidazol-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (Compound 65)
Figure PCTCN2022080065-appb-000110
Figure PCTCN2022080065-appb-000110
1. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备1. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]Benzo[1,2-d]imidazol-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine Preparation of -5(4H)-one
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-2,3,4,5-四氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐(315mg,0.4mmol)和异丙胺(235mg,4mmol)溶于乙腈(50mL)，升温至40℃后反应3小时。LCMS检测反应结束。柱层析分离，硅胶柱纯化(二氯甲烷:甲醇＝10:1)得标题化合物157mg，收率56.5％。6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocyclohepta[4, 5]Benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrothieno[3, 2-b] Pyridin-7-yl trifluoromethanesulfonate (315 mg, 0.4 mmol) and isopropylamine (235 mg, 4 mmol) were dissolved in acetonitrile (50 mL), and the temperature was raised to 40° C. and reacted for 3 hours. LCMS detected the end of the reaction. It was separated by column chromatography and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 157 mg of the title compound with a yield of 56.5%.
2. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备2. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Preparation of imidazol-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(157mg,0.22mmol)置于100mL单口瓶中，加入三氟乙酸(6mL)和浓盐酸(1mL)，升温至110℃反应24小时。LCMS检测反应结束。有机相浓缩，经反相柱层析纯化(水:甲醇＝10:3)得目标化合物38mg，收率39％。6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[4 ,5]Benzo[1,2-d]imidazol-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine- 5(4H)-ketone (157 mg, 0.22 mmol) was placed in a 100 mL single-neck flask, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110° C. to react for 24 hours. LCMS detected the end of the reaction. The organic phase was concentrated and purified by reverse-phase column chromatography (water:methanol=10:3) to obtain 38 mg of the target compound with a yield of 39%.
分子式:C 25H 29N 5OS 分子量:447.6 LC-MS(M/e):480.2(M+H +) Molecular formula: C 25 H 29 N 5 OS Molecular weight: 447.6 LC-MS (M/e): 480.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:13.08-13.03(d,J＝5.2Hz,1H),12.15-12.13(d,J＝5.2Hz,1H),8.02-8.00(d,J＝5.2Hz,1H),7.43-7.37(d,J＝5.2Hz,1H),7.30(s,1H),7.06(s,1H),7.04(s,1H),4.43-4.48(m,1H),3.08-3.30(m,4H),2.6-2.7(m,2H),2.49-2.51(m,2H),2.32-2.30(m,1H),2.24-2.23(m,4H),2.22-2.00(m,6H),1.89-1.97(m,2H). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 13.08-13.03 (d, J=5.2 Hz, 1H), 12.15-12.13 (d, J=5.2 Hz, 1H), 8.02-8.00 (d, J= 5.2Hz, 1H), 7.43-7.37(d, J=5.2Hz, 1H), 7.30(s, 1H), 7.06(s, 1H), 7.04(s, 1H), 4.43-4.48(m, 1H), 3.08-3.30(m, 4H), 2.6-2.7(m, 2H), 2.49-2.51(m, 2H), 2.32-2.30(m, 1H), 2.24-2.23(m, 4H), 2.22-2.00(m ,6H),1.89-1.97(m,2H).
制备例48：2-(7-氨基-1-甲基-5-氧代-4,5-二氢-1H-吡唑并[4,3-b]吡啶-6-基)-7-环丙基-5,7,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-6(1H)-酮(化合物66)Preparation 48: 2-(7-Amino-1-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-6-yl)-7-cyclo Propyl-5,7,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-6(1H)-one (Compound 66)
Figure PCTCN2022080065-appb-000111
Figure PCTCN2022080065-appb-000111
将2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯(200mg,0.61mmol)溶于四氢呋喃(10mL)中，加入4-氨基-1-甲基-1H-吡唑-5-甲腈(89mg,0.73mmol)，40℃滴加LDA(2.44mL,4.88mmol)，继续反应6h，LCMS检测反应完成。倒入饱和氯化铵水溶液中淬灭，乙酸乙酯萃取，有机相旋干,甲醇打浆得目标化合物粗品40mg，经反相色谱纯化(甲醇:水＝0-50％)得目标化合物2.4mg，收率1.0％。2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d ] ethyl azepin-2-yl)acetate (200 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (89 mg, 0.73 mmol) was added ), LDA (2.44 mL, 4.88 mmol) was added dropwise at 40° C., the reaction was continued for 6 h, and the reaction was completed by LCMS detection. It was poured into saturated aqueous ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, slurried with methanol to obtain 40 mg of crude target compound, which was purified by reverse phase chromatography (methanol:water=0-50%) to obtain 2.4 mg of target compound, Yield 1.0%.
分子式:C 21H 21N 7O 2 分子量:403.4 LC-MS(M/e):404.1(M+H +) Molecular formula: C 21 H 21 N 7 O 2 Molecular weight: 403.4 LC-MS (M/e): 404.1 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.93(d,J＝10.4Hz,1H),11.23(d,J＝7.9Hz,1H),7.35-7.45 (m,3H),4.46(s,3H),4.26(s,3H),3.88(d,J＝11.6Hz,2H),3.71(t,J＝5.4Hz,2H),3.15-3.19(m,2H),2.68-2.72(m,1H),0.68-0.73(m,2H),0.50-0.60(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.93 (d, J=10.4 Hz, 1H), 11.23 (d, J=7.9 Hz, 1H), 7.35-7.45 (m, 3H), 4.46 (s ,3H),4.26(s,3H),3.88(d,J=11.6Hz,2H),3.71(t,J=5.4Hz,2H),3.15-3.19(m,2H),2.68-2.72(m, 1H),0.68-0.73(m,2H),0.50-0.60(m,2H).
制备例49：7-氨基-1-甲基-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物67)Preparation Example 49: 7-Amino-1-methyl-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one Preparation (Compound 67)
Figure PCTCN2022080065-appb-000112
Figure PCTCN2022080065-appb-000112
1. 8-硝基-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备1. Preparation of 8-nitro-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine
将8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(500mg,5.42mmol)、氧杂环丁酮(523mg,7.26mmol)溶于甲醇(20mL)中，加入乙酸(1.5g,24.2mmol)和氰基硼氢化钠(900mg,14.5mmol)，25℃下反应16h，LCMS检测反应完成。用饱和碳酸氢钠水溶液调节pH＝7-8，二氯甲烷萃取，有机相旋干，硅胶柱纯化(二氯甲烷:甲醇＝15:1)得目标化合物420mg，收率66.0％。Dissolve 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (500 mg, 5.42 mmol) and oxetanone (523 mg, 7.26 mmol) In methanol (20 mL), acetic acid (1.5 g, 24.2 mmol) and sodium cyanoborohydride (900 mg, 14.5 mmol) were added, and the reaction was carried out at 25° C. for 16 h, and the reaction was completed by LCMS. Adjust pH=7-8 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, spin dry the organic phase, and purify on silica gel column (dichloromethane:methanol=15:1) to obtain 420 mg of the target compound with a yield of 66.0%.
2. 2-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备2. 2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azepin-2-yl)ethyl acetate
将8-硝基-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(420mg,1.6mmol)溶于乙醇(10mL)中，加入Pd/C(200mg)，25℃下氢化反应2小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(657mg,3.36mmol)，升温至50℃继续反应4h。LCMS检测反应完成。硅藻土过滤，滤液旋干，二氯甲烷稀释，饱和碳酸氢钠洗涤，有机相旋干，经硅胶柱纯化(二氯甲烷:甲醇＝10:1)得目标化合物370mg，收率70.1％。8-Nitro-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (420 mg, 1.6 mmol ) was dissolved in ethanol (10 mL), added with Pd/C (200 mg), and hydrogenated at 25°C for 2 hours. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (657 mg, 3.36 mmol) was added, and the temperature was raised to 50° C. to continue the reaction for 4 h. The reaction was complete by LCMS. Filter through celite, spin dry the filtrate, dilute with dichloromethane, wash with saturated sodium bicarbonate, spin dry the organic phase, and purify by silica gel column (dichloromethane:methanol=10:1) to obtain 370 mg of the target compound with a yield of 70.1%.
3. 7-氨基-1-甲基-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备3. 7-Amino-1-methyl-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5' : Preparation of 4,5]benzo[1,2-d]azepin-2-yl)-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one
将2-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(80mg,0.24mmol)溶于四氢呋喃(5mL)中，加入4-氨基-1-甲基-1H-吡唑-5-甲腈(29mg,0.24mmol)，45℃下滴加LDA(0.96mL,1.92mmol)，继续反应5h，LCMS检测反应完成。倒入饱和氯化铵水溶液中淬灭，乙酸乙酯萃取，有机相旋干,甲醇打浆得目标化合物17.5mg，收率17.8％。2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Ethyl 2-d]azepin-2-yl)acetate (80 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (29 mg) was added , 0.24 mmol), LDA (0.96 mL, 1.92 mmol) was added dropwise at 45° C., the reaction was continued for 5 h, and the reaction was completed by LCMS detection. It was poured into saturated aqueous ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, and slurried with methanol to obtain 17.5 mg of the target compound with a yield of 17.8%.
分子式:C 21H 23N 7O 2 分子量:405.5 LC-MS(M/e):406.2(M+H +) Molecular formula: C 21 H 23 N 7 O 2 Molecular weight: 405.5 LC-MS (M/e): 406.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.90(s,1H),11.23(s,1H),7.30-7.45(m,3H),4.40-4.58(m,4H),4.26(s,3H),3.40-3.50(m,1H),2.85-2.95(m,4H),2.35-2.45(m,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.90(s, 1H), 11.23(s, 1H), 7.30-7.45(m, 3H), 4.40-4.58(m, 4H), 4.26(s, 3H), 3.40-3.50(m, 1H), 2.85-2.95(m, 4H), 2.35-2.45(m, 4H).
制备例50：7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基并[4,5]苯并[1,2-d]咪唑-2-基)-1-甲基-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物68)Preparation Example 50: 7-Amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocyclohepta[4,5]benzo Preparation of [1,2-d]imidazol-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Compound 68)
Figure PCTCN2022080065-appb-000113
Figure PCTCN2022080065-appb-000113
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(200mg,0.61mmol)和3-氨基-1,5-二甲基-1氢-吡咯-2-氰基(112mg,0.92mmol)溶于四氢呋喃(50mL)中，氮气保护下升温至40℃，缓慢加入LDA(3.1mL,6.1mmoL)，加毕，40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥浓缩，用乙酸乙酯/甲醇混合溶剂(乙酸乙酯:甲醇＝10:1,200mL×4次)萃取，有机相干燥浓缩，经反相柱层析纯化(水:甲醇＝10:4)得目标化合物100mg，收率40.6％。2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazole -2-yl)ethyl acetate (200 mg, 0.61 mmol) and 3-amino-1,5-dimethyl-1hydro-pyrrole-2-cyano (112 mg, 0.92 mmol) were dissolved in tetrahydrofuran (50 mL), The temperature was raised to 40° C. under nitrogen protection, and LDA (3.1 mL, 6.1 mmol) was slowly added. After the addition was completed, the reaction was carried out at 40° C. for 2 hours. LCMS detected the end of the reaction. Saturated aqueous ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate, the organic phase was dried and concentrated, extracted with ethyl acetate/methanol mixed solvent (ethyl acetate:methanol=10:1, 200 mL×4 times), the organic phase was dried and concentrated, Purified by reverse-phase column chromatography (water:methanol=10:4) to obtain 100 mg of the target compound with a yield of 40.6%.
分子式:C 22H 25N 7O 分子量:403.5 LC-MS(M/e):404.2(M+H +) Molecular formula: C 22 H 25 N 7 O Molecular weight: 403.5 LC-MS (M/e): 404.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.87(s,1H),11.21(s,1H),7.39-7.33(m,3H),4.27(s,3H),7.33(s,1H),3.17-3.08(m,4H),2.98-2.94(m,2H),2.67-2.56(m,2H),2.33-2.26(m,1H),1.99-1.85(m,4H),1.23-1.4(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.87(s, 1H), 11.21(s, 1H), 7.39-7.33(m, 3H), 4.27(s, 3H), 7.33(s, 1H) ,3.17-3.08(m,4H),2.98-2.94(m,2H),2.67-2.56(m,2H),2.33-2.26(m,1H),1.99-1.85(m,4H),1.23-1.4( m, 2H).
制备例51：4-氨基-5-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1-甲基-1,7-二氢-6H-吡唑[3,4-b]吡啶-6-酮的制备(化合物69)Preparation Example 51: 4-Amino-5-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (Compound 69)
Figure PCTCN2022080065-appb-000114
Figure PCTCN2022080065-appb-000114
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.32mmol)溶于四氢呋喃(5mL)，在氮气保护下加入6-甲基-1-甲基-1H-吡唑-4-腈(39mg,0.32mmol)，40℃下加入LDA(2M,1.3mL,2.6mmol)，加毕，40℃下反应3小时。LCMS检测反应结束。倒入饱和氯化铵溶液中淬灭反应，乙酸乙酯萃取，有机相经干燥、浓缩后，经甲醇和二氯甲烷打浆得目标化合物10mg，收率8.1％。2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), 6-methyl-1-methyl-1H-pyrazole-4-carbonitrile (39 mg, 0.32 mmol) was added under nitrogen protection, LDA (2M, 1.3 mL, 2.6 mmol) was added at 40°C, the addition was completed, and the reaction was carried out at 40°C for 3 hours. LCMS detected the end of the reaction. The reaction was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and slurried with methanol and dichloromethane to obtain 10 mg of the target compound with a yield of 8.1%.
分子式:C 21H 23N 7O 2 分子量:389.5 LC-MS(M/e):390.2(M+H +) Molecular formula: C 21 H 23 N 7 O 2 Molecular weight: 389.5 LC-MS (M/e): 390.2 (M+H + )
1H-NMR(400MHz,DMSO-d 6)δ:12.17(s,1H),10.71(s,1H),10.55(s,1H),7.60(s,1H),7.33(s,1H),7.25(s,1H),7.10(s,1H),2.92(s,3H),2.91(s,4H),4.40-2.72(s,4H),1.75(s,1H),0.37-0.46(d,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ: 12.17(s, 1H), 10.71(s, 1H), 10.55(s, 1H), 7.60(s, 1H), 7.33(s, 1H), 7.25 (s,1H),7.10(s,1H),2.92(s,3H),2.91(s,4H),4.40-2.72(s,4H),1.75(s,1H),0.37-0.46(d,4H) ).
使用与上述制备例相同或相似的方法制备了以下表格所示的化合物：The compounds shown in the following tables were prepared using the same or similar methods as the above preparations:
Figure PCTCN2022080065-appb-000115
Figure PCTCN2022080065-appb-000115
Figure PCTCN2022080065-appb-000116
Figure PCTCN2022080065-appb-000116
实验方案Experimental program
以下提供本发明部分化合物的示例性实验方案，以显示本发明化合物有利活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。Exemplary experimental protocols for some of the compounds of the present invention are provided below to demonstrate the beneficial activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental scheme is only an example of the content of the present invention, rather than a limitation of the scope of the present invention.
实验例1本发明化合物对体外激酶活性的抑制实验Experimental Example 1 Inhibition Experiment of the Compounds of the Invention on In Vitro Kinase Activity
测试物：本发明部分化合物，其结构式和制备方法见本发明制备例。Test substance: some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
下述实验中所用缩写代表的含义如下：The abbreviations used in the experiments below have the following meanings:
DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;
HEPES：羟乙基哌嗪乙硫磺酸HEPES: hydroxyethylpiperazine ethanethiosulfonic acid
实验方法：用Lantha screen Assay方法，在体外6个激酶上对化合物进行评价。Experimental methods: Compounds were evaluated on 6 kinases in vitro using the Lantha screen Assay method.
实验步骤：Experimental steps:
1.制备含50mM HEPES溶液，10mM氯化镁，4mM二硫苏糖醇，0.01％牛血清白蛋白和0.01％吐温-20的1×激酶缓冲液：1. Prepare 1X Kinase Buffer containing 50 mM HEPES solution, 10 mM magnesium chloride, 4 mM dithiothreitol, 0.01% bovine serum albumin and 0.01% Tween-20:
2.化合物稀释：2. Compound dilution:
1)取90μl的100％DMSO，再加入10μl 10mM化合物溶液，即配制成1mM化合物溶液。在96孔板上第二个孔中加入90μl的100％DMSO，再加入10μl 1mM化合物溶液，即配制成100μM化合物溶液，其他孔加入60μl的100％DMSO。从第二孔中取30μl化合物加入第三孔中，依次往下做3倍稀释，共稀释10个浓度。1) Take 90 μl of 100% DMSO and add 10 μl of 10 mM compound solution to prepare a 1 mM compound solution. Add 90 μl of 100% DMSO to the second well of the 96-well plate, and then add 10 μl of 1mM compound solution to prepare a 100 μM compound solution, and add 60 μl of 100% DMSO to other wells. Take 30 μl of compound from the second well and add it to the third well, and make 3-fold dilutions in sequence, with a total of 10 dilutions.
转移40μl上述配制的100μM化合物溶液到384孔Echo板中；Transfer 40 μl of the 100 μM compound solution prepared above to a 384-well Echo plate;
2)转移40μl 100％DMSO到两个空孔中作为不加化合物的阳性对照和不加酶的阴性对照；2) Transfer 40 μl of 100% DMSO to two empty wells as a positive control without compound and a negative control without enzyme;
3)使用Echo 550转移100nl化合物到384孔测试板中，化合物的检测起始浓度为1μM。3) Use Echo 550 to transfer 100nl of compound to 384-well assay plate, and the starting concentration of compound for detection is 1 μM.
3.用1×激酶缓冲液配置2×激酶溶液，转移5μl 2×激酶溶液到384孔板反应孔中，阴性对照孔加入1×激酶缓冲液，450转/分钟振荡混匀，室温下静置孵育10分钟。3. Prepare 2× kinase solution with 1× kinase buffer, transfer 5 μl of 2× kinase solution to the reaction well of 384-well plate, add 1× kinase buffer to the negative control well, shake and mix at 450 rpm, and let stand at room temperature Incubate for 10 minutes.
4.用1×激酶缓冲液配置2×底物溶液，转移5μl 2×底物溶液到384孔板反应孔中，450转/分钟振荡混匀。4. Prepare 2× substrate solution with 1× kinase buffer, transfer 5 μl of 2× substrate solution to the reaction well of 384-well plate, and mix by shaking at 450 rpm.
5.室温进行反应90分钟。5. The reaction was carried out at room temperature for 90 minutes.
6.配置2×含抗体的终止反应液，转移10μl 2×终止反应液到384孔板反应孔中，1000转/分钟离心1分钟，室温放置60分钟，检测。6. Prepare 2× stop reaction solution containing antibody, transfer 10 μl of 2× stop reaction solution to reaction wells of 384-well plate, centrifuge at 1000 rpm for 1 minute, and place at room temperature for 60 minutes for detection.
7.数据读取：Envision2104 Multilable Reader上读取在340nm处激发，520nm和495nm处发射的数值。7. Data reading: read the values of excitation at 340nm, emission at 520nm and 495nm on Envision2104 Multilable Reader.
8.数据计算8. Data calculation
1)将荧光读数的数值比(Lantha signal(520nm/495nm))通过公式转换为抑制百分率：1) Convert the numerical ratio of fluorescence readings (Lantha signal (520nm/495nm)) to percent inhibition by the formula:
抑制百分率＝(最大值-Lantha signal)/(最大值-最小值)*100Inhibition percentage = (max-Lantha signal)/(max-min)*100
“最小值”为不加酶的阴性对照样孔读数；“最大值”为不加化合物的阳性对照孔读数。The "minimum" is the negative control well reading without enzyme; the "maximum" is the positive control well reading without compound.
2)将数据导入MS Excel，IC 50结果使用XLFit excel add-in version 5.4.0.8进行曲线拟合。 2) The data were imported into MS Excel, and the IC 50 results were curve-fitted using XLFit excel add-in version 5.4.0.8.
实验结果Experimental results
表1本发明化合物体外酶学抑制活性Table 1 In vitro enzymatic inhibitory activity of the compounds of the present invention
Figure PCTCN2022080065-appb-000117
Figure PCTCN2022080065-appb-000117
Figure PCTCN2022080065-appb-000118
Figure PCTCN2022080065-appb-000118
Figure PCTCN2022080065-appb-000119
Figure PCTCN2022080065-appb-000119
实验结论Experimental results
本发明化合物对MAP4K1/HPK1有很好的抑制活性，并且本发明化合物对HPK1具有优异的选择性。The compounds of the present invention have good inhibitory activity on MAP4K1/HPK1, and the compounds of the present invention have excellent selectivity for HPK1.
实验例2本发明化合物对体外细胞学活性的抑制实验Experimental Example 2 Inhibition test of the compounds of the present invention on cytological activity in vitro
测试物：本发明部分化合物，其结构式和制备方法见本发明制备例。Test substance: some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
下述实验中所用缩写代表的含义如下：The abbreviations used in the experiments below have the following meanings:
ELISA：酶联免疫吸附试验；ELISA: enzyme-linked immunosorbent assay;
Jurkat：人急性T细胞白血病细胞；Jurkat: human acute T-cell leukemia cells;
SLP76：含SH2结构域的76kDa白细胞蛋白；SLP76: 76kDa leukocyte protein with SH2 domain;
CD3：分化簇3(白细胞分化抗原)；CD3: cluster of differentiation 3 (leukocyte differentiation antigen);
PBS缓冲液：磷酸盐平衡生理盐水；PBS buffer: Phosphate-balanced saline;
TMB：3,3',5,5'-四甲基联苯胺。TMB: 3,3',5,5'-tetramethylbenzidine.
实验方法：用ELISA方法，在体外Jurkat细胞上检测化合物对SLP76的376位丝氨酸磷酸化的抑制水平。Experimental method: ELISA method was used to detect the inhibitory level of compounds on the phosphorylation of serine 376 of SLP76 in Jurkat cells in vitro.
实验步骤：Experimental steps:
1.细胞准备：收获对数生长期的Jurkat细胞，调整至合适的细胞浓度；每孔81μL细胞悬液加至96孔板中。1. Cell preparation: Harvest Jurkat cells in logarithmic growth phase and adjust to an appropriate cell concentration; add 81 μL of cell suspension per well to a 96-well plate.
2.药物稀释和加药：2. Drug dilution and dosing:
1)配制10倍药物溶液，最高浓度为3μM，3倍稀释，6个浓度；1) Prepare 10 times the drug solution, the highest concentration is 3 μM, 3 times dilution, 6 concentrations;
2)在接种有细胞的96孔板中每孔加入9μL药物溶液，每个药物浓度设置两个复孔。将96孔板中的细胞置于37℃、5％CO 2条件下培养1h。 2) Add 9 μL of drug solution to each well of the 96-well plate seeded with cells, and set two duplicate wells for each drug concentration. The cells in the 96-well plate were cultured for 1 h at 37°C and 5% CO 2 .
3.细胞刺激：每孔加入10μL 50μg/mL的CD3抗体处理30min，裂解细胞进行pSLP76检测。3. Cell stimulation: 10 μL of 50 μg/mL CD3 antibody was added to each well for 30 min, and the cells were lysed for pSLP76 detection.
4.细胞收集、裂解4. Cell collection and lysis
1)将细胞吹起转移到离心管中，3000rpm 4℃离心3min；1) Blow up the cells and transfer them to a centrifuge tube, centrifuge at 3000rpm and 4°C for 3min;
2)弃上清液，加入100μL/孔预冷的PBS缓冲液重悬，3000rpm 4℃离心3min；2) Discard the supernatant, add 100 μL/well of pre-cooled PBS buffer to resuspend, and centrifuge at 3000 rpm and 4 °C for 3 min;
3)弃上清液，加入100μL/管细胞裂解液；3) Discard the supernatant and add 100 μL/tube of cell lysate;
4)超声裂解5min，14000rpm离心5min。4) Ultrasonic lysis for 5 min, and centrifugation at 14000 rpm for 5 min.
5.pSLP76检测5. pSLP76 detection
1)转移50μL/孔样品上清液到96孔板中；1) Transfer 50 μL/well of sample supernatant to a 96-well plate;
2)加入50μL/孔混合抗体；2) Add 50 μL/well of mixed antibody;
3)室温震荡1h；3) Shake at room temperature for 1h;
4)弃上清液，用清洗液清洗3次，200μL/孔；4) Discard the supernatant, wash three times with washing solution, 200 μL/well;
5)加入100μL/孔TMB底物，室温震荡15min；5) Add 100 μL/well of TMB substrate and shake at room temperature for 15 min;
6)加入100μL/孔终止液，30min内在450nm下检测。6) Add 100 μL/well of stop solution, and detect at 450 nm within 30 min.
6、数据处理6. Data processing
使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 Data were analyzed using GraphPad Prism 5.0 software, and a dose-response curve was fitted to the data using nonlinear S-curve regression, from which IC50 values were calculated.
pSLP76抑制(％)＝(测试物孔读数-细胞不加CD3孔读数均值)/(细胞加CD3孔读数均值-细胞不加CD3孔读数均值)×100％Inhibition of pSLP76 (%) = (well readings of test substance - mean readings of cells without CD3 well)/(mean readings of cells plus CD3 wells - mean readings of cells without CD3 wells) x 100%
实验结论Experimental results
实验结果证明，本发明化合物对MAP4K1/HPK1下游蛋白SLP76的376位丝氨酸磷酸化有很好的抑制活性，例如化合物1、化合物10、化合物11、化合物12、化合物14-1、化合物15、化合物23-1、化合物26、化合物49、化合物50、化合物53、化合物55、化合物58、化合物63、化合物64等的IC 50值均小于100nM，即本发明化合物对HPK1具有很好的抑制活性。 The experimental results show that the compounds of the present invention have good inhibitory activity on the phosphorylation of serine 376 of the downstream protein SLP76 of MAP4K1/HPK1, such as compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, compound 23 -1. The IC 50 values of compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64, etc. are all less than 100 nM, that is, the compounds of the present invention have good inhibitory activity on HPK1.

Claims (14)

  1. 式(I)所示化合物、其药学上可接受的盐或其立体异构体，The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer,
    Figure PCTCN2022080065-appb-100001
    Figure PCTCN2022080065-appb-100001
    其中，in,
    X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
    X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
    Y 2、Y 4分别独立地选自-C(R 2)或-N-； Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
    Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
    Y 5选自-C(R 6)； Y 5 is selected from -C(R 6 );
    Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
    各R 2、R 3、各R 4分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； Each R 2 , R 3 , and each R 4 are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- 6 alkoxy or halogenated C 1-6 alkoxy;
    R 5和R 7中有一个与R 6以及和它们各自相连的环原子一起形成任选被1-5个Q1取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基；未成环的R 5或R 7选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； One of R 5 and R 7 together with R 6 and the ring atoms to which they are attached respectively form 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered optionally substituted by 1-5 Q1 A membered aryl group or a 5-10 membered heteroaryl group; the uncyclic R 5 or R 7 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
    R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、-(CH 2) p-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
    各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl;
    各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2 ) m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1 -6 alkoxy or halogenated C 1-6 alkyl;
    各m、各p分别独立地选自0、1、2、3、4或5。Each m and each p are independently selected from 0, 1, 2, 3, 4, or 5.
  2. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其具有通式(II-1)或通式(II-2)所示的结构：The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, which has the structure represented by general formula (II-1) or general formula (II-2):
    Figure PCTCN2022080065-appb-100002
    Figure PCTCN2022080065-appb-100002
    其中，in,
    各R 2、各R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基； Each R 2 , each R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
    R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、-(CH 2) p-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
    环A选自3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基；Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl;
    各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2 ) m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1 -6 alkoxy or halogenated C 1-6 alkyl;
    各m、各n、各p分别独立地选自0、1、2、3、4或5；each m, each n, each p is independently selected from 0, 1, 2, 3, 4 or 5;
    X 1、X 2、X 3、X 4、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6如权利要求1所定义。 X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are as defined in claim 1 .
  3. 如权利要求2所述的化合物、其药学上可接受的盐或其立体异构体，其中，The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
    各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基； Each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
    R 1选自氢、卤素、羟基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基、-(CH 2) p-5-8元杂芳基、-(CH 2) p-苯基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基 或卤代C 1-6烷基； R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected substituted by substituents: -( CH2 ) p -3-6 membered cycloalkyl, -( CH2 ) p -3-6 membered heterocyclyl, -( CH2 ) p -5-8 Member heteroaryl, -(CH 2 ) p -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
    环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基；Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基； Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -( CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;
    各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1- 4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷硫基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、羟基C 1-4烷氧基、羟基C 1-4烷硫基、氨基C 1-4烷氧基、氨基C 1-4烷硫基或任选被取代基取代的以下基团：-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基、-(CH 2) m-苯基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基； Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , Di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio , halogenated C 1-4 4 alkoxy, halogenated C 1-4 alkylthio, hydroxy C 1-4 alkoxy, hydroxy C 1-4 alkylthio, amino C 1-4 alkoxy, amino C 1-4 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, -(CH 2 ) m -5 -8-membered heteroaryl, -(CH 2 ) m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
    各m、各n、各p分别独立地选自0、1、2或3。Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其立体异构体，其具有通式(III-1)或通式(III-2)所示的结构：The compound according to any one of claims 1-3, its pharmaceutically acceptable salt or its stereoisomer, which has the structure shown by general formula (III-1) or general formula (III-2):
    Figure PCTCN2022080065-appb-100003
    Figure PCTCN2022080065-appb-100003
    其中，Y 1选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-； wherein, Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
    Y 4选自-C(R 2)或-N-； Y 4 is selected from -C(R 2 ) or -N-;
    Y 3选自-C(R 5)或-N-； Y 3 is selected from -C(R 5 ) or -N-;
    Y 6选自-C(R 7)或-N-； Y 6 is selected from -C(R 7 ) or -N-;
    X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-； X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
    各R 2、R 3、R 4、R 5、R 7分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； each of R 2 , R 3 , R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
    R 1选自氢、卤素、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、3-6元环烷基、3-6元杂环基、-NR a-C(O)-R b-、-NR aR b、-OR a或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基； R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR a - C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1- 4 alkyl;
    环A选自
    Figure PCTCN2022080065-appb-100004
    Figure PCTCN2022080065-appb-100005
    Figure PCTCN2022080065-appb-100006
    Figure PCTCN2022080065-appb-100007
    其中，环A中的各环原子任选的被氧代，     Ring A is selected from
    Figure PCTCN2022080065-appb-100004
    Figure PCTCN2022080065-appb-100005
    Figure PCTCN2022080065-appb-100006
    Figure PCTCN2022080065-appb-100007
    wherein each ring atom in Ring A is optionally oxo,
    各Q1分别独立地选自卤素、硝基、氨基、氰基、羧基、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基；所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或羟基C 1-4烷基； Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O)NR a or optionally 1-2 The following groups substituted by Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkane base, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or hydroxy C 1-4 alkyl;
    各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、四氢呋喃基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基； Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxane , oxetanyl, azetidinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
    各R b分别独立地选自氢或C 1-4烷基； each R b is independently selected from hydrogen or C 1-4 alkyl;
    各m、各n、各p分别独立地选自0、1、2或3。Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
  5. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中：The compound of any one of claims 1-3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
    各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基； each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
    R 1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、-NR a-C(O)-R b-、-NR aR b或-OR a，优选选自-NR aR b； R 1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, Imidazolidinyl, tetrahydrofuranyl, -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b ;
    环A选自
    Figure PCTCN2022080065-appb-100008
    Figure PCTCN2022080065-appb-100009
    Figure PCTCN2022080065-appb-100010
    优选选自
    Figure PCTCN2022080065-appb-100011
    Figure PCTCN2022080065-appb-100012
    Figure PCTCN2022080065-appb-100013
    优选选自
    Figure PCTCN2022080065-appb-100014
    Figure PCTCN2022080065-appb-100015
    优选选自
    Figure PCTCN2022080065-appb-100016
    Figure PCTCN2022080065-appb-100017
    其中，环A中的各环原子任选的被氧代；     Ring A is selected from
    Figure PCTCN2022080065-appb-100008
    Figure PCTCN2022080065-appb-100009
    Figure PCTCN2022080065-appb-100010
    preferably selected from
    Figure PCTCN2022080065-appb-100011
    Figure PCTCN2022080065-appb-100012
    Figure PCTCN2022080065-appb-100013
    preferably selected from
    Figure PCTCN2022080065-appb-100014
    Figure PCTCN2022080065-appb-100015
    preferably selected from
    Figure PCTCN2022080065-appb-100016
    Figure PCTCN2022080065-appb-100017
    wherein each ring atom in Ring A is optionally oxo;
    各Q1分别独立地选自卤素、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基； Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy propylpropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH2 ) m -cyclopentyl, -( CH2 ) m -cyclohexyl, -( CH2 ) m -oxopropyl, -( CH2 ) m -oxygen Heterobutyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -azetidinyl, -(CH 2 ) m -tetrahydrofuranyl, -(CH 2 ) m -oxa Cyclohexyl, -( CH2 ) m -tetrahydropyranyl, -( CH2 ) m -pyrrolidinyl, -( CH2 ) m -piperidinyl, -( CH2 ) m -piperazinyl, - (CH 2 ) m -pyridyl, -(CH 2 ) m -pyrimidinyl, -(CH 2 ) m -pyridazinyl, -(CH 2 ) m -pyrazinyl; the Q2 are each independently selected from fluorine , chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoro methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;
    各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基；所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基； Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine , oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl radical, ethyl, propyl, isopropyl or trifluoromethyl;
    各R b分别独立地选自氢、甲基、乙基、丙基或异丙基； each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
    各m、各n分别独立地选自0、1、2或3。Each m and each n are independently selected from 0, 1, 2 or 3.
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，The compound of any one of claims 1-5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
    X 2、X 3、X 4中的一个选自S、O、N或-N(R 4)-，另两个分别独立地是-C(R 2)-。 One of X 2 , X 3 , and X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-.
  7. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐或其立体异构体，其具有通式(IV-1)或通式(IV-2)所示的结构：The compound according to any one of claims 1-5, its pharmaceutically acceptable salt or its stereoisomer, which has the structure represented by general formula (IV-1) or general formula (IV-2):
    Figure PCTCN2022080065-appb-100018
    Figure PCTCN2022080065-appb-100018
    其中，X 2、X 3、X 4、环A、R 1、R 2、R 4、R a、R b、Q1、Q2、m、n、p的定义如权利要求1-5任一项所述。 Wherein, the definitions of X 2 , X 3 , X 4 , ring A, R 1 , R 2 , R 4 , R a , R b , Q1 , Q2 , m, n, and p are as defined in any one of claims 1-5 described.
  8. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其立体异构体，其具有通式(VII-1)、通式(VII-2)、通式(VII-3)、通式(VII-4)、通式(VII-5)或通式(VII-6)所示的结构：The compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which has the general formula (VII-1), the general formula (VII-2), the general formula (VII) -3), the structure represented by the general formula (VII-4), the general formula (VII-5) or the general formula (VII-6):
    Figure PCTCN2022080065-appb-100019
    Figure PCTCN2022080065-appb-100019
    其中，环A、R 1、R 4、R a、R b、Q1、Q2、m、n、p的定义如权利要求1-3任一项所述。 Wherein, the definitions of ring A, R 1 , R 4 , R a , R b , Q1 , Q2 , m, n, and p are as described in any one of claims 1-3 .
  9. 如权利要求8所述的化合物、其药学上可接受的盐或其立体异构体，其中，The compound of claim 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
    R 1选自-NR aR b、-OR a、-SR a、-NH-C(O)-R b-、或任选被取代基取代的以下基团：-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基；所述取代基选自卤素、C 1-4烷基或卤代C 1-4烷基； R 1 is selected from -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, or the following groups optionally substituted with substituents: -(CH 2 ) p -3 -6-membered cycloalkyl, -(CH 2 ) p -3-6-membered heterocyclyl; the substituent is selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
    各R 4分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基； each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
    环A选自
    Figure PCTCN2022080065-appb-100020
    Figure PCTCN2022080065-appb-100021
    Figure PCTCN2022080065-appb-100022
    其中，环A中的各环原子任选的被氧代；     Ring A is selected from
    Figure PCTCN2022080065-appb-100020
    Figure PCTCN2022080065-appb-100021
    Figure PCTCN2022080065-appb-100022
    wherein each ring atom in Ring A is optionally oxo;
    各Q1分别独立地选自-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、3-6元环烷基、3-6元杂环基、5-6元杂芳基或苯基；所述Q2分别独立地选自卤素、羟基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或羟基C 1-4烷基； Each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: C 1-4 alkane group, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or benzene base; the Q2 are independently selected from halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl;
    各R a分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、或任选被取代基取代的以下基团：3-6元环烷基、3-6元杂环基；所述取代基选自卤素、羟基、C 1-6烷基或卤代C 1-6烷基； Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1-6 alkyl or halogenated C 1-6 alkyl;
    各R b分别独立地选自氢或C 1-4烷基； each R b is independently selected from hydrogen or C 1-4 alkyl;
    各n、各p分别独立地选自0、1或2。Each n and each p are independently selected from 0, 1 or 2.
  10. 如权利要求9所述的化合物、其药学上可接受的盐或其立体异构体，其中，The compound of claim 9, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
    R 1选自氮杂环丁基、氧杂环丁基、-NR a-C(O)-R b-、-NR aR b或-OR a； R 1 is selected from azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a ;
    各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基或三氟甲基； each R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl , difluoromethyl or trifluoromethyl;
    环A选自
    Figure PCTCN2022080065-appb-100023
    Figure PCTCN2022080065-appb-100024
    Figure PCTCN2022080065-appb-100025
    其中，环A中的各环原子任选的被氧代；     Ring A is selected from
    Figure PCTCN2022080065-appb-100023
    Figure PCTCN2022080065-appb-100024
    Figure PCTCN2022080065-appb-100025
    wherein each ring atom in Ring A is optionally oxo;
    各Q1分别独立地选自-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡咯烷基、吡啶基或哒嗪基；所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基； Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 is independently selected from fluorine, chlorine, bromine , hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;
    各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷 基；所述取代基选自卤素、羟基、甲基、乙基、丙基、异丙基或三氟甲基； Each R a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl Fluoromethoxy or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl , tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
    各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。 Each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  11. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，选自如下化合物：The compound of claim 1, its pharmaceutically acceptable salt or its stereoisomer, is selected from the following compounds:
    Figure PCTCN2022080065-appb-100026
    Figure PCTCN2022080065-appb-100026
    Figure PCTCN2022080065-appb-100027
    Figure PCTCN2022080065-appb-100027
    Figure PCTCN2022080065-appb-100028
    Figure PCTCN2022080065-appb-100028
    Figure PCTCN2022080065-appb-100029
    Figure PCTCN2022080065-appb-100029
  12. 含有权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体的药物制剂，其特征在于，包含一种或多种药学上可接受的赋形剂，该药物制剂为药学上可接受的任一剂型。A pharmaceutical preparation containing the compound according to any one of claims 1-11, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that it comprises one or more pharmaceutically acceptable excipients, The pharmaceutical preparation is any pharmaceutically acceptable dosage form.
  13. 含有权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体的药物组合物，其特征在于，包含一种或多种第二治疗活性剂，所述的第二活性治疗剂选自有丝***抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。A pharmaceutical composition containing the compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that it comprises one or more second therapeutically active agents, the The second active therapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, Vitamin A receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors and Isoprenyl protein transferase inhibitor.
  14. 权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体、权利要求12所述的药物制剂、或权利要求13所述的药物组合物在制备用于治疗和/或预防由HPK1所介导的疾病及相关病症的药物中的应用，所述由HPK1所介导的疾病及相关病症选自癌症或良性肿瘤，所述癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、非小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤。The compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the pharmaceutical formulation of claim 12, or the pharmaceutical composition of claim 13 is prepared for use in Use in the medicine for the treatment and/or prevention of diseases mediated by HPK1 and related conditions, the diseases and related conditions mediated by HPK1 are selected from cancer or benign tumors, and the cancer is selected from lung cancer, squamous epithelium Cell cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, Prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, hypertrophy Cellular tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma.
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